AU2017204161B2 - SiRNA therapy for transthyretin (TTR) related ocular amyloidosis - Google Patents

Abstract

The invention relates to a method of treating ocular amyloidosis by reducing TTR expression in a subject by administering a double-stranded ribonucleic acid (dsRNA) that targets aTTR gene to the retinal pigment epithelium of the subject.

Description

The invention relates to a method of treating ocular amyloidosis by reducing TTR expression in a subject by administering a double-stranded ribonucleic acid (dsRNA) that targets a TTR gene to the retinal pigment epithelium of the subject.

2017204161 20 Jun 2017

ABSTRACT

2017204161 20 Jun 2017 siRNA Therapy for Transthyretin (TTR) Related Ocular Amyloidosis Cross Reference to Related Applications

This application is a divisional application of Australian Patent Application No. 2015264811 which is a divisional of Australian Patent Application No. 2011235276 which corresponds to International Application No. PCT/US2011/030392, filed on 29 March 2011 which claims the benefit ofU.S. Provisional Application No. 61/318,704, filed March 29, 2010, and U.S. Provisional Application No. 61/318,702, filed March 29, 2010, the entirety of which is hereby incorporated by reference.

Field of the Invention

The invention relates to methods for treating TTR related ocular amyloidosis with siRNA.

Background of the Invention

Transthyretin (TTR) is a secreted thyroid hormone-binding protein. TTR binds and transports retinol binding protein (RBP)/ Vitamin A, and serum thyroxine (T4) in plasma and cerebrospinal fluid.

Both normal-sequence TTR and variant-sequence TTR cause amyloidosis. Normal-sequence TTR causes cardiac amyloidosis in people who are elderly and is termed senile systemic amyloidosis (SSA) (also called senile cardiac amyloidosis (SCA)). SSA often is accompanied by microscopic deposits in many other organs. TTR mutations accelerate the process of TTR amyloid formation and are the most important risk factor for the development of clinically significant TTR amyloidosis (also called ATTR (amyloidosis-transthyretin type)). More than 85 amyloidogenic TTR variants are known to cause systemic familial amyloidosis. The liver is the major site of TTR expression. Other significant sites of expression include the choroid plexus, retina and pancreas.

TTR amyloidosis manifests in various forms. When the peripheral nervous system is affected more prominently, the disease is termed familial amyloidotic polyneuropathy (FAP). When the heart is primarily involved but the nervous system is not, the disease is called familial amyloidotic cardiomyopathy (FAC). A third major type of TTR amyloidosis is called leptomeningeal/CNS (Central Nervous System) amyloidosis.

2017204161 01 Jul 2019

Double-stranded RNA molecules (dsRNA) have been shown to block gene expression in a highly conserved regulatory mechanism known as RNA interference (RNAi). WO 99/32619 (Fire et al.) disclosed the use of a dsRNA of at least 25 nucleotides in length to inhibit the expression of genes in C. elegans. dsRNA has also been shown to degrade target RNA in other organisms, including plants (see, e.g., WO 99/53050, Waterhouse et al.; and WO 99/61631, Heifetz et al.), Drosophila (see, e.g., Yang, D., et al., Curr. Biol. (2000) 10:1191-1200), and mammals (see WO 00/44895, Limmer; and DE 101 00 586.5, Kreutzer et al.).

U.S. 20070207974 discloses functional and hyperfunctional siRNAs. U.S. 20090082300 discloses antisense molecules directed against TTR. U.S. Pat. No. 7,250,496 discloses microRNAs directed against TTR.

Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present disclosure as it existed before the priority date of each claim of this application.

Throughout this specification the word comprise, or variations such as comprises or comprising, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

Summary of the Invention

The invention provides a method for reducing transthyretin (TTR) expression in the retinal pigment epithelium (RPE) of a subject by administering a sufficient amount of a double stranded ribonucleic acid (dsRNA) to the retina of the subject.

In one aspect, the invention provides a method for reducing transthyretin (TTR) expression in a retinal pigment epithelium of a subject comprising administering a sufficient amount of a dsRNA to the retina of the subject, wherein the dsRNA is AD-18324 (SEQ ID NOs: 1413 and 1414) orAD-18534 (SEQ ID NOs: 1411 and 1412) orAD-23043 (SEQ ID NOs: 1421 and 1422); and the dsRNA is encapsulated in a lipid formulation.

In one aspect, the invention provides a method of treating, preventing or managing TTRrelated ocular amyloidosis comprising administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of AD-18324 (SEQ ID NOs: 1413 and 1414) encapsulated in a lipid formulation to the retina of said patient.

2017204161 01 Jul 2019

In one aspect, the invention provides a method of treating a human comprising:

identifying a human diagnosed as having TTR-related ocular amyloidosis or at risk for developing TTR-related ocular amyloidosis and administering to the human a therapeutically or prophylactically effective amount of AD-18324 (SEQ ID NOs: 1413 and 1414) encapsulated in a lipid formulation to the retina of said human.

In one aspect, the invention provides a method for inhibiting TTR expression in a retinal epithelium cell, the method comprising: (a) introducing into the retinal epithelium cell a dsRNA, wherein the dsRNA is AD-18324 (SEQ ID NOs: 1413 and 1414) or AD-18534 (SEQ 10 ID NOs: 1411 and 1412) wherein the dsRNA is encapsulated in a lipid formulation; and (b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a TTR gene, thereby inhibiting expression of the TTR gene in the cell.

In one aspect, the invention provides use of a dsRNA in the preparation of a medicament for the treatment, prevention or management of ocular amyloidosis, wherein the 15 dsRNA is AD-18324 (SEQ ID NOs: 1413 and 1414) or AD-18534 (SEQ ID NOs: 1411 and 1412) or AD-23043 (SEQ ID NOs: 1421 and 1422); and the dsRNA is encapsulated in a lipid formulation.

In one aspect, the invention provides use of a dsRNA to treat, prevent or manage ocular amyloidosis, wherein the dsRNA is AD-18324 (SEQ ID NOs: 1413 and 1414) or AD-18534 20 (SEQ ID NOs: 1411 and 1412) or AD-23043 (SEQ ID NOs: 1421 and 1422); and the dsRNA is encapsulated in a lipid formulation.

In some embodiments, the dsRNA is AD-18324 or AD-18534. The dsRNA can be conjugated to, e.g., cholesterol.

In one embodiment, the subject is a human. In another embodiment, the subject is a human in need of treatment for TTR-related ocular amyloidosis. In yet another embodiment, the dsRNA is AD-18324. In a related embodiment, the method results in reduced TTR expression in the RPE. In another related embodiment, the method results in reduced TTR mRNA expression by at least 40% or by at least 60% compared to a control. In other embodiments, the administration of the dsRNA does not result in an inflammatory response in the human as measured by IL-6 or TNF-alpha levels.

In another embodiment, the subject is a human possessing a ATTR (amyloidogenic transthyretin) V30M gene in need of treatment for TTR-related ocular amyloidosis. In one embodiment, the dsRNA administered to the ATTR V30M subject is AD-18324. In a related embodiment, the method results in a reduction of V30M TTR expression in the retinal pigment

2A epithelium. In another embodiment, the method results in reduction of V30M TTR mRNA expression by at least 60% compared to a control. In other embodiments, the administration of the dsRNA does not result in an inflammatory response in the human possessing a ATTR

V30M gene as measured by IL-6 or TNF-alpha levels.In another embodiment, the subject is a

Dark Agouti (DA) rat. In one embodiment, the dsRNA that is administered to the DA rat is

AD-18534. In another embodiment, the method results in a reduction of TTR expression in the retinal pigment epithelium. In yet another

2017204161 01 Jul 2019

2B

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 embodiment, the method results in reduction of TTR mRNA expression in the DA rat by at least

60% compared to a control. In another embodiment, the administration of the dsRNA does not result in an inflammatory response in the DA rat as measured by IL-6 or TNF-alpha levels.

In some embodiments, the subject is a transgenic rat possessing a human ATTR (amyloidogenic transthyretin) V30M gene. In one embodiment, the dsRNA administered to the ATTR V30M transgenic rat is AD-18324. In a related embodiment, the method results in a reduction of TTR expression in the retinal pigment epithelium. In another embodiment, the method results in reduction of TTR mRNA expression by at least 60% compared to a control. In other embodiments, the administration of the dsRNA does not result in an inflammatory response in the ATTR V30M Tg rat as measured by IL-6 or TNF-alpha levels.

In one embodiment, the invention provides a method for treating, preventing or managing TTR-related ocular amyloidosis by administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of AD-18324 to the retina of the patient.

In another embodiment, the invention provides a method of treating a human, which includes identifying a human diagnosed as having TTR-related ocular amyloidosis or at risk for developing TTR-rclatcd ocular amyloidosis and administering to the human a therapeutically or prophylactically effective amount of AD-18324 to the retina of the human.

In a related embodiment, the invention includes a method for inhibiting TTR expression in a retinal epithelium cell, wherein the method comprises (a) introducing into the retinal epithelium cell a dsRNA, wherein the dsRNA is AD-18324 or AD-18534, and (b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a TTR gene, thereby inhibiting expression of the TTR gene in the cell. In one embodiment, the dsRNA administered in this method is AD-18324. In some embodiments, the retinal epithelium cell is a human retinal pigment epithelium transgenic cell. In another embodiment, the method results in inhibition of TTR expression by at least 10%, 40%, or at least 60%. In a related embodiment, introducing the dsRNA into the retinal epithelium cell does not result in an inflammatory response as measured by IL-6 or TNF-alpha levels.

The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and the drawings, and from the claims.

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Description of the Drawings

FIG. 1 is a graph of TNFalpha and IFNalpha levels in cultured human PBMCs following transfection with TTR siRNAs.

FIG. 2A and 2B are dose response curves for AD-18324 and AD-18328, respectively, in

HcpG2 cells,

FIG. 3 is a dose response curve for AD-18246 in HcpG2 cells,

FIG. 4A and FIG. 4B show inhibition of liver mRNA and plasma protein levels, respectively, in transgenic H129-mTTR-KO/iNOS-KO/hTTR mice by an intravenous bolus administration ofTTR-dsRNA (AD-18324, AD-18328 and AD-18246) formulated in LNP01.

FIG. 5 is a graph summarizing the measurements of TTR mRNA levels in livers of nonhuman primates following 15-minutc intravenous infusion ofTTR-dsRNA (AD-18324 and AD18328) formulated in SNALP.

FIG. 6A and FIG. 6B show inhibition of human V30M TTR liver mRNA and scrum protein levels, respectively, in transgenic mice by an intravenous bolus administration of

SNALP-18328. Group means were determined, normalized to the PBS control group, and then plotted. Error bars represent standard deviations. The percentage reduction of the group mean, relative to PBS, is indicated for the SNALP-1955 and SNALP-18328 groups. (*** p< 0.001, One-way ANOVA, with Dunn’s post-hoc test).

FIG. 7A and FIG. 7B show the durability of reduction of human V30M TTR liver mRNA and serum protein levels, respectively, in transgenic mice over 22 days following a single intravenous bolus administration of SNALP-18328. Group means were determined. TTR/GAPDH mRNA levels were normalized to day 0 levels and plotted. The percent reduction of normalized TTR mRNA levels relative to SNALP-1955 for each time point were calculated and are indicated for the SNALP-18328 groups. (*** p< 0.001, One-way ANOVA, with Dunn’s post-hoc test).

FIG. 8 shows the timecourse of TTR serum protein levels in non-human primates over 14 days following a single 15-minute intravenous infusion of SNALP-18328.

FIG. 9 shows reduction of TTR-immunorcactivity in various tissues of human V30M TTR/HSF-1 knock-out mice following intravenous bolus administration of SNALP-18328. E, esophagus; S, stomach; 11, intestine/duodenum; 14, intestine/colon; N, nerve; D, dorsal root ganglia.

FIG. 10 shows the measurements ofTTR mRNA levels in livers of non-human primates following 15-minutc intravenous infusion of XTC-SNALP-18328.

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

FIGs. 11A and 1 IB show the measurements of TTR mRNA and scrum protein levels, respectively, in livers of non-human primates following I5-minute intravenous infusion of

LNP09-18328 or LNP11-18328. FIG. 11C shows the timecourse of TTR scrum protein levels over 28 days following a 15-minute intravenous infusion of 0.3mg/kg LNP09-18328, as compared to the PBS control group.

FIG. 12 shows the sequence of human TTR mRNA (Ref. Seq. NM_000371.3, SEQ ID NO:1331).

FIGs. 13A and 13 B are the sequences of human and rat TTR mRNA, respectively. FIG. 13A is the sequence of human TTR mRNA (Ref. Seq. NM_000371.2, SEQ ID NO :1329). FIG.

13B is the sequence of rat TTR mRNA (Ref. Seq. NM_01268l.!, SEQ ID NO:1330).

FIG. 14 shows the nucleotide alignment of NM_000371.3, NM_000371,2, and A ΟΙ 8328.

FIG. 15 illustrates symptoms and mutations in TTR associated with familial amyloidotic neuropathy, familial amyloidotic cardiomyopathy and CNS amyloidosis.

FIG. 16 shows reduction of TTR mRNA levels in the liver with SN'ALP-18534 with different infusion durations. Groups of animals (n=4/group) were administered 1 mg/kg SNALP-18534 via a 15-minute, or 1,2, or 3 hour infusion. Forty-eight hours later, rats were euthanized and livers harvested. TTR and GAPDH mRNA levels were measured from liver lysates using the Quantigcnc bDNA assay. The ratio of TTR to GAPDH mRNA levels was calculated for each animal. Group means were determined and normalized to a PBS control group, and then plotted. Error bars represent standard deviations. (*** p < 0.001, One-way ANOVA with Bonfcrroni post- hoc test, relative to PBS).

FIG. 17 shows the measurements of TTR mRNA levels in livers of rats following 15minute intravenous infusion of LNP07-18534 or LNP08-18534.

FIG. 18 shows in vivo inhibition of endogenous TTR mRNA levels in livers of SpragueDawley Rats following a 15-miil IV infusion of LNP09-I8534 or LNP1 1-18534. Groups of animals (n=4/group) were intravenously administered 0.01,0.03, 0.1, or 0.3 mg/kg LNP0918534, LNP-11-18534; or PBS via a 15-minute infusion. Forty-eight hours later, animals were euthanized and livers harvested. TTR and GAPDH mRNA levels were measured from liver biopsy lysates using the Quantigene bDNA assay. The ratio of TTR to GAPDH mRNA levels was calculated for each animal. Group means were determined, normalized to the PBS control group, and then plotted. Error bars represent standard deviations.

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

FIG. 19 shows the efficacy of LNP12 formulated siRNA targeting TTR in non-human primates. Data points represent group mean ± s.d.

FIG. 20 is a graph with results from a GLP study in NHP illustrating the durability of mRNA suppression by ALN-TTR01.

FIG. 21 is a graph illustrating regression of TTR deposits in various tissues of mature animals (hV30M TTR/HSF-1 knock-out mice) following intravenous bolus administration of SNALP-18328 (ALN-TTR01).

FIG. 22 is a graph showing the effects of human TTR siRNA AD-18324 on TTR mRNA expression in ARPE 19 cells. AD-18324 was compared with rat TTR siRNA AD-18534. The human TTR mRNA expression was calculated relative to human GAPDH expression.

FIG. 23 is a graph showing the effect of AD-18534 on TTR mRNA expression in retinal pigment epithelium cells of Dark Agouti (DA) rats. AD-18534 was compared to a control siRNA group, a saline group, and no treatment group. Endogenous rat TTR mRNA expression was calculated relative to rat GAPDH expression.

FIG. 24 is a graph showing the effect of AD-18324 on ATTR mRNA expression in retinal pigment epithelium cells in ATTR V30M transgenic rats. AD-18324 was compared to a control siRNA group, a saline group, and no treatment group. Human TTR mRNA expression was calculated relative to rat GAPDH expression.

FIG. 25 is a Western blot showing the effect of human TTR siRNA on human TTR protein expression in retinal pigment epithelial cells in ATTR V30M transgenic rats compared to a control siRNA.

FIG. 26 is a graph showing the effect of AD-23043 (cho-TTR siRNA) on rat TTR mRNA expression in retinal pigment epithelium cells of Dark Agouti (DA) rats 14 and 21 days after administration. Endogenous rat TTR mRNA expression was calculated relative to rat 25 GAPDH expression.

FIG. 27 is a graph showing the effect of AD-23043 (cho-TTR siRNA) on rat TTR mRNA expression in retinal pigment epithelium cells of Dark Agouti (DA) rats 21 days after administration. Endogenous rat TTR mRNA expression was calculated relative to rat GAPDH expression.

Detailed Description of the Invention

The invention provides dsRNAs and methods of using the dsRNAs for inhibiting the expression of a TTR gene in a cell or a mammal where the dsRNA targets a TTR gene. The invention also provides compositions and methods for treating pathological conditions and

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 diseases, such as a TTR amyloidosis, in a mammal caused by the expression of a TTR gene.

dsRNA directs the sequence-specific degradation of mRNA through a process known as RNA interference (RNAi).

The dsRNAs of the compositions featured herein include an RNA strand (the antisense strand) having a region which is less than 30 nucleotides in length, generally 19-24 nucleotides in length, and is substantially complementary to at least part of an mRNA transcript of a TTR gene. The use of these dsRNAs enables the targeted degradation of mRNAs of genes that are implicated in pathologies associated with TTR expression in mammals. Very low dosages of TTR dsRNAs in particular can specifically and efficiently mediate RNAi, resulting in significant 10 inhibition of expression of a TTR gene. Using cell-based assays, the present inventors have demonstrated that dsRNAs targeting TTR can specifically and efficiently mediate RNAi, resulting in significant inhibition of expression of a TTR gene. Thus, methods and compositions including these dsRNAs are useful for treating pathological processes that can be mediated by down regulating TTR, such as in the treatment of a liver disorder or a TTR amyloidosis, e.g.,

FAP.

The methods and compositions containing a TTR dsRNA are useful for treating pathological processes mediated by TTR expression, such as a TTR amyloidosis. In an embodiment, a method of treating a disorder mediated by TTR expression includes administering to a human in need of such treatment a therapeutically effective amount of a 20 dsRNA targeted to TTR. In an embodiment, a dsRNA is administered to the hitman at about 0.01,0.1,0.5, 1.0,2,2.5,3,4,5,6,7,8,9, 10, II, 12, 13, 14, 15, 16, 17, 18, 19,20,21,22,23, 24, or 25 mg/kg.

The following detailed description discloses how to make and use the compositions containing dsRNAs to inhibit the expression of a TTR gene, as well as compositions and 25 methods for treating diseases and disorders caused by the expression of this gene. The pharmaceutical compositions featured in the invention include a dsRNA having an antisense strand comprising a region of complementarity which is less than 30 nucleotides in length, generally 19-24 nucleotides in length, and is substantially complementary to at least part of an RNA transcript of a TTR gene, together with a pharmaceutically acceptable carrier. The 30 compositions featured in the invention also include a dsRNA having an antisense strand having a region of complementarity which is less than 30 nucleotides in length, generally 19-24 nucleotides in length, and is substantially complementary to at least part of an RNA transcript of a TTR gene.

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

The sense strand of a dsRNA can include 15, 16, 17, 18, 19, 20, 21, or more contiguous nucleotides of any of the sense strands disclosed herein. The antisense strand of a dsRNA can include 15, 16, 17, 18, 19, 20, 21, or more contiguous nucleotides of any of the antisense strands disclosed herein.

In an embodiment, a dsRNA can include at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more modified nucleotides. In an embodiment, a modified nucleotide can include a 2'-O-methyl modified nucleotide, a nucleotide comprising a 5’-phosphorothioate group, and/or a terminal nucleotide Linked to a cholesteryl derivative or dodecanoic acid bisdecylamidc group. In an embodiment, a modified nucleotide can include a 2^,-dcoxy-2'-fluoiO modified nucleotide, a 2'10 deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, 2’-amino-modified nucleotide, 2’-alkyl-modificd nucleotide, morpholino nucleotide, a phosphoramidatc, and/or a non-natural base comprising nucleotide.

In an embodiment, the region of complementary of a dsRNA is at least 10, 11, 12, 13, 14,

15, 16, 17, 18, 19, 20, 21, or more nucleotides in length. In an embodiment, the region of complementary includes 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or more contiguous nucleotides of SEQ ID NO: 169.

In an embodiment, each strand of a dsRNA is 15, 16,17, 18,19, 20, 21,22,23, 24,25, 26, 27, 28, 29, 30 or more nucleotides in length. In an embodiment, the dsRNA includes a sense strand, or 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 nucleotide fragment thereof, selected from Tables 3A, 3B, 4, 6A, 6B, 7, and 16, and an antisense strand, or 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 nucleotide fragment thereof, selected from Tables 3A, 3B, 4, 6A, 6B, 7, and

16.

In an embodiment, administration of a dsRNA to a cell results in about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95% or more inhibition of TTR mRNA expression as measured by a real time PCR assay. In an embodiment, administration of a dsRNA to a cell results in about 40% to 45%, 45% to 50%, 50% to 55%, 55% to 60%, 60% to 65%, 65% to 70%, 70% to 75%, 75% to 80%, 80% to 85%, 85% to 90%, 90% to 95% or more inhibition of TTR mRNA expression as measured by a real time PCR assay. In an embodiment, administration of a dsRNA to a cell results in about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95% or more inhibition of TTR mRNA expression as measured by a branched DNA assay. In an embodiment, administration of a dsRNA to a cell results in about 40% to 45%, 45% to 50%, 50% to 55%, 55% to 60%, 60% to 65%, 65% to 70%, 70% to 75%, 75% to 80%, 80% to 85%,

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

85% to 90%, 90% to 95% or more inhibition of TTR mRNA expression as measured by a branched DNA assay.

In an embodiment, a dsRNA has an 1C50 of less than O.OlpM, O.lpM, IpM, 5pM, 10 pM, lOOpM, or lOOOpM. In an embodiment, a dsRNA has an ED50 of about 0.01,0.1, 1, 5, or

10 mg/kg.

In an embodiment, administration of a dsRNA can reduce TTR mRNA by about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95% or more in cynomolgus monkeys. In an embodiment, administration of a dsRNA reduces liver TTR mRNA levels by about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95% or more or serum TTR protein levels by about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95% or more. In an embodiment, administration of a dsRNA reduces liver TTR mRNA levels and/or serum TTR protein levels up to 1,2,3,4,5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20,21,22,23, 24, 25, or more days.

In an embodiment, a dsRNA is formulated in a LNP formulation and reduces TTR mRNA levels by about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95% or more at a dose of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 mg/kg, relative to a PBC control group. In an embodiment, a dsRNA is formulated in a LNP formulation and reduces TTR protein levels about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95% or more relative to a PBC control group as measured by a western blot. In an embodiment, a dsRNA suppresses scrum

TTR protein levels up to day 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 post-treatment when administered to a subject in need thereof at 1,2, 3, 4, 5, 6, 7,8,9, 10, 11, 12. 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 mg/kg.

Accordingly, in some aspects, pharmaceutical compositions containing a TTR dsRNA and a pharmaceutically acceptable carrier, methods of using the compositions to inhibit expression of a TTR gene, and methods of using the pharmaceutical compositions to treat diseases caused by expression of a TTR gene are featured in the invention.

L_____Definitions

For convenience, the meaning of certain terms and phrases used in the specification, examples, and appended claims, are provided below. If there is an apparent discrepancy between the usage of a term in other parts of this specification and its definition provided in this section, the definition in this section shall prevail.

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

G, C, A and U each generally stand for a nucleotide that contains guanine, cytosine, adenine, and uracil as a base, respectively. “T” and “dT” are used interchangeably herein and refer to a dcoxyribonuclcotidc wherein the nucleobase is thymine, e.g., deoxyribothymine. However, it will be understood that the term “ribonucleotide” or “nucleotide” or “dcoxyribonuclcotidc” can also refer to a modified nucleotide, as further detailed below, or a surrogate replacement moiety. The skilled person is well aware that guanine, cytosine, adenine, and uracil may be replaced by other moieties without substantially altering the base pairing properties of an oligonucleotide comprising a nucleotide bearing such replacement moiety. For example, without limitation, a nucleotide comprising inosine as its base may base pair with nucleotides containing adenine, cytosine, or uracil. Hence, nucleotides containing uracil, guanine, or adenine may be replaced in the nucleotide sequences of the invention by a nucleotide containing, for example, inosine. Sequences comprising such replacement moieties are embodiments of the invention.

As used herein, “transthyretin” (“TTR”) refers to a gene in a cell. TTR is also known as

ATTR, HsT2651, PALB, prcalbumin, TBPA, and transthyretin (prcalbumin, amyloidosis type 1). The sequence of a human TTR mRNA transcript can be found at NM_000371. The sequence of mouse TTR mRNA can be found at NM_013697.2, and the sequence of rat TTR mRNA can be found at NM 012681.1.

As used herein, “target sequence” refers to a contiguous portion of the nucleotide sequence of an mRNA molecule formed during the transcription of a TTR gene, including mRNA that is a product of RNA processing of a primary transcription product.

As used herein, the term “strand comprising a sequence” refers to an oligonucleotide comprising a chain of nucleotides that is described by the sequence referred to using the standard nucleotide nomenclature.

As used herein, and unless otherwise indicated, the term “complementary,” when used to describe a first nucleotide sequence in relation to a second nucleotide sequence, refers to the ability of an oligonucleotide or polynucleotide comprising the first nucleotide sequence to hybridize and form a duplex structure under certain conditions with an oligonucleotide or polynucleotide comprising the second nucleotide sequence, as will be understood by the skilled person. Such conditions can, for example, be stringent conditions, where stringent conditions may include: 400 mM NaCl, 40 mM PIPES pH 6.4, 1 mM EDTA, 50°C or 70^l’C for 12-16 hours followed by washing. Other conditions, such as physiologically relevant conditions as may be encountered inside an organism, can apply. The skilled person will be able to determine the set

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 of conditions most appropriate for a test of complementarity of two sequences in accordance with the ultimate application of the hybridized nucleotides.

This includes base-pairing of the oligonucleotide or polynucleotide comprising the first nucleotide sequence to the oligonucleotide or polynucleotide comprising the second nucleotide 5 sequence over the entire length of the first and second nucleotide sequence. Such sequences can be referred to as “fully complementary” with respect to each other herein. However, where a first sequence is referred to as “substantially complementary” with respect to a second sequence herein, the two sequences can be fully complementary, or they may form one or more, but generally not more than 4, 3 or 2 mismatched base pairs upon hybridization, while retaining the 10 ability to hybridize under the conditions most relevant to their ultimate application. However, where two oligonucleotides arc designed to form, upon hybridization, one or more single stranded overhangs, such overhangs shall not be regarded as mismatches with regard to the determination of complementarity. For example, a dsRNA comprising one oligonucleotide 21 nucleotides in length and another oligonucleotide 23 nucleotides in length, wherein the longer 15 oligonucleotide comprises a sequence of 21 nucleotides that is fully complementary to the shorter oligonucleotide, may yet be referred to as “fully complementary” for the purposes described herein.

“Complementary” sequences, as used herein, may also include, or be formed entirely from, non-Watson-Crick base pairs and/or base pairs formed from non-natural and modified 20 nucleotides, in as far as the above requirements with respect to their ability to hybridize are fulfilled. Such non-Watson-Crick base pairs includes, but not limited to, G:U Wobble or Hoogstcin base pairing.

The terms “complementary,” “fully complementary” and “substantially complementary” herein may be used with respect to the base matching between the sense strand and the antisense 25 strand of a dsRNA, or between the antisense strand of a dsRNA and a target sequence, as will be understood from the context of their use.

As used herein, a polynucleotide that is “substantially complementary to at least part of’ a messenger RNA (mRNA) refers to a polynucleotide that is substantially complementary to a contiguous portion of the mRNA of interest (e.g., an mRNA encoding TTR) including a 5’ UTR, 30 an open reading frame (ORF), or a 3’ UTR. For example, a polynucleotide is complementary to at least a part of a TTR mRNA if the sequence is substantially complementary to a noninterrupted portion of an mRNA encoding TTR.

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

The term double-stranded RNA” or “dsRNA,” as used herein, refers to a complex of ribonucleic acid molecules, having a duplex structure comprising two anti-parallel and substantially complementary, as defined above, nucleic acid strands. In general, the majority of nucleotides of each strand are ribonucleotides, but as described in detail herein, each or both strands can also include at least one non-ribonucleotide, e.g., a deoxyribonucleotide and/or a modified nucleotide. In addition, as used in this specification, “dsRNA” may include chemical modifications to ribonucleotides, including substantial modifications at multiple nucleotides and including all types of modifications disclosed herein or known in the art. Any such modifications, as used in an siRNA type molecule, arc encompassed by “dsRNA” for the purposes of this specification and claims.

The two strands forming the duplex structure may be different portions of one larger RNA molecule, or they may be separate RNA molecules. Where the two strands are part of one larger molecule, and therefore are connected by an uninterrupted chain of nucleotides between the 3’-end of one strand and the 5’-end of the respective other strand forming the duplex structure, the connecting RNA chain is referred to as a hairpin loop.” Where the two strands are connected covalently by means other than an uninterrupted chain of nucleotides between the 3’-end of one strand and the 5’-end of the respective other strand forming the duplex structure, the connecting structure is referred to as a “linker.” The RNA strands may have the same or a different number of nucleotides. The maximum number of base pairs is the number of nucleotides in the shortest strand of the dsRNA minus any overhangs that arc present in the duplex. In addition to the duplex structure, a dsRNA may comprise one or more nucleotide overhangs. The term “siRNA” is also used herein to refer to a dsRNA as described above.

As used herein, a “nucleotide overhang” refers to the unpaired nucleotide or nucleotides that protrude from the duplex structure of a dsRNA when a 3'-end of one strand of the dsRNA 25 extends beyond the 5’-end of the other strand, or vice versa. “Blunt” or “blunt end” means that there are no unpaired nucleotides at that end of the dsRNA, i.e., no nucleotide overhang. A “blunt ended” dsRNA is a dsRNA that is double-stranded over its entire length, i.e., no nucleotide overhang at either end of the molecule.

The term “antisense strand” refers to the strand of a dsRNA which includes a region that 30 is substantially complementary to a target sequence. As used herein, the term “region of complementarity” refers to the region on the antisense strand that is substantially complementary to a sequence, for example a target sequence, as defined herein. Where the region of complementarity is not fully complementary to the target sequence, the mismatches are most

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 tolerated in the terminal regions and, if present, arc generally in a terminal region or regions,

e.g., within 6, 5, 4, 3, or 2 nucleotides of the 5’ and/or 3’ terminus.

The term “sense strand,” as used herein, refers to the strand of a dsRNA that includes a region that is substantially complementary to a region of the antisense strand.

As used herein, the term SNALP refers to a stable nucleic acid-lipid particle. A

SNALP represents a vesicle of lipids coating a reduced aqueous interior comprising a nucleic acid such as a dsRNA or a plasmid from which a dsRNA is transcribed. SNALP are described, e.g„ in U.S. Patent Application Publication Nos. 20060240093, 20070135372, and USSN 61/045,228 filed on April 15, 2008. These applications are hereby incorporated by reference.

“Introducing into a ceil,” when referring to a dsRNA, means facilitating uptake or absorption into the cell, as is understood by those skilled in the art. Absorption or uptake of dsRNA can occur through unaided diffusive or active cellular processes, or by auxiliary agents or devices. The meaning of this term is not limited to cells in vitro; a dsRNA may also be introduced into a cell,” wherein the cell is part of a living organism. In such instance, introduction into the cell will include the delivery to the organism. For example, for in vivo delivery, dsRNA can be injected into a tissue site or administered systemically. In vitro introduction into a cell includes methods known in the art such as electroporation and lipofection. Further approaches are described herein or known in the art.

The terms “silence,” “inhibit the expression of,” “down-regulate the expression of,” “suppress the expression of’ and the like in as far as they refer to a TTR gene, herein refer to the at least partial suppression of the expression of a TTR gene, as manifested by a reduction of the amount of mRNA which may be isolated from a first cell or group of cells in which a TTR gene is transcribed and which has or have been treated such that the expression of a TTR gene is inhibited, as compared to a second cell or group of cells substantially identical to the first cell or group of cells but which has or have not been so treated (control cells). The degree of inhibition is usually expressed in terms of (mRNA in control cells)- (mRNA in treated cells) ,_Ληη, --------------------------------------------------· 100% (mRNA in control cells)

Alternatively, the degree of inhibition may be given in terms of a reduction of a parameter that is functionally linked to TTR gene expression, e.g., the amount of protein encoded by a TTR gene which is secreted by a cell, or the number of cells displaying a certain phenotype, e.g., apoptosis. In principle, TTR gene silencing may be determined in any cell

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 expressing the target, cither constitutively or by genomic engineering, and by any appropriate assay. However, when a reference is needed in order to determine whether a given dsRNA inhibits the expression of a TTR gene by a certain degree and therefore is encompassed by the instant invention, the assays provided in the Examples below shall serve as such reference.

For example, in certain instances, expression of a TTR gene is suppressed by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% by administration of the double-stranded oligonucleotide featured in the invention. In some embodiments, a TTR gene is suppressed by at least about 60%, 70%, or 80% by administration of the double-stranded oligonucleotide featured in the invention. In some embodiments, a TTR gene is suppressed by at 10 Least about 85%, 90%, or 95% by administration of the double-stranded oligonucleotide featured in the invention.

As used herein in the context of TTR expression, the terms “treat,” “treatment,” and the like, refer to relief from or alleviation of pathological processes mediated by TTR expression. In the context of the present invention insofar as it relates to any of the other conditions recited 15 herein below (other than pathological processes mediated by TTR expression), the terms “treat,” “treatment,” and the like mean to relieve or alleviate at least one symptom associated with such condition, or to slow or reverse the progression of such condition, such as the slowing the progression of a TTR amyloidosis, such as FAP. Symptoms of TTR amyloidosis include sensory neuropathy (e.g. paresthesia, hypesthesia in distal limbs), autonomic neuropathy (e.g., gastrointestinal dysfunction, such as gastric ulcer, or orthostatic hypotension), motor neuropathy, seizures, dementia, myelopathy, polyneuropathy, carpal tunnel syndrome, autonomic insufficiency, cardiomyopathy, vitreous opacities, renal insufficiency, nephropathy, substantially reduced mBMI (modified Body Mass Index), cranial nerve dysfunction, and corneal lattice dystrophy.

As used herein, the phrases “therapeutically effective amount” and “prophylactically effective amount” refer to an amount that provides a therapeutic benefit in the treatment, prevention, or management of pathological processes mediated by TTR expression or an overt symptom of pathological processes mediated by TTR expression. The specific amount that is therapeutically effective can be readily determined by an ordinary medical practitioner, and may vary depending on factors known in the art, such as, for example, the type of pathological processes mediated by TTR expression, the patient’s history and age, the stage of pathological processes mediated by TTR expression, and the administration of other anti-pathological processes mediated by TTR expression agents.

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

As used herein, a “pharmaceutical composition” comprises a pharmacologically effective amount of a dsRNA and a pharmaceutically acceptable carrier. As used herein, “pharmacologically effective amount,” “therapeutically effective amount” or simply “effective amount” refers to that amount of an RNA effective to produce the intended pharmacological, 5 therapeutic or preventive result. For example, if a given clinical treatment is considered effective when there is at least a 25% reduction in a measurable parameter associated with a disease or disorder, a therapeutically effective amount of a drug for the treatment of that disease or disorder is the amount necessary to effect at least a 25% reduction in that parameter. For example, a therapeutically effective amount of a dsRNA targeting TTR can reduce TTR serum 10 levels by at least 25%. In another example, a therapeutically effective amount of a dsRNA targeting TTR can improve liver function or renal function by at least 25%.

The term “pharmaceutically acceptable carrier” refers to a carrier for administration of a therapeutic agent. Such earners include, but arc not limited to, saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof. The term specifically excludes cell culture 15 medium. For drugs administered orally, pharmaceutically acceptable carriers include, but are not limited to pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid arc suitable disintegrating 20 agents. Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.

As used herein, a “transformed cell” is a cell into which a vector has been introduced from which a dsRNA molecule may be expressed.

II. Double-stranded ribonucleic acid (dsRNA)

As described in more detail herein, the invention provides double-stranded ribonucleic acid (dsRNA) molecules for inhibiting the expression of a TTR gene in a cell or mammal, e.g., in a human having a TTR amyloidosis, where the dsRNA includes an antisense strand having a 30 region of complementarity which is complementary to at least a part of an mRNA formed in the expression of a TTR gene, and where the region of complementarity is less than 30 nucleotides in length, generally 19-24 nucleotides in length, and where said dsRNA, upon contact with a cell expressing said TTR gene, inhibits the expression of said TTR gene by at least 30% as assayed by, for example, a PCR or branched DNA (bDNA)-based method, or by a protein-based method.

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 such as by Western blot. Expression of a TTR gene can be reduced by at least 30% when measured by an assay as described in the Examples below. For example, expression of a TTR gene in cell culture, such as in Hep3B cells, can be assayed by measuring TTR mRNA levels, such as by bDNA or TaqMan assay, or by measuring protein levels, such as by ELISA assay.

The dsRNA of the invention can further include one or more single-stranded nucleotide overhangs.

The dsRNA can be synthesized by standard methods known in the art as further discussed below, e.g._f by use of an automated DNA synthesizer, such as arc commercially available from, for example, Bioscarch, Applied Biosystems, Inc. The dsRNA includes two 10 RNA strands that are sufficiently complementary to hybridize to form a duplex structure. One strand of the dsRNA (the antisense strand) includes a region of complementarity that is substantially complementary, and generally fully complementary, to a target sequence, derived from the sequence of an mRNA formed during the expression of a TTR gene, the other strand (the sense strand) includes a region that is complementary to the antisense strand, such that the 15 two strands hybridize and form a duplex structure when combined under suitable conditions.

Generally, the duplex structure is between 15 and 30 or between 25 and 30, or between 18 and 25, or between 19 and 24, or between 19 and 21, or 19, 20, or 21 base pairs in length. In one embodiment the duplex is 19 base pairs in length. In another embodiment the duplex is 21 base pairs in length. When two different siRNAs arc used in combination, the duplex lengths can be 20 identical or can differ.

Each strand of the dsRNA of invention is generally between 15 and 30, or between 18 and 25, or 18, 19, 20, 21,22, 23, 24, or 25 nucleotides in length. In other embodiments, each is strand is 25-30 nucleotides in length. Each strand of the duplex can be the same length or of different lengths. When two different siRNAs are used in combination, the lengths of each 25 strand of each siRNA can be identical or can differ.

The dsRNA of the invention can include one or more single-stranded overhang(s) of one or more nucleotides. In one embodiment, at least one end of the dsRNA has a single-stranded nucleotide overhang of 1 to 4, generally 1 or 2 nucleotides. In another embodiment, the antisense strand of the dsRNA has 1-10 nucleotides overhangs each at the 3’ end and the 5’ end 30 over the sense strand. In further embodiments, the sense strand of the dsRNA has 1-10 nucleotides overhangs each at the 3’ end and the 5’ end over the antisense strand.

A dsRNAs having at least one nucleotide overhang can have unexpectedly superior inhibitory properties than the blunt-ended counterpart. In some embodiments the presence of only one nucleotide overhang strengthens the interference activity of the dsRNA, without

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 affecting its overall stability. A dsRNA having only one overhang has proven particularly stable and effective in vivo, as well as in a variety of cells, cell culture mediums, blood, and serum. Generally, the single-stranded overhang is located at the 3'-tcrminal end of the antisense strand or, alternatively, at the 3‘-terminal end of the sense strand. The dsRNA can also have a blunt 5 end, generally located at the 5’-end of the antisense strand. Such dsRNAs can have improved stability and inhibitory activity, thus allowing administration at low dosages, i.e., less than 5 mg/kg body weight of the recipient per day. Generally, the antisense strand of the dsRNA has a nucleotide overhang at the 3’-end, and the 5’-end is blunt. In another embodiment, one or more of the nucleotides in the overhang is replaced with a nucleoside thiophosphatc.

In one embodiment, a TTR gene is a human TTR gene. In specific embodiments, the sense strand of the dsRNA is one of the sense sequences from Tables 3A, 3B, 4, 6A, 6B, or 7, and the antisense strand is one of the antisense sequences of Tables 3A, 3B, 4, 6A, 6B, or 7. Alternative antisense agents that target elsewhere in the target sequence provided in Tables 3 A, 3B, 4, 6A, 6B, or 7 can readily be determined using the target sequence and the flanking TTR sequence.

The skilled person is well aware that dsRNAs having a duplex structure of between 20 and 23, but specifically 21, base pairs have been hailed as particularly effective in inducing RNA interference (Elbashir et al., EMBO 2001,20:6877-6888). However, others have found that shorter or longer dsRNAs can be effective as well. In the embodiments described above, by 20 virtue of the nature of the oligonucleotide sequences provided in Tables 3A, 3B, 4, 6A, 6B, and

7, the dsRNAs featured in the invention can include at least one strand of a length described herein. It can be reasonably expected that shorter dsRNAs having one of the sequences of Tables 3A, 3B, 4, 6A, 6B, or 7 minus only a few nucleotides on one or both ends may be similarly effective as compared to the dsRNAs described above. Hence, dsRNAs having a partial sequence of at least 15, 16, 17, 18, 19, 20, or more contiguous nucleotides from one of the sequences of Tables 3, 4, 6 or 7, and differing in their ability to inhibit the expression of a TTR gene in an assay as described herein below by not more than 5, 10, 15, 20, 25, or 30 % inhibition from a dsRNA comprising the full sequence, are contemplated by the invention. Further, dsRNAs that cleave within a desired TTR target sequence can readily be made using the corresponding TTR antisense sequence and a complementary sense sequence.

In addition, the dsRNAs provided in Tables 3A, 3B, 4, 6A, 6B, or 7 identify a site in a TTR that is susceptible to RNAi based cleavage. As such, the present invention further features dsRNAs that target within the sequence targeted by one of the agents of the present invention. As used herein, a second dsRNA is said to target within the sequence of a first dsRNA if the

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 second dsRNA cleaves the message anywhere within the mRNA that ls complementary to the antisense strand of the first dsRNA. Such a second dsRNA will generally consist of at least 15 contiguous nucleotides from one of the sequences provided in Tables 3A, 3B, 4, 6A, 6B, or 7 coupled to additional nucleotide sequences taken from the region contiguous to the selected sequence in a TTR gene.

Cleavage of the RNA target can be routinely detected by gel electrophoresis and, if necessary, associated nucleic acid hybridization techniques known in the art. The cleavage site on the target mRNA of a dsRNA can be determined using methods generally known to one of ordinary skill in the art, e.g., the 5’-RACE method described in Soutschek et al., Nature; 2004, 10 Vol. 432, pp. 173-178 (which is herein incorporated by reference for all purposes). In an embodiment, using the 5’-RACE method described by Soutschek et al., ALN-18328 was determined to cleave a TTR mRNA between the guanine nucleotide at position 636 of SEQ ID NO: 1331 (NM_000371.3) and the adenine nucleotide at position 637 of SEQ ID NO: 1331. In an embodiment, it was determined that ALN-18328 does not cleave a TTR mRNA between the 15 adenine nucleotide at position 637 of SEQ ID NO: 1331 and the guanine nucleotide at position 638 of SEQ ID NO: 1331.

The dsRNA featured in the invention can contain one or more mismatches to the target sequence. In one embodiment, the dsRNA featured in the invention contains no more than 3 mismatches. If the antisense strand of the dsRNA contains mismatches to a target sequence, it 20 is preferable that the area of mismatch not be located in the center of the region of complementarity. If the antisense strand of the dsRNA contains mismatches to the target sequence, it is preferable that the mismatch be restricted to 5 nucleotides from either end, for example 5, 4, 3, 2, or 1 nucleotide from either the 5’ or 3’ end of the region of complementarity. For example, for a 23 nucleotide dsRNA strand which is complementary to a region of a TTR 25 gene, the dsRNA generally does not contain any mismatch within the central 13 nucleotides. The methods described within the invention can be used to determine whether a dsRNA containing a mismatch to a target sequence is effective in inhibiting the expression of a TTR gene. Consideration of the efficacy of dsRNAs with mismatches in inhibiting expression of a TTR gene is important, especially if the particular region of complementarity in a TTR gene is known 30 to have polymorphic sequence variation within the population.

Modifications

In yet another embodiment, the dsRNA is chemically modified to enhance stability. The nucleic acids featured in the invention may be synthesized and/or modified by methods well

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 established in the art, such as those described in “Current protocols in nucleic acid chemistry,”

Beaucage, S.L. et al. (Eds.), John Wiley & Sons, Inc., New York, NY, USA, which is hereby incorporated herein by reference. Specific examples of dsRNA compounds useful in this invention include dsRNAs containing modified backbones or no natural intemucleoside linkages. As defined in this specification, dsRNAs having modified backbones include those that retain a phosphorus atom in the backbone and those that do not have a phosphorus atom in the backbone. For the purposes of this specification, and as sometimes referenced in the art, modified dsRNAs that do not have a phosphorus atom in their intemucleoside backbone can also be considered to be oligonuclcosides.

Modified dsRNA backbones include, for example, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotri esters, methyl and other alkyl phosphonates including 3'-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3'-amino phosphoramidate and aminoalkyIphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriestcrs, and boranophosphates having normal 3-5' linkages, 2'-5' linked analogs of these, and those) having inverted polarity wherein the adjacent pairs of nucleoside units arc linked 3'-5' to 5-3' or 2'-5' to 5’-2'. Various salts, mixed salts and free acid forms are also included.

Representative U.S. patents that teach the preparation of the above phosphorus20 containing linkages include, but arc not limited to, U.S. Pat. Nos. 3,687,808; 4,469,863; 4,476,301; 5,023,243; 5,177,195; 5,188,897; 5,264,423; 5,276,019; 5,278,302; 5,286,717; 5,321,131; 5,399,676; 5,405,939; 5,453,496; 5,455,233; 5,466,677; 5,476,925; 5,519,126; 5,536,821; 5,541,316; 5,550,111; 5,563,253; 5,571,799; 5,587,361; and 5,625,050, each of which is herein incorporated by reference

Modified dsRNA backbones that do not include a phosphorus atom therein have backbones that are formed by short chain alkyl or cycloalkyl intemucleoside linkages, mixed heteroatoms and alkyl or cycloalkyl intemucleoside linkages, or ore or more short chain hcteroatomic or heterocyclic intemucleoside linkages. These include those having morpholino linkages (formed tn part from the sugar portion of a nucleoside); siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacctyl and thioformacetyl backbones; alkene containing backbones; sulfamate backbones; methyleneimino and mcthylcnehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; and others having mixed N, O, S and CH₂ component parts.

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Representative U.S. patents that teach the preparation of the above oligonucleosides include, but are not limited to, U.S. Pat. Nos. 5,034,506; 5,166,315; 5,185,444; 5,214,134;

5,216,141; 5,235,033; 5,64,562; 5,264,564; 5,405,938; 5,434,257; 5,466,677; 5,470,967;

5,489,677; 5,541,307; 5,561,225; 5,596,086; 5,602,240; 5,608,046; 5,610,289; 5,618,704;

5,623,070; 5,663,312; 5,633,360; 5,677,437; and, 5,677,439, each of which is herein incorporated by reference.

In other suitable dsRNA mimetics, both the sugar and the internucleoside linkage, i.e., the backbone, of the nucleotide units arc replaced with novel groups. The base units are maintained for hybridization w'ith an appropriate nucleic acid target compound. One such oligomeric compound, a dsRNA mimetic that has been shown to have excellent hybridization properties, is referred to as a peptide nucleic acid (PNA). In PNA compounds, the sugar backbone of a dsRNA is replaced with an amide containing backbone, in particular an aminoethylglycine backbone. The nucleobases are retained and are bound directly or indirectly to aza nitrogen atoms of the amide portion of the backbone. Representative U.S. patents that teach the preparation of PNA compounds include, but are not limited to, U.S. Pat. Nos. 5,539,082; 5,714,331; and 5,719,262, each of which is herein incorporated by reference. Further teaching of PNA compounds can be found in Nielsen et al.. Science, 1991, 254, 1497-1500.

Other embodiments of the invention arc dsRNAs with phosphorothioatc backbones and oligonucleosides with heteroatom backbones, and in particular —CH₂—NH—CH?—, —CH₂—

N(CHa)—O-CHj—[known as a methylene (methylimino) or MM1 backbone], —CH?—O—

N(CH₃)-CH₂-, -CH₂-N(CH₃)-N(CH₃)-CH₂- and -N(CH₃)-CH₂-CH₂-[wherein the native phosphodiester backbone is represented as —Ο—P—O—CH₂—] of the above-referenced U.S. Pat. No. 5,489,677, and the amide backbones of the above-referenced U.S. Pat. No. 5,602,240. Also preferred are dsRNAs having morpholino backbone structures of the above-referenced U.S, Pat.

No. 5,034,506.

Modified dsRNAs may also contain one or more substituted sugar moietics. Preferred dsRNAs comprise one of the following at the 2' position; OH; F; O-, S-, or N-alkyl; O-, S-, or Nalkcnyl; O-, S- or N-atkynyl; or O-alkyl-O-alkyl, wherein the alkyl, alkenyl and alkynyl may be substituted or unsubstituted Ci to Cjo alky! or C₂ to Cio alkenyl and alkynyl. Particularly preferred are O[(CH₂)_nO]_mCH₃, O(CH₂)„OCH₃, O(CH₂)_nNH₂, O(CH₂)_nCH₃, O(CH₂)_nONH₂, and O(CH₂)_nON[(CH₂)_nCH₃)]₂, where n and m are from 1 to about 10. Other preferred dsRNAs comprise one of the following at the 2' position: C] to Cio lower alkyl, substituted lower alkyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH₃. OCN, Cl, Br, CN, CFj. OCF₃, SOCH₃.

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

SO2CH3. ONOj. NO2. Νί, NEL hcterocycloalkyl, hctcrocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercaiator, a group for improving the pharmacokinetic properties of an dsRNA, or a group for improving the pharmacodynamic properties of an dsRNA, and other substituents having similar properties, A preferred modification includes 2'-methoxycthoxy (2'-O—CH2CH2OCH3, also known as 2-0-(2methoxyethyl)or 2-MOE) (Martin et al., Helv. Chim. Acta, 1995, 78, 486-504) i.e., an alkoxyalkoxy group. A further preferred modification includes 2'-dimcthylaminooxycthoxy, i.e., a O(CH2)2ON(CH3)₂ group, also known as 2-DMAOE, as described in examples herein below, and 2'-dimcthylaminocthoxycthoxy (also known in the art as 2^,-O-dimcthylaminocthoxycthyl or 10 2'-DMAEOE), i.e., 2'-O--( l I —i also described in examples herein below.

Other preferred modifications include 2'-methoxy (2'-OCEh), 2'-aminopropoxy (2¹OCH2CH2CH2NH2) and 2’-fluoro (2'-F). Similar modifications may also be made at other positions on the dsRNA, particularly the 3' position of the sugar on the 3' terminal nucleotide or in 2'-5’ linked dsRNAs and the 5' position of 5' terminal nucleotide. DsRNAs may also have sugar mimetics such as cyclobutyl moieties in place of the pen to furanosy 1 sugar. Representative U.S. patents that teach the preparation of such modified sugar structures include, but are not limited to, U.S. Pat. Nos. 4,981,957; 5,118,800; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633; and 5,700,920, certain of which are commonly owned with the instant application, and each of which is herein incorporated by reference in its entirety.

dsRNAs may also include nucleobase (often referred to in the art simply as “base”) modifications or substitutions. As used herein, “unmodified” or “natural” nucleobases include the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine 25 (C) and uracil (U). Modified nucleobases include other synthetic and natural nucleobases such as

5-mcthylcytosinc (5-me-C), 5-hydroxymcthyl cytosine, xanthine, hypoxanthine, 2aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothyminc and 2-thiocytosinc, 5halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 530 uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl anal other 8substituted adenines and guanines, 5-halo, particularly 5-bromo, 5-trifluoromethyl and other 5substituted uracils and cytosines, 7-methylguanine and 7-mcthyladcnine, 8-azaguaninc and 8azaadenine, 7-deazaguanine and 7-daazaadenine and 3-deazaguanine and 3-deazaadenine.

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Further nucleobases include those disclosed in U.S. Pat. No. 3,687,808, those disclosed in The

Concise Encyclopedia Of Polymer Science And Engineering, pages 858-859, Kroschwitz, J. L, ed. John Wiley & Sons, 1990, these disclosed by Englisch et al., Angewandte Chemie,

International Edition, 1991, 30, 613, and those disclosed by Sanghvi, Y S., Chapter 15, DsRNA

Research and Applications, pages 289-302, Crooke, S. T. and Lebleu, B., Ed., CRC Press, 1993. Certain of these nucleobases are particularly useful for increasing the binding affinity of the oligomeric compounds featured in the invention. These include 5-substitutcd pyrimidines, 6azapyrimidines and N-2, N-6 and 0-6 substituted purines, including 2-ami nopropyladenine, 5propynyluracil and 5-propynylcytosinc. 5-mcthylcytosinc substitutions have been shown to increase nucleic acid duplex stability by 0.6-1,2°C. (Sanghvi, Y. S., Crooke, S. T. and Lebleu, B., Eds., DsRNA Research and Applications, CRC Press, Boca Raton, 1993, pp. 276-278) and are exemplary base substitutions, even more particularly when combined with 2'-Omcthoxyethyl sugar modifications.

Representative U.S. patents that teach the preparation of certain of the above noted modified nucleobases as well as other modified nucleobases include, but arc not limited to, the above noted U.S. Pat. No. 3,687,808, as well as U.S. Pat. Nos. 4,845,205; 5,130,30; 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,594,121, 5,596,091; 5,614,617; and 5,681,941, each of which is herein incorporated by reference, and U.S. Pat. No. 5,750,692, also herein incorporated by reference.

Conjugates

Another modification of the dsRNAs of the invention involves chemically linking to the dsRNA one or more moieties or conjugates which enhance the activity, cellular distribution or cellular uptake of the dsRNA. Such moieties include but are not limited to lipid moieties such as a cholesterol moiety (Lctsinger et al., Proc. Natl. Acid. Sci. USA, 1989, 86: 6553-6556), cholic acid (Manoharan etal., Biorg. Med. Chem. Let,, 1994, 4:1053-1060), a thioether, e.g., beryl-Stritylthiol (Manoharan et a!., Ann. N.Y. Acad. Sci,, 1992, 660:306-309; Manoharan et al., Biorg. Med. Chem. Let., 1993, 3:2765-2770), a thiocholesterol (Oberhauser et al., Nucl. Acids Res., 1992, 20:533-538), an aliphatic chain, e.g., dodccandiol or undecyl residues (Saison-Bchmoaras et al., EMBO J, 1991, 10:1111-1118; Kabanov etal., FEBS Lett., 1990,259:327-330;

Svinarchuk et al., Biochimic, 1993, 75:49-54), a phospholipid, e.g., di-hcxadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-Hphosphonate (Manoharan etal.. Tetrahedron Lett., 1995, 36:3651-3654; Shea etal., Nucl. Acids Res., 1990, 18:3777-3783), a polyamine or a polyethylene glycol chain (Manoharan etal.. Nucleosides & Nucleotides, 1995,

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

14:969-973), or adamantane acetic acid (Manoharan et al.. Tetrahedron Lett., 1995, 36:36513654), a palmityl moiety (Mishra et al., Biochim. Biophys. Acta, 1995, 1264:229-237), or an octadccylamine or hexylamino-carbonyloxycholcsterol moiety (Crookc et al., J. Pharmacol. Exp.

Ther., 1996, 277:923-937).

Representative U.S. patents that teach the preparation of such dsRNA conjugates include, but arc not limited to, U.S. Pat. Nos. 4,828,979; 4,948,882; 5,218,105; 5,525,465; 5,541,313; 5,545,730; 5,552,538; 5,578,717, 5,580,731; 5,591,584; 5,109,124; 5,118,802; 5,138,045; 5,414,077; 5,486,603; 5,512,439; 5,578,718; 5,608,046; 4,587,044; 4,605,735; 4,667,025; 4,762,779; 4,789,737; 4,824,941; 4,835,263; 4,876,335; 4,904,582; 4,958,013; 5,082,830;

5,112,963; 5,214,136; 5,082,830; 5,112,963; 5,214,136; 5,245,022; 5,254,469; 5,258,506;

5,262,536; 5,272,250; 5,292,873; 5,317,098; 5,371,241,5,391,723; 5,416,203, 5,451,463; 5,510,475; 5,512,667; 5,514,785; 5,565,552; 5,567,810; 5,574,142; 5,585,481; 5,587,371; 5,595,726; 5,597,696; 5,599,923; 5,599,928 and 5,688,941, each of which is herein incorporated by reference.

It is not necessary for all positions in a given compound to be uniformly modified, and in fact more than one of the aforementioned modifications may be incorporated in a single compound or even at a single nucleoside within a dsRNA. The present invention also includes dsRNA compounds which arc chimeric compounds. “Chimeric” dsRNA compounds or “chimeras,” in the context of this invention, are dsRNA compounds, particularly dsRNAs, which 20 contain two or more chemically distinct regions, each made up of at least one monomer unit, i.e., ά nucleotide in the case of a dsRNA compound. These dsRNAs typically contain at least one region wherein the dsRNA is modified so as to confer upon the dsRNA increased resistance to nuclease degradation, increased cellular uptake, and/or increased binding affinity forthe target nucleic acid. An additional region of the dsRNA may serve as a substrate for enzymes capable of 25 cleaving RNA:DNA or RNA:RNA hybrids. By way of example, RNase H is a cellular endonuclease which cleaves the RNA strand of an RNA:DNA duplex. Activation of RNase H, therefore, results in cleavage of the RNA target, thereby greatly enhancing the efficiency of dsRNA inhibition of gene expression. Consequently, comparable results can often be obtained with shorter dsRNAs when chimeric dsRNAs are used, compared to phosphorothioate deoxydsRNAs hybridizing to the same target region.

In certain instances, the dsRNA may be modified by a non-ligand group. A number of non-ligand molecules have been conjugated to dsRNAs in order to enhance the activity, cellular distribution or cellular uptake of the dsRNA, and procedures for performing such conjugations

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 arc available in the scientific literature. Such non-ligand moieties have included lipid moieties, such as cholesterol (Letsinger et al., Proc. Natl. Acad. Sci. USA, 1989, 86:6553), cholic acid (Manoharan et al., Bioorg. Med. Chem. Lett., 1994, 4:1053), a thioethcr, e.g., hexyl-S-tritylthiol (Manoharan et al., Ann, N.Y. Acad. Sci., 1992, 660:306; Manoharan etal., Bioorg. Med. Chem.

Let., 1993, 3:2765), a thiocholestcrol (Oberhauser etal., Nucl. Acids Res., 1992, 20:533), an aliphatic chain, e.g., dodecandiol or undecyl residues (Saison-Behmoaras et al., EMBO J., 1991, 10:111; Kabanov et al., FEBS Lett., 1990, 259:327; Svinarchuk et al., Biochimic, 1993, 75:49), a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethylammonium 1,2-di-O-hexadecyl-racglyccro-3-H-phosphonate (Manoharan et al.. Tetrahedron Lett., 1995, 36:3651; Shea et al., Nucl.

Acids Res., 1990, 18:3777), a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides & Nucleotides, 1995, 14:969), or adamantane acetic acid (Manoharan et al., Tetrahedron Lett., 1995, 36:3651), a palmityi moiety (Mishra et al., Biochim. Biophys. Acta, 1995, 1264:229), or an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety (Crookc et al., J. Pharmacol. Exp. Ther., 1996, 277:923). Representative United States patents that teach the preparation of such dsRNA conjugates have been listed above. Typical conjugation protocols involve the synthesis of dsRNAs bearing an aminolinker at one or more positions of the sequence. The amino group is then reacted with the molecule being conjugated using appropriate coupling or activating reagents. The conjugation reaction may be performed either with the dsRNA still bound to the solid support or following cleavage of the dsRNA in solution phase.

Purification of the dsRNA conjugate by HPLC typically affords the pure conjugate.

Vector encoded dsRNAs

In another aspect, TTR dsRNA molecules are expressed from transcription units inserted into DNA or RNA vectors (see, e.g., Couture, A, et al., TIG. (1996), 12:5-10; Skillern, A., et al., International PCT Publication No. WO 00/22113, Conrad, International PCT Publication No.

WO 00/22114, and Conrad, U.S. Pat. No. 6,054,299). These transgenes can be introduced as a linear construct, a circular plasmid, or a viral vector, which can be incorporated and inherited as a transgene integrated into the host genome. The transgene can also be constructed to permit it to be inherited as an extrachromosomal plasmid (Gassmann, etal., Proc. Natl. Acad. Sci. USA (1995)92:1292).

The individual strands of a dsRNA can be transcribed by promoters on two separate expression vectors and co-transfcctcd into a target cell. Alternatively each individual strand of the dsRNA can be transcribed by promoters both of which arc located on the same expression plasmid. In one embodiment, a dsRNA is expressed as an inverted repeat joined by a linker polynucleotide sequence such that the dsRNA has a stem and loop structure.

2017204161 20 Jun 2017

WO 2011/123468 PCT/US2011/030392

The recombinant dsRNA expression vectors are generally DNA plasmids or viral vectors. dsRNA expressing viral vectors can be constructed based on, but not limited to, adenoassociatcd virus (for a review, see Muzyczka, et al., Curr. Topics Micro. Immunol. (1992) 158:97-129)); adenovirus (see, for example, Berkner, etal., BioTechniques (1998) 6:616),

Rosenfeld et al. (1991, Science 252:431-434), and Rosenfeld et al. (1992), Cell 68:143-155)); or alphavirus as well as others known in the art. Retroviruses have been used to introduce a variety of genes into many different cell types, including epi thelial cells, in vitro and/or in vivo (see, e.g., Eglitis, et al., Science (1985) 230:1395-1398; Danos and Mulligan, Proc. Natl. Acad. Sci. USA (1998) 85:6460-6464; Wilson etal., 1988, Proc. Natl. Acad. Sci. USA 85:3014-3018;

Armentano etal., 1990, Proc. Natl. Acad. Sci. USA 87:61416145; Huber etal., 1991, Proc. Natl. Acad. Sci. USA 88:8039-8043; Ferry etal., 1991, Proc. Natl. Acad. Sci. USA 88:83778381; Chowdhury etal., 1991, Science 254:1802-1805; van Beusechem. et al., 1992, Proc. Natl. Acad. Sci. USA 89:7640-19 ; Kay etal., 1992, Human Gene Therapy 3:641-647; Dai etal., 1992, Proc. Natl. Acad. Sci. USA 89:10892-10895; Hwueta/., 1993, J. Immunol. 150:410415 4115; U.S. Patent No. 4,868,116; U.S. Patent No. 4,980,286; PCT Application WO 89/07136;

PCT Application WO 89/02468; PCT Application WO 89/05345; and PCT Application WO 92/07573). Recombinant retroviral vectors capable of transducing and expressing genes inserted into the genome of a cell can be produced by transfecting the recombinant retroviral genome into suitable packaging cell lines such as PA317 and Psi-CRIP (Comcttc et al., 1991, Human Gene

Therapy 2:5-10; Cone et al., 1984, Proc. Natl. Acad. Sci. USA 81:6349). Recombinant adenoviral vectors can be used to infect a wide variety of cells and tissues in susceptible hosts (e.g., rat, hamster, dog, and chimpanzee) (Hsu et al., 1992, J. Infectious Disease, 166:769), and also have the advantage of not requiring mitotically active cells for infection.

Any viral vector capable of accepting the coding sequences for the dsRNA molecule(s) to be expressed can be used, for example vectors derived from adenovirus (AV); adenoassociatcd vims (AAV); retroviruses (e.g, lentiviruses (LV), Rhabdoviruses, murine leukemia virus); herpes virus, and the like. The tropism of viral vectors can be modified by pseudotyping the vectors with envelope proteins or other surface antigens from other viruses, or by substituting different viral capsid proteins, as appropriate,

For example, lentiviral vectors featured in the invention can be pseudotyped with surface proteins from vesicular stomatitis virus (VSV), rabies, Ebola, Mokola. and the like. AAV vectors featured in the invention can be made to target different cells by engineering the vectors to express different capsid protein serotypes. For example, an AAV vector expressing a serotype 2

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 capsid on a serotype 2 genome is called AAV 2/2. This serotype 2 capsid gene in the AAV 2/2 vector can be replaced by a serotype 5 capsid gene to produce an AAV 2/5 vector. Techniques for constructing AAV vectors which express different capsid protein serotypes arc within the skill in the art; see, e.g., Rabinowitz J E et al. (2002), J Virol 76:791-801, the entire disclosure of which is herein incorporated by reference.

Selection of recombinant viral vectors suitable for use in the invention, methods for inserting nucleic acid sequences for expressing the dsRNA into the vector, and methods of delivering the viral vector to the cells of interest are within the skill in the art. See, for example, Dornburg R (1995), Gene Therap. 2: 301-310; Eglitis M A (1988), Biotechniques 6: 608-614;

Miller A D (1990), Hum Gene Therap. 1:5-14; Anderson W F (1998), Nature 392: 25-30; and Rubinson D A et al., Nat. Genet. 33: 401-406, the entire disclosures of which are herein incorporated by reference.

Viral vectors can be derived from AV and AAV. In one embodiment, the dsRNA featured in the invention is expressed as two separate, complementary single-stranded RNA 15 molecules from a recombinant AAV vector having, for example, either the U6 or Η1 RNA promoters, or the cytomegalovirus (CMV) promoter.

A suitable AV vector for expressing the dsRNA featured in the invention, a method for constructing the recombinant AV vector, and a method for delivering the vector into target cells, arc described in Xia H et al. (2002), Nat. Biotech. 20: 1006-1010.

Suitable AAV vectors for expressing the dsRNA featured in the invention, methods for constructing the recombinant AV vector, and methods for delivering the vectors into target cells are described in Samulski R et al. (1987), J. Virol. 61: 3096-3101; Fisher K J et al. (1996), J. Virol, 70: 520-532; Samulski R et al. (1989), J. Virol. 63: 3822-3826; U.S. Pat. No. 5,252,479;

U.S. Pat. No. 5,139,941; International Patent Application No. WO 94/13788; and International 25 Patent Application No. WO 93/24641, the entire disclosures of which arc herein incorporated by reference.

The promoter driving dsRNA expression in cither a DNA plasmid or viral vector featured in the invention may be a eukaryotic RNA polymerase I (e.g., ribosomal RNA promoter), RNA polymerase II (e.g., CMV early promoter or actin promoter or U1 snRNA 30 promoter) or generally RNA polymerase III promoter (e.g., U6 snRNA or 7SK RNA promoter) or a prokaryotic promoter, for example the T7 promoter, provided the expression plasmid also encodes T7 RNA polymerase required for transcription from a T7 promoter. The promoter can

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 also direct trans gene expression to the pancreas (sec, e.g., the insulin regulatory sequence for pancreas (Bucchini etui., 1986, Proc. Natl. Acad. Sci. USA 83:2511-2515)).

In addition, expression of the transgene can be precisely regulated, for example, by using an inducible regulatory sequence and expression systems such as a regulatory sequence that is sensitive to certain physiological regulators, e.g., circulating glucose levels, or hormones (Docherty etal., 1994, FASEB J. 8:20-24). Such inducible expression systems, suitable for the control of transgene expression in cells or in mammals include regulation by ecdysone, by estrogen, progesterone, tetracycline, chemical inducers of dimerization, and isopropyl-bcta-D 1 thiogalactopyranosidc (EPTG). A person skilled in the art would be able to choose the appropriate regulatory/promoter sequence based on the intended use of the dsRNA transgene.

Generally, recombinant vectors capable of expressing dsRNA molecules are delivered as described below, and persist in target cells. Alternatively, viral vectors can be used that provide for transient expression of dsRNA molecules. Such vectors can be repeatedly administered as necessary. Once expressed, the dsRNAs bind to target RNA and modulate its function or expression. Delivery of dsRNA expressing vectors can be systemic, such as by intravenous or intramuscular administration, by administration to target cells ex-planted from the patient followed by reintroduction into the patient, or by any other means that allows for introduction into a desired target cell.

dsRNA expression DNA plasmids are typically transfected into target cells as a complex 20 with cationic lipid carriers (e.g.. Oiigofectaminc) or non-cationic lipid-based carriers (e.g.,

Transit-TKO^ΙΆ1). Multiple lipid transfections for dsRNA-mediatcd knockdowns targeting different regions of a single TTR gene or multiple TTR genes over a period of a week or more arc also contemplated by the invention. Successful introduction of vectors into host cells can be monitored using various known methods. For example, transient transfection can be signaled 25 with a reporter, such as a fluorescent marker, such as Green Fluorescent Protein (GFP). Stable transfection of cells ex vivo can be ensured using markers that provide the transfected cell with resistance to specific environmental factors (e.g., antibiotics and drugs), such as hygromycin B resistance.

TTR specific dsRNA molecules can also be inserted into vectors and used as gene therapy vectors for human patients. Gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (sec U.S. Patent 5,328,470) or by stereotactic injection (see e.g., Chen etal. (1994) Proc. Natl. Acad. Sci. USA 91:3054-3057). The pharmaceutical preparation of the gene therapy vector can include the gene therapy vector in an acceptable diluent, or can include a slow release matrix in which the gene delivery vehicle is

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 imbedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells, e.g., retroviral vectors, the pharmaceutical preparation can include one or more cells which produce the gene delivery system.

111. Pharmaceutical compositions containing dsRNA

In one embodiment, the invention provides pharmaceutical compositions containing a dsRNA, as described herein, and a pharmaceutically acceptable carrier. The pharmaceutical composition containing the dsRNA is useful for treating a disease or disorder associated with the expression or activity of a TTR gene, such as pathological processes mediated by TTR expression. Such pharmaceutical compositions are formulated based on the mode of delivery.

One example is compositions formulated for direct delivery to the eye. Another example is compositions that are formulated for systemic administration via parenteral delivery, e.g., by intravenous (IV) delivery. Another example is compositions that are formulated for direct delivery into the brain parenchyma, e.g., by infusion into the brain, such as by continuous pump infusion.

The pharmaceutical compositions featured herein are administered in dosages sufficient to inhibit expression of TTR genes.

In general, a suitable dose of dsRNA will be in the range of 0.00001 to 200.0 milligrams per kilogram body weight of the recipient per day, generally in the range of 1 to 50 mg per kilogram body weight per day.

In some embodiments, the dosage does not scale with body weight when the siRNA is administered to the eye.

The dosage can be, e.g., 25 ug for a 75 kg person, e.g, 0.3 pg/kg. Other dosages include, 0.01,0.03, 0.05, 0.07, 0.1, 0.3, 0.5,0.7, 1.0, 3.0. 5.0, 7.0, 10.0, 30.0, 50.0, 70.0, or 100.0 gg/kg.

For example, the dsRNA can be administered at 0.0059 mg/kg, 0.01 mg/kg, 0.0295 mg/kg, 0.05 mg/kg, 0.0590 mg/kg, 0.163 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.543 mg/kg, 0.5900 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1 mg/kg, 1.1 mg/kg, 1.2 mg/kg, 1.3 mg/kg, 1.4 mg/kg, i .5 mg/kg, 1.628 mg/kg, 2 mg/kg, 3 mg/kg, 5.0 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 40 mg/kg, or 50 mg/kg per single dose.

In one embodiment, the dosage is between 0.01 and 0.2 mg/kg. For example, the dsRNA can be administered at a dose of 0.01 mg/kg, 0.02 mg/kg, 0.03 mg/kg, 0.04 mg/kg, 0.05 mg/kg, 0.06 mg/kg, 0.07 mg/kg 0.08 mg/kg 0.09 mg/kg , 0.10 mg/kg, 0.11 mg/kg, 0.12 mg/kg, 0.13 mg/kg, 0.14 mg/kg, 0.15 mg/kg, 0.16 mg/kg, 0.17 mg/kg, 0.18 mg/kg, 0.19 mg/kg, or 0.20 mg/kg.

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

In one embodiment, the dosage is between 0.005 mg/kg and 1.628 mg/kg. For example, the dsRNA can be administered at a dose of 0.0059 mg/kg. 0.0295 mg/kg, 0.0590 mg/kg, 0.163 mg/kg, 0.543 mg/kg, 0.5900 mg/kg, or 1.628 mg/kg.

In one embodiment, the dosage is between 0.2 mg/kg and 1.5 mg/kg. For example, the dsRNA can be administered at a dose of 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1 mg/kg, 1.1 mg/kg, 1.2 mg/kg, 1.3 mg/kg, 1.4 mg/kg, or 1.5 mg/kg.

The dsRNA can be administered at a dose of 0.03 mg/kg, or 0.03, 0.1, 0.2, or 0.4 mg/kg.

The pharmaceutical composition may be administered once daily, or the dsRNA may be administered as two, three, or more sub-doses at appropriate intervals throughout the day or even using continuous infusion or delivery through a controlled release formulation. In that case, the dsRNA contained in each sub-dose must be correspondingly smaller in order to achieve the total daily dosage. The dosage unit can also be compounded for delivery over several days, e.g., using a conventional sustained release formulation which provides sustained release of the dsRNA over a several day period. Sustained release formulations arc well known in the art and are particularly useful for delivery of agents at a particular site, such as could be used with the agents of the present invention. In this embodiment, the dosage unit contains a corresponding multiple of the daily dose.

The effect of a single dose on TTR levels is long lasting, such that subsequent doses are 20 administered at not more than 3, 4, or 5 day intervals, or at not more than 1,.2,3, or 4 week intervals, or at not more than 5, 6, 7, 8, 9, or 10 week intervals.

The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other 25 diseases present. Moreover, treatment of a subject with a therapeutically effective amount of a composition can include a single treatment or a series of treatments. Estimates of effective dosages and in vivo half-lives for the individual dsRNAs encompassed by the invention can be made using conventional methodologies or on the basis of in vivo testing using an appropriate animal model, as described elsewhere herein.

Advances in mouse genetics have generated a number of mouse models for the study of various human diseases, such as pathological processes mediated by TTR expression. Such models are used for in vivo testing of dsRNA, as well as for determining a therapeutically effective dose. A suitable mouse model is, for example, a mouse containing a plasmid

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 expressing human TTR. Another suitable mouse model is a transgenic mouse carrying a transgene that expresses human TTR.

The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of compositions featured in the invention lies 5 generally within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the methods featured in the invention, the therapeutically effective dose can be estimated initially from cell culture assays, A dose may be formulated in animal models to achieve a circulating plasma concentration range 10 of the compound or, when appropriate, of the polypeptide product of a target sequence (e.g., achieving a decreased concentration of the polypeptide) that includes the IC50 (i.e,, the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid 15 chromatography.

The dsRNAs featured in the invention can be administered in combination with other known agents effective in treatment of pathological processes mediated by target gene expression. In any event, the administering physician can adjust the amount and timing of dsRNA administration on the basis of results observed using standard measures of efficacy 20 known in the art or described herein.

Administration

The present invention also includes pharmaceutical compositions and formulations which include the dsRNA compounds featured in the invention. The pharmaceutical compositions of the present invention may be administered in a number of ways depending upon whether local or 25 systemic treatment is desired and upon the area to be treated. Administration may be topical, pulmonary, e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal, oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., Inlraparcnchymal, Intrathecal or intraventricular, administration.

The dsRNA can be delivered in a manner to target a particular tissue, such as the liver (e.g., the hepatocytes of the liver).

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

The dsRNA can be delivered in a manner to target a particular tissue, such as the eye.

Modes of ocular delivery include retrobulbar, subcutaneous eyelid, subconjunctival, subtenon, anterior chamber or intravitreous injection (or internal injection or infusion).

The present invention includes pharmaceutical compositions that can be delivered by injection directly into the brain. The injection can be by stereotactic injection into a particular region of the brain (e.g., the substantia nigra, cortex, hippocampus, striatum, or globus pallidus), or the dsRNA can be delivered into multiple regions of the central nervous system (e.g., into multiple regions of the brain, and/or into the spinal cord). The dsRNA can also be delivered into diffuse regions of the brain (e.g., diffuse delivery to the cortex of the brain).

In one embodiment, a dsRNA targeting TTR can be delivered by way of a cannula or other delivery device having one end implanted in a tissue, e.g., the brain, e.g., the substantia nigra, cortex, hippocampus, striatum, corpus callosum or globus pallidus of the brain. The cannula can be connected to a reservoir of the dsRNA composition. The flow or delivery can be mediated by a pump, e.g., an osmotic pump or minipump, such as an Alzct pump (Durcct,

Cupertino, CA). In one embodiment, a pump and reservoir are implanted in an area distant from the tissue, e.g., in the abdomen, and delivery is effected by a conduit leading from the pump or reservoir to the site of release. Infusion of the dsRNA composition into the brain can be over several hours or for several days, e.g., for 1, 2, 3, 5, or 7 days or more. Devices for delivery to the brain are described, for example, in U.S. Patent Nos. 6,093,180, and 5,814,014.

Pharmaceutical compositions and formulations for topical administration may include transderma] patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. Coated condoms, gloves and the like may also be useful. Suitable topical formulations include those in which the dsRNAs featured in the invention arc in admixture with a topical delivery agent such as lipids, liposomes, fatty acids, fatty acid esters, steroids, chelating agents and surfactants. Suitable lipids and liposomes include neutral (e.g., dioleoylphosphatidyl DOPE ethanolamine, dimyristoylphosphatidyl choline DMPC, distearoylphosphatidyl choline) negative (e.g., dimyristoylphosphatidyl glycerol DMPG) and cationic (e.g., dioleoyltetramethylaminopropyl DOTAP and dioleoylphosphatidyl ethanolamine

DOTMA). DsRNAs featured in the invention may be encapsulated within liposomes or may form complexes thereto, in particular to cationic liposomes. Alternatively, dsRNAs maybe complexed to lipids, in particular to cationic lipids. Suitable fatty acids and esters include but are not limited to arachidonic acid, oleic acid, eicosanoic acid, lauric acid, caprylic acid, capric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricapratc,

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 monoolein, dilaurin, glyceryl 1 -monocapratc, 1 -dodccylazacyclohcptan-2-onc, an acylcamitine, an acylcholine, or a Clio alkyl ester (e.g., isopropylmyristate IPM), monoglyceride, diglyceride or pharmaceutically acceptable salt thereof. Topical formulations are described in detail in U.S.

Patent No. 6,747,014, which is incorporated herein by reference.

Cholesterol conjugation

An siRNA can be conjugated to a ligand such as cholesterol and vitamin E as described herein. It is understood that other conjugates can be linked to the oligonucleotides via a similar method known to one of ordinary skill in the art, such methods can be found in US publication nos. 2005/0107325, 2005/0164235, 2005/0256069 and 2008/0108801, which are hereby 10 incorporated by their entirety.

Liposomal formulations

There are many organized surfactant structures besides microemulsions that have been studied and used for the formulation of drugs. These include monolayers, micelles, bilayers and vesicles. Vesicles, such as liposomes, have attracted great interest because of their specificity 15 and the duration of action they offer from the standpoint of drug delivery. As used in the present invention, the term liposome means a vesicle composed of amphiphilic lipids arranged in a spherical bilayer or bilayers.

Liposomes arc unilamellar or multilamcllar vesicles which have a membrane formed from a lipophilic material and an aqueous interior. The aqueous portion contains the composition 20 to be delivered. Cationic liposomes possess the advantage of being able to fuse to the cel! wall.

Non-cationic liposomes, although not able to fuse as efficiently with the cell wall, are taken up by macrophages in vivo.

In order to cross intact mammalian skin, lipid vesicles must pass through a series of fine pores, each with a diameter less than 50 nm, under the influence of a suitable transdcrmal gradient. Therefore, it is desirable to use a liposome which is highly deformable and able to pass through such fine pores.

Further advantages of liposomes include; liposomes obtained from natural phospholipids arc biocompatible and biodegradable; liposomes can incorporate a wide range of water and lipid soluble drugs; liposomes can protect encapsulated drugs in their internal compartments from 30 metabolism and degradation (Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245). Important considerations in the preparation of liposome formulations are the lipid surface charge, vesicle size and the aqueous volume of the liposomes.

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Liposomes arc useful for the transfer and delivery of active ingredients to the site of action. Because the liposomal membrane is structurally similar to biological membranes, when liposomes arc applied to a tissue, the liposomes start to merge with the cellular membranes and as the merging of the liposome and cell progresses, the liposomal contents are emptied into the cell where the active agent may act.

Liposomal formulations have been the focus of extensive investigation as the mode of delivery for many drugs. There is growing evidence that for topical administration, liposomes present several advantages over other formulations. Such advantages include reduced sideeffects related to high systemic absorption of the administered drug, increased accumulation of 10 the administered drug at the desired target, and the ability to administer a wide variety of drugs, both hydrophilic and hydrophobic, into the skin.

Several reports have detailed the ability of liposomes to deliver agents including highmolecular weight DNA into the skin. Compounds including analgesics, antibodies, hormones and high-molecular weight DNAs have been administered to the skin. The majority of applications resulted in the targeting of the upper epidermis

Liposomes fall into two broad classes. Cationic liposomes are positively charged liposomes which interact with the negatively charged DNA molecules to form a stable complex. The positively charged DNA/Iiposomc complex binds to the negatively charged cell surface and is internalized in an endosome. Due to the acidic pH within the endosome, the liposomes are 20 ruptured, releasing their contents into the cell cytoplasm (Wang et al., Biochcm. Biophys. Res, Commun., 1987, 147,980-985).

Liposomes which arc pH-scnsitive or negatively-charged, entrap DNA rather than complex with it. Since both the DNA and the lipid are similarly charged, repulsion rather than complex formation occurs. Nevertheless, some DNA is entrapped within the aqueous interior of 25 these liposomes. pH-sensitive liposomes have been used to deliver DNA encoding the thymidine kinase gene to cell monolayers in culture. Expression of the exogenous gene was detected in the target cells (Zhou et al.. Journal of Controlled Release, 1992, 19, 269-274).

One major type of liposomal composition includes phospholipids other than naturallyderived phosphatidylcholine. Neutral liposome compositions, for example, can be formed from 30 dimyristoyl phosphatidylcholine (DMPC) or dipalmitoyl phosphatidylcholine (DPPC). Anionic liposome compositions generally are formed from dimyristoyl phosphatidylglycerol, while anionic fusogenic liposomes are formed primarily from dioleoyl phosphatidylethanolamine (DOPE). Another type of liposomal composition is formed from phosphatidylcholine (PC) such

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 as, for example, soybean PC, and egg PC. Another type is formed from mixtures of phospholipid and/or phosphatidylcholine and/or cholesterol.

Several studies have assessed the topical delivery of liposomal drug formulations to the skin. Application of liposomes containing interferon to guinea pig skin resulted in a reduction of 5 skin herpes sores while delivery of interferon via other means (i?.g., as a solution or as an emulsion) were ineffective (Weiner eta!., Journal of Drug Targeting, 1992, 2, 405-410). Further, an additional study tested the efficacy of interferon administered as part of a liposomal formulation to the administration of interferon using an aqueous system, and concluded that the liposomal formulation was superior to aqueous administration (du Plessis et al., Antiviral

Research, 1992, 18, 259-265).

Non-ionic liposomal systems have also been examined to determine their utility in the delivery of drugs to the skin, in particular systems comprising non-ionic surfactant and cholesterol. Non-ionic liposomal formulations comprising Novasome™ I (glyceryl dilaurate/cholesterol/polyoxyethylene-10-stearyl ether) and Novasome™ II (glyceryl distearatc/cholestcrol/polyoxycthylcnc-10-stcaryl ether) were used to deliver cyclosporin-A into the dermis of mouse skin. Results indicated that such non-ionic liposomal systems were effective in facilitating the deposition of cyclosporin-A into different layers of the skin (Hu et al.

S.T.P.Pharma. Sci., 1994, 4, 6, 466).

Liposomes also include “sterically stabilized” liposomes, a term which, as used herein, 20 refers to liposomes comprising one or more specialized lipids that, when incorporated into liposomes, result in enhanced circulation Lifetimes relative to liposomes lacking such specialized lipids. Examples of sterically stabilized liposomes are those in which part of the vesicle-forming lipid portion of the liposome (A ) comprises one or more glycolipids, such as monosialoganglioside Gmi, or (B) is derivatized with one or more hydrophilic polymers, such as 25 a polyethylene glycol (PEG ) moiety. While not wishing to be bound by any particular theory, it is thought in the art that, at least for sterically stabilized liposomes containing gangliosides, sphingomyelin, or PEG-derivatizcd lipids, the enhanced circulation half-life of these sterically stabilized liposomes derives from a reduced uptake into cells of the reticuloendothelial system (RES) (Allen et al., FEBS Letters, 1987, 223, 42; Wu eta/., Cancer Research, 1993, 53, 3765).

Various liposomes comprising one or more glycolipids are known in the art.

Papahadjopoulos et al. (Ann, N.Y. Acad. Sci., 1987, 507, 64) reported the ability of monosialoganglioside Gmi, galactocerebroside sulfate and phosphatidylinositol to improve blood half-lives of liposomes. These findings were expounded upon by Gabizon et al. (Proc. Natl. Acad. Sci. U.S.A., 1988, 85, 6949). U.S. Pat. No. 4,837,028 and WO 88/04924, both to Allen et

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 al., disclose liposomes comprising (1) sphingomyelin and (2) the ganglioside G«i or a galactocerebroside sulfate ester. U.S. Pat. No. 5,543,152 (Webb et al.} discloses liposomes comprising sphingomyelin. Liposomes comprising 1,2-sn-dimyristoy[phosphatidylcholine are disclosed in WO 97/13499 (Lim etal).

Many liposomes comprising lipids derivatized with one or more hydrophilic polymers, and methods of preparation thereof, are known in the art. Sunamoto et al. (Bull. Chem. Soc. Jpn., 1980, 53, 2778) described liposomes comprising a nonionic detergent, 2C]215g·. that contains a PEG moiety. Ilium et al. (FEBS Lett., 1984, 167, 79) noted that hydrophilic coating of polystyrene particles with polymeric glycols results in significantly enhanced blood half-lives.

Synthetic phospholipids modified by the attachment of carboxylic groups of polyalkylene glycols (e.g., PEG) arc described by Scars (U.S. Pat. Nos. 4,426,330 and 4,534,899). Klibanov et al. (FEBS Lett., 1990, 268, 235) described experiments demonstrating that liposomes comprising phosphatidylethanolamine (PE) derivatized with PEG or PEG stearate have significant increases in blood circulation half-lives. Blume et al. (Biochimica et Biophysica

Acta, 1990, 1029, 91) extended such observations to other PEG-dcrivatizcd phospholipids, e.g., DSPE-PEG, formed from the combination of distearoylphosphatidylethanolamine (DSPE) and PEG. Liposomes having covalently bound PEG moieties on their external surface arc described in European Patent No. EP 0 445 131 Bl and WO 90/04384 to Fisher. Liposome compositions containing 1-20 mole percent of PE derivatized with PEG, and methods of use thereof, are described by Woodie et al. (U.S. Pat. Nos. 5,013,556 and 5,356,633) and Martin et al. (U.S. Pat. No. 5,213,804 and European Patent No. EP 0 496 813 Bl). Liposomes comprising a number of other lipid-polymer conjugates are disclosed in WO 91/05545 and U.S. Pat. No. 5,225,212 (both to Martin etal.) and in WO 94/20073 (Zalipsky etal.) Liposomes comprising PEG-modifled ceramide lipids are described in WO 96/10391 (Choi etal). U.S. Pat. No. 5,540,935 (Miyazaki et al.) and U.S. Pat. No. 5,556,948 (Tagawa etal.) describe PEG-containing liposomes that can be further derivatized with functional moieties on their surfaces.

A number of liposomes comprising nucleic acids are known in the art. WO 96/40062 to Thierry et al. discloses methods for encapsulating high molecular weight nucleic acids in liposomes. U.S. Pat. No. 5,264,221 to Tagawa et al. discloses protein-bonded liposomes and asserts that the contents of such liposomes may include a dsRNA. U.S. Pat. No. 5,665,710 to Rahman et al. describes certain methods of encapsulating oligodeoxynucleotidcs in liposomes. WO 97/04787 to Love et al. discloses liposomes comprising dsRNAs targeted to the raf gene.

Transfersomes are yet another type of liposomes, and are highly deformable lipid aggregates which are attractive candidates for drug delivery vehicles. Transfersomes may be

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 described as lipid droplets which arc so highly deformable that they arc easily able to penetrate through pores which are smaller than the droplet. Transfersomes are adaptable to the environment in which they arc used, e.g., they arc self-optimizing (adaptive to the shape of pores in the skin), self-repairing, frequently reach their targets without fragmenting, and often self5 loading. To make transfersomes it is possible to add surface edge-activators, usually surfactants, to a standard liposomal composition. Transfersomes have been used to deliver serum albumin to the skin. The transfcrsomc-mcdiatcd delivery of scrum albumin has been shown to be as effective as subcutaneous injection of a solution containing serum albumin.

Surfactants find wide application in formulations such as emulsions (including microemulsions) and liposomes. The most common way of classifying and ranking the properties of the many different types of surfactants, both natural and synthetic, is by the use of the hydrophile/lipophile balance (HLB). The nature of the hydrophilic group (also known as the head) provides the most useful means for categorizing the different surfactants used in formulations (Rieger, in Pharmaceutical Dosage Forms, Marcel Dekker, Inc., New York, N.Y.,

1988, p. 285).

If the surfactant molecule is not ionized, it is classified as a nonionic surfactant. Nonionic surfactants find wide application in pharmaceutical and cosmetic products and are usable over a wide range of pH values. In general their HLB values range from 2 to about 18 depending on their structure. Non ionic surfactants include nonionic esters such as ethylene glycol esters, propylene glycol esters, glyceryl esters, polyglyceryl esters, sorbitan esters, sucrose esters, and ethoxylated esters. Nonionic alkanolamidcs and ethers such as fatty alcohol ethoxylates, propoxylated alcohols, and ethoxylated/propoxylated block polymers are also included in this class. The polyoxyethylene surfactants are the most popular members of the nonionic surfactant class.

If the surfactant molecule carries a negative charge when it is dissolved or dispersed in water, the surfactant is classified as anionic. Anionic surfactants include carboxylates such as soaps, acyl lactylatcs, acyl amides of amino acids, esters of sulfuric acid such as alkyl sulfates and ethoxylated alky! sulfates, sulfonates such as alkyl benzene sulfonates, acyl isethionates, acyl taurates and sulfosuccinates, and phosphates. The most important members of the anionic surfactant class are the alkyl sulfates and the soaps.

If the surfactant molecule carries a positive charge when it is dissolved or dispersed in water, the surfactant is classified as cationic. Cationic surfactants include quaternary ammonium salts and ethoxylated amines. The quaternary ammonium salts are the most used members of this class.

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

If the surfactant molecule has the ability to carry either a positive or negative charge, the surfactant is classified as amphoteric. Amphoteric surfactants include acrylic acid derivatives, substituted alkyiamides, N-alkylbetaines and phosphatides.

The use of surfactants in drug products, formulations and in emulsions has been reviewed 5 (Rieger, in Pharmaceutical Dosage Forms, Marcel Dekker, Inc., New York, N.Y., 1988, p. 285).

Nucleic acid lipid particles

In one embodiment, a TTR dsRNA featured in the invention is fully encapsulated in the lipid formulation, e.g., to form a SPLP, pSPLP, SNALP, or other nucleic acid-lipid particle. As used herein, the term SNALP refers to a stable nucleic acid-lipid particle, including SPLP. As 10 used herein, the term SPLP refers to a nucleic acid-lipid particle comprising plasmid DNA encapsulated within a lipid vesicle. SNALPs and SPLPs typically contain a cationic lipid, a noncationic lipid, and a lipid that prevents aggregation of the particle (e.g., a PEG-lipid conjugate). SNALPs and SPLPs are extremely useful for systemic applications, as they exhibit extended circulation lifetimes following intravenous (i.v.) injection and accumulate at distal sites (e.g., 15 sites physically separated from the administration site). SPLPs include pSPLP, which inchide an encapsulated condensing agent-nucleic acid complex as set forth in PCT Publication No. WO 00/03683. The particles of the present invention typically have a mean diameter of about 50 nm to about 150 nm, more typically about 60 nm to about 130 nm, more typically about 70 nm to about 1 10 nm, most typically about 70 nm to about 90 nm, and are substantially nontoxic. In addition, the nucleic acids when present tn the nucleic acid- lipid particles of the present invention arc resistant in aqueous solution to degradation with a nuclease. Nucleic acidlipid particles and their method of preparation are disclosed in, e.g., U.S. Patent Nos. 5,976,567; 5,981,501; 6,534,484; 6,586,410; 6,815,432; and PCT Publication No. WO 96/40964.

In one embodiment, the lipid to drug ratio (rnass/mass ratio) (e.g., lipid to dsRNA ratio) 25 will be in the range of from about 1:1 to about 50:1, from about 1:1 to about 25:1, from about 3:1 to about 15:1, from about 4:1 to about 10:1, from about 5:1 to about 9:1, or about 6:1 to about 9:1. In some embodiments the lipid to dsRNA ratio can be about 1:1, 2:1,3:1,4:1,5:1, 6:1,7:1,8:1,9:1, 10:1,or 11:1.

In general, the lipid-nucleic acid particle is suspended in a buffer, e.g., PBS, for administration. In one embodiment, the pH of the lipid formulated siRNA is between 6.8 and 7.8, c.g„ 7.3 or 7.4. The osmolality can be, e.g., between 250 and 350 mOsm/kg, e.g., around 300, e.g., 298, 299, 300, 301, 302, 303, 304, or 305.

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

The cationic lipid may be, for example, N,N-dioleyl-N,N-dimcthylammonium chloride (DODAC), N,N-distearyl-N,N-dimethylammonium bromide (DDAB), N-(I -(2,3diolcoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTAP), N-(I -(2,3dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA), N,N-dimethyl-2,35 dio!eyloxy)propylaminc (DODMA), 1,2-DiLinolcyloxy-N,N-dimethylaminopropanc (DLinDMA), l,2-Dilinolcnyloxy-N,N-dimcthylaminopropane (DLcnDMA), 1,2Dilinoleylcarbamoyloxy-3-dLmethylaniinopropanc (DLin-C-DAP), 1,2-Dilinolcyoxy-3(dimethylamino)acetoxypropane (DLin-DAC), l,2-Dilinoleyoxy-3-morpholinopropane (DLinMA), l,2-Dilinoleoyl-3-dimethylaminopropane (DLinDAP), 1,2-Di]inoieylthio-310 dimcthylaminopropanc (DLin-S-DMA), l-Linolcoyl-2-linoleyloxy-3-dimcthylaminopropane (DLin-2-DMAP), 1,2-Di lino ley loxy-3-trim ethy laminopropanc chloride salt (DLin-TMA.Cl), l,2-Dilinoleoyl-3-trimethylaminopropane chloride salt (DLin-TAP.Cl), 1,2-Dilinoleyloxy-3-(Nmcthylpiperazino)propane (DLin-MPZ), or 3-(N,N-Dilinoleylamino)-l,2-piOpanediol (DLinAP), 3-(N,N-Dioleylamtno)-1,2-propancdio (DOAP), 1,2-Dilinoleyloxo-3-(2-N,N15 dimethyl ami no )ethoxypropane (DLin-EG-DMA), l,2-Dilinolenyloxy-N,Ndimcthylaminopropanc (DLinDMA), 2,2-Dilinolcyl-4-dimethylaminonicthyl-[ 1,3]-dioxolanc (DLin-K-DMA) or analogs thereof, (3aR,5s,6aS)-N,N-dimcthyl-2,2-di((9Z,12Z)-octadeca-9,12dieny!)tetrahydro-3aH-cyclopenta[d][ 1,3]dioxol-5-amine (ALN100), (6Z,9Z,28Z,31Z)hcptatriaconta-6,9,28,3I-tetraen-19-yl 4-(dimethylamino)butanoate (MC3), 1,1 '-(2-(4-(2-((220 (bis(2-hydiOxydodecyl)am!no)cthyl)(2-hydroxydodccyl )amino)cthyl)pipcrazin-1 yl)ethylazanediyl)didodecan-2-oi (Tech GI), or a mixture thereof. The cationic lipid may comprise from about 20 mol % to about 50 mol % or about 40 mol % of the total lipid present in the particle.

The non-cationic lipid may be an anionic lipid or a neutral lipid including, but not limited to, distcaroylphosphatidylcholinc (DSPC), diolcoylphosphatidylcholinc (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglyccrol (DPPG), dioleoyl-phosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholinc (POPC), palmitoyloleoylphosphatidylethanolamine (POPE), diolcoyl- phosphatidylcthanolamine 4-(N-maleimidomethyl)-cyclohcxanc-l- carboxylate (DOPE-mal), dipalmitoyl phosphatidyl ethanolamine (DPPE), dimyristoylphosphoethanolainine (DMPE), distearoyl-phosphatidyl-ethanolamine (DSPE), 16-O-monomethyl PE, I6-O-dimcthyl PE, 18-1 -trans PE, 1 -stcaroyl-2-oleoyl- phosphatidyethanolamine (SOPE), cholesterol, or a mixture thereof. The non-cationic lipid may be from about 5 mol % to about 90 mol %, about 10 mol %, or about 58 mol % if cholesterol is included, of the total lipid present in the particle.

2017204161 20 Jun 2017

WO 2011/123468 PCT/US2011/030392

The conjugated lipid that inhibits aggregation of particles may be, for example, a polyethyleneglyco! (PEG)-lipid including, without limitation, a PEG-diacylglycerol (DAG), a PEG-dialkyloxypropyl (DAA), a PEG-phospholipid, a PEG-ccramide (Ccr), or a mixture thereof. The PEG-DAA conjugate may be, for example, a PEG-dilauryloxypropyl (C12), a PEG5 dimyristyloxypropyl (Ctj, a PEG-dipalmityloxypropyl (CU), or a PEG- distearyloxypropyl (Cis). Other examples of PEG conjugates include PEG-cDMA (N-[(mcthoxy poly(ethylene glycoi)2000)carbamyl]-l ,2-dimyristyloxlpropyl-3-aminc), mPEG2000-DMG (mPEGdimyrysty]glycerol (with an average molecular weight of 2,000) and PEG-C-DOMG (R-3-[(wmethoxy-poly(ethylene glycol)2000)carbamoyl)]-l ,2-dimyristyloxlpropyl-3-amine). The conjugated lipid that prevents aggregation of particles may be from 0 mol % to about 20 mol % or about 1.0, I.E, 1.2,.13, 1.4, 1.5, 1.6,1.7, 1.8, 1.9, or 2 mol % of the total lipid present in the particle.

In some embodiments, the nucleic acid-lipid particle further includes cholesterol at, e.g., about 10 mol % to about 60 mol % or about 48 mol % of the total lipid present in the particle.

In one embodiment, the compound 2,2-Dilinoleyl-4-dimcthylaminocthy!-[ 1,3]-dioxolane can be used to prepare lipid-siRNA nanoparticles. Synthesis of 2,2-Dilinolcyl-4dimcthylaminoethyl-[l,3]-dioxolane is described in United States provisional patent application number 61/107,998 filed on October 23, 2008, which is herein incorporated by reference.

For example, the lipid-siRNA particle can include 40% 2, 2-Dilinolcyl-420 dimcthylaminocthyl-[l,3]-dioxolanc: 10% DSPC: 40% Cholesterol: 10% PEG-C-DOMG (mole percent) with a particle size of 63.0 ± 20 nm and a 0.027 siRNA/Lipid Ratio.

In still another embodiment, the compound l,l'-(2-(4-(2-((2-(bis(2hydroxydodecy 1 )am ino )ethy l)(2-hy droxydodecy l)am i no )ethy 1 )piperazin-1yl)cthylazanediyl)didodccan-2-ol (Tech G1) can be used to prepare lipid-siRNA particles. For example, the dsRNA can be formulated in a lipid formulation comprising Tcch-G I, distearoyl phosphatidylcholine (DSPC), cholesterol and mPEG2000-DMG at a molar ratio of 50:10:38.5:1.5 at a total lipid to siRNA ratio of 7:1 (wt:wt).

LNP01

In one embodiment, the lipidoid ND98-4HC1 (MW 1487) (Formula 1), Cholesterol (Sigma-Aldrich), and PEG-Ccramidc Cl 6 (Avanti Polar Lipids) can be used to prepare lipidsiRNA nanoparticles (i.e., LNP01 particles). Stock solutions of each in ethanol can be prepared as follows: ND98, 133 mg/ml; Cholesterol, 25 mg/ml, PEG-C’eramide Cl6, 100 mg/ml. The ND98, Cholesterol, and PEG-Ceramide Cl6 stock solutions can then be combined in a, e.g.,

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

42:48:10 molar ratio. The combined lipid solution can be mixed with aqueous siRNA (e.g., in sodium acetate pH 5) such that the final ethanol concentration is about 35-45% and the final sodium acetate concentration is about 100-300 mM. Lipid-siRNA nanoparticlcs typically form spontaneously upon mixing. Depending on the desired particle size distribution, the resultant nanoparticle mixture can be extruded through a polycarbonate membrane (e.g., 100 nm cut-off) using, for example, a thermobarrel extruder, such as Lipex Extruder (Northern Lipids, Inc). In some cases, the extrusion step can be omitted. Ethanol removal and simultaneous buffer exchange can be accomplished by, for example, dialysis or tangential flow filtration. Buffer can be exchanged with, for example, phosphate buffered saline (PBS) at about pH 7, e.g., about pH

6.9, about pH 7.0. about pH 7.1, about pH 7.2, about pH 7.3, or about pH 7.4.

ND98 Isomer I

Formula 1

LNP01 formulations are described, e.g., in International Application Publication

No. WO 2008/042973, which is hereby incorporated by reference.

Additional exemplary lipid-siRNA formulations are as follows:

	Cationic Lipid	cationic lipid/non-cationic1 ΐpid/choleste rol/ P EG -li pid conjugateLipitksiRNA ratio	Process
SNALP	1,2-Dilinol enyloxy-Ν,Ν -d ime thy laminopropane (D Li nDMA)	DL i n DM AT) PPC/Cholcsterol/PECicDMA(57.1/7.1/34.4/1.4)Jipid:siRNA — 7:1
SNALP-XTC	2,2- Di 1 inol ey 1 -4 -d i met hy 1 am i noet hy 1 [l,3]-dioxolane (XTC)	XTC/DPPC/Cholesterol/PEG-cDMA57.1/7.1/34.4/1.4lipid:siRNA - 7:1
LNP05	2,2-Dilinoleyl-4-dimeihylaminoethyl-[l,3]-dioxolane (XTC)	XTC/DSPC/Cholesterol/PEG-DMG57.5/7.5/31.5/3.5lipid:siRNA - 6:1	Extrusion
LNP06	2,2-Dilinoleyl-4-dimclhylammocl1iyl-[i,3]-dioxolane (XTC)	XTC/DSPC/Cholesterol/PEG-DMG57.5/7.5/31.5/3.5lipid:siRNA ~ 11:1	Extrusion
LNP07	2.2-Dilinoleyl-4-dimethylaminoethyl-[l,3]-dioxolanc (XTC)	XTC/DSPC/Cholesterol/PEG-DMG60/7.5/31/1.5,lipid:siRNA - 6:1	In-linemixing

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

LNP08	2,2-Dilinoleyl-4-dimelhylaminoethyl-[1.3]-dioxolane (XTC)	XTC/DSPC/Cholcslerol/PEG-DMG60/7.5/31/1.5,lipid:siRNA -11:1	In-line mixing
LNP09	2,2-Di 1 inoleyl-4-d imelhy lam i nocthy 1 [l.3]-dioxolane(XTC)	XTC/DSPC/Choleslerol/PEG-DMG50/10/38.5/1.5Lipid: siRNA 10:1	In-line mixing
LNP10	(3aR,5s,6aS)-N,N-dimethyl-2,2di((9Z, 12Z)-octadeca-9,12dicnyl )tctrahydro-3aHcy clopent a[ d] [ 1,3 ] d ioxol- 5 -ami ne (ALNI 00)	A LN 100/DSPC/Cholcsterol/PEG- DMG50/10/38.5/1.5Lipid:siRNA 10:1	In-line mixing
LN PH	(6Z,9Z,2 8Z,31Z)-hcplalriaconla-6,9,28,3 i-telraen-19-yl 4-(d imc thy lamin o )bulanoa te (MC 3)	MC-3/DSPC/Choleslerol/PEG-DMG50/10/38.5/1.5Lipid:siRNA 10:1	In-line mixing
LNP12	l,)'-(2-(4-(2-((2-(bis(2-hydroxy dodecy 1) ami no)elhy I) (2 by droxy dodccy 1) am i no )cthy ljpiperazi n1 -yl )c thy la zaned iy 1) didodecan- 2 -ol (Tech GI)	Tech Gl/DSPC/Cholesterol/PEG-DMG50/10/38.5/1.5LipidisiRNA 10:1	In-line mixing

LNP09 formulations and XTC comprising formulations are described, e.g., in U.S.

Provisional Serial No. 61/239,686, filed September 3, 2009, which is hereby incorporated by reference.

LNP11 formulations and MC3 comprising formulations are described, e.g., in U.S.

Provisional Serial No. 61/244,834, filed September 22, 2009, which is hereby incorporated by reference.

LNP12 formulations and TechG 1 comprising formulations are described, e.g., in U.S. Provisional Serial No. 61/175,770, filed May 5, 2009, which is hereby incorporated by reference.

Formulations prepared by either the standard or extrusion-free method can be characterized in similar manners. For example, formulations are typically characterized by visual inspection. They should be whitish translucent solutions free from aggregates or sediment. Particle size and particle size distribution of lipid-nanoparticles can be measured by light scattering using, for example, a Malvern Zetasizer Nano ZS (Malvern, USA). Particles should be about 20-300 nm, such as 40-100 nm in size. The particle size distribution should be unimodal. The total siRNA concentration in the formulation, as well as the entrapped fraction, is estimated using a dye exclusion assay. A sample of the formulated siRNA can be incubated

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 with an RNA-binding dye, such as Ribogreen (Molecular Probes) in the presence or absence of a formulation disrupting surfactant, e.g., 0.5% Triton-XI00. The total siRNA in the formulation can be determined by the signal from the sample containing the surfactant, relative to a standard curve. The entrapped fraction is determined by subtracting the “free” siRNA content (as measured by the signal in the absence of surfactant) from the total siRNA content. Percent entrapped siRNA is typically >85%. For SNALP formulation, the particle size is at least 30 nm, at least 40 nm, at least 50 nm, at least 60 nm, at least 70 nm, at least 80 nm, at least 90 nm, at least 100 nm, at least 110 nm, and at least 120 nm. The suitable range is typically about at least 50 nm to about at least 110 nm, about at least 60 nm to about at least 100 nm, or about at least

80 nm to about at least 90 nm.

Compositions and formulations for oral administration include powders or granules, microparticulates, nanoparticulates, suspensions or solutions in water or non-aqueous media, capsules, gel capsules, sachets, tablets or minitablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids or binders may be desirable. In some embodiments, oral formulations are those in which dsRNAs featured in the invention arc administered in conjunction with one or more penetration enhancers surfactants and chelators. Suitable surfactants include fatty acids and/or esters or salts thereof, bile acids and/or salts thereof. Suitable bile acids/salts include chenodeoxycholic acid (CDCA) and ursodcoxychenodeoxycholic acid (UDCA), cholic acid, dchydrocholic acid, dcoxycholic acid, glucholic acid, giycholic acid, glycodeoxycholic acid, taurochoHc acid, taurodeoxycholic acid, sodium tauro-24,25-dihydro-fusidate and sodium glycodi hydrofusidate. Suitable fatty acids include arachidonic acid, undecanoic acid, oleic acid, lauric acid, caprylic acid, capric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicapratc, tricaprate, monoolein, di I aurin, glyceryl 1-monocapratc, i-dodecylazacycloheptan-2-one, an acylcamitine, an acylcholine, or a monoglyccridc, a diglyccridc or a pharmaceutically acceptable salt thereof (e.g., sodium). In some embodiments, combinations of penetration enhancers arc used, for example, fatty acids/salts in combination with bile acids/salts. One exemplary combination is the sodium salt of lauric acid, capric acid and UDC'A. Further penetration enhancers include polyoxy ethyl ene-9-lauryl ether, polyoxyethylene-20-cetyl ether. DsRNAs featured in the invention may be delivered orally, in granular form including sprayed dried particles, or complexed to form micro or nanoparticles. DsRNA complexing agents include poly-amino acids; polyimines; poly acrylates; polyalkylacrylates, polyoxcthancs, polyalkylcyanoacrylatcs; cationized gelatins, albumins, starches, acrylates, polyethyleneglycols (PEG) and starches; polyalkylcyanoacrylatcs; DEAE-dcrivatizcd polyimines, pollulans, celluloses and starches.

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Suitable complexing agents include chitosan, N-trimcthylchitosan, poly-L-lysine, polyhistidine, polyornithine, polyspermines, protamine, polyvinylpyridine, polythiodiethylaminOmethylethylene P(TDAE), polyaminostyrenc (e.g., p-amino), poly(methyicyanoacrylate), poly(cthylcyanoacrylate), poly(butylcyanoacrylate), poly(isobutylcyanoacrylate), poly(isohexylcynaoacrylate), DEAE-methacrylate, DEAEhexylacrylate, DEAE-acrylamide, DEAE-albumin and DEAE-dextran, polymethylacrylate, polyhexylacrylate, poly(D,L-lactic acid), poly(DL-lactic-co-gfycolic acid (PLGA), alginate, and polyethyleneglycol (PEG). Oral formulations for dsRNAs and their preparation are described in detail in U.S. Patent 6,887,906, US Publn. No. 20030027780, and U.S. Patent No. 6,747,014, each of which is incorporated herein by reference.

Compositions and formulations for parenteral, intraparenchymal (into the brain), intrathecal, intraventricular or intrahcpatic administration may include sterile aqueous solutions which may also contain buffers, diluents and other suitable additives such as, but not limited to, penetration enhancers, carrier compounds and other pharmaceutically acceptable earners or 15 excipients.

Pharmaceutical compositions of the present invention include, but are not limited to, solutions, emulsions, and liposome-containing formulations. These compositions may be generated from a variety of components that include, but arc not limited to, preformed liquids, self-emulsifying solids and self-emulsifying semisolids. Particularly preferred are formulations 20 that target the liver when treating hepatic disorders such as hepatic carcinoma.

The pharmaceutical formulations of the present invention, which may conveniently be presented in unit dosage form, may be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general, 25 the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid earners or finely divided solid carriers or both, and then, if necessary, shaping the product.

The compositions of the present invention may be formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, gel capsules, liquid syrups, soft gels, 30 suppositories, and enemas. The compositions of the present invention may also be formulated as suspensions in aqueous, non-aqueous or mixed media. Aqueous suspensions may further contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylccllulose, sorbitol and/or dextran. The suspension may also contain stabilizers.

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Emulsions

The compositions of the present invention may be prepared and formulated as emulsions.

Emulsions are typically heterogeneous systems of one liquid dispersed in another in the form of droplets usually exceeding 0.1 pm in diameter (Idson, in Pharmaceutical Dosage Forms,

Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p.

199; Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., Volume 1, p. 245; Block in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds,), 1988, Marcel Dekker, Inc., New York, N.Y., volume 2, p. 335; Higuchi et al., in Remington's Pharmaceutical Sciences, Mack Publishing Co., 10 Easton, Pa., 1985, p. 301). Emulsions are often biphasic systems comprising two immiscible liquid phases intimately mixed and dispersed with each other. In general, emulsions may be of either the water-in-oil (w/o) or the oil-in-water (o/w) variety. When an aqueous phase is finely divided into and dispersed as minute droplets into a bulk oily phase, the resulting composition is called a water-in-oil (w/o) emulsion. Alternatively, when an oily phase is finely divided into and 15 dispersed as minute droplets into a bulk aqueous phase, the resulting composition is called an oil-in-water (o/w) emulsion. Emulsions may contain additional components in addition to the dispersed phases, and the active drug which may be present as a solution in cither the aqueous phase, oily phase or itself as a separate phase. Pharmaceutical excipients such as emulsifiers, stabilizers, dyes, and anti-oxidants may also be present in emulsions as needed. Pharmaceutical 20 emulsions may also be multiple emulsions that are comprised of more than two phases such as, for example, in the case of oil-in-water-in-oil (o/w/o) and water-in-oil-in-water (w/o/w) emulsions. Such complex formulations often provide certain advantages that simple binary emulsions do not. Multiple emulsion.s in which individual oil droplets of an o/w emulsion enclose small water droplets constitute a w/o/w emulsion. Likewise a system of oil droplets enclosed in globules of water stabilized in an oily continuous phase provides an o/w/o emulsion.

Emulsions are characterized by little or no thermodynamic stability. Often, the dispersed or discontinuous phase of the emulsion is well dispersed into the externa! or continuous phase and maintained in this form through the means of emulsifiers or the viscosity of the formulation. Either of the phases of the emulsion may be a semisolid or a solid, as is the case of emulsion30 style ointment bases and creams. Other means of stabilizing emulsions entail the use of emulsifiers that may be incorporated into cither phase of the emulsion. Emulsifiers may broadly be classified into four categories: synthetic surfactants, naturally occurring emulsifiers, absorption bases, and finely dispersed solids (Idson, in Pharmaceutical Dosage Forms,

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p.

199).

Synthetic surfactants, also known as surface active agents, have found wide applicability in the formulation of emulsions and have been reviewed in the literature (Rieger, in

Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 285; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), Marcel Dekker, Inc., New York, N.Y., 1988, volume I, p. 199). Surfactants are typically amphiphilic and comprise a hydrophilic and a hydrophobic portion. The ratio of the hydrophilic to the hydrophobic nature of the surfactant has been termed the hydrophile/lipophile balance (HLB) and is a valuable tool in categorizing and selecting surfactants in the preparation of formulations. Surfactants may be classified into different classes based on the nature of the hydrophilic group: nonionic, anionic, cationic and amphoteric (Rieger, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 285).

Naturally occurring emulsifiers used in emulsion formulations include lanolin, beeswax, phosphatides, lecithin and acacia. Absorption bases possess hydrophilic properties such that they can soak up water to form w/o emulsions yet retain their semisolid consistencies, such as anhydrous lanolin and hydrophilic petrolatum. Finely divided solids have also been used as good emulsifiers especially in combination with surfactants and in viscous preparations. These include polar inorganic solids, such as heavy metal hydroxides, nonswelling clays such as bentonite, attapulgite, hectorite, kaolin, montmorillonite, colloidal aluminum silicate and colloidal magnesium aluminum silicate, pigments and nonpolar solids such as carbon or glyceryl tristearatc.

A large variety of non-emulsifying materials are also included in emulsion formulations and contribute to the properties of emulsions. These include fats, oils, waxes, fatty acids, fatty alcohols, fatty esters, humectants, hydrophilic colloids, preservatives and antioxidants (Block, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 335; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y,, volume 1, p. 199).

Hydrophilic colloids or hydrocolloids include naturally occurring gums and synthetic polymers such as polysaccharides (for example, acacia, agar, alginic acid, carrageenan, guar gum, karaya gum, and tragacanth), cellulose derivatives (for example, carboxymethyl cellulose and carboxypropyl cellulose), and synthetic polymers (for example, carbomers, cellulose ethers, and carboxyvinyl polymers). These disperse or swell in water to form colloidal solutions that

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 stabilize emulsions by forming strong intcrfacial films around the dispcrscd-phase droplets and by increasing the viscosity of the external phase.

Since emulsions often contain a number of ingredients such as carbohydrates, proteins, sterols and phosphatides that may readily support the growth of microbes, these formulations often incorporate preservatives. Commonly used preservatives included in emulsion formulations include methyl paraben, propyl paraben, quaternary ammonium salts, benzalkonium chloride, esters of p-hydroxybenzoic acid, and boric acid. Antioxidants arc also commonly added to emulsion formulations to prevent deterioration of the formulation. Antioxidants used may be free radical scavengers such as tocopherols, alkyl gallates, butylated hydroxyanisole, butylated hydroxytoluene, or reducing agents such as ascorbic acid and sodium metabisulfite, and antioxidant synergists such as citric acid, tartaric acid, and lecithin.

The application of emulsion formulations via dermatological, oral and parenteral routes and methods for their manufacture have been reviewed in the literature (Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, 15 N.Y., volume 1, p. 199). Emulsion formulations for oral delivery have been very widely used because of ease of formulation, as well as efficacy from an absorption and bioavailability standpoint (Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume I, p. 199). Mineral-oil base laxatives, oil-soluble vitamins and high fat nutritive preparations are among the materials that have commonly been administered orally as o/w emulsions.

In one embodiment of the present invention, the compositions of dsRNAs and nucleic acids are formulated as microemulsions. A microemulsion may be defined as a system of water, 25 oil and amphiphile which is a single optically isotropic and thermodynamically stable liquid solution (Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245). Typically microemulsions arc systems that are prepared by first dispersing an oil in an aqueous surfactant solution and then adding a sufficient amount of a fourth component, generally an intermediate chain-length alcohol to form 30 a transparent system. Therefore, microemulsions have also been described as thermodynamically stable, isotropically clear dispersions of two immiscible liquids that are stabilized by interfacial films of surface-active molecules (Leung and Shah, in: Controlled Release of Drugs: Polymers and Aggregate Systems, Rosoff, M., Ed., 1989, VCH Publishers, New York, pages 185-215). Microemulsions commonly arc prepared via a combination of three to five components that

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 include oil, water, surfactant, cosurfactant and electrolyte. Whether the microcmulsion is of the water-in-oil (w/o) or an oil-in-water (o/w) type is dependent on the properties of the oil and surfactant used and on the structure and geometric packing of the polar heads and hydrocarbon tails of the surfactant molecules (Schott, in Remington's Pharmaceutical Sciences, Mack

Publishing Co., Easton, Pa., 1985, p. 271).

The phenomenological approach utilizing phase diagrams has been extensively studied and has yielded a comprehensive knowledge, to one skilled in the art, of how to formulate microemulsions (Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, P- 245; Block, in Pharmaceutical

Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 335). Compared to conventional emulsions, microcmulsions offer the advantage of solubilizing water-insoluble drugs in a formulation of thermodynamically stable droplets that are formed spontaneously.

Surfactants used in the preparation of microemulsions include, but are not limited to, ionic surfactants, non-ionic surfactants, Brij 96, polyoxyethylene oleyl ethers, polyglyccrol fatty acid esters, tctraglycerol monolaurate (ML310), tctraglyccrol monoolcate (MO310), hexaglycerol monooleate (PO310), hcxaglycerol pentaoleate (PO500), decaglycerol monocaprate (MCA750), decaglycerol monooleate (MO750), decaglycerol sequioleatc (SO750), decaglycerol decaoieatc (DAO750), alone or in combination with cosurfactants. The cosurfactant, usually a short-chain alcohol such as ethanol, 1-propanol, and I-butanol, serves to increase the intcrfacial fluidity by penetrating into the surfactant film and consequently creating a disordered film because of the void space generated among surfactant molecules. Microemulsions may, however, be prepared without the use of cosurfactants and alcohol-free self-emulsifying microemulsion systems are known in the art. The aqueous phase may typically be, but is not limited to, water, an aqueous solution of the drug, glycerol, PEG300, PEG400, poly glycerols, propylene glycols, and derivatives of ethylene glycol. The oil phase may include, but is not limited to, materials such as Captex 300, Captcx 355, Capmul MCM, fatty acid esters, medium chain (C8-C12) mono, di, and tri-glycerides, polyoxyethylated glyceryl fatty acid esters, fatty alcohols, polyglyco lized glycerides, saturated polyglycolized C8-C10 glycerides, vegetable oils and silicone oil.

Microemulsions arc particularly of interest from the standpoint of drug solubilization and the enhanced absorption of drugs. Lipid based microemulsions (both o/w and w/o) have been proposed to enhance the oral bioavailability of drugs, including peptides (Constantinides et al., Pharmaceutical Research, 1994, 1 1, 1385-1390; Ritschel, Meth. Find. Exp. Clin. Pharmacol.,

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

1993, 13, 205). Microcmulsions afford advantages of improved drug solubilization, protection of drug from enzymatic hydrolysis, possible enhancement of drug absorption due to surfactantinduced alterations in membrane fluidity and permeability, ease of preparation, case of oral administration over solid dosage forms, improved clinical potency, and decreased toxicity (Constantinides et al.. Pharmaceutical Research, 1994, 11, 1385; Ho et al., J. Pharm. Sci., 1996, 85, 138-143). Often microemulsions may form spontaneously when their components are brought together at ambient temperature. This may be particularly advantageous when formulating thermolabile drugs, peptides or dsRNAs. Microemulsions have also been effective in the transdcrmal delivery of active components in both cosmetic and pharmaceutical applications. It is expected that the microemulsion compositions and formulations of the present invention will facilitate the increased systemic absorption of dsRNAs and nucleic acids from the gastrointestinal tract, as well as improve the local cellular uptake of dsRNAs and nucleic acids.

Microcmulsions of the present invention may also contain additional components and additives such as sorbitan monostearatc (Grill 3), Labrasol, and penetration enhancers to improve the properties of the formulation and to enhance the absorption of the dsRNAs and nucleic acids of the present invention. Penetration enhancers used in the microemulsions of the present invention may be classified as belonging to one of five broad categories—surfactants, fatty acids, bile salts, chelating agents, and non-chelating non-surfactants (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, p. 92). Each of these classes has been discussed above.

Penetration Enhancers

In one embodiment, the present invention employs various penetration enhancers to effect the efficient delivery of nucleic acids, particularly dsRNAs, to the skin of animals. Most drugs are present in solution in both ionized and nonionized forms. However, usually only lipid 25 soluble or lipophilic drags readily cross cell membranes. It has been discovered that even nonlipophi I ic drags may cross cell membranes if the membrane to be crossed is treated with a penetration enhancer. In addition to aiding the diffusion of non-lipophilic drugs across cell membranes, penetration enhancers also enhance the permeability of lipophilic drags.

Penetration enhancers may be classified as belonging to one of five broad categories, i.e., 30 surfactants, fatty acids, bile salts, chelating agents, and non-chelating non-surfactants (Lee et al.. Critical Reviews in Therapeutic Drag Carrier Systems, 1991, p.92). Each of the above mentioned classes of penetration enhancers are described below in greater detail.

Surfactants: In connection with the present invention, surfactants (or surface-active agents) are chemical entities which, when dissolved in an aqueous solution, reduce the surface 48

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 tension of the solution or the interfacial tension between the aqueous solution and another liquid, with the result that absorption of dsRNAs through the mucosa is enhanced. In addition to bile salts and fatty acids, these penetration enhancers include, for example, sodium lauryl sulfate, polyoxyethylene-9-lauryl ether and polyoxycthylene-20-cetyl ether) (Lee etal.. Critical Reviews 5 in Therapeutic Drug Carrier Systems, 1991, p.92); and perfluorochemical emulsions, such as FC-43. Takahashi et al., J. Pharm. Pharmacol., 1988, 40, 252).

Fatty acids: Various fatty acids and their derivatives which act as penetration enhancers include, for example, oleic acid, lauric acid, capric acid (n-decanoic acid), myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicapratc, tricapratc, monoolein (1-monoolcoyl10 rac-glycerol), dilaurin, caprylic acid, arachidonic acid, glycerol 1-monocaprate, 1dodccylazacycloheptan-2-onc, acyl carnitines, acylcholincs, C.sub.1-10 alkyl esters thereof (e.g., methyl, isopropyl and t-butyl), and mono- and di-glycerides thereof (i.e., oleate, laurate, caprate, myristate, palmitate, stearate, linoleate, etc.) (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, p.92; Muranishi, Critical Reviews in Therapeutic Drug Carrier Systems, 15 1990, 7, 1-33; El Hariri etal., J. Pharm. Pharmacol., 1992, 44, 651-654).

Bile salts: The physiological role of bile includes the facilitation of dispersion and absorption of lipids and fat-soluble vitamins (Brunton, Chapter 38 in: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 9th Ed., Hardman et al. Eds., McGraw-Hill, New York, 1996, pp. 934-935). Various natural bile salts, and their synthetic derivatives, act as penetration 20 enhancers. Thus the term bile salts includes any of the naturally occurring components of bile as well as any of their synthetic derivatives. Suitable bile salts include, for example, cholic acid (or its pharmaceutically acceptable sodium salt, sodium cholate), dehydrocholic acid (sodium dehydrocholate), deoxycholic acid (sodium deoxycholate), glucholic acid (sodium glucholatc), glycholic acid (sodium glycocholate), glycodeoxycholic acid (sodium glycodeoxycholate), 25 taurocholic acid (sodium taurocholate), taurodcoxycholic acid (sodium taurodcoxycholatc), chenodeoxycholic acid (sodium chenodeoxycholate), ursodeoxycholic acid (UDCA), sodium tauro-24,25-dihydro-fusidatc (STDHF), sodium glycodi hydro fusidate and polyoxyethylene-9lauryl ether (POE) (Lee et al.. Critical Reviews in Therapeutic Drug Carrier Systems, 1991, page 92; Swinyard, Chapter 39 In: Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., 30 Mack Publishing Co., Easton, Pa., 1990, pages 782-783; Muranishi, Critical Reviews in Therapeutic Drug Carrier Systems, 1990, 7, 1-33; Yamamoto et al., J. Pharm. Exp. Thcr., 1992, 263, 25; Yamashita etal., J. Pharm. Sci., 1990, 79, 579-583).

Chelating Agents: Chelating agents, as used in connection with the present invention, can be defined as compounds that remove metallic ions from solution by forming complexes

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 therewith, with the result that absorption of dsRNAs through the mucosa is enhanced. With regards to their use as penetration enhancers in the present invention, chelating agents have the added advantage of also serving as DNase inhibitors, as most characterized DNA nucleases require a divalent metal ion for catalysis and arc thus inhibited by chelating agents (Jarrett, J.

Chromatogr., 1993, 618,315-339). Suitable chelating agents include but are not limited to disodium cthylenediaminetetraacetate (EDTA), citric acid, salicylates (e.g., sodium salicylate, 5mcthoxysalicylatc and homovanilate), N-acyl derivatives of collagen, laurcth-9 and N-amino acyl derivatives of beta-diketones (enamines)(Lee et al.. Critical Reviews in Therapeutic Drug Carrier Systems, 1991, page 92; Muranishi, Critical Reviews in Therapeutic Drug Carrier

Systems, 1990, 7, 1-33; Buur et al., J. Control Rel., 1990, 14,43-51).

Non-chelating non-surfactants; As used herein, non-chelating non-surfactant penetration enhancing compounds can be defined as compounds that demonstrate insignificant activity as chelating agents or as surfactants but that nonetheless enhance absorption of dsRNAs through the alimentary mucosa (Muranishi, Critical Reviews in Therapeutic Drug Carrier Systems, 1990, 15 7, 1-33). This class of penetration enhancers include, for example, unsaturated cyclic ureas, Ialkyl- and 1-alkenylazacyclo-alkanone derivatives (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, page 92); and non-steroidal anti-inflammatory agents such as diclofenac sodium, indomethacin and phenylbutazone (Yamashita etal., J. Pharm. Pharmacol., 1987, 39, 621-626).

Carriers

Certain compositions of the present invention also incorporate carrier compounds in the formulation. As used herein, “carrier compound” or “carrier” can refer to a nucleic acid, or analog thereof, which is inert (i.e., docs not possess biological activity per se) but is recognized as a nucleic acid by in vivo processes that reduce the bioavailability of a nucleic acid having 25 biological activity by, for example, degrading the biologically active nucleic acid or promoting its removal from circulation. The coadministration of a nucleic acid and a carrier compound, typically with an excess of the latter substance, can result in a substantial reduction of the amount of nucleic acid recovered in the liver, kidney or other extracirculatory reservoirs, presumably due to competition between the earner compound and the nucleic acid for a common 30 receptor. For example, the recovery of a partially phosphorothioate dsRNA in hepatic tissue can be reduced when it is coadministered with polyinosinic acid, dextran sulfate, polycytidic acid or 4-acctamido-4'isothiocyano-stilbcnc-2,2'-disulfonic acid (Miyao etal., DsRNA Res. Dev., 1995, 5, 115-121 ;Takakura etal., DsRNA & Nucl. Acid Drug Dev., 1996,6, 177-183.

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Excipients

In contrast to a carrier compound, a “pharmaceutical carrier” or “excipient” is a pharmaceutically acceptable solvent, suspending agent or any other pharmacologically inert vehicle for delivering one or more nucleic acids to an animal. The excipient may be liquid or solid and is selected, with the planned manner of administration in mind, so as to provide for the desired bulk, consistency, etc., when combined with a nucleic acid and the other components of a given pharmaceutical composition. Typical pharmaceutical carriers include, but are not limited to, binding agents (e.g., prcgelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl mcthylcellulosc, etc.)', fillers (e.g., lactose and other sugars, microcrystal line cellulose, pectin, gelatin, calcium sulfate, ethyl cellulose, poly acrylates or calcium hydrogen phosphate, ete.); lubricants (e.g„ magnesium stearate, talc, silica, colloidal silicon dioxide, stearic acid, metallic stearates, hydrogenated vegetable oils, com starch, polyethylene glycols, sodium benzoate, sodium acetate, etc.); disintegrants (e.g., starch, sodium starch glycolate, etc.); and wetting agents (e.g., sodium lauryl sulphate, etc).

Pharmaceutically acceptable organic or inorganic excipients suitable for non-parentcral administration which do not deletcriously react with nucleic acids can also be used to formulate the compositions of the present invention. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulosc, polyvinylpyrrolidone and the like.

Formulations for topical administration of nucleic acids may include sterile and nonstcrile aqueous solutions, non-aqueous solutions in common solvents such as alcohols, or solutions of the nucleic acids in liquid or solid oil bases. The solutions may also contain buffers, diluents and other suitable additives. Pharmaceutically acceptable organic or inorganic excipients suitable for non-parenteral administration which do not deletcriously react with nucleic acids can be used.

Suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylccllulose, polyvinylpyrrolidone and the like.

Other Components

The compositions of the present invention may additionally contain other adjunct components conventionally found in pharmaceutical compositions, at their art-established usage levels. Thus, for example, the compositions may contain additional, compatible,

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 pharmaceutically-active materials such as, for example, antipruritics, astringents, local anesthetics or anti-inflammatory agents, or may contain additional materials useful in physically formulating various dosage forms of the compositions of the present invention, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers.

However, such materials, when added, should not unduly interfere with the biological activities of the components of the compositions of the present invention. The formulations can be sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not dclctcriously interact with the nucleic acid(s) of the formulation.

Aqueous suspensions may contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran. The suspension may also contain stabilizers.

In some embodiments, pharmaceutical compositions featured in the invention include (a) one or more dsRNA compounds and (b) one or more anti-cytokine biologic agents which function by a non-RNAi mechanism. Examples of such biologies include, biologies that target IL 1 β (e.g,, anakinra), IL6 (tocilizumab), or TNF (etanercept, infliximab, adlimumab, or certolizumab).

Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. Compounds that exhibit high therapeutic indices are preferred.

The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of compositions featured in the invention lies generally within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the methods featured in the invention, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range of the compound or, when appropriate, of the polypeptide product of a target sequence (e.g., achieving a decreased concentration of the polypeptide) that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography.

In addition to their administration, as discussed above, the dsRNAs featured in the invention can be administered in combination with other known agents effective in treatment of pathological processes mediated by TTR expression. In any event, the administering physician can adjust the amount and timing of dsRNA administration on the basis of results observed using standard measures of efficacy known in the art or described herein.

Methods for treating ocular disease caused bv expression of a TTR gene

The invention relates in particular to the use of a dsRNA targeting TTR for the treatment of a TTR-related ocular amyloidosis. The invention features a method of treating, preventing or managing TTR-related ocular amyloidosis by administering to the patient in need of such treatment, prevention or management a therapeutically or prophylacticlaly effective amount of AD-18324 to the retina of the patient. In one embodiment, the method involves treating a human by identifying a human diagnosed as having TTR-related ocular amyloidosis or at risk for developing TTR-related ocular amyloidosis and administering to the human a therapeutically or prophylactical ly effective amount of AD-18324 to the retina of the human. The invention also includes the method of treating a human with TTR-related ocular amyloidosis by introducing into the retinal epithelium cell a dsRNA, wherein the dsRNA is AD-18324 or AD-18534; and maintaining the cell produced in the previous step for a time sufficient to obtain degradation of the mRNA transcript of a TTR gene, thereby inhibiting expression of the TTR gene in the cell.In some embodiments, TTR siRNA of the invention are used in methods of transthyretin (TTR)rclated familial amyloidotic polyneuropathy (FAP) patients and treatment of ocular manifestations, such as vitreous opacity and glaucoma. It is know to one of skill in the art that amyloidogenic transthyretin (ATTR) synthesized by retinal pigment epithelium (RPE) plays important roles in the progression of ocular amyloidosis. Previous studies have shown that panretinal laser photocoagulation, which reduced the RPE cells, prevented the progression of amyloid deposition in the vitreous, indicating that the effective suppression of ATTR expression in RPE may become a novel therapy for ocular amyloidosis (see, e.g,, Kawaji, T., et al.,

Ophthalmology. (2010) 117: 552-555). Administration of any of the TTR siRNA disclosed herein can be used for treatment of ocular manifestations of TTR related FAP, e.g., ocular amyloidosis. The dsRNA can be delivered in a manner to target a particular tissue, such as the eye. Modes of ocular delivery include retrobulbar, subcutaneous eyelid, subconjunctival,

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 subtenon, anterior chamber or intravitreous injection (or internal injection or infusion). Specific formulations for ocular delivery include eye drops or ointments.

The dsRNA and an additional therapeutic agent can be administered in the same combination, e.g., parenterally, or the additional therapeutic agent can be administered as part of 5 a separate composition or by another method described herein.

The invention features a method of administering a dsRNA targeting TTR to a patient having a disease or disorder mediated by TTR expression, such as a TTR amyloidosis, e.g., FAP. Administration of the dsRNA can stabilize and improve peripheral neurological function, for example, in a patient with FAP. Patients can be administered a therapeutic amount of dsRNA, 10 such as 0.1 mg/kg, 0.2 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 1.5 mg/kg, 2.0 mg/kg, or 2.5 mg/kg dsRNA. The dsRNA can be administered by intravenous infusion over a period of time, such as over a 5 minute, 10 minute, 15 minute, 20 minute, 25 minute, 60 minute, 120 minute or 180 minute period. The administration is repeated, for example, on a regular basis, such as biweekly (i.e., every two weeks) for one month, two months, three months, four months or longer. After 15 an initial treatment regimen, the treatments can be administered on a less frequent basis. For example, after administration biweekly for three months, administration can be repeated once per month, for six months or a year or longer. Administration of the dsRNA can reduce TTR levels in the blood or urine of the patient by at least 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80 % or 90% or more.

Before administration of a full dose of the dsRNA, patients can be administered a smaller dose, such as a dose that is 5% of the full dose, and monitored for adverse effects, such as an allergic reaction or a change in liver function. For example, in patients monitored for changes in liver function, a low incidence of LFT (Liver Function Test) change (e.g., a 10-20% incidence of LFT) is acceptable (e.g., a reversible, 3-fold increase in ALT (alanine aminotransferase) and/or

AST (aspartate aminotransferase) levels).

Many TTR-associated diseases and disorders arc hereditary. Therefore, a patient in need of a TTR dsRNA can be identified by taking a family history. A healthcare provider, such as a doctor, nurse, or family member, can take a family history before prescribing or administering a TTR dsRNA. A DNA test may also be performed on the patient to identify a mutation in the 30 TTR gene, before a TTR dsRNA is administered to the patient.

The patient may have a biopsy performed before receiving a TTR dsRNA. The biopsy can be, for example, on a tissue, such as the gastric mucosa, peripheral nerve, skin, abdominal fat, liver, or kidney, and the biopsy may reveal amyloid plaques, which are indicative of a TTR54

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 mediated disorder. Upon the identification of amyloid plaques, the patient is administered a

TTR dsRNA.

Methods for inhibiting expression of a TTR gene

In yet another aspect, the invention provides a method for inhibiting the expression of a 5 TTR gene in a mammal. The method includes administering a composition featured in the invention to the mammal such that expression of the target TTR gene is silenced.

When the organism to be treated is a mammal such as a human, the composition may be administered by any means known in the art including, but not limited to oral or parenteral routes, including intracranial (e.g., intraventricular, intraparenchymal and intrathecal), intravenous, intramuscular, subcutaneous, transdcrmal, airway (aerosol), nasal, rectal, and topical (including buccal and sublingual) administration, in certain embodiments, the compositions are administered by intravenous infusion or injection.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention 15 belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the dsRNAs and methods featured in the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein arc incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, 20 methods, and examples arc illustrative only and not intended to be limiting.

EXAMPLES

Example 1. dsRNA synthesis

Source of reagents

Where the source of a reagent is not specifically given herein, such reagent may be 25 obtained from any supplier of reagents for molecular biology at a quality/purity standard for application in molecular biology.

siRNA synthesis

Single-stranded RNAs were produced by solid phase synthesis on a scale of 1 gmole using an Expedite 8909 synthesizer (Applied Biosystems, Applcra Deutschland GmbH, 30 Darmstadt, Germany) and controlled pore glass (CPG, 500A, Proligo Biochcmie GmbH, Hamburg, Germany) as solid support. RNA and RNA containing 2'-O-mcthyl nucleotides were generated by solid phase synthesis employing the corresponding phosphoramidites and 2'-O55

WO 2011/123468

PCT/US2011/030392 methyl phosphoramidites, respectively (Proligo Biochemic GmbH, Hamburg, Germany). These building blocks were incorporated at selected sites within the sequence of the oligoribonucleotidc chain using standard nucleoside phosphoramidite chemistry such as described in Current protocols in nucleic acid chemistry, Bcaucage, S.L. etal. (Edrs.), John

2017204161 20 Jun 2017

Wiley & Sons, Inc., New York, NY, USA. Phosphorothioate linkages were introduced by replacement of the iodine oxidizer solution with a solution of the Bcaucage reagent (Chruachem Ltd, Glasgow, UK) in acetonitrile (1%). Further ancillary reagents were obtained from Mallinckrodt Baker (Griesheim, Germany).

Deprotection and purification of the crude oligoribonuclcotidcs by anion exchange HPLC were carried out according to established procedures. Yields and concentrations were determined by UV absorption of a solution of the respective RNA at a wavelength of 260 nm using a spectral photometer (DU 640B, Beckman Coulter GmbH, UntcrschlciBheim, Germany). Double stranded RNA was generated by mixing an equimolar solution of complementary strands in annealing buffer (20 mM sodium phosphate, pH 6.8; 100 mM sodium chloride), heated in a water bath at 85 - 90°C for 3 minutes and cooled to room temperature over a period of 3 - 4 hours. The annealed RNA solution was stored at -20 °C until use.

For the synthesis of 3’-cholesterol-conjugated siRNAs (herein referred to as -Chol-3'), an appropriately modified solid support was used for RNA synthesis. The modified solid support was prepared as follows:

Dicthyl-2-azabutane-1,4-dicarboxylatc AA

AA

A 4.7 M aqueous solution of sodium hydroxide (50 mL) was added into a stirred, icccoolcd solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) was added and the mixture was stirred at room temperature 25 until completion of the reaction was ascertained by TLC. After 19 h the solution was partitioned with dichloromcthane (3 x 100 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was distilled to afford AA (28.8 g, 61%).

3-{Ethoxycarbonylmethyl-[6-(9H-fluoren-9-ylmethoxycarbonyl-amino)4iexanoyl]amino}-propionic acid ethyl ester AB

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

FmocHN

AB

Fmoc-6-amino-hexanoic acid (9.12 g, 25.83 mmol) was dissolved in dichloromethane (50 mL) and cooled with ice. Diisopropylcarbodiimde (3.25 g, 3.99 mL, 25.83 mmol) was added 5 to the solution at 0°C. It was then followed by the addition of Dicthyl-azabutane-1,4dicarboxylate (5 g, 24.6 mmol) and dimethylamino pyridine (0.305 g, 2.5 mmol). The solution was brought to room temperature and stirred further for 6 h. Completion of the reaction was ascertained by TLC. The reaction mixture was concentrated under vacuum and ethyl acetate was added to precipitate diisopropyl urea. The suspension was filtered. The filtrate was washed with 10 5% aqueous hydrochloric acid, 5% sodium bicarbonate and water. The combined organic layer was dried over sodium sulfate and concentrated to give the crude product which was purified by column chromatography (50 % EtOAC/Hexancs) to yield 11.87 g (88%) of AB.

3-[(6-Amino-hexanoyl)-cthoxycarbonylmcthyl-amino]-propionic acid ethyl ester AC

¹⁵ AC

3-(Ethoxycarbonylmcthyl-[6-(9H-fluorcn-9-ylmethoxycarbonylamino)-hcxanoyl]amino [-propionic acid ethyl ester AB (11.5 g, 21.3 mmol) was dissolved in 20% piperidine in dimethyl formamide at 0°C. The solution was continued stirring for 1 h. The reaction mixture was concentrated under vacuum, water was added to the residue, and the product was extracted 20 with ethyl acetate. The crude product was purified by conversion into its hydrochloride salt.

3-( (6-[l 7-( l,5-Dimcthyl-hexyl)-10,13-dimcthyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17tetradecahydro-lH-cyclopenta[a]phenanthren-3-yloxycarbonylamino]hcxanoyl[cthoxycarbonylmcthyl-amino)-propionic acid ethyl ester AD

WO 2011/123468

PCT/US2011/030392

AD

The hydrochloride salt of 3-((6-Amino-hcxanoyl)-ethoxycarbonyImcthyl-amino]propionic acid ethyl ester AC (4.7 g, 14.8 mmol) was taken up in dichloromethanc. The suspension was cooled to 0°C on ice. To the suspension di isopropylethylamine (3.87 g, 5.2 mL,

30 mmol) was added. To the resulting solution cholesteryl chloroformatc (6.675 g, 14.8 mmol) was added. The reaction mixture was stirred overnight. The reaction mixture was diluted with dichloromethanc and washed with 10% hydrochloric acid. The product was purified by flash chromatography (10.3 g, 92%).

2017204161 20 Jun 2017 l-(6-[17-(l,5-Dimethyl-hexyl)-I0,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,1710 tctradecahydro-1 H-cyclopenta[a] phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxopyrrolidine-3-carboxylic acid ethyl ester AE

O

AE

Potassium t-butoxide (1.1 g, 9.8 mmol) was slurried in 30 mL of dry toluene. The mixture was cooled to 0°C on ice and 5 g (6.6 mmol) of dicstcr AD was added slowly with stirring within 20 mins. The temperature was kept below 5°C during the addition. The stirring was continued for 30 mtns at 0°C and 1 mL of glacial acetic acid was added, immediately followed by 4 g of NaHjPOrfLO in 40 mL of water The resultant mixture was extracted twice with 100 mL of dichloromethanc each and the combined organic extracts were washed twice with. 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue was dissolved in 60 mL of toluene, cooled to 0°C and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts were adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which were combined, dried and evaporated to dryness. The residue was purified by column chromatography using 25% ethylacetatc/hexane to afford 1.9 g of b-ketoester (39%).

WO 2011/123468

PCT/US2011/030392 [6-(3-HydiOxy-4-hydiOxymethyl-pyrrolidin-1-yl)-6-oxo-hexyl]-carbamic acid 17-(1,5dimethyl-hexyl )-10,13-dimethyl-2,3,4,7,8,9,10,11,12 J 3,14,15,16,17-tetradecahydro-1Hcyclopenta[a]phcnanthren-3-yl ester AF

2017204161 20 Jun 2017

AF

Methanol (2 mL) was added dropwisc over a period of 1 h to a refluxing mixture of bketoester AE (1.5 g, 2.2 mmol) and sodium borohydride ¢0.226 g, 6 mmol) in tetrahydrofuran (10 mL). Stirring was continued at reflux temperature for 1 h. After cooling to room temperature, 1 N HC1 (12.5 mL) was added, the mixture was extracted with ethylacetate (3 x 40 mL). The combined ethylacetate layer was dried over anhydrous sodium sulfate and concentrated under vacuum to yield the product which was purified by column chromatography (10% MeOH/CHCh) (89%).

(6-{3-[Bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-4-hydroxy-pyrtOlidin-l-yL-6oxo-hexyl)-carbamic acid 17-( 1,5-dimethyl-hexyl)-10,13-dimethyl15 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-lH-cyclopenta[a]phcnanthren-3-yl ester AG

Diol AF (1.25 gm 1.994 mmol) was dried by evaporating with pyridine (2x5 mL) in vacuo. Anhydrous pyridine (10 mL) and 4,4’-dimethoxytritylchloridc (0.724 g, 2.13 mmol)

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 were added with stirring. The reaction was carried out at room temperature overnight. The reaction was quenched by the addition of methanol. The reaction mixture was concentrated under vacuum and to the residue dichloromcthanc (50 mL) was added. The organic layer was washed with 1M aqueous sodium bicarbonate. The organic layer was dried over anhydrous 5 sodium sulfate, filtered and concentrated. The residual pyridine was removed by evaporating with toluene. The crude product was purified by column chromatography (2% McOH/Chloroform, Rf= 0.5 in 5% McOH/CHCl3) (1,75 g, 95%).

Succinic acid mono-(4-[bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-l-{6-[l7-(l,5dimethy 1-hcxy 1)-10,13-dimethyl 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradccahydro-lH cyclopen ta[a]phenan th ren-3-yl oxycarbonyl am ino]-hexanoy I}-pyrrol idin-3-yl) ester AH

AH

Compound AG (1.0 g, 1.05 mmol) was mixed with succinic anhydride (0.150 g, 1.5 mmol) and DMAP (0.073 g, 0.6 mmol) and dried in a vacuum at 40°C overnight. The mixture was dissolved in anhydrous dichloroethane (3 mL), triethylamine (0.318 g, 0.440 mL, 3.15 mmol) was added and the solution was stirred at room temperature under argon atmosphere for 16 h. It was then diluted with dichloromethane (40 mL) and washed with ice cold aqueous citric acid (5 wt%, 30 mL) and water (2 X 20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to diyness. The residue was used as such for the next step.

Al

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Succinate AH (0.254 g, 0.242 mmol) was dissolved in a mixture of dichloromethane/acetonitrile (3:2, 3 mL). To that solution DMAP (0.0296 g, 0.242 mmol) in acetonitrile (1.25 mL), 2,2’-Dithio-bis(5-nitropyridine) (0.075 g, 0.242 mmol) in acetonitrile/dichloroethane (3:1, 1.25 mL) were added successively. To the resulting solution triphenylphosphine (0.064 g, 0.242 mmol) in acetonitrile (0.6 ml) was added. The reaction mixture turned bright orange in color. The solution was agitated briefly using a wrist-action shaker (5 mins). Long chain alkyl aminc-CPG (LCAA-CPG) (1.5 g, 61 mM) was added. The suspension was agitated for 2 h. The CPG was filtered through a sintered funnel and washed with acetonitrile, dichloromethane and ether successively. Unreacted amino groups were masked using acetic anhydride/pyridine. The achieved loading of the CPG was measured by taking UV measurement (37 mM/g).

The synthesis of siRNAs bearing a 5’-12-dodecanoic acid bisdecylamide group (herein referred to as 5'-C32-) or a 5'-cholestery! derivative group (herein referred to as 5'-Chol-) was performed as described in WO 2004/065601, except that, for the cholesteryl derivative, the oxidation step was performed using the Bcaucage reagent in order to introduce a phosphorothioate linkage at the 5'-end of the nucleic acid oligomer.

Nucleic acid sequences are represented below using standard nomenclature, and specifically the abbreviations of Table 1.

Table 1: Abbreviations

Abbreviations of nucleotide monomers used in nucleic acid sequence representation. It will be understood that these monomers, when present in an oligonucleotide, are mutually linked by 5'-3'-phosphodiester bonds.

Abbreviation	Nucleotide(s)
A	adenosine-3'-phosphate
C	cytidinc-3'-phosphatc
G	guanos ine-3'-phosphate
U	u rid i ne-3 '-phosphate
N	any nucleotide (G, A, C, U, dT, T)
a	2'-O-methyladenosine-3’-phosphate
c	2'-O-methylcytidinc-3'-phosphate
g	2'-0-methylguanosinc-3,-phosphate
u	2'-O-methyluridine-3'-phosphatc
T, dT	2'-deoxythymidine-3'-phosphate
sT; sdT	2’-deoxy-thymidine-5’phosphate-phosphorothioate

Conjugated siRNAs

Preparation of siRNAs conjugated to a ligand such as cholesterol and vitamin E are shown in schemes 1 and 2.

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

X = O or S

Scheme 1

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Scheme 2, Syntheses of sIRNA-llpophillc conjugates. A, B: On column and C: Postsynthetic conjugations. (1} a. solid phase synthesis; b. deprotection and c. HPLC purification; (li) Annealing with complementary strand; (ill) a. Post-synthetic conjugation to ligand and b. annealing with complementary strand. X = O or S.

Example 2A. TTR siRNA Design

Transcripts siRNA design was carried out to identify siRNAs targeting the gene transthyretin from human (symbol TTR) and rat (symbol Ttr). The design used the TTR transcripts NM_000371.2 (SEQ ID NO: 1329) (human) and NM_012681.1 (SEQ ID NO: 1330) (rat) from the NCBI Refscq collection. The siRNA duplexes were designed with 100% identity to their respective TTR genes.

siRNA Design and Specificity Prediction

The predicted specificity of all possible 19mers was determined for each sequence. The TTR siRNAs were used in a comprehensive search against the human and rat transcriptomes (defined as the set ofNM_and XM records within the NCBI Refscq set) using the FASTA algorithm. The Python script ‘offtargetFasta.py’ was then used to parse the alignments and 15 generate a score based on the position and number of mismatches between the siRNA and any potential ‘off-target’ transcript. The off-target score is weighted to emphasize differences in the ‘seed’ region of siRNAs, in positions 2-9 from the 5’ end of the molecule. The off-target score is calculated as follows: mismatches between the oligo and the transcript are given penalties. A mismatch in the seed region in positions 2-9 of the oligo is given a penalty of 2.8; mismatches in

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 the putative cleavage sites 10 and 11 arc given a penalty of 1.2, and mismatches in positions 1219 a penalty of I. Mismatches in position 1 are not considered. The off-target score for each oligo-transcript pair is then calculated by summing the mismatch penalties. The lowest offtarget score from all the oligo-transcript pairs is then determined and used in subsequent sorting of oligos. Both siRNA strands were assigned to a category of specificity according to the calculated scores: a score above 3 qualifies as highly specific, equal to 3 as specific, and between 2.2 and 2.8 as moderately specific. In picking which oligos to synthesize, off-target scores of the antisense strand were sorted from high to low, and the 144 best (lowest off-target score) oligo pairs from human, and the best 26 pairs from rat were selected.

siRNA sequence selection

A total of 140 sense and 140 antisense human TTR derived siRNA oligos were synthesized and formed into duplexes. A total of 26 sense and 26 antisense rat TTR derived siRNA oligos were synthesized and formed into duplexes. Duplexes are presented in Tables 2-4 (human TTR) and Tables 5-7 (rat TTR).

WO 2011/123468

PCT/US2011/030392

Table 2. Identification numbers for human TTR dsRNAs

2017204161 20 Jun 2017

See Table 4 for sequences and modifications of oligos.

Duplex #	Sense Oligo #	Antisense Oligo #
AD-18243	A-32153	A-32154
AD-18244	A-32155	A-32156
AD-18245	A-32157	A-32158
AD-18246	A-32159	A-32160
AD-18247	A-32163	A-32164
AD-18248	A-32165	A-32166
AD-18249	A-32167	A-32168
AD-18250	A-32169	A-32170
AD-18251	A-3217I	A-32172
AD-18252	A-32175	A-32176
AD-18253	A-32177	A-32178
AD-18254	A-32179	A-32180
AD-18255	A-32181	A-32182
AD-18256	A-32183	A-32184
AD-18257	A-32187	A-32188
AD-18258	A-32189	A-32190
AD-18259	A-32191	A-32192
AD-18260	A-32193	A-32194
AD-18261	A-32195	A-32196
AD-18262	A-32199	A-32200
AD-18263	A-32201	A-32202
AD-18264	A-32203	A-32204
AD-18265	A-32205	A-32206
AD-18266	A-32207	A-32208
AD-18267	A-32211	A-32212
AD-18268	A-32213	A-32214
AD-18269	A-322I5	A-32216
AD-18270	A-32217	A-32218
AD-18271	A-32219	A-32220
AD-18272	A-3222I	A-32222
AD-18273	A-32223	A-32224
AD-18274	A-32225	A-32226
AD-18275	A-32227	A-32228
AD-18276	A-32229	A-32230
AD-18277	A-32231	A-32232
AD-18278	A-32233	A-32234
AD-18279	A-32235	A-32236
AD-18280	A-32237	A-32238
AD-18281	A-32239	A-32240
AD-18282	A-32241	A-32242
AD-182 83	A-32243	A-32244

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Duplex #	Sense Oligo #	Antisense Oligo #
AD-18284	A-32247	A-32248
AD-182 85	A-32249	A-32250
AD-182 86	A-32251	A-32252
AD-18287	A-32253	A-32254
AD-18288	A-32255	A-32256
AD-18289	A-32259	A-32260
AD-18290	A-32261	A-32262
AD-18291	A-32263	A-32264
AD-18292	A-32265	A-32266
AD-18293	A-32267	A-32268
AD-18294	A-32269	A-32270
AD-18295	A-32271	A-32272
AD-18296	A-32273	A-32274
AD-18297	A-32275	A-32276
AD-18298	A-32277	A-32278
AD-18299	A-32279	A-32280
AD-18300	A-32281	A-32282
AD-18301	A-32283	A-32284
AD-18302	A-32285	A-32286
AD-18303	A-32287	A-32288
AD-18304	A-32289	A-32290
AD-18305	A-3229I	A-32292
AD-18306	A-32295	A-32296
AD-18307	A-32297	A-32298
AD-18308	A-32299	A-32300
AD-18309	A-32301	A-32302
AD-18310	A-32303	A-32304
AD-18311	A-32307	A-32308
AD-18312	A-32309	A-32310
AD-18313	A-3231 1	A-32312
AD-18314	A-323I3	A-32314
AD-18315	A-32315	A-32316
AD-183I6	A-32319	A-32320
AD-183I7	A-32321	A-32322
AD-18318	A-32323	A-32324
AD-18319	A-32325	A-32326
AD-18320	A-32327	A-32328
AD-18321	A-32331	A-32332
AD-183 22	A-32333	A-32334
AD-18323	A-32335	A-32336
AD-18324	A-32337	A-32338
AD-18325	A-32339	A-32340
AD-18326	A-32341	A-32342
AD-18327	A-32343	A-32344

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Duplex #	Sense Oligo #	Antisense Oligo #
AD-18328	A-32345	A-32346
AD-18329	A-32347	A-32348
AD-18330	A-32349	A-32350
AD-18331	A-32351	A-32352
AD-18332	A-32353	A-32354
AD-18333	A-32355	A-32356
AD-18334	A-32357	A-32358
AD-18335	A-32359	A-32360
AD-18336	A-32363	A-32364
AD-18337	A-32367	A-32368
AD-18338	A-32369	A-32370
AD-18339	A-32371	A-32372
AD-18340	A-32373	A-32374
AD-18341	A-32375	A-32376
AD-18342	A-32379	A-32380
AD-18343	A-32381	A-32382
AD-18344	A-32383	A-32384
AD-18345	A-32385	A-32386
AD-18346	A-32387	A-32388
AD-18347	A-3239I	A-32392
AD-18348	A-32393	A-32394
AD-18349	A-32395	A-32396
AD-18350	A-32397	A-32398
AD-18351	A-32399	A-32400
AD-18352	A-3240I	A-32402
AD-18353	A-32403	A-32404
AD-18354	A-32405	A-32406
AD-18355	A-32407	A-32408
AD-18356	A-32409	A-32410
AD-18357	A-32411	A-32412
AD-18358	A-32415	A-32416
AD-18359	A-32417	A-32418
AD-18360	A-32419	A-32420
AD-18361	A-32421	A-32422
AD-18362	A-32423	A-32424
AD-18363	A-32427	A-32428
AD-18364	A-32429	A-32430
AD-18446	A-32161	A-32162
AD-18447	A-32173	A-32174
AD-18448	A-32185	A-32186
AD-18449	A-32197	A-32198
AD-18450	A-32209	A-32210
AD-18451	A-32245	A-32246
AD-18452	A-32257	A-32258

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Duplex #	Sense Oligo #	Antisense Oligo #
AD-18453	A-32293	A-32294
AD-18454	A-32305	A-32306
AD-18455	A-32317	A-32318
AD-18456	A-32329	A-32330
AD-18457	A-32361	A-32362
AD-18458	A-32365	A-32366
AD-18459	A-32377	A-32378
AD-18460	A-32389	A-32390
AD-18461	A-3240I	A-32402
AD-18462	A-32413	A-32414
AD-18463	A-32425	A-32426

Table 3A, Sense and antisense strand sequences of human TTR dsRNAs

Strand: s= sense; as= antisense; Position: position of 5' base on transcript (NM_000371.2, SEQ ID NO: 1329)

Strand	Position	Sequence (5' to 3' )	SEQIDNO:	Sequence with 3' dinucleotide overhang (5' to 3')	SEQ IDNO:
S	100	CCGGUGAAUCCAAGUGUCC	1	CCGGOGAAUCCAAGOGUCCNN	281
as	118	GGACACUUGGAUUCACCGG	2	GGACACUUGGAUUCACCGGN1I	282
s	11	ACUCAUUCUUGGCAGGAUG	3	ACUCAUUCUUGGCAGGAUGIIH	283
as	29	CAUCCUGCCAAGAAUGAGO	4	CAUCCUGCCAAGAAUGAGUW	284
s	111	AAGUGOCCUCUGAUGGOCA	5	AAGUGUCCUCUGAUGGUCAUH	285
as	129	UGACCAUCAGAGGACACUU	6	UGACCAUCAGAGGACACUUtlH	286
s	13	UCAHUCUUGGCAGGADGGC	7	UCAUUCUUGGCAGGAUGGCHH	287
as	31	GCCAUCCUGCCAAGAAUGA	8	GCCAUCCUGCCAAGAAUGANN	288
S	130	AAGUUCUAGAUGCDGDCCG	9	aaguucuagaugcuguccgnh	289
as	148	CGGACAGCAUCUAGAACUU	10	CGGAC AGC AUC U AG AAC 0 UM II	290
s	132	GUUCUAGAUGCUGUCCGAG	11	GUUCQAGAUGCUGtlCCGAGltll	291
as	150	CUCGGACAGCAUCUAGAAC	12	CUCGGACAGCAUCUAGAACH1J	292
s	135	CUAGAUGCUGUCCGAGGCA	13	CUAGAUGCUGUCCGAGGCAH11	293
as	153	UGCCtJCGGACAGCAUCUAG	14	UGCCUCGGACAGCAUCUAGHM	294
s	138	GAUGCUGUCCGAGGCAGUC	15	GAUGCUGUCCGAGGCAGUCU1I	295
as	156	GACUGCCUCGGACAGCAUC	16	GACUGCCUCGGACAGCAUCini	296
s	14	CAUUCUOGGCAGGAUGGCO	17	CAUUCUUGGCAGGAUGGCUHN	297
as	32	AGCCAUCCUGCCAAGAAOG	18	AGCCAUCCUGCCAAGAAUGHN	298
s	140	UGCUGUCCGAGGCAGUCCU	19	UGCUGUCCGAGGCAGUCCUim	299
as	158	AGGACDGCCU.CGGACAGCA	20	AGGACUGCCUCGGACAGCANll	300
s	146	CCGAGGCAGUCCUGCCAUC	21	CCGAGGCAGUCCUGCCAUCWH	301
as	164	GAUGGCAGGACUGCCOCGG	22	GAUGGCAGGACUGCCUCGGHll	302
s	152	CAGUCCUGCCAUCAAUGUG	23	CAGUCCUGCCAUCAAUGUGHH	303
as	170	CACAUUGAUGGCAGGACUG	24	CACAUUGAUGGCAGGACUGH1I	304
s	164	CAAUGUGGCCGUGCAUGUG	25	CAAUGUGGCCGUGCAUGUG1IN	305
as	182	CACAUGCACGGCCACAUOG	26	CACAUGCACGGCCACAUUGIIN	306
s	178	AUGUGUUCAGAAAGGCUGC	27	AUGUGUUCAGAAAGGCUGCHN	307
as	196	GCAGCCUUUCUGAACACAU	28	GCAGCCUUUCUGAACACAUNH	308
s	2	CAGAAGUCCACUCAUUCUU	29	CAGAAGUCCACUCAUUCUUNH	309

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Strand	Position	Sequence (5' to 3' )	SEQ IDNO:	Sequence with 3' dinucleotide overhang (5' to 3')	SEQ IDNO:
as	20	AA G AAUGAGUGGACUUCOG	30	AAGAAUGAGUG GAC UU CU GUN	310
s	21	GGCAGGAUGGCUUCUCAUC	31	GG CAGGAUGGCU UC UCAU Cl IN	311
as	39	GAUGAGAAGCCAUCCUGCC	32	GAUGAGAAGCCAUCCUGCCUN	312
s	210	GAGCCAUUUGCCUCUGGGA	33	GAGCCAUUUGCCUCUGGGAHH	313
a.s	228	UCCCAGAGGCAAAUGGCUC	34	UCCCAGAGGCAAAUGGCUCNN	314
s	23	CAGGAUGGCUUCOCAUCGU	35	CAGGAUGGCUUCUCAUCGUHU	315
as	41	ACGAUGAGAAGCCAUCCOG	36	ACGAUGAGAAGCCAUCCUGNN	316
s	24	AGGAUGGCUUCUCAUCGUC	37	AG GAUGGCUUCUCAUC G OCNH	317
as	42	GACGAUGAGAAGCCAUCCU	38	GACGAUGAGAAGCCAUCCUIIII	318
s	245	AGAGCUGCAUGGGCUCACA	39	AGAGCOGCAUGGGCUCACANN	319
as	263	UGUGAGCCCAUGCAGCUCU	40	UGUGAGCCCAUGCAGC.UCUHH	320
s	248	GCUGCAUGGGCUCACAACU	41	GCUGCAUGGGCUCACAACUtlll	321
as	266	AGUUGDGAGCCCAUGCAGC	42	AGUUGUGAGCCCAUGCAGCHN	322
3	25	GGAUGGCOUCUCAUCGUCU	43	GGAUGGCUUCUCAUCGUCUWH	323
as	43	AGACGAUGAGAAGCCAUCC	44	AGACGAUGAGAAGCCAUCCNlt	324
s	251	GCAUGGGCUCACAACUGAG	45	GCAUGGGCUCACAACUGAGHU	325
as	269	CUCAGUUGUGAGCCCAUGC	46	CUCAGU UGUGAGCCCAUGCWH	326
s	253	AU GG GC UCACAACU GAGGA	47	AU GG GCUCAC AACU GAGGAN11	327
as	271	UCCUCAGUUGUGAGCCCAU	48	UCCUCAGUUGUGAGCCCAOT1H	328
s	254	UGGGCOCACAACUGAGGAG	49	UGGGCUCACAACUGAGGAGHH	329
as	272	CUCCUCAGUUGUGAGCCCA	50	CUCCOCAGUUGUGAGCCCANH	330
s	270	GAGGAAUUUGUAGAAGGGA	51	GAGGAAUUOGOAGAAGGGANN	331
as	288	UCCCUUCUACAAAUUCCUC	52	UCCCUUCUACAAAUUCCUCU1I	332
s	27 6	UUUGUAGAAGGGAUAUACA	53	uuuguagaagggauauacanii	333
as	294	UGUAUAUCCCUUCUACAAA	54	UG UAUAUC CCUUCUACAAANN	334
s	277	UUGUAGAAGGGAUAUACAA	55	OUGUAGAAGGGAUAUACAAHH	335
as	295	OUGUAOAUCCCUUCUACAA	56	UUGUAUAUCCCUUCUACAAMH	336
s	278	UGUAGAAGGGAUAUACAAA	57	UGUAGAAGGGAUAUACAAAKH	337
as	296	UUUGUAUAUCCCUUCUACA	58	UUUGUAUAUCCCOUCUACAHll	330
s	281	AG AAGG GAU AUACAAAGOG	59	AG AAGG GAU AUACAAAGU GNU	339
as	299	CACUUUGUADAUCCCUUCU	60	CACUUUGUAUAUCCCUUCUNN	34 0
s	295	AAGUGGAAAUAGACACCAA	61	AAGU GG AAAU AG AC AC CAA1111	341
as	313	UUGGUGUCUAUUUCCACUU	62	UUGGUGUCUAUUUCCACUUKN	342
s	299	GGAAAUAGACACCAAAUCU	63	GGAAAUAGACACCAAAUCUHII	343
as	317	AGAUUUGGUGUCUAUUUCC	64	AGAUUUGGOGUCUAUUUCCIIH	344
S	300	GAAAUAGACACCAAAOCOU	65	GAAAUAGACACCAAADCODHN	345
as	318	AAGAUUUGG.UGUCUAUUUC	66	AAGAUUUGGUGUCUAUUUCNII	34 6
s	303	AU AG AC AC CAAAUC UU AC U	67	AU AG AC AC C AAA UC UUAC U till	347
as	321	AGUAAGAUUUGGUGUCUAU	68	AGUAAGAUUUGGUGUCUAUNII	348
s	304	UAGACACCAAAUCUUACUG	69	UAGACACCAAAUCUUACUG1IH	349
as	322	CAGUAAGAUUUGGUGUCUA	70	CAGUAAGAUUOGGOGUCOAHN	350
s	305	AGACACCAAAUCUUACUGG	71	AGACACCAAAUCUUACUGGlllJ	351
as	323	CCAGUAAGAUUUGGUGUCU	72	CCAGUAAGAUUUGGUGUCUNN	352
s	317	UUACUGGAAGGCACUUGGC	73	UUAC UGGAAGGCACUUGGCN 11	353
as	335	GGCAAGUGCCUUCCAGUAA	74	GCCAAGOGCCUUCCAGUAANII	354
S	32	UUCUCAUCGUCUGCUCCUC	75	UUCUCAUCGUCUGCUCCUC111I	355
as	50	GAGGAGCAGAGGAUGAGAA	76	GAGGAGCAGACGAUGAGAAMW	356
s	322	GGAAGGCACUUGGCAUCUC	77	GGAAGGCACUUGGCAUCUCllll	357
as	340	GAGAUGCCAAGUGCCUUCC	78	GAGAUGCCAAGUGCCUUCCNU	358

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Strand	Position	Sequence (5' to 3' )	SEQ IDNO:	Sequence with 3' dinucleotide overhang (5' to 3')	SEQ IDNO:
s	326	GGCACUUGGCAUCUCCCCA	79	GG CACUU GGCAU C U CC CC AHI I	359
as	344	UGGGGAGAUGCCAAGUGCC	80	UGGGGAGAUGCCAAGUGCCIJN	360
s	333	GGCAUCUCCCCAUUCCAUG	81	GGCAUCUCCCCAUUCCAUG13N	361
as	3.51	AUGGAAUGGGGAGAUGCCTT	82	AUGGAAUGGGGAGAUGCCTTIJI1	362
s	334	GCAUCUCCCCAUUCCAUGA	83	GCAUCUCCCCAUUCCAUGAMN	363
as	352	UCAUGGAAUGGGGAGAUGC	84	UCAUGGAAUGGGGAGAUGCNH	364
3	335	CAUCUCCCCAUUCCAUGAG	85	CAUCUCCCCAUUCCAUGAGHN	365
as	353	CUCAUGGAAUGGGGAGAUG	86	CUCAUGGAAUGGGGAGAUGHH	366
s	336	AUCUCCCCAU UCCAUGAGC	87	AU CU CCCCAU UCCA UGAG CHH	367
as	354	GCUCAUGGAAUGGGGAGAU	88	GCUCAUGGAAUGGGGAGAUHN	368
s	338	CUCCCCAUUCCAUGAGCAU	89	CUCCCCAUUCCAUGAGCAUHH	369
as	356	AUGCUCAUGGAAUGGGGAG	90	AUGCUCAUGGAAUGGGGAGHH	370
s	341	CCCAUUCCAUGAGCAUGCA	91	CCCAUUCCAUGAGCAUGCAHN	371
as	359	UGCAUGCUCAUGGAAUGGG	92	UGCAUGCUCAUGGAAUGGGHU	372
3	34 7	CCAUGAGCAUGCAGAGGUG	93	CCAUGAGCAUGCAGAGGUGIJH	37 3
as	365	CACCUCUGCAUGCUCAUGG	94	CACCUCUGCAUGCUCAUGGHH	374
s	352	AGCAUGCAGAGGUGGUAUU	95	AGCAUGCAGAGGUGGOAUUHH	375
as	3.7 0	AAUACCACCUCUGCAUGCU	96	AAUACCACC UC U CC AU GC UN11	376
s	354	CAUGCAGAGGUGGUAUUCA	97	CAUGCAGAGGUGGUAUUCAHll	377
as	372	UGAAUACCACCUCUGCAUG	98	UGAAUACCACCUCUGCAUG1J1I	378
s	355	AUGCAGAGGUGGUAUUCAC	99	AUGCAGAGGUGGUAUUCACNH	379
as	373	GUGAAUACCACCUCUGCAU	100	GUGAAUACCACCUCUGCAUHH	380
s	362	GGUGGUAUUCACAGCCAAC	101	GGUGGUAUUCACAGCCAACNH	381
as	380	GUUGGCUGUGAAUACCACC	102	GUUGGCUGUGAAUACCACCH11	382
s	363	GUGGUAUUCACAGCCAACG	103	GUGGUAUUCACAGCCAACGHH	383
as	381	CGUUGGCUGUGAAUACCAC	104	CGUUGGCUGUGAAUACCACHH	384
s	364	UGGUAUUCACAGCCAACGA	105	UGGUAUUCACAGCCAACGAHH	385
as	382	UCGUUGGCUGUGAAUACCA	106	UCGUUGGCUGUGAAUACCAHH	386
s	365	GGUAUUCACAGCCAACGAC	107	GGUAUUCACAGCCAACGACHll	387
as	383	GUCGUUGGCUGUGAAUACC	108	GUCGUUGGCUGUGAAUACCNH	388
s	366	GUAUUCACAGCCAA CGAC U	109	GUAUUCACAGCCAACGACUHH	389
as	384	AGUCGUUGGCUGUGAAUAC	110	AGUCGOUGGCUGUGAAUACHII	390
s	367	UAUUCACAGCCAACGACUC	111	UAUUCACAGCCAACGACUCHH	391
as	385	GAGUCGUUGGCUGUGAAUA	112	GAGUCGUUGGCUGUGAAOAHII	392
3	370	UCACAGCCAACGACUCCGG	113	UCACAGCCAACGACUCCGGUH	393
as	388	CCGGAGUCGUUGGCUGUGA	114	CCGGAGUCGUUGGCUGUGAHN	394
3	390	CCCCGCCGCUACACCAUUG	115	CCCCGCCGCUACACCAUUGNII	395
as	408	CAAUGGUGUAGCGGCGGGG	116	CAAUGG UGU AGCGG CG GGGHII	396
s	4	GAAGUCCACUCAUUCUUGG	117	GAAG UCCACUCAUUCUUGGHH	397
as	22	CCAAGAAUGAGUGGACUUC	118	CCAAGAAUGAGUGGACUUCHH	398
s	412	CCCUGCUGAGCCCCUACUC	119	CCCUGCUGAGCCCCUACUCHN	399
as	430	GAGUAGGGGCUCAGCAGGG	120	GAGUAGGGGC UCAGCAGGGHll	400
s	417	CUGAGCCCCUACUCCUAOU	121	CUGAGCCCCUACUCCUAUUHN	401
as	435	AAUAGGAGOAG GGG CU CAG	122	AA UAGGAGUAGG GGCUCAGHH	402
3	418	UGAGCCCCUACUCCUAUUC	123	UGAGCCCCUACUCCUAUUCHH	403
as	436	GAAUAGGAGUAGGGGCUCA	124	GAAUAGGAGUAGGGGCUCANH	404
s	422	CCCCUACUCCUAUUCCACC	125	CCCCUACUCCIJAUUCCACC1111	405
as	440	GGUGGAAUAGGAGUAGGGG	126	GGUGGAAUAGGAGUAGGGGHH	406
s	425	CUACUCCUAUUCCACCACG	127	CUACUCCUAUUCCACCACGini	407

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Strand	Position	Sequence(5' to 3' )	SEQ IDNO:	Sequence with 3' dinucleotide overhang (5' to 3')	SEQ IDNO:
as	443	C GUG GU GGAAUAGGAG UAG	128	C G UG G UGGAAUAGGAGUAGHH	408
Ξ	42 6	UACUCCUAUUCCACCACGG	129	UACUCCUAUUCCACCACGGWN	409
as	444	CCGUGGUGGAAUAGGAGUA	130	CCGUGGUGGAAUAGGAGUANN	410
s	427	ACUCCUAUUCCACCACGGC	131	ACUCCUAUUCCACCACGGCII11	411
as	445	GCCGUGGUGGAAUAGGAGU	132	GCCGUGGUGGAAUAGGAGUHN	412
s	429	UCCUAUUCCACCACGGCUG	133	UCCUAUUCCACCACGGCUGIIU	413
as	447	CAGCCGUGGUGGAAUAGGA	134	CAGCCGUGGUGGAAUAGGAUN	414
S	432	UAUU CCACCAC GGCUGUCG	135	UAUU CC AC CAC GGC UG UC GUN	415
as	450	CGACAGCCGUGGUGGAAUA	136	CGACAGCCGUGGUGGAAUAlllI	416
s	433	AUUCCACCACGGCUGUCGU	137	AUUCCACCACGGCUGUCGU!·™	417
as	451	ACGACAGCCGUGGUG.GAAU	138	ACGACAGCCGUGGUGGAAUHH	418
s	437	CACCACGGCUGUCGUCACC	139	CACCACGGCUGUCGUCACCllll	419
as	455	GGUGACGACAGCCGUGGUG	140	GGUGACGACAGCCGUGGUGHN	420
s	438	ACCACGGCUGUCGUCACCA	141	ACCACGGCUGUCGUCACCAHH	421
as	456	UGGUGACGACAGCCGUGGU	142	UGGUGACGACAGCCGUGGU!·™	422
s	439	CCACGGCUGUCGUCACCAA	143	CCACGGCUGUCGUCACCAAHII	423
as	457	UUGGUGACGACAGCCGUGG	144	UUGGUGACGACAGCCGUGG!™	424
s	441	ACGGCUGUCGUCACCAAUC	145	ACGGCUGUCGUCACCAAUCUll	425
as	459	GAUUGGUGACGACAGCCGU	14 6	GAUUGG UGACGACAGCCGUMU	426
s	442	CGGCUGUCGUCACCAAUCC	147	CGGCUGUCGUCACCAAUCCI11I	427
as	460	GGAUUGGUGACGACAGCCG	148	GGAUUGGUGACGACAGCCG!™	428
s	449	CG UCAC CAAUC CCAAG GAA	149	CGUCACCAAUCCCAAGGAAi™	429
as	467	UUCCUUGGGAUUGGUGACG	150	UUCCUUGGGAUUGGUGACG!·™	430
s	455	CAAUCCCAAGGAAUGAGGG	151	CAAUCCCAAGGAAUGAGGG!·™	431
as	473	CCCUCAUUCCUUGGGAUUG	152	CCCUCAUUCCUUGGGAUUGUH	432
s	491	CCUGAAGGACGAGGGAUGE	153	CCUGAAGGACGAGGGAUGG!™	433
as	509	CCAUCCCUCGUCCUUCAGG	154	CCAUCCCUCGUCCUUCAGGim	434
3	497	GGACGAGGGAUGGGAUUUC	155	GGACGAGGGAUGGGAUUUC!·™	435
as	515	GAAAUCCCAUCCCUCGUCC	156	GAAAUCCCAUCCCUCGUCCHll	436
s	5	AAGUCCACUCAUUCUUGGC	157	AAGUCCACUCAUUCUUGGCi™	437
as	23	GCCAAGAAUGAGUGGACUU	158	GCCAAGAAUGAGUGGACUUHN	438
s	508	GGGAUUUCAUGUAACCAAG	159	GG GAU UUCAUGU AACC AAGtlll	439
as	526	CU.UGGUUACAUGAAAUCCC	160	CUUGGUUACAUGAAAUCCCNN	440
s	509	GGAUUUCAUGUAACCAAGA	161	GGAUUUCAUGUAACCAAGAHI!	441
as	527	UCUUGGUUACAUGAAAUCC	162	UCUUGGUUACAUGAAAUCCIffl	442
S	514	UCAUGUAACCAAGAGUAUU	163	UCAUGUAACCAAGAGUAUUHN	44.3
as	532	AAUACUCUUGGUUACAUGA	164	AAUACUC UUGGU UA C AUGA11II	444
s	516	AUGUAACCAAGAGUAUUCC	165	AU GU AACC AAGAGU AU UC CI III	445
as	534	GGAAUACUCUUGGUUACAU	166	GGAAUACUCUUGGUUACAU!·™	446
s	517	UGUAACCAAGAGUAUUCCA	167	UGUAACCAAGAGUAUUCCAIIH	447
as	535	UGGAAUACUCUUGGUUACA	168	UGGAAUACUCUUGGUUACA!·™	448
s	518	GUAACCAAGAGUAUUCCAU	169	GUAACCAAGAGUAUUCCAUllll	449
as	536	AUGGAAUACUCUUGGUUAC	170	AUGGAAUACUCUUGGUUACim	450
s	54	UGCCUUGCUGGACUGGUAU	171	UGCCUUGCUGGACUGGUAU!™	451
as	72	AUACCAGUCCAGCAAGGCA	172	AUACCAGUCCAGCAAGGCA!·™	452
S	543	UAAAGCAGUGUUUUCACCU	173	UAAAGCAGUGUUUUCACCUIIU	453
as	561	AGGUGAAAACACUGCUUUA	174	AGGUGAAAACACUGCUUUAi™	454
s	55	GCCUUGCUGGACUGGUAUU	175	GCCUUGCUGGACUGGUAUUllll	455
as	73	AAUACCAGUCCAGCAAGGC	176	AAUACCAGUCCAGCAAGGC!™	456

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Strand	Position	Sequence(5' to 3' )	SEQ IDNO:	Sequence with 3' dinucleotide overhang (5' to 3')	SEQ IDNO:
s	551	UGUU UUCACCUCAUAUGC U	177	UGUU U UCACCUCAUAU GC UHH	457
as	569	AGCAUAUGAGGUGAAAACA	178	AG CAUAUGAGGU GAAAAC AHN	458
s	552	GUUUUCACCUCAUAUGCUA	179	GUUUUCACCUCAUAUGCUAHN	459
as	57 0	UAGCAUAUGAGGUGAAAAC	180	UAGCAUAUGAGGUGAAAACHH	460
s	553	UUUUCACCUCAUAUGCUAU	181	UUUUCACCUCAUAUGCUAUHN	461
as	571	AUAGCAUAUGAGGUGAAAA	182	AUAGCAUAUGAGGUGAAAAHH	462
3	555	UUCACCUCAUAUGCUAUGU	183	UUCACCUCAUAUGCUAUGUHN	463
as	573	ACAUAGCAUA U GAG GU GAA	184	AC AUAGCAUAUG AG GU G AA1IH	464
s	557	CACCUCAUAUGCUAUGUVA	185	CACCUCAUAUGCUAUGUUAHII	465
as	575	UAACAUAGCAUAUGAGGUG	186	UAACAUAGCAUAUGAGGUGHN	466
s	56	CCUUGCUGGACUGGUAUUU	187	CCUUGCUGGACUGGUAUUUHH	467
as	74	AAAUACCAGUCCAGCAAGG	138	AAAUACCAGUCCAGCAAGGHH	468
s	563	AUAUGCUAUGUUAGAAGUC	189	auaugcoanguuagaagocnn	469
as	581	GACUUCUAACAUAGCAUAU	190	GACUUCUAACAUAGCAUAUHll	470
3	564	UAUGCUAUGUUAGAAGUCC	191	UAUGCUAUGUUAGAAGUCCHH	471
as	582	GGACUUCUAACAUAGCAUA	192	GG AC U UC UAAC AUAGC AUAI1II	472
s	566	UGCUAUGUUAGAAGUCCAG	193	UGCUAUGUUAGAAGUCCAGHH	473
as	584	CUGGACUUCUAACAUAGCA	194	C U GGACU UC UAACAUAGC AH11	474
s	57	CUUGCUGGACUGGUAUUUG	195	CUUGCUGGACUGGUAUUUGHll	475
as	75	CAAAUACCAGUCCAGCAAG	196	CAAAUACCAGUCCAGCAAGH1I	476
s	578	AGUCCAGGCAGAGACAAUA	197	AGUCCAGGCAGAGACAAUAHH	477
as	596	AUUGUCUCUGCCUGGACUTT	198	AUUGUCUCUGCCUGGACUTT Nil	4 78
s	580	UCCAGG C AGAGACAAU AAA	199	UCCAGG C AG AGACAAU AAAHTI	479
as	598	UUUAUUGUCUCUGCCUGGA	200	UUUAUUGUCUCUGCCUGGAHll	480
s	607	GUGAAAGGCACUUUUCAUU	201	GU GAAAGGC ACU UU UC AU UHH	481
as	625	AAUGAAAAGUGCCUUUCAC	202	AAUGAAAAGUGCCUUUCACHll	482
s	62	UGGACUGGOAUUUGUGUCU	203	UGGACUGGUAUUUGUGUCUtlll	483
as	80	AGACACAAAUACCAGUCCA	204	AGACACAAAUACCAGUCCAKH	484
s	77	GUCUGAGGCUGGCCCUACG	205	GUCUGAGGCUGGCCCUACGHll	485
as	95	CGUAGGGCCAGCCUCAGAC	206	CGUAGGGCCAGCCUCAGACHH	486
s	79	CUGAGGCUGGCCCUACGGG	207	CUGAGGCUGGCCCUACGGGHH	487
as	97	CCCGUAGGGCCAGCCUCAG	208	CCCGUAGGGCCAGCCUCAGMIl	488
s	81	GAGGCUGGCCCUACGGGCA	209	GAGGCUGGCCCUACGGGCAUH	489
as	99	UGCCCGUAGGGCCAGCCUC	210	UGCCCGUAGGGCCAGCCUCTH	490
3	82	AGGCUGGCCCUACGGGCAC	211	AGGCUGGCCCUACGGGCACHH	491
as	100	GUGCCCGUAGGGCCAGCCU	212	GUGCCCGUAGGGC.CAGCCU1IN	492
3	84	GCUGGCCCUACGGGCACCG	213	GCUGGCCCUACGGGCACCGNII	493
as	102	CGGU GCCC G UAGGG CCAG C	214	CG GUGC CCGU AGGGCC AG Cl III	4 94
s	85	CUGGCCCUACGGGCACCGG	215	CUGGCCCUACGGGCACCGGHII	495
as	103	CCGGUGCCCGUAGGGCCAG	216	CCGGUGCCCGUAGGGCCAGHH	496
S	87	GGCCCUACGGGCACCGGUG	217	GGCCCUACGGGCACCGGUGHH	497
as	105	CACCGGUGCCCGUAGGGCC	218	CACCGGUGCCCGUAGGGCCH11	498
s	9	CCACUCAUUCUUGGCAGGA	219	CCACUCAUUCUUGGCAGGAHII	499
as	27	UCCUGCCAAGAAUGAGUGG	220	UCCU GC CAAG AA UGAG UG GH II	500
3	90	CC UACG GGCAC CGG UGAAU	221	CCUACGGGCACCGGUGAAUim	501
as	108	AUUCACCGGUGCCCGUAGG	222	AUUCACCGGUGCCCGUAGGHH	502
s	91	CUACGGGCACCGGUGAAOC	223	CUACGGGCACCGGUGAAUCHH	503
as	109	GAUUCACCGGUGCCCGUAG	224	GAUUCACCGGUGCCCGUAGHH	504
s	92	UACGGGCACCGGUGAAUCC	225	UACGGGCACCGGUGAADCCHH	505

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Strand	Position	Sequence (5' to 3' )	SEQ IDNO:	Sequence with 3' dinucleotide overhang (5' to 3')	SEQ IDNO:
as	110	GGAU UCAC CGGUGC CC GU A	226	GG AU UC AC C GGU GC CC GU Aim	506
s	93	ACGG GCAC CGG UGAAUCCA	227	AC GGGC AC CGGU GAAUCC ANN	507
as	111	UGGAUUCACCGGUGCCCGU	228	UGGAUUCACCGGUGCCCGUNN	508
s	97	GCACCGGUGAAUCCAAGUG	223	GCACCGGUGAAUCCAAGUGim	509
as	115	CACUUGGAUUCACCGGUGC	230	CACUUGGAUUCACCGGUGCNN	510
s	98	CACCGGUGAAUCCAAGUGU	231	CA CC GG UGAAUCCAAGUGUim	511
as	116	ACACUUGGAUUCACCGGUG	232	ACACUOGGAUUCACCGGUGHN	512
s	167	UGUGGCCAUGCAUGUGUUC	233	UGUGGCCAUGCAUGUGUUCim	513
as	185	GAACACAUGCAUGGCCACA	234	GAACACAUGCAUGGCCACAim	514
s	168	GUGGCCAUGCAUGUGUUCA	235	GUGGCCAUGCAUGUGUUCAHN	515
as	186	UGAACACAUGCAUGGCCAC	236	UGAACACAUGCAUGGCCACHII	516
s	171	GCCAUGCAOGUGUUCAGAA	237	GCCAUGCAUGUGUUCAGAAllH	517
as	189	UUCUGAACACAUGCAUGGC	238	UU CUGAACACAUGCAtfGGCMN	518
s	432	UAUUCCACCACGGCUGUCA	239	UAUUCCACCACGGCUGUCAim	519
as	44 9	UGACAGCC GUGGUGGAAUA	240	UGACAGCCGUGGUGGAAUAI-m	520
s	447	GUCAUCACCAAUCCCAAGG	241	GUCAUCACCAAUCCCAAGGI-m	521
as	465	CCUUGGGAUUGGUGAUGAC	242	CCUUGGGAUUGGUGAUGACWH	522
s	115	GUCCUCUGAUGGUCAAAGU	243	GUCCUCUGAUGGUCAAAGUHH	523
as	133	ACUUUGACCAUCAGAGGAC	244	ACUUUGACCAUCAGAGGACHll	524
s	122	GAUGGUCAAAGUUCUAGAU	245	GAUGGUCAAAGUUCUAGAUim	525
as	140	AUCUAGAACUOUGACCAUC	246	AUCUAGAACUUUGACCAUCNH	526
s	139	AUGCUGUCCGAGGCAGUCC	247	AUGCUGUCCGAGGCAGUCCI1H	527
as	157	GGACUGCCUCGGACAGCAU	248	GGACUGCCUCGGACAGCAUlffl	528
s	172	CCGUGCAUGUGUUCAGAAA	249	CCGUGCAUGUGUUCAGAAAim	529
as	190	UUUCUGAACACAUGCACGG	250	UUUCUGAACACAUGCACGG1I1I	530
s	238	AGUCUGGAGAGCOGCAUGG	251	AGUCUGGAGAGCUGCAUGGUH	531
as	256	CCAUGCAGC.UCUCCAGACU	252	CCAUGCAGCUCUCCAGACUHH	532
5	252	CAUGGGCUCACAACUGAGG	253-	CAUGGGCUCACAACUGAGGim	533
as	270	CCUCAGUUGUGAGCCCAUG	254	CCUCAGUUGUGAGCCCAUGim	534
3	33	UCUCAUCGUCUGCUCCUCC	255	UCUCAUCGUCUGCUCCUCCim	535
as	51	GGAG GAGCAGACGAUGAGA	256	GGAGGAGCAGACGAUGAGAHH	536
s	340	CCCCAUUCCAUGAGCAUGC	257	CCCCAUUCCAUGAGCAUGCtm	537
as	358	GCAUGCUCAUGGAAUGGGG	258	GCAUGC UCAUGGAAUGGGGim	538
s	421	GCCCCUACUCCUAUUCCAC	25 9	GCCCCUACUCCUAUUCCACMll	539
as	439	GUGGAAOAGGAGUAGGGGC	260	GUGGAAUAGGAGUAGGGGCHH	540
S	431	CUAUUCCACCACGGCOGUC	261	CUAUUCCACCACGGCUGUCHN	541
as	449	GACAGCCGUGGUGGAAUAG	262	GACAGCCGUG.GUGGAAUAGM1I	542
s	440	CACGGCUGUCGUCACCAAU	263	CACG GC UGU C GUCACC AAUtlll	543
as	458'	AUUGGUGACGACAGCCGUG	264	AUUGGUGACGACAGCCGUGim	544
s	496	AGGACGAGGGAUGGGAUU U	265	AGGACGAGGGAUGGGAUUUNH	545
as	514	AAAUCCCAUCCCUCGUCCU	266	AAAOCCCAUCCCUCGOCCUHN	54 6
s	556	UCACCUCAUAUGCUAUGUU	267	UCACCUCAUAUGCUAUGUUUll	547
as	574	AACA UAGCAUAUGAGG UGA	268	AACAUAGCAUAUGAGGUGAtm	548
S	559	CC UCAUAUGC UAUG UUAGA	269	CCUCAUAUGCUAUGUUAGAim	549
as	577	UCUAACAUAGCAUAUGAGG	270	UCUAACAUAGCAUAUGAGGHU	550
S	570	AU GU UAGAAG UCCAGGCAG	271	AUGUUAGAAGUCCAGGCAGlffl	551
as	588	CUGCCUGGACUUCUAACAU	27 2	CUGCCUGGACUUCUAACAUim	552
s	78	UCUGAGGCUGGCCCUACGG	273	UCUGAGGCUGGCCCUACGGHH	553
as	96	CCGUAGGGCCAGCCUCAGA	274	CCGUAGGGCCAGCCUCAGAHll	554

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Strand	Position	Sequence (5' to 3' )	SEQ IDNO:	Sequence with 3' dinucleotide overhang (5' to 3')	SEQ IDNO:
s	87	GGCCCUACGGGCACCGGOG	275	GG CC C U AC G GG C AC CG G U Gil 11	555
as	105	CACCGGUGCCCGUAGGGCC	27 6	CACCGGUGCCCGUAGGGCC1JN	556
s	95	GGGCACCGGUGAAUCCAAG	277	GGGCACCGGUGAAUCCAAGlllI	557
as	113	CUUGGAUUCACCGGUGCCC	278.	CUUGGAUUCACCGGUGCCCHH	558
s	167	CCAUGCAUGUGUUCAGAAA	27 9	CCAUGCAUGUGUUCAGAAAllN	559
as	185	UUUCUGAACACAUGCAUGG	280	UUUCUGAACACAUGCAUGGMU	560

Table 3B. Sense and antisense strand sequences of human TTR dsRNAs

Strand: s= sense; as= antisense; Position: position of 5' base on transcript (NM_000371.2, SEQ ID NO: 1329)

Strand	Position	Sequence with 3'deoxythimidine overhang (5' to 3')	SEQ ID NO:
3	100	CCGGUGAAUCCAAGUGUCCdTdT	561
as	118	GGACACUUG GAUUCAC C GGdT dT	562
s	11	AC UCAUU CUUGGCAGGAUGdT dT	563
aS	29	CAUCCUGCCAAGAAUGAGUdTdT	564
s	111	AAGUGUCCUCUGAUGGUCAdTdT	565
as	129	UGACCAUCAGAGGACACUUdTdT	566
s	13	UCA UUCUUGGCAGGAUGGC dT dT	567
as	31	GCCAUCCUGCCAAGAAUGAdTdT	568
s	130	AAGUUCUAGAUGCUGUCCGdTdT	569
as	148·	CGGACAGCAUCUAGAACUUdTdT	570
s	132	GUUCUAGAUGCUGUCCGAGdTdT	571
as	150	CUCGGACAGCAUCUAGAACdTdT	572
s	135	CUAGAUGCUGUCCGAGGCAdTdT	573
as	153	UGCCUCGGACAGCAUCUAGdTdT	574
s	138	GAUGCUGUCCGAGGCAGUCdTdT	575
as	156	GACUGCCUCGGACAGCAUCdTdT	576
s	14	CAUUCUUGGCAGGAUGGCUdTdT	577
as	32	AGCCAUCCUGCCAAGAAUGdTdT	578
s	140	UGCUGUCCGAGGCAGUCCUdTdT	57 9
as	158	AGGACUGCCUCGGACAGCAdTdT	580
s	146	CCGAGGCAGUCCUGCCAUCdTdT	581
as	164	GAUGGCAGGACUGCCUCGGdTdT	582
s	152	CAGUCCUGCCAUCAAUGUGdTdT	583
as	170	CACAUUGAUGGCAGGACUGdTdT	584
s	164	CAAUGUGGCCGUGCAUGUGdTdT	585
as	182	CACAUGCAC GGCCACAU UGdT dT	586
s	178	AUGUG UUCAGAAAGGCU GCdTdT	587
as	196	GCAGCCUUUCUGAACACAUdTdT	588
s	2	CAGAAGUCCACUCAUUCUUdTdT	589
as	20	AAGAAUGAGUGGACUUCUGdTdT	590
s	21	GGCAGGAUGGCUUCUCAUCdTdT	591
as	39	GAUGAGAAGCCAUCCUGCCdTdT	592
s	210	GAGCCAUUUGCCUCUGGGAdTdT	593
as	22 8	U C CCAGAGGCAAAU G GC UC dT dT	594
5	23	CAGGAUGGCUUCUCAUCGUdTdT	595
as	41	ACGAUGAGAAGCCAUCCUGdTdT	596
s	24	AGGAUGGCUUCUCAUCGUCdTdT	597
as	42	GACGAUGAGAAGCCAUCCUdTdT	598
s	245	AGAGCUGCAUGGGCUCACAdTdT	599
as	263	UGUGAGCCCAUGCAGCUCUdTdT	600
Ξ	248	GCUGCAUGGGCUCACAACUdTdT	601

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Strand	Position	Sequence with 3'deoxythimidine overhang (5' to 3')	SEQ ID NO:
as	266	AGUUGUGAGCCCAUGCAGCdTdT	602
s	25	GGAUGGCUUCUCAUCGUCUdTdT	603
as	43	AGACGAUGAGAAGCCAUCCdTdT	604
s	251	GCAUGGGCUCACAACUGAGdTdT	605
as	269	CUCAGUUGUGAGCCCAUGCdTdT	606
s	253	AUGGGCUCACAACUGAGGAdTdT	607
as	271	UCCUCAGUUGlIGAGCCCAUdTdT	608
s	254	UGGGCtICACAACUGAGGAGdTdT	609
as	272	CUCCUCAGUUGUGAGCCCAdTdT	610
3	270	GAGGAAU U UG0AGAAGGGAdTdT	611
as	288	UCCCUUCUACAAAUUCCUCdTdT	612
s	276	UUUGUAGAAGGGAUAUACAdTdT	613
as	294	UGUAUAUCCCUUCUACAAAdTdT	614
s	277	OUGUAGAAGGGAUAUACAAdTdT	615
as	295	UUGUAOAUCCCUUCUACAAdTdT	616
8	278	UGUAGAAGGGAUAUACAAAdTdT	617
as	296	UUUGUAOAUCCCUUCUACAdTdT	618
s	281	AGAAGGGAUAUACAAAGUGdTdT	619
as	299	CACUUUGUAUAOCCCUUCUdTdT	620
s	295	AAGUGGAAAUAGACAC.CAAdTdT	621
as	313	UUGGOGUCOAOUUCCACUUdTdT	622
s	299	GGAAAUAGACACCAAAUCUdTdT	623
as	317	AGAUOUGGUGOCUAUUUCCdTdT	624
s	300	GAAAUAGACACCAAAUCUUdTdT	625
as	318	AAGAUUUGGOGUCUAUOUCdTdT	62 6
s	303	AUAGACACCAAAUCOUACUdTdT	627
as	321	AGUAAGAOUUGGUGUCUAUdTdT	628
8	304	(JAGACACCAAAUCUUACUGdTdT	62 9
as	322	CAGtlAAGAUDUGGUGUCUAdTdT	630
s	305	AGACACCAAAUCUUACOGGdTdT	631
as	323	CCAGUAAGAUUUGGUGUCUdTdT	632
s	317	UUACUGGAAGGCACUUGGCdTdT	633
as	335	GCCAAGUGCCUUCCAGUAAdTdT	634
8	32	UUCUCAUCGUCUGCUCCUCdTdT	635
as	50	GAGGAGCAGACGAOGAGAAdTdT	636
s	322	GGAAGGCACUUGGCAUCUCdTdT	637
as	340	GAGAUGCCAAGUGCCUUCCdTdT	638
s	326	GGCACUUGGCAUCUCCCCAdTdT	639
as	34 4	UGGGGAGAUGCGAAGUGCCdTdT	640
3	333	GGCAUCUCCCCAUUCCAUGdTdT	641
as	351	AUGGAAOGGGGAGAUGCCTTdTdT	642
s	334	GCAUCUCCCCAUUCCAUGAdTdT	643
as	352	UCAUGGAAUGGGGAGAUGCdTdT	644
s	335	CAUCUCCCCAUOCCAUGAGdTdT	645
as	353	CUCAUGGAAUGGGGAGAUGdTdT	64 6
8	336	AUCUCCCCAOTJCCAUGAGCdTdT	647
as	354	GCUCAUGGAAUGGGGAGAUdTdT	648
s	338	CUCCCCAUUCCAUGAGCAOdTdT	649
as	356	AUGCUCAUGGAAUGGGGAGdTdT	650
8	341	CCCAUOCCAUGAGCAUGCAdTdT	651
as	359	UGCAUGCUCAOGGAAUGGGdTdT	652
3	347	CCAUGAGCAUGCAGAGGUGdTdT	653
as	365	CACCUCOGCAUGCUCAUGGdTdT	654
s	352	AGCAUGCAGAGGUGGUAUUdTdT	655
as	370	AAUACCACCUCUGCAUGCUdTdT	656
3	354	CAUGCAGAGGUGGUAUUCAdTdT	657
as	372	UGAAU AC CACCUC OGCA OG dT dT	658

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Strand	Position	Sequence with 3'deoxythimidine overhang (5' to 3')	SEQ ID NO:
s	355	AUGCAGAGGUGGUAUUCACdTdT	659
as	373	GUGAADACCACCUCUGCAUdTdT	660
s	362	GGUGGUAUUCACAGCCAACdTdT	661
as	380	GUUGGCOGUGAAUACCACCdTdT	662
s	363	GUGGUAUUCACAGCCAACGdTdT	663
as	381	CGUUGGCUGUGAAUACCACdTdT	664
s	364	UGGUAUUCACAGCCAACGAdTdT	665
as	382	UCGUUGGCUGUGAAUACCAdTdT	666
s	365	GGUAUUCACAGCCAACGACdTdT	667
as	383	GUCGUUGGCGGUGAAUACCdTdT	668
s	366	GUAUUCACAGCCAACGACUdTdT	669
as	384	AGUCGUUGGCUGUGAAUACdTdT	670
3	367	UAUUCACAGCCAACGACUCdTdT	671
as	385	GAGUCGUUGGCUGDGAAUAdTdT	672
s	370	UCACAGCCAACGACUCCGGdTdT	67'3
as	388	CCGGAGUCGUUGGCGGUGAdTdT	674
s	390	CCCCGCCGCUACACCAUUGdTdT	675
as	408	CAAUGGUGUAGCGGCGGGGdTdT	676
s	4	GAAGU CCACUCAUUCUUGGdTdT	677
as	22	CCAAGAAOGAGUGGACUUCdTdT	678
s	412	CCCUGOTGAGCCCCUACUCdTdT	679
as	430.	GAGUAGGGGCUCAGCAGGGdTdT	680
s	417	CUGAGCCCCUACUCCUAUUdTdT	681
as	435	AAUAGGAGUAGGGGCUCAGdTdT	682
s	418	UGAGCCCCUACUCCUAUUCdTdT	683
as	436	GAAOAGGAGUAGGGGCUCAdTdT	684
s	422	CCCCUACUCCUAUUCCACCdTdT	685
as	440	GGUGGAAOAGGAGUAGGGGdTdT	686
s	425	CUACUCCUAQUCCACCACGdTdT	687
as	443	CGUGGUGGAAUAGGAGUAGdTdT	688
s	426	UACUCCUAUUCCACCACGGdTdT	689
as	444	CCGUGGUGGAAUAGGAGUAdTdT	690
s	427	ACUCCUAOUCCACCACGGCdTdT	691
as	445	GC CGU GG UGGAAU AGGA GUdT dT	692
s	429	UCCUAUUCCACCACGGCUGdTdT	693
as	447	CAGCCGBGGUGGAAUAGGAdTdT	694
s	432	UAUUCCACCACGGCUGUCGdTdT	695
as	450	CGACAGCCGUGGUGGAAUAdTdT	696
s	433	AUUCCACCACGGCOGUCGUdTdT	697
as	451	ACGACAGCCGUGGUGGAAUdTdT	698
s	437	CACGACGGCOGUCGUCACCdTdT	699
as	455	GGOGACGACAGCCGUGGUGdTdT	700
s	438	ACCACGGCUGUCGUCACCAdTdT	701
as	456	UGGOGACGACAGCCGUGGBdTdT	702
s	439	CCACGGCOGUCGUCACCAAdTdT	703
as	457	UUGGUGACGACAGCCGUGGdTdT	704
s	441	ACGGCUGOCGOCACCAAUCdTdT	705
as	459	GAUUGGUGACGACAGCCGUdTdT	706
s	442	CGGCUGUCGUCACCAAUCCdTdT	707
as	460	GGAOUGGUGACGACAGCCGdTdT	708
s	449	CGUCACCAAUCCCAAGGAAdTdT	709
as	467	UUCCOUGGGAUUGGUGACGdTdT	710
s	455	CAAUCCCAAGGAAUGAGGGdTdT	711
as	473	CCCUCAUUCCUUGGGAUUGdTdT	712
s	491	CCOGAAGGACGAGGGAUGGdTdT	713
as	509	CCAUCCCHCGUCCUUCAGGdTdT	714
s	497	GGACGAGGGAUGGGAUUUCdTdT	715

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Strand	Position	Sequence with 3'deoxythimidine overhang (5' to 3')	SEQ ID NO:
as	515	GAAAUCCCAUCCCUCGUCCdTdT	716
s	5	AAGUCCACUCAUUCUUGGCdTdT	717
as	23	GCCAAGAAUGAGUGGACUUdTdT	718
s	508	GGGAU UU CAUGUAAC CAAG dT dT	719
as	526	CUUGGUUACAUGAAAUCCCdTdT	720
s	509	GGAUUUCAUGUAACCAAGAdTdT	721
as	527	UC UUGGU UACAUGAAAU CC dTdT	722
s	514	UCAUGUAACCAAGAGUAUUdTdT	723
as	532	AAUACUCUUGGUUACAUGAdTdT	724
3	516	AUG UAAC CAAGAG UAUUCC dT dT	725
as	534	GGAAUACUCUUGGUUACAUdTdT	726
s	517	UGUAACCAAGAGUAUUCCAdTdT	727
as	535	UGGAAUACUCUUGGUUACAHTdT	728
s	518	GUAACCAAGAGUAUUCCAUdTdT	729
as	536	AUGGAAUACUCUUGGUUACdTdT	730
8	54	UGCCUUGCUGGACUGGUAUdTdT	731
as	72	AUACCAGUCCAGCAAGGCAdTdT	7 32
s	543	UAAAGCAGUGUUUUCACCUdTdT	733
as	561	AGGUGAAAACACUGCUUUAdTdT	734
s	55	GCCUUGCUGGACUGGUAUUdTdT	735
as	73	AAUACCAGUCCAGCAAGGCdTdT	736
s	551	UGUUUUCACCUCAUAUGCUdTdT	737
as	569	AGCAUAUGAGGUGAAAACAdTdT	738
s	552	GUUUUCACCUCAUAUGCUAdTdT	739
as	570	UAGC AUAUG AGG UG AAAAC dT dT	740
s	553	UUUUCACCUCAUAUGCUAUdTdT	741
as	.571	AUAGCAUAUGAGGUGAAAAdTdT	742
8	555	UUCACCUCAUAUGCUAUGUdTdT	743
as	573	ACAUAGCAUAUGAGGUGAAdTdT	7 44
s	557	CACCUCAUAUGCUAUGUUAdTdT	745
as	575	UAAC AUAGC AUAUG AGG UG dTdT	746
s	56	CCUUGCUGGACUGGUAUUUdTdT	747
as	74	AAAUACCAGUCCAGCAAGGdTdT	748
8	563	AUAUG CUAUG U UAGAAG UC dT dT	749
as	581	GACUUCUAACAUAGCAUAUdTdT	750
s	564	UAUGCUAUGUUAGAAGUCCdTdT	751
as	582	GGACUUCUAACAUAGCAUAdTdT	752
s	5.66	UGCUAUGUUAGAAGUCCAGdTdT	753
as	584	CUGGACUUCUAACAUAGCAdTdT	754
3	57	CUUGCUGGACUGGUAUUUGdTdT	755
as	75	CAAAUACCAGUCCAGCAAGdTdT	756
s	57 8	AGUCCAGGCAGAGACAAUAdTdT	757
as	596	AUUGUCUCUGCCUGGACUTTdTdT	758
s	580	UCCAGGCAGAGACAAUAAAdTdT	759
as	598	UUUAUUGUCUCUGCCUGGAdTdT	760
8	607	GUGAAAGGCACU U UUCAUUdTdT	761
as	625	AAUGAAAAGUGCCUUUCACdTdT	762
s	62	UGGACUGGUAUUUGUGUCUdTdT	763
as	80	AGACACAAAUACCAGUCCAdTdT	764
8	77	GUCUGAGGCUGGCCCUACGdTdT	765
as	95	CGUAGGGCCAGCCUCAGACdTdT	766
3	79	CUGAGGCUGGCCCUACGGGdTdT	767
as	97	CCCGUAGGGCCAGCCUCAGdTdT	768
s	81	GAGGCUGGCCCUACGGGCAdTdT	769
as	99	UGCCCGUAGGGCCAGCCUCdTdT	770
3	82	AGGCUGGCCCUACGGGCACdTdT	771
as	100	GUGCC CG UAGGGCCAGC CUdT dT	7 72

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Strand	Position	Sequence with 3'deoxythimidine overhang (5' to 3')	SEQ ID NO:
s	84	GCUGGCCCUACGGGCACCGdTdT	7 73
as	102	CGGUGCCCGUAGGGCCAGCdTdT	774
S	85	CUGGCCCUACGGGCACCGGdTdT	775
as	103	CCGGUGCCCGUAGGGCCAGdTdT	776
s	87	GGGCCUACGGGCACCGGUGdTdT	777
as	105	CACCGGUGCCCGUAGGGCCdTdT	778
s	9	CCACUCAUUCUUGGCAGGAdTdT	779
as	27	UCCUGCCAAGAAUGAGUGGdTdT	780
s	90	CCUACGGGCACCGGUGAAUdTdT	781
as	108	AUUCACCGGUGCCCGUAGGdTdT	782
Ξ	91	CUACGGGCACCGGDGAAUCdTdT	783-
as	109	GAUUCACCGGUGCCCGUAGdTdT	784
3	92	UACGGGCACCGGUGAAUCCdTdT	785
as	110	GGAUUCACCGGUGCCCGUAdTdT	786
s	93	ACGGGCACCGGUGAAUCCAdTdT	787
as	111	UGGAUUCACCGGUGCCCGUdTdT	788
s	97	GCACCGGUGAAUCCAAGUGdTdT	789
as	115	CACUUGGAUUCACCGGUGCdTdT	790
s	98	CACCGGUGAAUCCAAGUGUdTdT	791
as	lie-	ACACUUGGAUUCACCGGUGdTdT	792
s	167	UGUGGCCAUGCAUGUGUUCdTdT	793
as	185	GAACACAUGCAUGGCCACAdTdT	794
s	168	GUGGCCAUGCAUGUGUUCAdTdT	795
as	136	OGAACACAUGCAUGGCCACdTdT	796
s	171	GCCAUGCAUGUGUUCAGAAdTdT	797
as	189	UUCUGAACACAUGCAUGGCdTdT	798
s	432	UAUUCCACCACGGCUGUCAdTdT	799
as	449	UGACAGC C GU GG UGGAAUAdTdT	800
s	447	GUCAUGACCAAUCCCAAGGdTdT	801
as	465	CCUUGGGAUUGGUGAUGACdTdT	802
s	115	GUCCUCUGAUGGUCAAAGUdTdT	803
as	133	ACUUUGACCAUCAGAGGACdTdT	804
s	122	GAUGGUCAAAGUUCUAGAUdTdT	805
as	140	AUG UAGAAC U UUGACCAUC dT dT	806
s	139	AUGCOGUCCGAGGCAGUCCdTdT	807
as	157	GGACUGCCUCGGACAGCAUdTdT	808
s	172	CCGUGCAUGUGUUCAGAAAdTdT	809
as	190	UUUCUGAACACAUGCACGGdTdT	810
s	238.	AGUCUGGAGAGCUGCAUGGdTdT	811
as	256	CCAUGCAGCUCUCCAGACUdTdT	812
s	252	CAUGGGCUCACAACUGAGGdTdT	813
as	270	CCUCAGUUGUGAGCCCAUGdTdT	814
s	33	UCUCAUCGUCUGCUCCUCCdTdT	815
as	51	GGAGGAGCAGACGAUGAGAdTdT	816
s	340	CCCCAUUCCAUGAGCAUGCdTdT	817
as	358	GCAUGCUCAUGGAAUGGGGdTdT	818
s	421	GCCCCUACUCCUAUUCCACdTdT	819
as	439	GUGGAAUAGGAGUAGGGGCdTdT	820
s	431	CUAUUCCACCACGGCUGUCdTdT	821
as	449	GACAGCCGUGGOGGAAUAGdTdT	822
s	440	CACGGCUGUCGUCACCAAUdTdT	823
as	458	AUUGGUGACGACAGCCGUGdTdT	824
s	496	AGGACGAGGGAUGGGAUUUdTdT	825
as	514	AAAUCCCAUCCCUCGUCCUdTdT	82 6
s	556	UCACCUCAUAUGCUAUGUUdTdT	827
as	574	AACAUAGCAUAUGAGGUGAdTdT	828
s	559	CC UCA UAUGCU AUG U U AGAdT dT	829

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Strand	Position	Sequence with 3'deoxythimidine overhang (5' to 3')	SEQ ID NO:
as	57 7	UC UAACAUAGC AUAUGAGG dT dT	830
s	570	AUGUUAGAAGUCCAGGCAGdTdT	831
as	588	CUGCCUGGACUUCUAACAUdTdT	832
s	78	UCUGAGGCUGGCCCUACGGdTdT	833
as	96	CCGUAGGGCCAGCCUCAGAdTdT	834
s	87	GGCCCUACGGGCACCGGUGdTdT	835
as	105	CACCGGUGCCCGUAGGGCCdTdT	836
s	95	GGGCACCGGUGAAUGCAAGdTdT	837
as	113	CUUGGAUUCACCGGUGCCCdTdT	838
3	167	CCAUGCAUGUGU UCAGAAAdT dT	839
as	185	UUUCOGAACACAUGCAUGGdTdT	840

Table 4. -Chemically modified sense and antisense strand sequences of human TTR dsRNAs

See Table 2 for duplex #. Strand: s= sense; as= antisense; Position: position of 5' base on transcript (NM_000371.2, SEQ ID NO: 1329)

Strand	Oligo #	Position	Sequence (5' to 3')	SEQ ID NO:
s	A-32153	100	ccGGuGAAuccAAGuGuccdTdT	841
as	A-32154	118	GGAcACUUGGAUUcACCGGdTdT	842
s	A-32155	11	AcucAu u cu u G G cAG GAuGdT d T	843
as	A-32156	29	cAUCCUGCcAAGAAUGAGUdTdT	844
s	A-32157	111	AAGuGuccucuGAuGGucAdTdT	845
as	A-3215S	129	UGACcAUcAGAGGAcACUUdTdT	846
s	A-32163	13	ucAuucuuGGcAGGAuGGcdTdT	847
as	A-32164	31	GCcAUCCUGCcAAGAAUGAdTdT	848
s	A-32165	130	AAGuucuAGAuGcuGuccGdTdT	849
as	A-3216S	148	CGGAcAGcAUCuAGAACUUdTdT	850
s	A-32167	132	GuucuAGAuGcuGuccGAGdTdT	851
as	A-32168	150	CUCGGAcAGcAUCuAGAACdTdT	852
s	A-32169	135	cuAGAuGcuGuccGAGGcAdT d T	853
as	A-32170	153	UGCCUCGGAcAGcAUCuAGdTdT	854
s	A-32171	138	GAuGcuGuccGAGGcAGucdTdT	855
as	A-32172	156	GACUGCCUCGGAcAGcAUCdTdT	856
s	A-32175	14	cAuucuuGGcAGGAuGGcudTdl	857
as	A-32176	32	AGCcAUCCUGCcAAGAAUGdTdT	858
s	A-32177	140	uGcuGuccGAGGcAGuccudTdT	859
as	A-32178	158	AGGACUGCCUCGGAcAGcAdTdT	860
s	A-32179	146	ccGAGGcAGuccuGccAucdTdT	861
as	A-32180	164	GAUGGcAGGACUGCCUCGGdTdT	862
s	A-32181	152	CAGUCCUGCCAUCAAUGUGdTdT	863
as	A-32182	170	cAcAUUGAUGG cAGGACUGdTdT	864
s	A-32183	164	cAAu GuG G c cGuG cAu G uGdT dI	865
as	A-32184	182	CAcAUGcAGGGCcAcAUUGdTdT	866
s	A-32187	178	AuGuGuucAGAAAGGcuGcdTdT	867
as	A-32188	196	GcAGCCUUUCUGAAcAcAUdTdT	868
s	A-32189	2	cAGAAGuccAcucAuucuudTdI	869
as	A-32190	20	AAGAAUGAGUGGACUUCUGdTdT	870
s	A-32191	21	GG cAGGAu GGcuucucAucdTdT	871
as	A-32192	39	GAUGAGAAGCcAUCCUGCCdTdT	872
s	A-32193	210	GAGccAuuuGccucuGGGAdTdT	873
as	A-32194	228	UCCcAGAGGcAAAUGGCUCdTdT	874
s	A-32195	23	cAGGAuGGcuucucAucGudTdT	875
as	A-32196	41	ACGAUGAGAAGCcAUCCUGdTdT	876

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Strand	Oligo #	Position	Sequence (5' to 3')	SEQ ID NO:
s	A-32199	24	AGGAuGGcuucucAucGucdTdT	877
as	A-32200	42	GACGAUGAGAAGCcAUCCUdTdT	878
s	A-32201	245	AG AG C uG C AuGG G C UC Ac AdT cl T	879
as	A-32202	263	UGUGAGCCcAUGcAGCUCUdTdT	880
s	A-32203	248	GcuGcAuGGGcucAcAAcudTdT	881
as	A-32204	266	AGUUGUGAGCCcAUGcAGCdTdT	882
s	A-32205	25	GGAuGGcuucucAucGucudTdT	883
as	A-32206	43	AGACGAUGAGAAGCcAUCCdTdT	884
s	A-32207	251	GcAuGGGcucAcAAcuGAGdTdT	885
as	A-32208	269	CUcAGUUGUGAGCCcAUGCdTdT	886
s	A-32211	253	AuGGGcucAcAAcuGAGGAdTdT	887
as	A-32212	271	UCCUcAGUUGUGAGCCcAUdTdT	888
s	A-32213	254	uGGGcucAcAAcuGAGGAGdTdT	889
as	A-32214	272	CUCCUcAGUUGUGAGCCcAdTdT	890
s	A-32215	270	G AGG AA UU u Gu AG AAG G G AdT d T	891
as	A-32216	288	UCCCUUCuAqAAAUUCCUCdTdT	892
s	A-32217	276	UuuGuAGAAGG GAu AuAcAdTd T	893
as	A-32218	294	UGuAuAUCCCUUCuAcAAAdTdT	894
s	A-32219	277	uuGuAGAAGGGAuAuAcAAdTdT	895
as	A-32220	295	UUGuAuAUCCCUUCuAcAAdTdT	896
s	A-32221	278	uGuAGAAGGGAuAuAcAAAdTdT	897
as	A-32222	296	UUUGuAuAUCCCUUCuAcAdTdT	898
Ξ	A-32223	281	AGAAGGGAuAuAcAAAGuGdTdT	899
as	A-32224	299	cACUUUGuAuAUCCCUUCUdTdT	900
s	A-32225	295	AAGuGGAAAuAGAcAccAAdTdT	901
as	A-32226	313	UUGGUGUCuAUUUCcACUUdTdT	902
s	A-32227	299	GGAAAuAGAcAc CAAAu c udT d T	903
as	A-32228	317	AGAUUUGGUGUCuAUUUCCdTdT	904
s	A-32229	300	GAAAuAGAcAc cAAAu cuudTdT	905
as	A-32230	318	AAGAUUUGGUGUCuAUUUCdTdT	906
s	A-32231	303	AuAGAcAc cAAAu cu uAc udT d T	907
as	A-32232	321	AGuAAGAUUUGGUGDCuAUdTdT	908
s	A-32233	304	UAGAcAc CAAAu CUUAcuGdTdT	909
as	A-32234	322	cAGuAAGAUUUGGUGUCuAdTdT	910
s	A-32235	305	AGAcAccAAAu cuuAcuGGdTdT	911
as	A-32236	323	CcAGuAAGAUUOGGUGUCUdTdT	912
s	A-32237	317	uuAc uGGAAGGcAcuuGGcdTdT	913
as	A-32238	335	GCcAAGUGCCUUCcAGuAAdTdT	914
s	A-32239	32	uucucAucGucuGcuccucdTdT	915
as	A-3224Q	50	GAGGAGcAGACGAUGAGAAdTdT	916
5	A-32241	322	GGAAGGcAcuuGGcAucucdTdT	917
as	A-32242	340	GAGAUGCcAAGUGCCUUCCdTdT	918
3	A-32243	326	GG cAcuuGG cAu c u c c c cAdT d T	919
as	A-32244	344	UGGGGAGAUGCcAAGUGCCdTdT	920
s	A-32247	333	GGcAucuccccAuuccAuGdTdT	921
as	A-32248	351	cAUGGAAUGGGGAGAUGCCdTdT	922
s	A-32249	334	GcAucuccccAuuccAuGAdTdT	923
as	A-32250	352	UcAUGGAAUGGGGAGAUGCdTdT	924
s	A-32251	335	cAucuccccAuuccAuGAGdTdT	925
as	A-32252	353	CUcAOGGAAUGGGGAGAUGdTdT	926
s	A-32253	336	AucuccccAuuccAuGAGcdTdT	927
as	A-32254	354	GCUcAUGGAAUGGGGAGAUdTdT	928
s	A-32255	338	c uc c c cAu u c cAuGAG cAudTdT	929
as	A-32256	356	AUGCUcAUGGAAUGGGGAGdTdT	930
s	A-32259	341	c c c Au u c c AuGAG.c Au G c AdT d T	931
as	A-32260	359	UGcAUGCUcAUGGAAOGGGdTdT	932
s	A-32261	347	CcAuGAGcAuGcAGAGGuGdTdT	933
as	A-32262	365	cACCUCUGcAUGCUcAUGGdTdT	934

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Strand	Oligo #	Position	Sequence (5' to 3')	SEQ ID NO:
s	A-32263	352	AGcAuGcAGAGGuGGuAuudTdT	935
as	A-32264	370	AAuACcACCUCUGcAUGCUdTdT	936
s	A-32265	354	cAu G cAGAGGuGGuAuucAdTdT	937
as	A-32266	372	UGAAuACcACCUCUGcAUGdTdT	938
s	A-32267	355	AuG cAGAGGuGGuAuu c Ac dT d T	939
as	Ά-32268	373	GUGAAuACcACCUCUGcAUdTdT	940
s	A-32269	362	GGuGGuAuucAcAGccAAcdTdT	941
as	A-32270	380	GUUGGCUGUGAAuACcACCdTdT	942
s	A-32271	363	GuGGuAuucAcAGccAAcGdTdT	943
as	A-32272	381	CGUUGGCUGUGAAuACcACdTdT	944
s	A-32273	364	uGG uAuuc Ac AG c c AAc G AdT d T	945
as	A-32274	382	UCGUUGGCUGUGAAuACcAdTdT	946
s	A-32275	365	QGuAu u cAcAGc cAAc GAc dT d T	947
as	A-32276	383	GUCGUUGGCUGUGAAuACCdTdT	948
s	A-32277	366	GuAuucAcAGccAAcGAcudT d T	949
as	A-32278	384	AGUCGUUGGCUGUGAAuACdTdT	950
s	A-32279	367	u Au ucAcAG c cAAcG AcucdTdT	951
as	A-32280	385	GAGUCGUUGGCUGUGAAuAdTdT	952
s	A-32281	370	u cAcAG c cAAc GAcu ccGGdTdT	953
as	A-32282	388	CCGGAGUCGUUGGCUGUGAdTdT	954
s	A-32283	390	ccccGccGcuAcAccAuuGdTdT	955
as	A-32284	408	cAAUGGUGuAGCGGCGGGGdTdT	956
Ξ	A-32285	4	GAAGuccAcucAuucuuGGdTdT	957
as	Ά-32286	22	CcAAGAAUGAGUGGACUUCdTdT	958
s	A-32287	412	cccuGcuGAGccccuAcucdTdT	959
as	A-32288	430	GAGuAGGGGCUcAGcAGGGdTdT	960
s	A-32289	417	cuGAGccccuAcuccuAuudTdT	961
as	A-32290	435	AAuAGGAGuAGGGGCUcAGdTdT	962
s	A-32291	418	uGAGccccuAcuccuAuucdTdT	963
as	A-32292	436	GAAuAGGAGuAGGGGCUcAdTdT	964
s	A-32295	422	ccccuAcuccuAuuccAccdTdT	965
as	A-32296	440	GGUGGAAuAGGAGuAGGGGdTdT	966
s	A-32297	425	cuAcuccuAuuccAc CAcGdTdT	967
as	A-32298	443	CGUGGUGGAAuAGGAGuAGdTdT	968
s	A-32299	426	uAcuccuAuuccAccAcGGdTdT	969
as	A- 32300	444	CCGUGGUGGAAuAGGAGuAdTdT	970
s	A-32301	427	Acu ccuAuuccAc cAc G G cdTd T	971
as	A-32302	445	GCCGUGGUGGAAuAGGAGUdTdT	972
s	A-32303	429	uccuAuuccAc cAcGGcuGdTdT	973
as	A-32304	447	cAGCCGUGGUGGAAuAGGAdTdT	974
5	A-32307	432	uAu u c cAc cAc GG cuG ucG dT d T	975
as	A-32308	450	CGAcAGCCGUGGUGGAAuAdTdT	976
3	A-32309	433	AuuccAccAcGGcuGucGudTdT	977
as	A-32310	451	ACGAcAGCCGUGGUGGAAUdTdT	978
s	A-32311	437	cAccAcGGcuGucGucAccdTdT	979
as	A-32312	455	GGUGACGAcAGCCGUGGUGdTdT	980
s	A-32313	438	AccAcGGcuGucGucAccAdTdT	981
as	A-32314	456	UGGUGACGAcAGCCGUGGUdTdT	982
s	A-32315	439	ccAcGGcuGucGucAccAAdTdT	983
as	A-32316	457	UUGGUGACGAcAGCCGUGGdTdT	984
s	A-32319	441	AcGGcuGucGucAc C AAu cdTd T	985
as	A-32320	459	GAUUGGUGACGAcAGCCGUdTdT	986
s	A-32321	442	cGGc uGuc G UCAccAAuccdTdT	987
as	A-32322	460	GGAUUGGUGACGAcAGCCGdTdT	988
s	A-32323	449	eGueAccAAu c c cAAG GAAdTdT	989
as	A-32 3'2 4	467	UUCGUUGGGAUUGGDGACGdTdT	990
s	A-32 3'2 5	455	cAAucccAAGGAAuGAGGGdTdT	991
as	A-32326	473	CCCUcAUUCCUUGGGAUUGdTdT	992

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Strand	Oligo #	Position	Sequence (5' to 3')	SEQ ID NO:
s	A-32327	491	ccuGAAGGAcGAGGGAuGGdTdT	993
as	A-32328	509	CcAUCCCUCGUCCUUcAGGdTdT	994
s	A-32331	497	GG Ac G AGG G Au G GGAu u u c dT cl T	995
as	A-32332	515	GAAAUCCcAUCCCUCGUCCdTdT	996
s	A-32333	5	AAGuccAcucAuucuuGGcdTdT	997
as	A-32334	23	GC cAAGAAUGAGUGGACOUdTdT	998
s	A-32335	508	GGGAuuucAuGuAA c cAAGdT d T	999
as	A-32336	526	CUUGGUuAcAUGAAAUCCCdTdT	1000
s	A-32337	509	GGAuuucAuGuAAccAAGAdTdT	1001
as	A-32338	527	UCUUGGUuAcAUGAAAUCCdTdT	1002
s	A-32339	514	ucAuGuAAccAAGAGuAuudTdT	1003
as	A-32340	532	AAuACDCUUGGUuAcAOGAdTdT	1004
s	A-32341	516	AuG uAAc cAAGAGuAuuccdTdT	1005
as	A-32342	534	GGAAuACUCUUGGUuAcAUdTdT	1006
s	A-32343	517	uGuAAccAAGAGUAUuccAdTdT	1007
as	A-32344	535	UGGAAuACUCUUGGDuAcAdTdT	1008
s	A-32345	518	GuAAccAAGAGuAu u c c AudT d T	1009
as	A-32346	536	AUGGAAuACUCUUGGUuACdTdT	1010
s	A-32347	54	uG c cu uG cuGGAc uG G uAudT dT	1011
as	A-32348	72	AuACcAGUCcAGcAAGGcAdTdT	1012
s	A- 32 3.4 9	543	uAAAGcAGuGuuuucAccudTdT	1013
as	A-32350	561	AGGUGAAAAcACUGCUUuAdTdT	1014
s	A-32351	55	GccuuGcuGGAcuGGuAuudTdT	1015
as	A-32352	73	AAuACcAGOCcAGcAAGGCdTdT	1016
s	A-32353	551	uG u uuu cAccu cAuAuGcudTdT	1017
as	A-32354	569	AGcAuAUGAGGUGAAAAeAdTdT	1018
s	A-32355	552	GuuuucAccucAuAuGcuAdTdT	1019
as	A-32356	570	uAGcAuAUGAGGUGAAAACdTdT	1020
s	A-32357	553	uuuucAccucAuAuGcuAudTdT	1021
as	A-32358	571	AuAGcAuAUGAGGUGAAAAdTdT	1022
s	A-32359	555	uucAccucAuAuGcuAuGudTdT	1023
as	A-32360	573	AcAuAGcAuAUGAGGUGAAdTdT	1024
s	A-32363	557	cAcc u c AuAuG c uAuG u uAdT d T	1025
as	A-32364	575	uAAcAuAGcAuAUGAGGUGdTdT	1026
s	A-32367	56	ccuuGcuGGAcuGGUAuuudTdT	1027
as	A-32368	74	AAAuACcAGUCcAGcAAGGdTdT	1028
s	A-32369	563	AuAu G cuAuGuuAGAAG u cdTd T	1029
as	A-32370	581	GACUUCuAAcAuAGcAuAUdTdT	1030
s	A-32371	564	uAuGcuAuGuuAGAAGuccdTdT	1031
as	A-32372	582	GGACUUCuAAcAuAGcAuAdTdT	1032
5	A-32373	566	uG c uAuG u uAGAAGuccAGdT d T	1033
as	A-32374	584	CUGGACUUCuAAcAuAGcAdTdT	1034
3	A-32375	57	cuuGcuGGAcuGGuAuuuGdTdT	1035
as	A-32376	75	cAAAuACcAGUCcAGcAAGdTdT	1036
s	A-32379	578	AGuccAGGcAGAGAcAAuAdTdT	1037
as	A-32380	596	uAUUGUCUCUGCCUGGACUdTdT	1038
s	A-32381	580	UCCAGGcAGAGAcAAuAAAdTdT	1039
as	A 32382	598	UUuAUUGUCUCUGCCUGGAdTdT	1040
s	A-32383	607	GuGAAAGG cAc uu u ucAuudT dT	1041
as	A-32384	625	AAUGAAAAGUGCCUUUcACdTdT	1042
s	A-32385	62	UGGAc UGG UAuu UGUG U c udTd T	1043
as	A-32386	80	AGAcAcAAAuACcAGUCcAdTdT	1044
s	A-32387	77	GUCUGAGGcUGGcCCuAcGdTdT	1045
as	A-32388	95	CGuAGGGCcAGCCUcAGACdTdT	1046
s	A-32391	79	cuGAGG c u GG c c c uAc G GGdT d T	1047
as	A-32 3'92	97	CCCGuAGGGCcAGGCUcAGdTdT	1048
s	A-32393	81	GAGGcuGGcccuAcGGGcAdTdT	1049
as	A-32394	99	UGCCCGuAGGGCcAGCCUCdTdT	1050

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Strand	Oligo #	Position	Sequence (5' to 3')	SEQ ID NO:
s	A-32395	82	AGGcuGGcccuAcGGGcAcdTdT	1051
as	A-32396	100	GUGCCCGuAGGGCcAGCCUdTdT	1052
s	A-32397	84	GcuGGcccuAcGGGcAccGdTdT	1053
as	A-32398	102	CGGUGCCCGuAGGGCcAGCdTdT	1054
s	A-32399	85	cuGGcccuAcGGGcAccGGdTdT	1055
as	A-32400	103	CCGGUGCCCGuAGGGCcAGdTdT	1056
s	A-32401	87	GGcccuAcGGGcAccGGuGdTdT	1057
as	A-32402	105	cACCGGUGCCCGuAGGGCCdTdT	1058
s	Ά-32403	9	ccAcucAuucuuGGcAGGAdTdT	1059
as	A-32404	27	UCCUGCcAAGAAUGAGUGGdTdT	1060
s	A-32405	90	ccuAcGGGcAccGGuGAAudTdT	1061
as	A-32406	108	AOUcACCGGUGCCCGuAGGdTdT	1062
s	A-32407	91	cuAcGGGcAccGGuGAAucdTdT	1063
as	A-32408	109	GAUUcACCGGUGCCCGuAGdTdT	1064
s	A-32409	92	uAcGGGcAccGGuGAAuccdTdT	1065
as	A-32410	110	GGAUUcACCGGUGCCCGuAdTdT	1066
s	A-32411	93	AcGGGcAccGGuGAAuccAdTdT	1067
as	A-32412	111	UGGAUUcACCGGUGCCCGUdTdT	1068
s	A-32415	97	GcAccGGu GAAuccAAGuGdTdT	1069
as	A-32416	115	cACUUGGAUUcACCGGUGCdTdT	1070
s	A-32417	98	cAccGGuGAAuccAAGuGudTdT	1071
as	A-32418	116	AcACUUGGAUUcACCGGUGdTdT	1072
Ξ	A-32419	167	uGuGGccAuGcAuGuGuucdTdT	1073
as	A-32420	185	GAAcAcAUGcAUGGCcAcAdTdT	1074
s	A-32421	168	GuGGccAuGcAuGuGuucAdTdT	1075
as	A-32422	186	UGAAcAcAUGcAUGGCcACdTdT	1076
s	A-32423	.171	G C CAuG CAu Gu G U U cAGAAdT d T	1077
as	A-32424	189	UUCUGAAcAcAUGcAUGGCdTdT	1078
s	A-32427	432	uAuuccAccAcGGcuGucAdTdT	1079
as	A-32428	449	UGAcAGCCGUGGUGGAAuAdTdT	1080
s	A-32429	4 47	GucAucAccAAucccAAGGdTdT	1081
as	A-32430	4 65	CCUUGGGAUUGGUGAUGACdTdT	1082
s	A-32159	115	GuccucuGAuGGucAAAGudTdT	1083
as	A-32160	133	ACUUUGACcAUcAGAGGACdTdT	1084
s	A-32161	122	GAu G GucAAAG u u cuAGAudT d T	1085
as	A-32162	140	AUCuAGAACUUOGACcAUCdTdT	1086
s	A-32173	139	AuGcuGuccGAGGcAGuccdTdT	1087
as	A-32174	157	GGACUGCCUCGGAcAGcAUdTdT	1088
s	A-32185	172	CCGuGcAuGuGuucAGAAAdTdT	1089
as	A-32186	190	UUUCUGAAcAcAUGcACGGdTdT	1090
5	A-32197	238	AGucuGG AG AG cuG.c AuGGdTdT	1091
as	A-32198	256	CCAUGcAGCUCUCcAGACUdTdT	1092
3	A-32209	252	cAu G GG cueA c AAcu GAGGdTdT	1093
as	A-32210	270	CCUcAGUUGUGAGCCcAUGdTdT	1094
s	A-32245	33	ucucAucGuc uGcuccuccdTdT	1095
as	A-32246	51	GGAGGAGcAGACGAUGAGAdTdT	1096
s	A-32257	340	ccccAuuccAuGAGcAuGcdTdT	1097
as	A-32258	358	GcAUGCUcAUGGAAUGGGGdTdT	1098
s	A-32293	421	GccccuAcuccuAuuccAcdTdT	1099
as	A-32294	439	GUGGAAuAGGAGuAGGGGCdTdT	1100
s	A-32305	431	cuAuuccAccAcGGcuGucdTdT	1101
as	A-32306	449	GAcAGCCGUGGUGGAAuAGdTdT	1102
s	A-32317	440	c Ac G G cu Gu cG uc AccAAudTdT	1103
as	A-32318	458	AUUGGUGACGAcAGCCGUGdTdT	1104
s	A-32329	496	AGGAcGAGGGAuGGGAuuudTdT	1105
as	A-32330	514	AAAUCCcAUCCCUCGOCCOdTdT	1106
s	A-32361	556	ucAccucAuAuGcuAuGuudTdT	1107
as	A-32362	574	AAcAuAGcAuAUGAGGUGAdTdT	1108

S3

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Strand	Oligo #	Position	Sequence(5' to 3')	SEQ ID NO:
s	A-32365	559	ecucAuAuGcuAuGuuAGAdTdT	1109
as	A-32366	577	UCuAAcAuAGcAuAUGAGGdTdT	1110
s	A-32377	570	AuGUuAGAAGucCAGGcAGdTdT	1111
as	A-32378	588	CUGCCUGGACUUCuAAcAUdTdT	1112
s	A-32389	78	ucuGAGGcuGGccc uAcGGdTdT	1113
as	A-32390	96	CCGuAGGGCcAGCCUcAGAdTdT	1114
s	A-32401	87	GG cc cuAc GGG c Ac c G G uGdT d T	1115
as	A-32402	105	cACCGGUGCCCGuAGGGCCdTdT	1116
s	A-32413	95	GGGcAccGGuGAAuccAAGdTdT	1117
as	A-32414	113	CUUGGAUUcACCGGUGCCCdTdT	1118
s	A-32425	167	c cAu G cAu GuGuu cAGAAAdTd T	1119
as	A-32426	185	UUUCUGAAcAcAUGcAUGGdTdT	1120'

Table 5: Identification numbers for rat TTR dsRNAs

See Table 7 for sequences.

Duplex #	Sense Oligo #	Antisense Oligo #
AD-18529	A-32745	A-32746
AD-18530	A-32747	A-32748
AD-18531	A-32749	A-32750
AD-18532	A-32751	A-32752
AD-18533	A-32753	A-32754
AD-18534	A-32755	A-32756
AD-18535	A-32757	A-32758
AD-18536	A-32759	A-32760
AD-18537	A-32761	A-32762
AD-18538	A-32763	A-32764
AD-18539	A-32159	A-32160
AD-18540	A-32765	A-32766
AD-18541	A-32767	A-32768
AD-18542	A-32769	A-32770
AD-18543	A-32771	A-32772
AD-18544	A-32773	A-32774
AD-18545	A-32775	A-32776
AD-18546	A-32777	A-32778
AD-18547	A-32779	A-32780
AD-18548	A-32781	A-32782
AD-18549	A-32783	A-32784
AD-18550	A-32785	A-32786
AD-18551	A-32787	A-32788
AD-18552	A-32791	A-32792
AD-18553	A-32793	A-32794
AD-18554	A-32795	A-32796

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Table 6A. Sense and antisense strand sequences for rat TTR dsRNAs

Strand: s= sense; as= antisense; Position: position of 5' base on transcript (NM_012681.1, SEQ ID NO: 1330)

Strand	Position	Sequence (5' to 3'}	SEQ IDNO:	Sequence with 3' dinucleotide overhang (5' to 3' }	SEQ IDNO:
s	115	GUCCUCUGAUGGUCAAAGU	1121	GUCCUCUGAUGGUCAAAGUHH	1173
as	133	ACUUUGACCAUCAGAGGAC	1122	AC UU UGACC AU CAGAG G AC1 JIT	1174
s	537	UUCUUGCUCUAUAAACCGU	1123	UUCUUGCUCUAUAAACCGUIJIT	1175
as	555	ACGGUUUAUAGAGCAAGAA	1124	ACGGUUUAUAGAGCAAGAA»»	1176
s	543	CUCUAUAAAC CGUGUOAGC	1125	CUC UAUAAACCG UGUUAGCHII	1177
as	561	GC UAACAC GG UU UAU AGAG	1126	G C UAAC ACG GU UU AUAG AGWII	1178
s	392	UCGCCACUACACCAUCGCA	1127	UCGCCACUACACCAUCGCANTI	1179
as	410	UGCGAUGGUGUAGUGGCGA	1128	UGCGAUGGU GUAGUGGCGANIJ	1180
s	538	UC U U GCUCUA UAAACC G UG	1129	UC UUGCUCUAUAAACCGUGHI1	1181
as	556	CACGGUUUAUAGAGCAAGA	1130	CACGGUUUAUAGAGCAAGA»»	1182
s	541	UGCUCUAUAAACCGUGUUA	1131	UGCUCUAUAAACCGUGUUA»»	1183
as	559	U AAC ACG G UUUAUAGAGCA	1132	UAACACGGUUUAUAGAGCAim	1184
s	532	CAGUGUUCUUGCUCUAUAA	1133	CAGUGUUCUUGCUCUAUAA»»	1185
as	550	UUAUAGAGCAAGAACACUG	1134	U U AUAGAGC AAGAACAC UG1JH	1186
s	542	GCUCUAUAAACCGUGUUAG	1135	G C UCUAU AAAC CGUGU UAG1IN	1187
as	560	CUAACACGGUUUAUAGAGC	1136	CUAACACGGUUUAUAGAGCIT»	1188
s	134	CCUGGAUGCUGUCCGAGGC	1137	CCUGGAUGCUGUCCGAGGC»»	1189
as	152	GCCUCGGACAGCAUCCAGG	1138	GCC UCGGACAGCAUCCAGGHN	1190
s	119	UCUGAUGGUCAAAGUCCUG	1139	UCUGAUGGUCAAAGUCCUG»»	1191
as	137	CAGGAC UU UGAC CAUC AGA	1140	C AGG AC U UUG ACCAUC AGA1IIT	1192
3	241	CUGGAGAGCUGCACGGGCU	1141	CUGGAGAGCUGCACGGGCU»»	1193
as	259	AGCCCGUGCAGCUCUCCAG	1142	AGCCCGUGCAGCUCUCCAG1III	1194
s	544	UC UAUAAAC CGU GU UAGCA	1143	□CUAUAAAC CGUGU UAGCANH	1195
as	562	UGCUAACACGGUUUAUAGA	1144	UGCUAACACGGUUUAUAGAUH	1196
s	530	AACAGUGUUCUUGCUC UAU	1145	AACAGUGUUCUUGCU.CUAU»»	1197
as	548	AUAGAGCAAGAACACUGUU	1146	AUAGAGCAA GAACAC UG UU»H	1198
s	118	CUCUGAUGGUCAAAGUCCU	1147	CUCUGAUGGUCAAAGUCCU»»	1199
as	136	AGGACUUUGACCAUCAGAG	1148	AGGACUUUGACCAUCAGAG»»	1200
s	140	UGCUGUCCGAGGCAGCCCU	1149	UGCUGUCCGAGGCAGCCCU»»	1201
as	158	AGGGCUGCCUCGGACAGCA	1150	AGGGCUGCCUCGGACAGCAtJH	1202
s	239	GUCUGGAGAGCUGCACGGG	1151	GUCUGGAGAGCUGCACGGG»»	1203
as	257	CC CG UGC AGCUC UC CAGAC	1152	CCCGUGCAGCUCUCCAGACHN	1204
3	531	ACAGUGUUCUUGCUCUAUA	1153	ACAGUGUUCUUGCUCUAUA»»	1205
as	549	UAUAGAGCAAGAACACUGU	1154	UAUAGAGCAAGAACACUGU»»	1206
s	117	CC UC UG AUGGUC AAAG UCC	1155	CCUCUGAUGGU C AAAGUCCNIJ	1207
as	135	GGACUUUGACCAUCAGAGG	1156	GGACUUUGACCAUCAGAGG»»	1208
s	131	AGUCCUGGAUGCUGUCCGA	1157	AGUCCUGGAUGCUGUCCGA»»	1209
as	149	UCGGACAGCAUCCAGGACU	1158	UCGGACAGCAUCCAGGACU»»	1210
5	217	UUGCCUCUGGGAAGACCGC	1159	UUGCCUCUGGGAAGACCGCtm	1211
as	235	GCGGUCUUCCCAGAGGCAA	1160	GCGGUCUUCCCAGAGGCAA»»	1212
s	242	UGGAGAGCUGCACGGGCUC	1161	UGGAGAGCUGCACGGGCUC»»	1213
as	260	GAGCCCGUGCAGCUCUCCA	1162	GAGCCCGUGCAGCUCUCCA»»	1214
s	244	GAGAGCUGCACGGGCUCAC	1163	GAGAGCUGCACGGGCUCAC»»	1215
as	262	GUGAGCCCGUGCAGCUCUC	1164	GUGAGCCCGUGCAGCUCUC»»	1216
3	246	GAGC UGCACGGGCUCACCA	1165	GAGCUGCACGGGCUCACCAUH	1217
as	264	UGGUGAGCCCGUGCAGCUC	1166	UGGUGAGCCCGUGCAGCUC»»	1218
3	399	UACACCAUCGCAGCCCUGC	1167	UACACCAUCGCAGCCCUGC»»	1219
as	417	GCAGGGCUGCGAUGGUGUA	1168	GCAGGGCUGCGAUGGUGUA»»	1220
s	132	GUCCUGGAUGCUGUCCGAG	1169	GUCCUGGAUGCUGUCCGAG»»	1221
as	150	CUCGGACAGCAUCCAGGAC	1170	CUCGGACAGCAUCCAGGAC»»	1222

WO 2011/123468 PCT/US2011/030392

2017204161 20 Jun 2017

Strand	Position	Sequence (5' to 3'}	SEQ IDNO:	Sequence with 3' dinucleotide overhang {5' to 3'}	SEQ IDNO:
5	245	AGAGCUGCACGGGCUCACC	1171	AGAGC UGCACGGGCUCACC1JU	1223
as	263	GGUGAGCCCGUGCAGCUCU	1172	GGUGAGCCCGUGCAGCUCUHN	1224

Table 6B. Sense and antisense strand sequences for rat TTR dsRNAs

Strand: s= sense; as= antisense; Position: position of 5' base on transcript (NM 012681.1, SEQ ID NO: 1330)

Strand	Position	Sequence with 3'deoxythimidine overhang (5' to 3')	SEQ ID NO:
s	115	GUCCU CU GAUGGUCAAAGU dTdT	1225
as	133	ACUUUGACCAUCAGAGGACdTdT	1226
s	537	UUCUUGCUCUAUAAACCGUdTdT	1227
as	555	ACGGU UUAUAGAGC AAGAAdT dT	1228
s	543	CUCUAUAAACCGUGUUAGCdTdT	1229
as	561	GCUAACACGGUUUAUAGAGdTdT	1230
s	392	UCGCCACUACACCAUCGCAdTdT	1231
as	410	UGCGAUGGUGUAGUGGCGAdTdT	1232
s	538	UCUUGCUCUAUAAACCGUGdTdT	1233
as	556	CACGGUUUAUAGAGCAAGAdTdT	1234
s	541	UGCUCUAUAAACCGUGUUAdTdT	1235
as	559.	UAACACGGUUUAUAGAGCAdTdT	1236
s	532	CAGUGUUCUUGCUCUAUAAdTdT	1237
as	550	UUAUAGAGCAAGAACACUGdTdT	1238
s	542	GCUCUAUAAACCGUGUUAGdTdT	1239
as	560	CUAACACGGUUUAUAGAGCdTdT	1240
s	134	CCUGGAUGCUGUCCGAGGCdTdT	1241
as	152	GCCUCGGACAGCAUCCAGGdTdT	1242
s	119	UCUGAUGGUCAAAGUCCUGdTdT	1243
as	137	CAGGACUUUGACCAUCAGAdTdT	1244
s	241	CUGGAGAGCUGCACGGGCUdTdT	1245
as	259	AGCCCGUGCAGCUCUCCAGdTdT	1246
s	544	UCUAUAAACCGUGUUAGCAdTdT	1247
as	562	UGC UAACAC GGUU UAUAGAdT dT	1248
s	530	AACAGUGUUCUUGCUCUAUdTdT	1249
as	548	AUAGAGCAAGAACACUGUUdTdT	1250
s	118	CUCDGAUGGUCAAAGUCCUdTdT	1251
as	136	AGGAC UUUGAC CAUCAGAG dT dT	1252
s	140	UGCUGUCCGAGGCAGCCCUdTdT	1253
as	158	AGGGCUGCCUCGGACAGCAdTdT	1254
s	239	GUCUGGAGAGCUGCACGGGdTdT	1255
as	257	CCCGUGCAGCUCUCCAGACdTdT	1256
S	531	ACAGUGUUCUUGCUCUAUAdTdT	1257
as	549	UAUAGAGCAAGAACACUGUdTdT	1258
s	117	CCUCOGAUGGUCAAAGUCCdTdT	1259
as	135	GGACUUDGACCAUCAGAGGdTdT	1260
s	131	AGUCCUGGAUGCUGUCCGAdTdT	1261
as	149	UCGGACAGCAUCCAGGACUdTdT	1262
s	217	UUGCCUCUGGGAAGACCGCdTdT	1263
as	235	GCGGUCUUCCCAGAGGCAAdTdT	1264
s	242	UGGAGAGCUGCACGGGCUCdTdT	1265
as	260	GAGCCCGUGCAGCUCUCCAdTdT	1266
s	244	GAGAGCUGCACGGGCUCACdTdT	1267
as	262	GUGAGCCCGUGCAGCUCUCdTdT	1268
s	246	GAGCUGCACGGGCUCACCAdTdT	1269

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Strand	Position	Sequence with 3'deoxythimidine overhang (5' to 3')	SEQ ID NO:
as	264	UGGUGAGCCCGUGCAGCUCdTdT	1270
s	399	UACACCAUCGCAGCCCUGCdTdT	1271
as	417	GCAGGGCUGCGAUGGtJGUAdTdT	1272
s	132	GUCCUGGAUGCUGUCCGAGdTdT	127 3
as	150	CUCGGACAGCAUCCAGGACdTdT	1274
s	245	AGAGCUGCACGGGCUCACCdTdT	1275
as	263	GGUGAGCCCGUGCAGCUCUdTdT	1276

Table 7. Chemically modified sense and antisense strand sequences for rat TTR dsRNAs

See Table 5 for duplex # (dsRNA name). Strand: s= sense; as= antisense; Position: position of 5' base on transcript (NM_012681.1, SEQ ID NO: 1330)

Strand	Oligo #	Position	Sequence (5' to 3' )	SEQ ID NO:
	Ά-32159	115	Gu cc u c uGAuGGucAAAGudTdT	127 7
as	A-32160	133	ACUUUGACcAUcAGAGGACdTdT	1278
s	A-32745	537	uucuuGcucuAuAAAccGudTdT	1279
as	A-32746	555	ACGGUUuAuAGAGcAAGAAdTdT	1280
3	A-32747	5.43	cucuAuAAAccGuGuuAGcdTdT	1281
as	A-32748	561	GCuAAcACGGUUuAuAGAGdTdT	1282
s	Ά-32749	392	υ cGccAcuAcAc cAucGcAdTdT	1283
as	A-32750	410	UGCGAOGGUGuAGUGGCGAdTdT	1284
s	A-32751	538	ucuuGcuc uAuAAAcc GuGdTdT	1285
as	A-32752	556	cACGGUUuAuAGAGcAAGAdTdT	1286
s	A-32753	541	uGcucuAuAAAccGuGuuAdTdT	1287
as	A-32754	559	uAAcACGGUUuAuAGAGcAdTdT	1288
s	A-32755	532	cAGu Gu u c u u Gc u c uAuAAdTdT	1289
as	A-32756	550	UuAuAGAGcAAGAAcACUGdTdT	1290
s	A-32757	542	Gc ucuAuAAAccGuGuuAGdTdi	1291
as	A-32758	560	CuAAcACGGUUuAuAGAGCdTdT	1292
s	a-32759	134	cc uG GAuG cuGu ccGAGG cdTdT	1293
as	A-32760	152	GCCUCGGAcAGcAUCcAGGdTdT	1294
s	A-32761	119	ucuGAuGGucAAAGuccuGdTdT	1295
as	A-32762	137	CAGGACUUUGACcAUcAGAdTdT	1296
s	A-32763	241	cuGGAGAG c u GcAc GG G c udTdT	1297
as	A-32764	259	AGCCCGUGcAGCUCUCcAGdTdT	1298
s	A-32765	544	UC uAuAAA ccGuGuuAGc AdTdT	1299
as	A-32766	562	UGCuAAcACGGUUuAuAGAdTdT	1300
; s	Ά-32767	530	AAcAGuGuucuuGcucuAudTdT	1301
, as	A-32768	548	AuAGAGcAAGAAcACUGUUdTdT	1302
s	A-32769	118	cucuGAuGGu cAAAGu cc udT dT	1303
, as	A-32770	136	AGGACUUUGACcAUcAGAGdTdT	1304
s	A-32771	140	u G cu Gu c c GAGG cA Gcc c udTdT	1305
as	A-32772	158	AGGGCUGCCUCGGAcAGcAdTdT	130.6
s	A-32773	239	Guc uGGAGAGc uGc A c GG GdTdT	1307
as	A-32774	257	CCCGUGcAGCUCUCcAGACdTdT	1308
s	A-3.27 75	531	AcAG uG uu cu uG cucuAuAdTdT	1309
as	A-32776	54 9	uAuAGAGcAAGAAcACUGUdTdT	1310
s	A-32777	117	cc uc uGAuGGu cAAAGuccdTdT	1311
as	A-32778	135	GG AC U DUG AC cAUc AGAG GdTdT	1312
3	A-32779	131	AG uc cu GGAuG cu G uc cGAdTdT	1313
as	A—3’2780	149	UCGGAcAG CAUCcAGGACUdTdT	1314
s	A-32781	217	u u Gc cucuGGGAAGAccGcdTdT	1315
1 as	A-32782	235	GCGGUCUUCCcAGAGGcAAdTdT	1316
3	a-32783	242	uGGAGAGcuGcAcGGGcucdTdT	1317
as	a-32784	260	GAGCCCGUGcAGCUCUCcAdTdT	1318

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Strand	Oligo #	Position	Sequence {5' to 3' )	SEQ ID NO:
s	A-32785	244	GA GAG c uGcAcGGGcu cAcdTdT	1319
as	A-32786	262	GOGAGCCCGUGcAGCUCUCdTdT	1320
s	A-32787	246	GAGcuGcAcGGGcucAccAdTdT	1321
as	A-32788	264	UGGUGAGCCCGUGcAGCUCdTdT	1322
,s ...	a-327 91	399	uA cAccAu cGcAGcccuGcdTdT	1323
as	A-32792	417	GcAGGGCUGCGAUGGUGuAdTdT	1324
s	A-32793	132	GuccuGGAuGcuGuccGAGdTdT	1325
as	A-32794	150	CUCGGAcAGcADCcAGGACdTdT	1326
s	A-32795	245	AGAGcuGcAcGGGcucAccdTdT	1327
as	A-32796	263	GGUGAGCCCGUGcAGCUCUdTdT	1328'

Synthesis of TTR Sequences

TTR sequences were synthesized on MerMade 192 synthesizer at 1 μπιοί scale. For all the sequences in the list, ‘endolight’ chemistry was applied as detailed below.

· All pyrimidines (cytosine and uridine) in the sense strand were replaced with corresponding 2’-O-Methyl bases (2’ O-Mcthyl C and 2’-O-Methyl U) • In the antisense strand, pyrimidines adjacent to (towards 5’ position) ribo A nucleoside were replaced with their corresponding 2-O-Methyl nucleosides • A two base dTdT extension at 3 ’ end of both sense and antisense sequences was introduced • The sequence file was converted to a text file to make it compatible for loading in the MerMade 192 synthesis software

The synthesis of TTR sequences used solid supported oligonucleotide synthesis using phosphoram idite chemistry. The synthesis of the above sequences was performed at 1 um scale 15 in 96 well plates. The amiditc solutions were prepared at 0.1 M concentration and ethyl thio tetrazole (0.6M in Acetonitrile) was used as activator.

The synthesized sequences were cleaved and deprotected in 96 well plates, using methylamine in the first step and triethylamine.3HF in the second step. The crude sequences thus obtained were precipitated using acetone: ethanol mix and the pellet were re-suspended in 0.5M 20 sodium acetate buffer. Samples from each sequence were analyzed by LC-MS and the resulting mass data confirmed the identity of the sequences. A selected set of samples were also analyzed by I EX chromatography.

The next step in the process was purification. All sequences were purified on an AKTA explorer purification system using Source 15Q column. A single peak corresponding to the full 25 length sequence was collected in the eluent and was subsequently analyzed for purity by ion exchange chromatography.

The purified sequences were desalted on a Sephadex G25 column using AKTA purifier. The desalted TTR sequences were analyzed for concentration and purity. The single strands were then annealed to form TTR-dsRNA.

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Example 2B: In vitro screening of TTR siRNAs for mRNA suppression

Human TTR targeting dsRNAs (Table 2) were assayed for inhibition of endogenous TTR expression in HcpG2 and Hcp3B cells, using qPCR (real time PCR) and bDNA (branched DNA) assays to quantify TTR mRNA. Rodent TTR targeting dsRNA (Table 5) were synthesized and assayed for inhibition of endogenous TTR expression using bDNA assays in H.4.I1.E cells. Results from single dose assays were used to select a subset of TTR dsRNA duplexes for dose response experiments to calculate ICSO’s. 1C50 results were used to select TTR dsRNAs for further testing.

Cell culture and transfections:

The hepatocyte cell lines HepG2, Hep3B and H.4.I1.E cells (ATCC, Manassas, VA) were grown to near confluence at 37°C in an atmosphere of 5% COz in Dulbccco's modified Eagle’s medium (ATCC) supplemented with 10% FBS, streptomycin, and glutamine (ATCC) before being released from the plate by trypsinization. H.4.II.E cells were also grown in Earle’s minimal essential medium. Reverse transfection was earned out by adding 5 μΐ of Opti-MEM to

5 μΐ of siRNA duplexes per well into a 96-wefl plate along with 10 μΐ of Opti-MEM plus 0.2 μΐ of Lipofcctaminc RNAiMax per well (invitrogen, Carlsbad CA. cat# 13778-150) and incubated at room temperature for 15 minutes. 80μΙ of complete growth media without antibiotics containing 4xl0⁴ (HepG2), 2X10·¹ (Hep3B) or 2xlO^4,H.4.II.E) cells were then added. Cells were incubated for 24 hours prior to RNA purification. Single dose experiments were performed at 10 20 nM final duplex concentration and dose response experiments were done with 10, 1, 0.5,

0.1,0.05, 0.01, 0.005, 0.001,0.0005, 0.0001,0.00005, 0.0000 J nM.

Total RNA isolation using MagMAX-96 Total RNA Isolation Kit (Applied Biosys terns.

Foster City CA, part #: AM 1830):

Cells were harvested and lysed in 140 μΐ of Lysis/Binding Solution then mixed for 1 minute at 850rpm using and Eppendorf Thermo mixer (the mixing speed was the same throughout the process). Twenty micro liters of magnetic beads were added into cell-lysate and mixed for 5 minutes. Magnetic beads were captured using magnetic stand and the supernatant was removed without disturbing the beads. After removing supernatant, magnetic beads were washed with Wash Solution 1 (isopropanol added) and mixed for 1 minute. Beads were captured again and supernatant removed. Beads were then washed with 150μ1 Wash Solution 2 (Ethanol added), captured and supernatant was removed. 50μΙ of DNase mixture (MagMax turbo DNase Buffer and Turbo DNase) was then added to the beads and they were mixed for 10 to 15 minutes. After mixing, 100μ1 of RNA Rebinding Solution was added and mixed for 3 minutes. Supernatant was removed and magnetic beads were washed again with 150μΙ Wash

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Solution 2 and mixed for 1 minute and supernatant was removed completely. The magnetic beads were mixed for 2 minutes to dry before RNA it was eluted with 50μ1 of water.

cDNA synthesis using ABI High capacity cDNA reverse transcription kit (Applied Biosvstems, Foster Chy, CA. Cat #4368813):

A master mix of 2μ1 10X Buffer, 0.8ul 25X dNTPs, 2μ1 Random primers, 1 μΐ Reverse

Transcriptase, 1 μΐ RNase inhibitor and 3.2μ1 of H2O per reaction were added into 1 ΟμΙ total RNA. cDNA was generated using a Bio-Rad C-1000 or S-1000 thermal cycler (Hercules, CA) through the following steps: 25°C 10 min, 37°C 120 min, 85°C 5 sec, 4°C hold.

Real time PCR:

2μ.I of cDNA was added to a master mix of 1 μΐ i 8S TaqMan Probe (Applied Biosystems

Cat # 4319413E), 1 μΐ TTR TaqMan probe (Applied Biosystems cat # HS00174914 Μ1) and

ΟμΙ TaqMan Universal PCR Master Mix (Applied Biosystems Cat #4324018) per well in a MicroAmp Optical 96 well plate (Applied Biosystems cat # 4326659). Real time PCR was done in an ABI 7000 Prism or an ABI 7900HT Real Time PCR system (Applied Biosystems) using the ΔΔ Ct(RQ) assay. All reactions were done In triplicate.

Real time data were analyzed using the ΔΔ Ct method and normalized to assays performed from cells transfected with lOnM BlocklT fluorescent Oligo (Invitrogen Cat #2013) or lOnM AD-1955 (a control duplex that targets the non-mammalian luciferase gene) to calculate fold change.

Branched DNA assays- QuantiGene TO (Panomics, Fremont, CA, cat #; QG0004)- Used to screen rodent specific duplexes

Η.4.Π.Ε cells (ATCC) were transfected with 10 nM siRNA. After removing media, H.4.I1.E were lysed in lOOul of Diluted Lysis Mixture (a mixture of I volume of Lysis mixture, volume of nuclease-free water and lOul of Proteinase-K per ml for the final concentration of 25 20mg/ml) then incubated at 65 °C for 35 minutes. Then, 80μΙ of Working Probe Set (a mixture of TTR or GAPDH probe) and 20ul of cell-lysate were added into the Capture Plate. Capture Plates were incubated at 53 °C ±1 °C overnight (approximately 16-20hrs). Capture Plates were washed 3 times with IX Wash Buffer (a mixture of nuclcasc-frec water, Buffer Component 1 and Wash Buffer Component 2), then dried by centrifuging for 1 minute at lOOOrpm. 100μΙ of 30 Amplifier Working Reagent was added into the Capture Plate, which was then sealed and incubated for 1 hour at 46°C ±1°C. Wash and dry steps were repeated after 1 hour of incubation and 100j.il of Label Solution Reagent was added. The plate was then washed, dried and 100μ1 Substrate (a mixture of Lithium Lauryl Sulfate and Substrate solution) was added. Capture

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Plates were placed in the incubator for 30 minutes at 46 °C ±1 °C. Capture Plates were then removed from the incubator and incubated at room temperature for 30 minutes. Finally, the

Capture Plates were read using the Victor Luminometcr (Perkin Elmer, Waltham, MA).

Branched DNA assays- OuantiGene 2.0 (Panomics cat #: QS0011): Used to screen ail other duplexes

After a 24 hour incubation at the dose or doses stated, media was removed and cells were lysed in lOOul Lysis Mixture (1 volume lysis mixture, 2 volumes nucleasc-frec water and 10μ1 of Proteinase-K/ml for a final concentration of 20mg/ml) then incubated at 65°C for 35 minutes. 20μ1 Working Probe Set (TTR probe for gene target and GAPDH for endogenous control) and

80μΙ of cell-lysate were then added to the Capture Plates. Capture Plates were incubated at 55°C ±1°C (approx. 16-20hrs). The next day, the Capture Plates were washed 3 times with IX Wash Buffer (nuclease-free water, Buffer Component 1 and Wash Buffer Component 2), then dried by centrifuging for 1 minute at 240g. 100μ1 of pre-Amplifier Working Reagent was added to the Capture Plates, which were sealed with aluminum foil and incubated for 1 hour at 55°C ±1°C.

Following a 1 hour incubation, the wash step was repeated, then 100μ1 Amplifier Working Reagent was added. After 1 hour, the wash and dry steps were repeated, and ΙΟΟμΙ Label Probe was added. Capture plates were incubated 50°C ±1°C for 1 hour. The plates were then washed with I X Wash Buffer and dried, and then 100μ1 Substrate was added to the Capture Plates. Capture Plates were read using the SpectraMax Luminometer (Molecular Devices, Sunnyvale,

CA) following 5 to 15 minutes incubation.

bDNA data analysis:

bDNA data were analyzed by (i) subtracting the average background from each triplicate sample, (ii) averaging the resultant triplicate GAPDH (control probe) and TTR (experimental probe) values, and then (iii) taking the ratio: (experimental probe-background )/(control probc25 background).

Results

A summary of the single dose and IC50 results for TTR-dsRNAs (TTR siRNAs) are presented below in Table 8. Single dose results arc expressed as % TTR mRNA relative to control, assayed in HcpG2 cells. lC50s were determined in HepG2 and/or Hep3B cells, as indicated.

WO 2011/123468

PCT/US2011/030392

Table 8. Single dose and 1C50 results of in vitro screens of TTR siRNAs

2017204161 20 Jun 2017

ND: no data; * indicates result that represents average of two experiments.

Duplex #	Single Dose at lOnM % relative to control	1C50 (nM)
HepG2	HcpG2	Hcp3B
qPCR	bDNA	qPCR	bDNA	qPCR	bDNA
AD-18243	50.35	141.53	ND	ND	ND	ND
AD-18244	64.26	158.55	ND	ND	ND	ND
AD-18245	56.89	107.22	ND	ND	ND	ND
AD-18246	10.53	32.51*	0.265	0.086	ND	ND
AD-18247	125.56	69.57	ND	ND	ND	ND
AD-18248	127.78	66.97	ND	ND	ND	ND
AD-18249	48.77	48.76	ND	ND	ND	ND
AD-18250	96.94	86,42	ND	ND	ND	ND
AD-18251	170.41	129.15	ND	ND	ND	ND
AD-18252	73.52	81.90	ND	ND	ND	ND
AD-18253	25.25	61.25	ND	ND	ND	ND
AD-18254	95.13	103.96	ND	ND	ND	ND
AD-18255	119,46	ND	ND	ND	ND	ND
AD-18256	42.64	95.67	ND	ND	ND	ND
AD-18257	146.25	141.75	ND	ND	ND	ND
AD-18258	10,20	13.41*	0,007	0.005	0.004	0.005
AD-18259	9.30	20,91*	0.102	0.005	ND	ND
AD-18260	125.37	81.36	ND	ND	ND	ND
AD-18261	14.27	19.40*	0.210	ND	ND	ND
AD-18262	84.95	104.05	ND	ND	ND	ND
AD-18263	16.32	23.25*	0.110	ND	ND	ND
AD-18264	104.18	83.69	ND	ND	ND	ND
AD-18265	41.62	64.87	ND	ND	ND	ND
AD-18266	39.98	110.53	ND	ND	ND	ND
AD-18267	149.64	ND	ND	ND	ND	ND
AD-18268	152.93	174.04	ND	ND	ND	ND
AD-18269	37.27	92.28	ND	ND	ND	ND
AD-18270	99.44	164.75	ND	ND	ND	ND
AD-18271	18.89	28.33*	0,503	0.004	ND	ND
AD-18272	128.32	132.58	ND	ND	ND	ND
AD-18273	115.78	201.95	ND	ND	ND	ND
AD-18274	8.97	20.04*	0.009	0.176	0.036	0.012
AD-18275	4.09	22.25*	0.026	0.118	ND	ND
AD-18276	19.73	45,22*	0.198	0.677	ND	ND
AD-18277	10.55	26.31*	0.121	0.426	ND	ND
AD-18278	108.86	116.26	ND	ND	ND	ND
AD-18279	66.59	ND	ND	ND	ND	ND
AD-18280	103.26	170.52	ND	ND	ND	ND
AD-18281	87.98	123.88	ND	ND	ND	ND

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Duplex #	Single Dose at lOtiM % relative to control	IC50 (nM)
HepG2	HepG2	HcpJB
([PCR	hDNA	qPCR	hDNA	qPCR	hDNA
AD-18282	82.47	140.32	ND	ND	ND	ND
AD-18283	106.54	182.78	ND	ND	ND	ND
AD-18284	106.93	151.78	ND	ND	ND	ND
AD-18285	26.58	60,05*	ND	0.089	ND	ND
AD-18286	109.95	173.66	ND	ND	ND	ND
AD-18287	54.23	155.45	ND	ND	ND	ND
AD-18288	73.52	174.09	ND	ND	ND	ND
AD-18289	103.36	174.76	ND	ND	ND	ND
AD-18290	17.06	52.04*	1.253	0.181	ND	ND
AD-18291	7.71	169.29*	1,304	0,019	ND	ND
AD-18292	7.51	210.03*	0.604	0.005	ND	ND
AD-18293	3.61	62.53*	0.078	0.003	ND	ND
AD-18294	111.53	107.56	ND	ND	ND	ND
AD-18295	115.88	105.37	ND	ND	ND	ND
AD-18296	57,03	38,03	ND	ND	ND	ND
AD-18297	87.69	73.87	ND	ND	ND	ND
AD-18298	10.39	7.25*	0.455	0.008	ND	ND
AD-18299	J 8.79	18.06*	0.895	0.014	ND	ND
AD-18300	108.70	ND	ND	ND	ND	ND
AD-18301	114.22	70.50	ND	ND	ND	ND
AD-18302	116.19	122.40	ND	ND	ND	ND
AD-18303	124.89	ND	ND	ND	ND	ND
AD-18304	132.99	89.54	ND	ND	ND	ND
AD-18305	153,10	ND	ND	ND	ND	ND
AD-18306	159.22	ND	ND	ND	ND	ND
AD-18307	116.83	84.57	ND	ND	ND	ND
AD-18308	156.72	87.80	ND	ND	ND	ND
AD-18309	113.22	101.97	ND	ND	ND	ND
AD-18310	132.33	ND	ND	ND	ND	ND
AD-18311	161.68	92 92	ND	ND	ND	ND
AD-18312	103.01	71.17	ND	ND	ND	ND
AD-18313	120.65	53.26	ND	ND	ND	ND
AD-18314	116.33	ND	ND	ND	ND	ND
AD-18315	115.13	ND	ND	ND	ND	ND
AD-18316	118.73	122.34	ND	ND	ND	ND
AD-18317	114.03	121.10	ND	ND	ND	ND
AD-18318	80.85	122.57	ND	ND	ND	ND
AD-183I9	119.14	148.87	ND	ND	ND	ND
AD-18320	22.86	55,43*	ND	0.023	0.403	ND
AD-18321	6.44	31.56*	0.001	0.033	ND	ND
AD-18322	54.21	100.46	ND	ND	ND	ND
AD-18323	6.37	28,71*	0,005	0,023	ND	ND

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Duplex #	Single Dose at lOtiM % relative to control	IC50 (nM)
HepG2	HepG2	Hep3B
«PCR	hDNA	qPCR	hDNA	qPCR	hDNA
AD-18324	2.53	15.98*	0.002	0.006	0.005	0,014
AD-18325	2.52	11,96*	0.001	0.016	ND	ND
AD-18326	18.34	43.16*	0.025	0.186	ND	ND
AD-18327	18.28	13.90*	0.044	0.215	ND	ND
AD-18328	4.53	26.04*	0.003	0.004	0.006	0.006
AD-18329	96.93	131.54	ND	ND	ND	ND
AD-18330	11.80	45.18*	0.0004	0.010	0.020	ND
AD-18331	117.77	163.07	ND	ND	ND	ND
AD-18332	11.53	35.09*	0.001	0.076	0.065	ND
AD-18333	12,24	46.94*	0.001	0.115	0.075	ND
AD-18334	16.27	55.28*	0.0004	0.181	1.071	ND
AD-18335	53.52	112.80	ND	ND	ND	ND
AD-18336	6.39	33.00*	0.001	0.112	0.081	ND
AD-18337	51.77	105.33	ND	ND	ND	ND
AD-18338	48,21	102.86	ND	ND	ND	ND
AD-18339	6.48	26.56*	0.004	0.002	0.018	0.029
AD-18340	4.53	30.76*	0.002	0.002	ND	ND
AD-18341	31.27	100.41	ND	ND	ND	ND
AD-18342	7.60	42.89*	ND	0.016	0.076	ND
AD-18343	3.42	17,45*	ND	0.001	ND	ND
AD-18344	75.08	134.31	ND	ND	ND	ND
AD-18345	13.62	42.75*	0.002	0.013	ND	ND
AD-18346	59.25	121.10	ND	ND	ND	ND
AD-18347	91.23	139.54	ND	ND	ND	ND
AD-18348	89.95	159.29	ND	ND	ND	ND
AD-18349	108.01	144.96	ND	ND	ND	ND
AD-18350	123.65	125.87	ND	ND	ND	ND
AD-18351	108.36	104.02	ND	ND	ND	ND
AD-18352	87.82	128.72	ND	ND	ND	ND
AD-18353	14.40	65.77	0.012	0.027	ND	ND
AD-18354	99.27	123.53	ND	ND	ND	ND
AD-18355	135.04	150.88	ND	ND	ND	ND
AD-18356	100.76	178.96	ND	ND	ND	ND
AD-18357	125.30	162.85	ND	ND	ND	ND
AD-18358	103.15	136.01	ND	ND	ND	ND
AD-18359	34.74	140.48	ND	ND	ND	ND
AD-18360	103.86	146.86	ND	ND	ND	ND
AD-18361	105.74	152.74	ND	ND	ND	ND
AD-18362	J 06.96	188.22	ND	ND	ND	ND
AD-18363	124.22	58.46	ND	ND	ND	ND
AD-18364	113.75	66.87	ND	ND	ND	ND
AD-18446	29.73	13,30	ND	ND	ND	ND

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

	Single Dose at lOtiM % relative to control	IC50 (nM)
Duplex #	HepG2	He	>G2	He	>3B
apcr	bDNA	qPCR	bDNA	qPCR	bDNA
AD-18447	109.74	53,63	ND	ND	ND	ND
AD-18448	22.96	8.81	ND	ND	ND	ND
AD-18449	112.59	50.11	ND	ND	ND	ND
AD-18450	89.41	34.89	ND	ND	ND	ND
AD-18451	74.35	23.88	ND	ND	ND	ND
AD-18452	125.25	54.86	ND	ND	ND	ND
AD-18453	126.98	56.31	ND	ND	ND	ND
AD-18454	113.88	52.48	ND	ND	ND	ND
AD-18455	163.00	48.89	ND	ND	ND	ND
AD-18456	15.70	10,52	ND	ND	ND	ND
AD-18457	12.86	8.22	ND	ND	ND	ND
AD-18458	13.00	7.00	ND	ND	ND	ND
AD-18459	14.41	10.72	ND	ND	ND	ND
AD-18460	121.16	74.87	ND	ND	ND	ND
AD-18461	100.53	71.87	ND	ND	ND	ND
AD-18462	47.75	29.35	ND	ND	ND	ND
AD-18463	58.98	44.79	ND	ND	ND	ND

The dose response data used to identify the IC50 for 5 TTR-dsRNAs (AD-18258, AD18274, AD-18324, AD-18328, and AD-18339), are presented in detail below in Table 9. All 5 siRNAs were determined to have pM IC50s. The IC50 data for dsRNAs in Table 8 is a summary of the data presented in Table 9 below.

Table 9. Dose response data for 5 TTR-dsRNAs

1	% inhibition relative to control AD-1955
Duplex AD-18258	Dose of duplex (nM)
Cell type	Detection method	ID	1	0.5	D.l	0.G5	0.01	0.005	0.001	0.0005	0.0001	0.00005	0.00001	ICSO(nM)
HepG2	qPCR	14.4	14.1	16,2	23.9	27.26	40.19	68.46	78.1	74.48	104.37	98.28	113.68	0.007
HepG2	bDNA	14,3	14.5	11.1	12.8	18.82	19.77	51.21	56.03	63,63	58.35	43.64	51.05	0,005
Hep3B	qPCR	11,9	8,62	12.4	16,4	28.35	30.49	58.36	54.57	81,26	89.43	81.85	101.87	0.004
Hep3B	bDNA	7.65	7.5	11.3	12.6	28.85	27.89	64.57	73.48	72.03	91.44	86.71	89.31	0.005

1	% inhibition relative to control AD-1955
Duplex AD-18274	Dose of duplex (nM)
Cell type	Detection method	10	1	0.5	0.1	0.05	0.01	0.005	0.001	0.0005	0.0001	0.00005	0.00001	IC50
HepG2	qPCR	6.68	8.45	11.7	24.2	42.08	49.89	56.95	62.99	64.47	54.92	67.39	72.67	0.009
HepG2	bDNA	27.5	69	25.2	34.2	73.03	103.4	121.57	97.31	154.93	156.7	Nd	152.25	0.176
Hep3B	qPCR	7.58	17	15.6	43.9	42.22	60.55	78,8	77.81	79,97	85.84	86.13	83.99	0.036
Hep3B	bDNA	3.77	4.92	7.51	15	35,21	51.66	72.45	70,12	78.31	77.52	90.72	83.01	0,012

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

						% inhibition relative to control AD-1955
Duplex AD-18324						Dose of duplex (nM)
Cell type	Detection method	10	1	0.5	0.1	G.05	0.01	0.005	0.001	0.0005	0.0001	0.00005	0.00001	iCSO (nM)
HepG2	qPCR	2.07	2.27	2.74	6.36	8.18	15.23	28.82	52.79	90.86	94.72	116.07	98.97	0.002
HepG2	bDNA	14.5	7.88	11.8	15.9	17.2	46.44	40.4	91.86	0	95.57	0	52.15	0.006
Hep3B	qPCR	2.07	3.48	5,76	16.2	18.73	44;54	49.77	68.88	63.48	76.61	74.7	77.83	0.005
Hep3B	bDNA	3,48	3.8	5.15	15.2	30.84	55.36	74.75	99.39	88.89	110.83	96.55	110.26	0.014

1	% inhibition relative to control AD-1955
Duplex AD-18 3 28	Dose of duplex |nM)
Cell type	Detection method	10	1	0.5	0.1	0.05	0.01	0.005	0.001	0.0005	0.0001	0.00005	0.00001	ICSO (nM)
HepG2	qPCR	5.85	3.97	3,32	5.62	8	16,75	55.01	39.76	122.41	102.37	114.02	124.09	0.003
HepG2	bDNA	12.3	10.7	10.7	11.9	20.06	25	69.52	57.29	112.28	98.14	142.26	148.92	0.004
Hep38	qPCR	3.17	5,52	11.7	13.8	27,68	39.58	61.21	61.87	9051	87.56	106.03	108.72	0,006
Hep3B	bDNA	3.08	3.66	4.19	7.25	21.05	22.1	73.74	63.19	105.55	96.27	10557	96.46	0.006

Γ	% inhibition relative to control AD-1955
Duplex AD-18339	Dose of duplex |nM|
Cell type	Detection method	10	1	0.5	0.1	0.05	0.01	0.005	0.001	0.0005	0.0001	0.00005	0.00001	ICSO (nW)
HepG2	qPCR	6.27	7.28	Nd	11	15.25	38.69	38.78	71.7	84.09	62.2	75.61	85.46	0,004
HepG2	bDNA	15.1	8.14	5.13	6.89	12.17	32.14	42.98	64.01	60.76	79.95	81.97	95.43	0.002
Hep3B	qPCR	8.3	9.47	13.2	34.5	44.54	77.38	81.04	81.41	93.95	81.04	75.61	78.28	0,018
Hep3B	bDNA	10.5	9.43	11.7	27.1	44,88	72.32	79.88	79.6	87.46	96.53	95.13	89.88	0.029

A summary of the single dose results for rodent specific TTR-dsRNAs (TTR siRNAs) are presented below in Table 10, Single dose results arc expressed as % TTR mRNA relative to control, assayed in rat H.4.II.E cells, after transfection of rodent specific TTR siRNAs at 10 nM.

These results show that some rodent specific TTR siRNAs are effective in suppressing endogenous rat TTR mRNA in vitro.

Table 10. Single dose results of in vitro screen of rodent specific TTR-dsRNAs (TTR siRNAs)

Duplex #	% Relative to control at 10 nM	Duplex #	% Relative to control at 10 nM
AD-18529	19.83	AD-18542	6,3
AD-18530	44.49	AD-18543	16.46
AD-18531	6.01	AD-18544	17.55
AD-18532	24.06	AD-18545	3.53
AD-18533	37.78	AD-18546	2.75
AD-18534	8.19	AD-18547	7.01
AD-18535	10.18	AD-18548	5.02
AD-18536	16.13	AD-18549	1.61
AD-18537	15.88	AD-18550	9.58
AD-18538	19.93	AD-18551	7.74
AD-18539	49.24	AD-18552	3.74
AD-18540	2.99	AD-18553	50,39
AD-18541	1.32	AD-18554	111.06

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Example 3. In vitro assay of TTR siRNAs for induction of TNF-α and IFN-a secretion

To evaluate potential for immunostimulation, TTR. siRNAs were assayed in vitro for induction of TNF-α and IFN-α secretion.

Human PBMC were isolated from freshly collected huffy coats obtained from healthy donors (Research Blood Components, Inc., Boston, MA) by a standard Ficoll-Hypaque density centrifugation. Freshly isolated cells (1 xl0⁵/well/I00μ1) were seeded in 96-well plates and cultured in RPMI 1640 GlutaMax medium (Invitrogen) supplemented with 10% heat inactivated fetal bovine serum and 1% antibiotic/antimycotic (Invitrogen):

siRNAs were transfected into PBMC using DOTAP transfection reagent (Roche Applied

Science). The DOTAP was first diluted in Opti-MEM (Invitrogen) for 5 minutes before mixing with an equal volume of Opti-MEM containing the siRNA. siRNA/DOTAP complexes were incubated as specified by the manufacturer’s instructions and subsequently added to PBMC (50pl/well) which were then cultured for 24 hours. Positive and negative control siRNAs were included in all assays. AD-5048 was used as a positive control siRNA. AD-5048 corresponds to a sequence that targets human Apolipoprotein B (Soutschck et al., 2004) and elicits secretion of both IFN-α and TNF-α in this assay. AD-I955, which does not elicit IFN-α and TNF-a secretion in this assay, was used as a negative control siRNA. All siRNAs were used at a final concentration of 133 nM. The ratio of RNA to transfection reagent wasl6.5 pmoles per pg of

DOTAP.

Cytokines were detected and quantified in culture supernatants with a commercially available ELISA kit for IFN-α (BMS2161NST) and TNF-α (BMS223INST), both from Bender MedSystems (Vienna, Austria). TTR siRNA cytokine induction is expressed as percent IFN-a or TNF-α produced relative to the positive control siRNA AD-5048.

IFN-a and TNF-α stimulation results for a number of TTR siRNAs are presented in FIG.

(mean of quadruplicate wells ± SD) and below' in Table 11 (percentage compared with AD5048). None of the TTR siRNAs evaluated induced significant TNF-α or IFN-a secretion by cultured human PBMCs.

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Table 11. IFN-a and TNF-g stimulation results for TTR siRNAs

Duplex #	IFN-a (% of AD-5048)	T\l « (% of AD-5048)
AD-18246	0	4
AD-18258	0	0
AD-18259	0	0
AD-18261	0	0
AD-18263	0	0
AD-18271	0	0
AD-18274	2	1
AD-18275	()	0
AD-18276	0	0
AD-18277	0	0
AD-18285	0	0
AD-18290	0	0
AD-18291	0	0
AD-18292	0	0
AD-18293	0	0
AD-18298	0	0
AD-18299	0	0
AD-18320	0	0
AD-18321	0	0
AD-18323	0	0
AD-18324	0	0
AD-18325	0	0
AD-18326	0	0
AD-18327	0	0
AD-18328	0	0
AD-18330	0	0
AD-18332	1	0
AD-18333	0	1
AD-18334	0	1
AD-18336	1	0
AD-18339	0	0
AD-18340	0	0
AD-18342	0	0
AD-18343	0	0
AD-18345	0	0
AD-18353	0	0
AD-18448	0	0
AD-18456	0	0
AD-18457	0	0
AD-18458	0	0
AD-18459	0	0

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

The five lead TTR targeting dsRNAs (TTR siRNAs) were selected based on IC50s in the pM range in the human hepatocyte cell lines HepG2 and Hep3B, and the absence of immunostimulatory activity. Duplexes without any mismatches are more likely to achieve significant knockdown of the target transcript than duplexes with mismatches between the oligo 5 and the mRNA. To better enable interpretation of cross-species toxicology data and to have the broadest applicability to human patients, duplexes that have 100% identity in orthologous genes from rat, cynomolgus monkey and human, and that do not target regions with known polymorphisms are generally preferred. The five lead compounds were selected based on 1C50 in hepatocyte cell lines in the pM range, the absence of immunostimulatory activity, specificity 10 to the human TTR transcripts, and absence of known polymorphisms (mutations) in the region of the mRNA targeted by the duplex. In the case of TTR, no 19 base oligos were found with complete identity in human, rat and cynomolgus monkey. A summary of these data are presented in Table 12, which also includes information on known TTR mutations in the region targeted by the duplex and cross-spccics reactivity,

Table 12. Summary of data for five most potent TTR dsRNAs.

Duplex #	IC50 (qPCR): nM HepG2	IC50 (bDNA): nM HcpG2	IFNa/TNFa	Mutations not covered	Cross-spccics reactivity
AD-18258	0.007	0.005	Negative	None (non-coding region)	Cyno: I mismatch &, position14 A to GRat: no homology at any position
AD-18274	0.009	0.176	Negative	Lys70Asn;Val71Ala;Iie73Val;Asp74His	Cyno: no mismatchRai: no homology at any position
AD-18324	0.002	¢),006	Negative	None (non-coding region)	Cyno: no mismatchRat: no homology at any position
AD-18328	0.003	0.004	Negative	None (non-coding region)	Cyno: no mismatch Rat: 7 mismatches
AD-18339	0.004	0.002	Negative	None (non-coding region)	None

Example 4. In vivo reduction of liver TTR mRNA and plasma TTR protein by

LNP01-18324, LNP01-18328 and LNP01-18246 in transgenic mice

Two TTR siRNAs, AD-18324 and AD-18328, were chosen for in vivo evaluation. These duplexes exhibited potent dose-dependent silencing in vitro in hepatocyte cell lines (e.g.

HepG2). FIG. 2A and FIG. 2B show the dose responses in HepG2 cells after transfection with

WO 2011/123468

PCT/US2011/030392

AD-18324 (FIG. 2A) or AD-18328 (FIG. 2B) where the doses are expressed in nM on the x-axis and the responses are expressed as fraction TTR mRNA remaining relative to control, on the yaxis. In HepG2 cells, the IC50s of AD-18324 and AD-18328 were determined to be 2 pM and 3 pM, respectively. The TTR target sites for both lead dsRNA candidates are in the 3’ untranslated region of the TTR mRNA, in a region where there are no reported mutations in the literature.

2017204161 20 Jun 2017

The sequences of each strand of the two lead candidates are reproduced below from the

Tables. Strand: s= sense; as= antisense; Position: position of 5' base on transcript

NM 000371.2.

Duplex #	Strand	Oligo #	Position*	Sequence 5' to 3'	SEQ IDNO:
AD-18324	3	A-32337	509	GGAu UU cAuGuAAccAAGAdTdT	1001
AD-18324	as	A-32338	527	UCUUGGUuAcAUGAAAUCCdTdT	1002
AD-18328	s	A-32345	518	GuAAccAAQAGuAuuccAudTdT	1009
AD-18328	as	A-32346	536	AQGGAAuACUCUUGGUuACdTdT	1010

In addition, a rodent cross-reactive TTR dsRNA, AD-18246, was chosen for further evaluation in vivo. AD-18246 targets a sequence beginning at position 88 of the open reading frame, where there are three mutations reported in the literature. A dose response curve for AD18246 in HcpG2 cells is shown in FIG. 3. AD-18246 is substantially less potent than AD-18324 15 and AD-18328; the IC50 of AD-18246 was determined to be 265 pM.

AD-18324, AD-18328, and AD-18246 were administered to transgenic mice after formulation in LNP01,3-5 month old H129-mTTR-KO/iNOS-KO/hTTR transgenic mice (mouse transthyretin knock-out/ inducible nitric oxide synthase knock-out/human transthyretin transgenic) were intravenously (IV) administered 200 μΐ of LNP01-formulated transthyretin20 specific siRNA (AD-18324, AD-18328, or AD-18246), LNP01-formulated control siRNA targeting the non-mammalian luciferase gene (AD-1955) or PBS via the tail vein at concentrations of 1.0 mg/kg, 3.0 mg/kg, or 6.0 mg/kg for siRNAs AD-18324 and AD-18328, 3.0 mg/kg for siRNA AD-18246, and 6.0 mg/kg for siRNA AD-1955. LNP01 is a lipidoid formulation comprised ofND98, Cholesterol, and PEG-Ceramide C16.

After approximately forty-hours, mice were anesthetized with 200 μΐ of ketamine, and then exsanguinated by severing the right caudal artery. Whole blood was isolated and plasma was isolated and stored at -80° C until assaying. Liver tissue was collected, flash-frozen and stored at -80°C until processing.

100

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Efficacy of treatment was evaluated by (i) measurement of TTR. mRNA in liver at 48 hours post-dose, and (ii) measurement of TTR protein in plasma at prebleed and at 48 hours post-dose. TTR liver mRNA levels were assayed utilizing the Branched DNA assaysQuantiGcne 2.0 (Panomics cat #: QS0011). Briefly, mouse liver samples were ground and tissue 5 lysates were prepared. Liver lysis mixture (a mixture of 1 volume of lysis mixture, 2 volume of nuclease-free water and lOul of Proteinase-K/mI for a final concentration of20mg/ml) was incubated at 65 °C for 35 minutes. 20μ1 of Working Probe Set (TTR probe for gene target and GAPDH for endogenous control) and 80ul of tissue-lysate were then added into the Capture Plate. Capture Plates were incubated at 55 °C ±1 °C (aprx. 16-20hrs). The next day, the Capture 10 Plate were washed 3 times with IX Wash Buffer (nuclease-frec water, Buffer Component 1 and Wash Buffer Component 2), then dried by centrifuging for 1 minute at 240g. lOOul of preAmplifier Working Reagent was added into the Capture Plate, which was sealed with aluminum foil and incubated for 1 hour at 55°C ±1°C. Following 1 hour incubation, the wash step was repeated, then 100μΙ of Amplifier Working Reagent was added. After 1 hour, the wash and dry 15 steps were repeated, and 100μ1 of Label Probe was added. Capture plates were incubated 50 °C ±1 °C for 1 hour. The plate was then washed with IX Wash Buffer, dried and 1 OOul Substrate was added into the Capture Plate. Capture Plates were read using the SpcctraMax Luminometcr following a 5 to 15 minute incubation. bDNA data were analyzed by subtracting the average background fiani each triplicate sample, averaging the resultant triplicate GAPDH (control probe) and TTR (experimental probe) values, and then computing the ratio: (experimental probebackground)/(control probe-background).

TTR plasma levels were assayed utilizing the commercially available kit “AssayMax Human Prealbumin ELISA Kit” (AssayPro, St. Charles, MO, Catalog# EP3010-1) according to manufacturer’s guidelines. Briefly, mouse plasma was diluted 1:10,000 in IX mix diluents and 25 added to pre-coated plates along with kit standards, and incubated for 2 hours at room temperature followed by 5X washes with kit wash buffer. Fifty microliters of biotinylated prealbumin antibody was added to each well and incubated for 1 hr at room temperature, followed by 5X washes with wash buffer. Fifty microliters of strcptavidin-peroxidasc conjugate was added to each well and plates were incubated for 30 minutes at room temperature followed 30 by washing as previously described. The reaction was developed by the addition of 50 μΐ/well of chromogen substrate and incubation for 10 minutes at room temperature with stopping of reaction by the addition of 50 μΐ/well of stop solution. Absorbance at 450 nm was read on a Versamax microplate reader (Molecular Devices, Sunnyvale, CA) and data were analyzed utilizing the Softmax 4.6 software package (Molecular Devices).

101

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

LNP01-18324 and LNPO1-18328 were found to reduce liver TTR mRNA (FIG. 4A) and plasma TTR protein (FIG. 4B) levels in a dose-dependent manner with IV bolus administration. The mRNA ED50 of LNP01-18328 was determined to be ~I mg/kg whereas the ED50 of LNPO 1-18324 was determined to be ~ 2 mg/kg. The effects of LNPO 1-18324 and LNPO 1-18328 5 were specific, because the control, LNPO 1 -1955 at 6 mg/kg, did not significantly affect liver TTR mRNA levels, as compared with the PBS group. LNP01-18324 and LNPOl-18328 reduced plasma TTR protein levels relative to the PBS group, with potencies that were similar to those on TTR mRNA levels. At 3 mg/kg, LNP01-18246 reduced liver TTR mRNA levels to a lessor extent than 3 mg/kg LNP01-18324 or LNPOl-18328.

These results demonstrate that LNPO 1 -18324 and LNP01 -18328, administered by IV bolus, substantially reduce human TTR mRNA expressed by the transgenic mouse liver, which results in reduction of human TTR protein in the circulation.

Example 5. In vivo reduction of wild-type TTR mRNA hi the non-human primate liver bv SNALP-18324 and SNALP-f8328

To evaluate the efficacy of TTR siRNAs AD-18324 and AD-18328 in non-human primates on liver TTR mRNA levels, the siRNAs were formulated in SNALP and administered by 15-minute IV infusion. Cynomolgus monkeys (Macaco fascicularis) (2 to 5 kg, 3 animals per group) were administered 15-minutc IV infusions of SNALP-18324 (0.3, 1.0 or 3.0 mg/kg), SNALP-18328 (0.3, 1 or 3 mg/kg), or SNALP-1955 (3 mg/kg, with negative control siRNA AD20 1955 which targets the non-mammalian gene luciferase). At forty-eight hours post-dosing, monkeys were anesthetized with sodium pentobarbital and exsanguinated. Liver tissue for TTR mRNA determination was collected, flash-frozen, and stored at -80°C until processing.

TTR mRNA levels in the liver were assayed utilizing a custom designed Branched DNA assay, utilizing the QuantiGenel .0 technology. Briefly, monkey liver samples were ground and 25 tissue lysates were prepared. Liver lysis mixture (1 volume lysis mixture, 2 volume nucleasefree water, and 10μ1 of Proteinase-K/m I fora final concentration of20mg^zml) was incubated at 65°C for 35 minutes. 20μ1 Working Probe Set (TTR probe for gene target and GAPDH for endogenous control) and 80μ1 tissue-lysate were then added into the Capture Plate. Capture Plates were incubated at 55°C ±1°C (approx. 16-20hrs). The next day, the Capture Plates were 30 washed three times with IX Wash Buffer (nuclease-free water. Buffer Component 1 and Wash Buffer Component 2), then dried by centrifuging for 1 minute at 240g. 100μ1 of pre-Amplificr Working Reagent was added into the Capture Plate, which was sealed with aluminum foil and incubated for 1 hour at 55°C ±1°C. Following a 1-hour incubation, the wash step was repeated, and then 100μΙ Amplifier Working Reagent was added. After 1 hour, the wash and dry steps

102

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 were repeated, and ΙΟΟμΙ Label Probe was added. Capture plates were incubated 50°C ±1°C for

I hour. The plates were then washed with IX Wash Buffer and dried, and then ΙΟΟμΙ Substrate was added into the Capture Plate. Capture Plates were read using the SpcctraMax Luminometcr following a 5 to 15 minute incubation. bDNA data were analyzed by (i) subtracting the average background from each triplicate sample, (ii) averaging the resultant GAPDH (control probe) and TTR (experimental probe) values, and then (Hi) taking the ratio: (experimental probebackground)/! control probe-background).

The results are shown in FIG. 5. SNALP -18324 and SNALP -18328 reduced TTR mRNA levels in the liver in a dose-dependent manner, compared to the negative control

SNALP-1955. The mRNA ED50s of SNALP-18328 and SNALP-18324 were determined to be

-0.3 and - 1 mg/kg, respectively.

These results demonstrate that SNALP-18324 and SNALP-18328 are effective in suppressing wild-type TTR mRNA in non-human primate liver when administered by IV infusion.

Example 6. In vivo reduction of mutant (V30M) TTR mRNA and protein by

SNALP-18328 in the transgenic mouse

To evaluate the efficacy of TTR siRNA AD-18328 on mutant (V30M) TTR mRNA in the liver and mutant (V30M) TTR protein in the serum, AD-18328 was formulated in SNALP and administered by IV bolus to V30M hTTR transgenic mice. 8 to 12-week old V30M hTTR 20 transgenic mice (5 animals/ group) were intravenously (IV) administered 200 μΐ SNALP-18328 (0.03, 0.3 or 3 mg/kg), SNALP-1955 (3 mg/kg, with negative control siRNA AD-1955 which targets the non-mammalian gene luciferase), or PBS. Mice used were the Mus musculus strain H129-11TTR KO from Institute of Molecular and Cellular Biology, Porto, Portugal. Briefly, hTTR Hl 29 transgenic mice were crossed with a H129 endogenous TTR KO mice (null mice to 25 generate the H 129-hTTR transgenic mice, in a null mouse TTR background (Maeda, S., (2003), Use of genetically altered mice to study the role of serum amyloid P component in amyloid deposition. Amyloid Suppl. 1, 17-20.).

At 48 hrs post-injection, animals in all five treatment groups were given a lethal dose of ketamine/xyEazine. Scrum samples were collected and stored at -80°C until analysis. Liver 30 tissue was collected, flash-frozen and stored at -80oC until processing.

For TTR mRNA quantitation, frozen liver tissue was ground into powder, and lysates were prepared. TTR mRNA levels relative to those of GAPDH mRNA were determined in the lysates by using a branched DNA assay (QuantiGene Reagent System, Panomics, Fremont, CA).

103

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Briefly, the QuantiGcnc assay (Gcnospcctra) was used to quantify mRNA levels in tissue sample lysates according to the manufacturer’s instructions. The mean level of TTR mRNA was normalized to the mean level of GAPDH mRNA for each sample. Group means of the normalized values were then further normalized to the mean value for the PBS treated group, to obtain the relative level of TTR mRNA expression.

For TTR protein quantitation, serum was assayed using the AssayPro (St. Charles, MO) Assaymax PreAlbumin ELISA Kit according to the manufacturer’s protocol.

The results are shown in FIG. 6A and FIG. 6B for liver mRNA and serum protein, respectively. SNALP-18328 treated V30M hTTR transgenic mice had a dose-dependent and 10 significant decrease in liver TTR mRNA levels relative to the PBS control group, reaching a maximum reduction of 97% (p < 0.001) at 3 mg/kg SNALP-18328, and a 50% reduction (ED50) at ~ 0.15 mg/kg SNALP-18328. Serum TTR protein was also suppressed in a dose-dependent manner, with a maximum reduction of serum TTR protein of 99% (p < 0.01) (relative to predose levels) at 3 mg/kg SNALP-18328, consistent with the reduction in TTR mRNA levels.

SNALP-1955 at 3 mg/kg did not have a statistically significant effect on either TTR mRNA or protein levels, compared to PBS.

These results demonstrate that SNALP-18328, when administered IV, is active in suppressing mutant V30M TTR mRNA in the transgenic mouse liver, which results in reduction of mutant V30M TTR protein in the circulation,

Example 7. Durability of TTR mRNA and protein suppression bv SNALP-18328 in the transgenic mouse

To evaluate the durability of TTR mRNA and protein suppression by SNALP-18328, AD-18328 was formulated in SNALP and administered by IV bolus to V30M hTTR transgenic mice. At various timepoints post-dose, liver TTR mRNA levels and scrum TTR protein levels 25 were quantified. 8- to 12-week old V30M hTTR transgenic mice (4 animals/ group) were intravenously (IV) administered 200 μΐ SNALP-18328 (I mg/kg)or SNALP-1955 (1 mg/kg, with negative control siRNA AD-1955 which targets the non-mammalian gene luciferase). Mice used were Mus musculus strain H 129-hTTR KO from Institute of Molecular and Cellular Biology, Porto, Portugal. Briefly, hTTR Hl29 transgenic mice were crossed with a H129 endogenous TTR KO mice (null mice to generate the H 129-hTTR transgenic mice, in a null mouse TTR background (Maeda, S., (2003), Use of genetically altered mice to study the role of serum amyloid P component in amyloid deposition. Amyloid Suppl. 1, 17-20). Days 3, 8, 15, or 22 post-dose, animals in both treatment groups were given a lethal dose of ketamine/xylazinc.

104

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Serum samples were collected and stored at -80°C until analysis. Liver tissue was collected, flash-frozen and stored at -80”C until processing.

For TTR. mRNA quantitation, frozen liver tissue was ground into powder, and lysates were prepared. TTR mRNA levels relative to those of GAPDH mRNA were determined in the 5 lysates by using a branched DNA assay (QuantiGcnc Reagent System, Panomics, Fremont, CA). Briefly, the QuantiGene assay (Genospectra) was used to quantify mRNA levels in tissue sample Lysates according to the manufacturer’s instructions. The mean level of TTR mRNA was normalized to the mean level of GAPDH mRNA for each sample. Group means of the normalized values were then further normalized to the mean value for the PBS treated group, to 10 obtain the relative level of TTR mRNA expression.

For TTR protein quantitation, scrum was assayed using the AssayPro (St. Charles, MO) Assaymax PreAlbumin ELISA Kit according to the manufacturer's protocol.

The results arc shown in FIG. 7A and FIG. 7B for liver mRNA and scrum protein, respectively. A single IV bolus administration of SNALP-18328 in the hTTR V30M transgenic 15 mouse resulted in durable inhibition of TTR mRNA levels in the liver and TTR protein levels in the serum. Compared to the control group (1 mg/ml SNALP-1955), a single IV administration of SNALP-18328 at I mg/kg significantly reduced relative TTR mRNA levels on Days 3, 8, 15 and 22 post-dose by 96% (p < 0.001), 90% (p < 0.001), 82% (p < 0.001) and 73% (p < 0.001), respectively, and did not return to baseline levels at termination of the study (Day 22 post-dose).

Protein levels also decreased with a maximum reduction of scrum TTR of 97% (p < 0.001) (relative to SNALP-1955) at Day 3 post-dose. At Days 8, 15, and 22 post-dose, TTR protein levels were suppressed by 72% (p < 0.05), 32% (p < 0.05), and 40% (p < 0.001), respectively, relative to SNALP-1955.

These results demonstrate that a single IV administration of SNALP-18328 produces durable suppression of target liver mRNA and serum protein levels in the V30M hTTR transgenic mouse, with significant reductions of both liver TTR mRNA and serum TTR protein at 22 days post-dose.

Example 8. Durability of serum TTR protein and liver mRNA suppression by SNALP-18328 in the non-human primate

To evaluate the durability of serum TTR protein suppression by SNALP-18328, AD18328 was formulated in SNALP and administered by IV infusion to non-human primates. At various timepoints post-dose, scrum TTR protein levels were quantified.

105

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

C'ynomolgus monkeys (Macacofascicularis) (n= 5 animals/group for SNALP-18328 groups and n = 3 animals/group for SNALP-1955 and PBS groups) were administered a 15minute IV infusion of SNALP-18328 (0.3, 1 or 3 mg/kg), SNALP-1955 (3 mg/kg) with negative control siRNA AD-1955 which targets the non-mammalian gene luciferase), or PBS. At Days 0,

1,2, 3, 4, 5, 7, 10, and 14 of the dosing phase, scrum samples were collected and stored at -80°C until analysis.

Western blot analysis was used to evaluate TTR protein levels in scrum samples. Scrum samples from each group were pooled and diluted 1:1 with Laemmli sample buffer (βmcrcaptocthanol was added at a 1:20 dilution). The samples were heated at 95°C for 10 minutes. 12.5 μΙ of each sample was loaded in each lane of a 10-20% Criterion (Biorad, Hercules, CA) prep gel and separated by SDS-PAGE at I20V for 1.5 hrs, then transferred to a nitrocellulose membrane using a semi-dry system at 15V for 1 hour. The membrane was blocked overnight at 4°C in LiCOR (Lincoln, NE) blocking buffer diluted 1:1 with IX PBS, The blot was probed first with primary antibodies (goat anti-TTR from Santa Cruz (Santa Cruz,

CA) at a dilution of 1:1000 diluted in LiCOR blocking buffer/PBS on a rocker for I hr at room temperature. Blots were washed 4X with PBS + 0.2% Tween 20 (10 minutes per wash). The fluorescent labeled secondary antibodies (anti-goat 680nm from Invitrogen (Carlsbad, CA) were added at a dilution of 1:10,000 in LiCOR blocking buffer/PBS and the blot was incubated for 1 hour at room temperature. After incubation, blots were washed 4X with PBS + 0.2% Tween 20 20 followed by one wash with IX PBS. The Li-COR’s Odyssey Infrared Imaging System was used to detect the protein bands. TTR monomer migrates at 15 kDa.

The results are shown in FIG. 8. Serum TTR protein levels showed a dose-dependent reduction with 1 or 3 mg/kg SNALP-18328, as compared to pre-dose (Day 0) levels. The duration of suppression, following a single IV administration of SNALP-18328 is at least 14 25 days after I or 3 mg/kg SNALP-18328 treatment.

These results demonstrate that a single IV administration of SNALP-18328 produces durable suppression of TTR protein in the circulation in the non-human primate (Macaco fascicularis), with significant reduction of TTR protein at 14 days post-dose.

To evaluate the durability of liver TTR mRNA suppression by SNALP-18328, AD30 18328 was formulated in SNALP (ALN-TTR01) and administered by single IV infusion to nonhuman primates . Liver mRNA levels wer measured as described herein at day 3 or day 30 postadministration.

106

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

The results arc shown in FIG. 20 and demonstrate that ALN-TTR01 suppression of wild type TTR mRNA is durable in non-human primates after 3 days for dosages 1.0 and 3.0 mg/kg and for 30 days at a dose of 10 mg/kg.

Example 9: In vivo reduction of mutant (V30M) TTR in peripheral tissues bv

SNALP-18328 in the transgenic mouse

Propylactic efficacy

To evaluate the efficacy of SNALP-18328 (ALN-TTR01) in reducing TTR in peripheral tissues, hTTR V30M/HSF-1 knock-out mice were evaluated with immunohistochemical staining for TTR. Two-month old hTTR V30M/HSF-1 knock-out mice (Maeda, S., (2003), Use of genetically altered mice to study the role of serum amyloid P component in amyloid deposition. Amyloid Suppl. 1, 17-20) were administered an IV bolus of 3 mg/kg SNALP-18328 (12 animals), 3 mg/kg SNALP-1955 (with negative control siRNA AD-1955 which targets the nonmammalian gene luciferase, 4 animals), or PBS (4 animals) once every two weeks for a total of four doses on days 0, 14, 28, and 42. TTR liver mRNA levels and TTR-immunoreactivity in multiple peripheral tissues were evaluated at 8 weeks post-first dose on day 56.

Mice were anesthetised with I mg/kg medetomidine, and given a lethal dose of ketamine. Tissues and organs of interest were collected. For immunohistochemistry, esophagus (E), stomach (S), intestine (duodenum (11) and colon (14)), nerve (N) and dorsal root ganglia (D) were fixed in neutral buffered formalin and embedded in paraffin. For TTR detection, rabbit anti-human TTR primary antibody (1:1000, DAKO, Denmark), and anti-rabbit biotin-conjugatcd secondary antibody (1:20 Sigma, USA) were followed by extravidin labelling (1:20, Sigma, USA) in order to stain for the TTR protein. The reaction was developed with 3-amino-9-cthyl carbaxole, AEC (Sigma, USA). Semi-quantitative analysis of immunohistochemical slides was performed using Scion image quant program that measures the area occupied by the substrate reaction color and normalizes this value to the total image area. Mean values of % occupied area arc displayed with the corresponding standard deviation. Each animal tissue was evaluated in four different areas. The presence of human TTR in parasympathetic ganglia of the stomach and intestine was studied by double immuno fluorescent staining with rabbit anti-human TTR (1:1000, DAKO, Denmark) and mouse anti-PGP9.5 (1:40, Serotec, US A) as the primary antibodies; secondary antibodies were, respectively: anti-rabbit Alexa Fluor 488 (Molecular probes, UK)and goat anti-mouse Alexa Fluor 568 (Molecular probes, UK). Slides were mounted with vectashield ( Vector) and visualized in a Zeiss Cell Observer System microscope (Carl Zeiss, Germany) equipped with filters for FITC and rhodamine.

107

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

The results arc graphed in FIG. 9. In contrast with PBS and SNALP-I955 treated animals, SNALP-18328 treated animals had a significant reduction of TTR-immunoreactivity in all tissues examined (esophagus (E), stomach (S), intestine (duodenum (II) and colon (14)), nerve (N) and dorsal root ganglia (D).

These results demonstrate that SNALP-18328 administration to hTTR V30MZHSF-1 knock-out mice causes a significant reduction of TTR protein deposition in peripheral tissues and organs, including esophagus, stomach, intestine (duodenum and colon), nerve, and dorsal root ganglion.

Therapeutic efficacy

ALN-TTR01 was administered to mature hTTR V30M/HSF-1 knock-out mice to determine the effects of TTR siRNA treatment on regression of mutant human TTR deposits.

Groups of 21 month old animals (hTTR V30M/HSF-1 knock-out mice) were intravenously administered an IV bolus of ALN-TTR01 or control siRNA at a dose of 3 mg/kg on days 0, 14, 28, 14, 56, and 70. On day 77, the mice were euthanized, tissue was harvested, and TTR deposition was assayed via scmi-quantitativc analysis of immunohistochemical stained slides using Scion image quant program as described herein. Esophagus, colon; stomach, sciatic nerve; and dorsal root ganglia tissue were examined and results were compared to historical data in this animal model demonstrating both TTR deposition and TTR fibrils present in tissues at this age.

The results are shown in the graph in FIG. 21. The results demonstrate that treatment with TTR siRNA resulted in >90% regression of existing V30M hTTR tissue deposits.

Example 10. In vivo reduction of wild-type TTR mRNA in the non-human primate liver by XTC-SNALP-18328

To evaluate the efficacy of the novel lipid nanoparticle formulation XTC-SNALP for delivery of siRNA in non-human primate, TTR siRNA AD-18328 was formulated in XTCSNALP (XTC-SNALP-18328) and administered by 15-minute IV infusion, and liver TTR mRNA was quantified. Cynomolgus monkeys (Macaco fascicularis) were administered 15minutc IV infusions of XTC-SNALP-18328 (0.03, 0.1, 0.3 or 1 mg/kg) or XTC-SNALP-1955 (1 mg/kg, with negative control siRNA AD-1955 which targets the non-mammalian gene luciferase). At forty-eight hours post-dosing, monkeys were anesthetized with sodium pentobarbital and exsanguinated. Liver tissue for TTR mRNA determination was collected, flash-frozen, and stored at -80°C until processing. Methods used for TTR mRNA quantitation in liver tissue were similar to those described in Example 5 above.

108

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

The results arc shown in FIG. 10. XTC-SNALP -18328 reduced TTR mRNA levels in the liver in a dose-dependent manner, compared to the negative control XTC-SNALP -1955.

The mRNA ED50 was determined to be ~ 0.1 mg/kg XTC-SNALP -18328.

These results demonstrate that XTC-SNALP-18328 is effective in suppressing wild-type

TTR mRNA in non-human primate liver when administered by IV infusion.

Example 11; In vivo reduction of wild-type TTR mRNA in the non-human primate liver bv LNP09-18328 and LNP11-18328

To evaluate the efficacy of two novel lipid nanoparticle formulations, LNP09 and

LNP11, for delivery of siRNA in non-human primate, TTR siRNA AD-18328 was formulated in

LNP09 (LNP09-18328) or LNP11 (LNP11-18328), and administered by 15-minute IV infusion, and liver TTR mRNA and serum TTR protein levels were assayed. Cynomolgus monkeys (Macaco fascicularis) were administered 15-minute IV infusions of LNP09-18328 (0.03, 0.1, or 0.3 mg/kg), LNP11-18328 (0.03, 0.1, or 0.3 mg/kg), or PBS. Liver biopsy samples were collected at 48 hrs post-dosing, flash-frozen, and stored at -80 C until processing. Serum was collected before dosing (pre-blccd), and on Days 1, 2, 4, 7, 14, 21 and 28 post-dosing and stored at -80°C until processing. Methods used for TTR mRNA quantitation in liver tissue and serum TTR protein evaluation were similar to those described in Examples 5 and 8 above.

The results are shown in FIG. 11A for mRNA, and in FIG. 1 IB and FIG. 11C for protein. LNP09-18328 and LNP11-18328 treated animals showed a dose-dependent decrease in TTR mRNA levels in the liver, reaching a maximum reduction at 0.3 mg/kg of ~ 85% (LNPOO18328) and ~ 90% (LNP11-18328) mRNA relative to the PBS control. The mRNA ED50 was determined to be - 0,02 mg/kg for both LNP09-18328 and LN Pl 1-18328. At Day 7 postdosing, serum samples also exhibited a dose-dependent reduction of TTR protein for 0.1 and 0.3 mg/kg LNP09-18328 and LNP11-18328, compared to PBS control levels. FIG. 11C shows a decrease in TTR protein levels with a 0.3mg/kg dose of LNPQ9-18328 that persisted over at least days post-dosing, as compared to the PBS control group and as compared with the prc-blced samples.

109

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

These results demonstrate that LNP09-18328 and LNP11-18328 are effective in suppressing wild-type TTR mRNA in non-human primate liver and wild-type TTR protein in the circulation, when administered by IV infusion. Furthermore, the suppression with LN09-18328 is durable, persisting for at least 28 days following the IV infusion.

Example 12: In vivo reduction of wild-type TTR mRNA in the non-human m iniate liver by LN Pl 2-18328

LNP12 formulated AD-18328 was administered to non-human primates to evaluate the efficacy of this formulation.

LNP12-18328 formulations were prepared using a method adapted from Jeffs et al. (Jeffs 10 LB, et al. (2004) A Scalable, Extrusion-Free Method for Efficient Liposomal Encapsulation of Plasmid DNA. Pharm Res 22:362-372) Briefly, Tech-Gl (described above), distcaroyl phosphatidylcholine (DSPC), cholesterol and mPEG2000-DMG were solubilized in 90% ethanol at a molar ratio of 50:10:38.5:1.5. The siRNA was solubilized in 10 mM citrate, pH 3 buffer at a concentration of 0.4 mg/mL. The ethanolic lipid solution and the aqueous siRNA solution were 15 pumped by means of a peristaltic pump fitted with dual pump heads at equivalent volumetric flow rates and mixed in a “Τ’’-junction. Lipids were combined with siRNA at a total lipid to siRNA ratio of 7:1 (wt;wt). The spontaneously formed LNP 12-18328 formulations were dialyzed against PBS (155mM NaCl, 3mM Na2HPO4, ImM K.H2PO4, pH 7.5) to remove ethanol and exchange buffer. This formulation yields a mean particle diameter of SOnrn with approximately 90 percent siRNA entrapment efficiency.

Cynomolgus monkeys (n = 3 per group) received either PBS or 0.03, 0.1, or 0.3 mg/kg LNP12-18328 as 15 minute intravenous infusions (5 mL/kg) via the cephalic vein. Liver biopsies were collected from animals at 48 hours post-administration. TTR mRNA levels relative to GAPDH mRNA levels were determined in liver samples as described herein.

As shown in FIG. 19, high levels of specific knockdown of the wild -type transthyretin (TTR) gene was observed at doses as low as 0.03 mg/kg. This demonstrated that the LNP 12 formulation facilitates gene silencing at orders-of-magnitude lower doses than required by any previously-described siRNA liver delivery system.

Example 13. Synthesis of TTR Tiled Sequences

A set of TTR duplexes (“tiled duplexes”) were designed that targeted the TTR gene near the target region of AD-18328, which targets the human TTR gene starting at nucleotide 628 of NM_000371.3.

110

2017204161 20 Jun 2017

WO 2011/123468 PCT/US2011/030392

In the examples below, the numbering representing the position of the 5’ base of an siRNA on the transcript is based on NM_000371.3 (FIG. 12; SEQ ID NO:1331). In the examples shown above, the numbering for siRNA targeting human siRNA was based on NM-000371.2 (FIG. 13A). NM_000371.3 extends the sequence of the 5’ UTR by 110 bases compared to NM_000371.2, as shown in FIG. 14. Thus, as an example, the starting position of AD-18328 is 628 on NM_000371.3 and 518 on NM_000371.2 (FIG. 14).

TTR tiled sequences were synthesized on McrMade 192 synthesizer at lumol scale. For all the sequences in the list, ‘endolight’ chemistry was applied as detailed below.

• All pyrimidines (cytosine and uridine) in the sense strand contained 2’-O-Methyl bases (2’ O-Mcthyl C and 2’-O-Methyl U) • In the antisense strand, pyrimidines adjacent to(towards 5’ position) ribo A nucleoside were replaced with their corresponding 2-O-Methyl nucleosides • A two base dTdT extension at 3 ’ end of both sense and anti sense sequences was introduced • The sequence file was converted to a text file to make it compatible for loading in the MerMade 192 synthesis software

Synthesis. Cleavage and deprotection:

The synthesis of TTR sequences used solid supported oligonucleotide synthesis using phosphoramidite chemistry. The synthesis of the sequences was performed at 1 urn scale in 96 well plates. The amidite solutions were prepared at 0.1 M concentration and ethy! thio tctrazole (0.6M in Acetonitrile) was used as activator. The synthesized sequences were cleaved and deprotected in 96 well plates, using methylamine in the first step and fluoride reagent in the second step. The crude sequences were precipitated using acetone: ethanol (80:20) mix and the pellet were re-suspended in 0.2M sodium acetate buffer. Samples from each sequence were analyzed by LC-MS to confirm the identity, UV for quantification and a selected set of samples by IEX chromatography to determine purity.

Purification and desalting:

TTR tiled sequences were purified on A KTA explorer purification system using Source 15Q column. A column temperature of 65C was maintained during purification. Sample injection and collection was performed in 96 well (1.8mL -deep well) plates. A single peak corresponding to the full length sequence was collected in the eluent. The purified sequences were desalted on a Sephadex G25 column using AKTA purifier. The desalted TTR sequences were analyzed for concentration (by UV measurement at A260) and purity (by ion exchange HPLC). The single strands were then submitted for annealing.

Ill

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

TTR Single strands and duplexes:

A detailed list of TTR tiled duplexes and corresponding single strands (sense and antisense) arc shown in the table below (Table 13).

Table 13: TTR tiled duplexes and corresponding single strands

Strand: s= sense; as= antisense; Position: position of 5' base on transcript (NM_000371.3, SEQ ID NO: 1331).

Duplex#	Position	Oligo #	Strand	Sequence (S' to 3)	SEQ ID NO:
AD-18323	618	A-32335	S	GGGAuuucAuGuAAccAAGdTdT	1332
		A-32336	AS	CUUGGUuAcAUGAAAUCCCdTdT	1333
AD-18324	619	A-32337	S	GGAuuucAuGuAAccAAGAdTdT	1334
		A-32338	AS	UCUUGGUuAcAUGAAAUCCdTdT	1335
AD-23000	620	A-42927	S	GAuuucAuGuAAccAAGAGdTdT	1336
		A-42928	AS	CUCUUGGUuAcAUGAAAUCdTdT	1337
AD-23001	621	A-42929	S	AuuucAuGuAAccAAGAGudTdT	1338
		A-42930	AS	ACUCUUGGUuAcAUGAAAUdTdT	1339
AD-23002	622	A-42931	S	uuucAuGuAAccAAGAGuAdTdT	1340
		A-42932	AS	uACUCUUGGUuAcAUGAAAdTdT	1341
AD-23003	623	A-42933	S	UUcAuGuAAccAAGAGuAudTdT	1342
		A-42934	AS	AuACUClIUGGUuAcAUGAAdTdT	1343
AD-18325	624	A-32339	S	ucAuGuAAccAAGAGuAuudTdT	1344
		A-32340	AS	AAuACUCUUGGUuAcAUGAdTdT	1345
AD-23004	625	A-42935	S	cAu G u AAccAAG AG u Au ucdTdT	1346
		A-42936	AS	GAAuACUCUUGGUuAcAUGdTdT	1347
AD-18326	626	A-32341	S	AuGuAAccAAGAGuAuuccdTdT	1348
		A-32342	AS	GGAAuACUCUUGGUuAcAUdTdT	1349
AD-18327	627	A-32343	S	uGuAAccAAGAGuAuuccAdTdT	1350
		A-32344	AS	UGGAAuACUCUUGGUuAcAdTdT	1351
AD-23005	628	A-42937	S	u A Acc A AG AG u A u u cc Au u dTd T	1352
		A-42938	AS	AAUGGAAuACUCUUGGUuAdTdT	1353
AD-23006	629	A-42939	S	AAccAAGAGu Au uccAu u u dTdT	1354
		A-42940	AS	AAAUGGAAuACUCUUGGUUdTdT	1355
AD-23007	631	A-42941	S	AccAAGAGuAuuccAuuuudTdT	1356
		A-42942	AS	AAAAUGGAAuACUCUUGGUdTdT	1357
AD-23008	632	A-42943	S	ccAAGAGuAuuccAuuuuudTdT	1358
		A-42944	AS	AAAAAUGGAAuACUCUUGGdTdT	1359
AD-23009	633	A-42945	S	cAAGAGuAuuccAuuuuuAdTdT	1360
		A-42946	AS	uAAAAAUGGAAuACUCUUGdTdT	1361
AD-23010	634	A-42947	S	AAGAGuAuuccAuuuuuAcdTdT	1362
		A-42948	AS	GuAAAAAUGGAAuACUCUUdTdT	1363
AD-23011	635	A-42949	S	AGAGuAuuccAuuuuuAcudTdT	1364
		A-42950	AS	AGuAAAAAUGGAAuACUCUdTdT	1365
AD-23012	636	A-42951	S	GAGuAuuccAuuuuuAcuAdTdT	1366
		A-42952	AS	uAGuAAAAAUGGAAuACUCdTdT	1367
AD-23013	637	A-42953	S	AGuAuuccAuuuuuAcuAAdTdT	1368
		A-42954	AS	UuAGuAAAAAUGGAAuACUdTdT	1369
AD-23014	638	A-42955	S	GuAuuccAuuuuuAcuAAAdTdT	1370

112

WO 2011/123468 PCT/US2011/030392

2017204161 20 Jun 2017

Duplex#	Position	Oligo #	Strand	Sequence (5' to 3)	SEQ ID NO:
		A-42956	AS	U U u AGu AAAAAU GGAAuACdTdT	1371
AD-23015	639	A-42957	S	uAuuccAuuuuuAcuAAAGdTdT	1372
		A-42958	AS	CUUuAGuAAAAAUGGAAuAdTdT	1373
AD-23016	640	A-42959	S	AuuccAuuuuuAcuAAAGcdTdT	1374
		A-42960	AS	GCUUuAGuAAAAAUGGAAUdTdT	1375
AD-23017	641	A-42961	S	uuccAuuuuuAcuAAAGcAdTdT	1376
		A-42962	AS	U GCU U u AGu AAAAA UGGAAdTdT	1377
AD-23018	642	A-42963	S	uccAuuuuuAcuAAAGcAGdTdT	1378
		A-42964	AS	CUGCUUuAGuAAAAAUGGAdTdT	1379
AD-23019	643	A-42965	S	ccAuuuuuAcuAAAGcAGudTdT	1380
		A-42966	AS	ACUGCUUuAGuAAAAAUGGdTdT	1381
AD-23020	644	A-42967	S	cAuuuuuAcuAAAGcAGuGdTdT	1382
		A-42968	AS	cACUGCUUuAGuAAAAAUGdTdT	1383
AD-23021	645	A-42969	S	AuuuuuAcuAAAGcAGuGudTdT	1384
		A-42970	AS	AcACUGCUUuAGuAAAAAUdTdT	1385
AD-23022	646	A-42971	S	uuuuuAcuAAAGcAGuGuudTdT	1386
		A-42972	AS	AAcACUGCUUuAGuAAAAAdTdT	1387
AD-23023	647	A-42973	S	uuuuAcuAAAGcAGuGuuudTdT	1388
		A-42974	AS	AAAcACUGCUUuAGuAAAAdTdT	1389
AD-23024	648	A-42975	S	uuuAcuAAAGcAGuGuuuudTdT	1390
		A-42976	AS	AAAAc AC U GCU U u AGu AAAdTdT	1391
AD-23025	649	A-42977	S	u u Acu A AAGcAGuGu u u u cdT dT	1392
		A-42978	AS	GAAAAcACUGCUUuAGuAAdTdT	1393
AD-23026	650	A-42979	S	uAcuAAAGcAGuGuuuucAdTdT	1394
		A-42980	AS	UGAAAAcACUGCUUuAGuAdTdT	1395
AD-23027	651	A-42981	S	Acu AAAGcAG uG u u u ucAcdT dT	1396
		A-42982	AS	GUGAAAAcACUGCUUuAGUdTdT	1397
AD-23028	652	A-42983	S	cuAAAGcAGuGuuuucAccdTdT	1398
		A-42984	AS	GGUGAAAAcACUGCUUuAGdTdT	1399
AD-18330	653	A-32349	S	uAAAGcAGuGuuuucAccudTdT	1400
		A-32350	AS	AGGUGAAAAcACUGCUUuAdTdT	1401
AD-23029	654	A-42985	S	AAAGcAGuGuuuucAccucdTdT	1402
		A-42986	AS	GAGGUGAAAAcACUGCUUUdTdT	1403
AD-23030	655	A-42987	S	AAGcAGuGuuuucAccucAdTdT	1404
		A-42988	AS	U GAGG UGA AAAcACUGC U UdTdT	1405
AD-23031	656	A-42989	S	AGcAGuGuuuucAccucAudTdT	1406
		A-42990	AS	AUGAGGUGAAAAcACUGCUdTdT	1407
AD-18328	628	A-32345	S	G u AAccAAG AG u Au uccAu dT dT	1408
		A-32346	AS	AUGGAAuACUCUUGGUuACdTdT	1409

Example 14. In vitro Screening of TTR Tiled siRNAs

Tiled TTR duplexes were assayed in Hep3B cells for inhibition of endogenous TTR expression using real time PCR assays.

Cell culture and transfection: Hep3B cells (ATCC, Manassas, VA) were grown to near confluence at 37°C in an atmosphere of 5% CCl· in Eagle's Minimum Essential Medium

113

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 (EMEM, ATCC) supplemented with 10% FBS, streptomycin, and glutamine (ATCC) before being released from the plate by trypsinization. Reverse transfection was carried out by adding

5μ1 of Opti-MEM to 5μ1 of each siRNA in individual wells of a 96-well plate. To this 1 ΟμΙ of

Opti-MEM plus 0.2ul of Lipofectaminc RNAiMax was added per well (Invitrogcn, Carlsbad

CA. cat # 13778-150) and the mixture was incubated at room temperature for 15 minutes. 80μ1 of complete growth media described above, but without antibiotic containing 2.0 x 10^ Hep3B cells were then added. Cells were incubated for 24 hours prior to RNA purification. Experiments were performed at 0.1 or lOnM final duplex concentration.

Total RNA isolation using MagMAX-96 Total RNA Isolation Kit (Applied Biosystems,

Foster City CA, part #: AM 1830): Cells were harvested and lysed in 140μ1 of Lysis/Binding Solution then mixed for 1 minute at 850rpm using and Eppendorf Thermo mixer (the mixing speed was the same throughout the process). Twenty micro liters of magnetic beads and Lysis/Binding Enhancer mixture were added into cell-lysate and mixed for 5 minutes. Magnetic beads were captured using magnetic stand and the supernatant was removed without disturbing the beads. After removing supernatant, magnetic beads were washed with Wash Solution I (isopropanol added) and mixed for 1 minute. Beads were capture again and supernatant removed. Beads were then washed with 150u! Wash Solution 2 (Ethanol added), captured and supernatant was removed. 50μ1 of DNase mixture (MagMax turbo DNase Buffer and Turbo DNase) was then added to the beads and they were mixed for 10 to 15 minutes. After mixing,

100μ1 of RNA Rebinding Solution was added and mixed for 3 minutes. Supernatant was removed and magnetic beads were washed again with 150μ1 Wash Solution 2 and mixed for 1 minute and supernatant was removed completely. The magnetic beads were mixed for 2 minutes to dry before RNA was eluted with 50μ1 of water.

cDNA synthesis using ABI High capacity eDNA reverse transcription kit (Applied

Biosystems, Foster City, CA, Cat #4368813): A master mix of 2μ! 10X Buffer, 0.8μΙ 25X dNTPs, 2μΙ Random primers, l ul Reverse Transcriptase, 1 μΙ RNase inhibitor and 3.2μ1 of H2O per reaction were added into 10μ1 total RNA. cDNA was generated using a Bio-Rad C-1000 or S-l 000 thermal cycler (Hercules, CA) through the following steps: 25°C 10 min, 37°C 120 min, 85°C 5 sec, 4°C hold.

Real time PCR: 2 μΐ of cDNA were added to a master mix containing 0.5μΙ GAPDH

TaqMan Probe (Applied Biosystems Cat # 4326317E), 0.5 μ I TTR TaqMan probe (Applied Biosystems cat #HS00174914 Μ1) and 1 ΟμΙ Roche Probes Master Mix (Roche Cat # 04887301001) per well in a LightCycler 480 384 well plate (Roche cat # 0472974001). Real

114

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 time PCR was done in a LightCycler 480 Real Time PCR machine (Roche). Each duplex was tested in two independent transfections and each transfection was assayed in duplicate.

Real time data were analyzed using the AACt method. Each sample was normalized to GAPDH expression and knockdown was assessed relative to cells transfected with the non5 targeting duplex AD-1955. Table 14 shows the knockdown of TTR using the siRNAs. Data are expressed as the percent of message remaining relative to cells targeted with AD-1955,

Many but not all tiled TTR-dsRNAs, targeting TTR near the target of AD-18328, reduced TTR mRNA by at least 70% when transfected into Hcp3B cells at 0.1 nM.

Table 14: Inhibition of TTR by tiled dsRNA targeting TTR near target of AD-18328.

Duplex#	% message remaining O.lnM	% SD O.lnM	% message remaining lOnM	% SD lOnM
AD-18323	6.7	1.90	1.7	0.02
AD-18324	1.8	0.58	0.9	0.10
AD-23000	5.5	0.93	2.1	0,87
AD-23001	15.2	4.89	4.9	1.74
AD-23002	3.1	1.12	1.4	0.55
AD-23003	17.3	3.13	1.7	0.06
AD-18325	1.5	0.27	1.4	0.66
AD-23004	9.0	0.15	10.5	0.96
AD-18326	22.0	1.85	7.6	0.78
AD-18327	U.S	2.64	9.6	1.67
AD-18328	1.1	0.70	0.6	0.16
AD-23005	0.8	0.31	0.6	0.21
AD-23006	1.5	0.46	1.2	0.43
AD-23007	2.4	0.91	1.9	0.46
AD-23008	0.6	0.10	0.8	0.26
AD-23OO9	1.0	0.13	0.9	0.22
AD-23010	60.1	15.66	66.2	22.71
AD-23011	56.5	16.99	53.6	4.70
AD-23012	7.7	2.36	7.7	3.25
AD-23013	7.0	0.64	8.0	1.06
AD-23014	0.7	0.01	0.6	0.10
AD-23015	15.4	0.25	16.5	7.07
AD-23016	27.1	0,37	6.7	1.80
AD-23017	4.5	1.26	1.4	0.40
AD-23018	44.6	9.45	7.5	1.09
AD-23019	2.2	0.68	0.8	0.10
AD-23020	52.7	6.45	29.7	1.17
AD-23021	95.4	16.16	45.0	3.00
AD-23022	70.1	3.01	60.8	12.11
AD-23023	2.7	1.12	1.8	0.07

115

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Duplex#	% message remaining Q.lnM	%SD0.1nM	% message remaining IQnM	% SD lOnM
AD-23024	1.7	0.30	1.8	0.33
AD-23025	64.2	13.21	10.5	1.34
AD-23026	1.9	0.15	1.9	0.78
AD-23027	2.5	0.21	1.6	0.49
AD-23028	6.7	4.41	1.2	0.50
AD-18330	6.0	0.56	5.7	1.15
AD-23029	4.5	0.47	1.6	0.10
AD-23030	3.9	0.25	3.3	0.84
AD-23031	3.4	0,78	1.7	0.02

Example 15. Evaluation of Infusion Duration on Efficacy of a Single Intravenous Administration of SNALP-18534 in Sprague-Dawley Rats

Objectives

To determine the effect of infusion duration on efficacy of a single IV infusion of

SNALP-18534 on liver TTR mRNA levels in Sprague-Dawley rats.

Table 15: Abbreviations and definitions used

SNALP-18534	Rodent transthyretin specific siRNA formulated in SNALP
SNALP-1955	Non-mammalian luciferase specific siRNA formulated in SNALP

The sequences of the sense and antisense strands of AD-18534 arc reproduced below from the tables above:

Strand	Oligo #	Position	Sequence 5' to 3'	SEQ ID HO:
3	A-32755	532	cAGuGuucuuGcucu AuAAdTdT	1289 1
as	A-32756	550	UuAuAGAGcAAGAAcACOGdTdT	1290
Study Materia	S

Test Articlc(s)

SNALP-18534 is comprised of an siRNA targeting rodent TTR mRNA (AD-18534), formulated in stable nucleic acid lipid particles (SNALP) for delivery to target tissues. The 15 SNALP formulation (lipid particle) consists of a novel aminolipid (DLinDMA), a PEGylated lipid (mPEG2000-C-DMA), a neutral lipid (DPPC) and cholesterol. The ratio oflipid:nucleic acid in the SNALP formulation is approximately 5.8:1 (w:w). SNALP-1955 contains an siRNA targeting the non-mammalian luciferase mRNA, is formulated with the identical lipid particle as SNALP-18534, and serves as a non-pharmacologically active control. Dose levels are expressed 20 as mg/kg based on the weight of siRNA content.

116

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Study Design & Procedures

Animals and test article administration:

The study was comprised of 9 groups of Sprague-Dawley rats (4 males/ group). The animals were allowed to have at least a 2 day acclimation period before the study and all animals 5 were 7 weeks old at the initiation of dosing. The dose administered was calculated based upon body weight data collected prior to dosing on Day 1. The test and control articles were administered as a single 15-minute, 1-hour, 2-hour, or 3-hour IV infusion via the tail vein using a 24G %” cannula sealed with a Baxter Injection Site septum connected via 27G Terumo butterfly needle to a Baxter AS40A Syringe Pump. The dose volume was 3 ml/kg, the infusion 10 rate was 12 ml/kg/hr, and animals were freely moving in the cages during dosing. Rats were divided into nine treatment groups and administered a single IV infusion of SNALP-18534, SNALP-1955, or PBS as shown in Table 16:

Tabic 16: Test Animal Dosage Groups

Group	N	Tcst Article	Infusion Duration	Dose
A	4	PBS	15 minute	—
B	4	PBS	3 hour	...
C	4	SNALP-1955	1 hour	1 mg/kg
D	4	SNALP-1955	2 hour	1 mg/kg
E	4	SNALP-1955	3 hour	1 maLg
F	4	SNALP-18534	15 minute	1 mg/kg
G	4	SNALP-18534	1 hour	1 mg/kg
H	4	SNALP-18534	2 hour	1 mg/kg
1	4	SNALP-18534	3 hour	1 mg/kg

Tissue collection and RNA isolation:

On Day 0, animals were anesthetized by isofluoranc inhalation and pre-dosing blood samples were collected into serum separator tubes by retro-orbital bleed. The blood samples were allowed to clot at room temperature for approximately 30 minutes prior to centrifugation at 4°C. Scrum samples were then stored at -80°C until analysis was performed. On Day 3, animals 20 in all nine treatment groups were given a lethal dose of kctaminc/xylazine. Blood was collected via caudal vena cava into scrum separation tubes, and then allowed to clot at room temperature for approximately 30 minutes prior to centrifugation at 4°C. Seram samples were stored at 80°C until analysis was performed. Liver tissue was harvested and snap frozen on dry ice. Frozen liver tissue was ground and tissue lysates were prepared for liver mRNA quantitation.

117

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

TTR mRNA Quantitation:

TTR mRNA levels relative to those of GAPDH mRNA were determined in the lysates by using a branched DNA assay (QuantiGcne Reagent System, Panomics, Fremont, CA). Briefly, the QuantiGene assay (Genospectra) was used to quantify mRNA levels in tissue sample lysates according to the manufacturer’s instructions. The mean level of TTR mRNA was normalized to the mean level of GAPDH mRNA for each sample.

To obtain the relative level of TTR mRNA expression, group mean values for SNALP1955 and SNALP-18534 treated groups with 15-minute, 1 hour and 2 hour infusion durations were then normalized to the mean value for the PBS treated group with 15-minute infusion 10 whereas group mean values for SNALP-1955 and SNALP-18534 treated groups with 3 hour infusion duration were then normalized to the mean value for the PBS treated group with 3 hour infusion duration.

Results

As shown in FIG. 16, a single IV infusion of 1 mg/kg SNALP-18534 with different infusion durations of 15 minutes to 3 hours results in comparable inhibition of liver TTR mRNA levels measured two days after dosing. A single IV infusion of 1 mg/kg SNALP-18534 also showed durable TTR downregulation over 29 days following a single 15 minute IV infusion, as compared to SNALP-1955 control (data not shown). Compared to the PBS-trcated group, a single 15-minute, 1-hour, 2-hour, or3-hour IV infusion of SNALP-18534 at 1 mg/kg significantly reduced relative TTR mRNA expression levels by 94% ( p<0.001), 94% ( p < 0.001), 92% (p < 0.001) and 93% (p < 0.001), respectively. Specificity of SNALP-18534 activity is demonstrated by lack of significant target inhibition by SNALP-1955 administration via 1-hour, 2-hour, or 3-hour IV infusion at the same dose level.

Conclusions

This study demonstrates that varying the infusion duration from 15 minutes to up to 3 hours docs not affect the efficacy of a single IV administration of 1 mg/kg SNALP-18534 in rats, as assessed by reduction of TTR mRNA levels in the liver.

Example 16. In vivo reduction of wild-type TTR mRNA in the rat liver by LNPQ718534 and LNP08-I8534

To evaluate the efficacy of 2 novel lipid nanoparticle formulations, LNP07 and LNP08, for delivery of siRNA in the rat, the rodent-specific TTR siRNA, AD-18534, was formulated in LNP07 (LNP07-18534) or LNP08 (LNP08-18534), and administered by 15-minute IV infusion, and liver TTR mRNA was quantified. Sprague-Dawley rats (4 animals per group) were

118

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 administered 15-minutc IV infusions of LNP07-18534 (0.03, 0.1, 0.3 or I mg/kg), LNP08-18534 (0.01, 0.03 or 0.1 mg/kg), or LNP07-1955 (I mg/kg) or LNP08-I955 (0.1 mg/kg) containing the negative control siRNA AD-1955 which targets the non-mammalian gene luciferase. Fortyeight hours later, animals were euthanized and liver tissue was collected, flash-frozen and stored at -80°C until processing.

For TTR mRNA quantitation, frozen liver tissue was ground into powder, and lysates were prepared. TTR mRNA levels relative to those of GAPDH mRNA were determined in the lysates by using a branched DNA assay (QuantiGene Reagent System, Panomics, Fremont, CA). Briefly, the QuantiGene assay (Gcnospectra) was used to quantify mRNA levels in tissue sample 10 lysates according to the manufacturer’s instructions. The mean level of TTR mRNA was normalized to the mean level of GAPDH mRNA for each sample. Group means of the normalized values were then further normalized to the mean value for the PBS treated group, to obtain the relative level of TTR mRNA expression.

The results are shown in FIG. 17. LNP07-18534 reduced TTR mRNA levels in the liver 15 in a dose-dependent manner, with 94% suppression ofTTR mRNA at 1 mg/kg. The effect was specific, since the negative control LNP07-1955 at 1 mg/kg did not significantly affect TTR mRNA levels compared to the PBS control. The mRNA ED50 was determined to be - 0.05 mg/kg LNP07-18534. LNP08-18534 reduced TTR mRNA levels in the liver in a dosedependent manner, with 86% suppression of TTR mRNA at 0.1 mg/kg. The effect was specific, 20 since the negative control LNP08-1955 at 0.1 mg/kg did not significantly affect TTR mRNA levels compared to the PBS control. The mRNA ED50 was determined to be~ 0.02 mg/kg LNP08-18534.

These results demonstrate that LNP07-18534 and LNP08-18534 are effective in suppressing wild-type TTR mRNA in the rat liver when administered by IV infusion, and that 25 LNP07 and LNP08 are effective formulations for delivering siRNA to the liver.

Example 17: Reduction of TTR liver mRNA by a single intravenous administration of LNP09-18534 or LNP11-18534 in Sprague-Dawlev Rats

Objective:

To evaluate the efficacy of two novel lipid nanoparticlc (LNP) formulations for delivery 30 of the rodent TTR-specific siRNA, AD-18534 in the Sprague-Dawley rat for reducing endogenous (wild type) liver TTR mRNA levels. Rats were intravenously dosed via a 15 minute infusion with either 0.01, 0.03, 0.1, or 0.3 mg/kg LNP09-18534, LN Pl 1-18534, or phosphate buffered saline (PBS) and TTR liver mRNA levels were assayed at 48 hrs post-treatment.

119

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Material and Methods:

LNP09 formulation: (XTC/DSPC/Chol/PEG₂₀₀₀-C14) = 50/10/38.5/1.5 mol%; Lipid:siRNA -11:1. LNP11 formulation: (MC3/DSPC/Chol/PEG_200frC14) - 50/10/38.5/1.5 mol%; Lipid:siRNA~ 11.1

Tissue collection and RNA isolation: On Day 3, animals in all treatment groups were given a lethal dose of ketamine/xylazine. Blood was collected via caudal vena cava into serum separation tubes, and then allowed to clot at room temperature for approximately 30 minutes prior to centrifugation at 4°C. Scrum samples were stored at -80°C until for future analysis. Liver tissues were harvested and snap frozen on dry icc. Frozen liver tissue was ground and tissue lysates were prepared for liver mRNA quantitation.

TTR mRNA Quantitation: TTR mRNA levels relative to those of GAPDH mRNA were determined in the lysates by using a branched DNA assay (QuantiGcne Reagent System, Panomics, Fremont, CA). Briefly, the QuantiGcne assay (Gcnospectra) was used to quantify mRNA levels in tissue sample lysates according to the manufacturer’s instructions. The mean level of TTR mRNA was normalized to the mean level of GAPDH mRNA for each sample. Group mean values were then normalized to the mean value for the PBS treated group, to obtain the relative level of TTR mRNA expression.

Results:

As shown in FIG. 18, in contrast with PBS treated animals, LNP09-18534 and LNP1 ΙΣΟ 18534 treated animals had a significant dose-dependent decrease in TTR mRNA levels in the liver, reaching maximum reduction of - 90% mRNA reduction for both LNP09 and LNP11 formulated groups, relative to PBC control group at 0.3 mg/kg, and a dose achieving 50% reduction (ED₅o) of < 0.03 mg/kg for LN Pl 1-18534 and < 0.1 mg/kg for LNP09-18534.

Conclusions

This study demonstrates that a single 15 minute IV infusion of LNP09-18534 or LNP11 18534 in Sprague-Dawley rats results in a dose-dependent reduction of liver TTR mRNA. These data demonstrate the efficacy of LN P09-18534 and LN Pl 1-18534 in reducing endogenously expressed (wild type) TTR mRNA with ED50 levels of <0.03 and <0.1 mg/kg for LNP11-18534 and LNP09-18534, respectively.

Example 18: Assaying for toxicity in animals

ALN-TTR01 was assayed for safety and toxiclogoy under non-GLP and GLP conditions. ALN-TTR01 is the siRNA AD-18328 in a SNALP formulation (DLinDMA / DPPC/ Cholesterol/ PEG2000-cDMA (57.1/7.1 /34.4/1.4) lipid:siRNA - 7). Assays were performed in

120

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

Cynomolgus monkey (1,3, and 10 mg/kg) and Sprague- Dawley Rat (0.3, 1, 3, and 6 mg/kg).

No toxicity of ALN-TTR01 was found at < 1 mg/kg in rats and < 3 mg/kg in ΝΉΡ. (data not shown).

Example 19: Drug product ALN-TTR01

The ding product, ALN TTR01 Injection, is a white to off-white, homogeneous sterile liquid suspension of the siRNA ALN-18328 with lipid excipients (referred to as stable nucleic acid lipid particles [SNALP]) in isotonic phosphate buffered saline. The composition of ALN TTR01 is shown in the table below.

Table 17: Composition of druu product ALN-TTR01

Component, grade	Concentration (mg/mL)	Per vial (mg)	Function
ALN-1832 8, cGMP	2.0	11.0	Active ingredient
DLinDMA(1,2-Dilinolcyloxy-N,Ndimcthyl-3-aminopropane), cGMP	7.3	40.2	Novel excipient; titratable aminolipid for interaction with the active ingredient
PEG2U00-C-DMA (3-N-[(m-Mcthoxy poly(ethylenc glycol) 2000) carbamoyl]-1,2-dimyristy loxypropylamine),cGMP	0.8	4.4	Novel excipient; stability of drug product and desired biodistribution
DPPC (R-l,2-Dipaimitoyl-snglycero-3-phosphocliolinc), cGMP	1.1	6.1	Structural integrity of SNALP particles
Cholesterol, synthetic, cGMP	2.8	15.4	Structural integrity of SNALP particles
Phosphate buffered saline, cGMP	q.s.	to 5.5 mL	Buffer

The lipid excipients have the molecular weights and structures shown in the table below.

Table 18: Lipid excipients

Lipid	Molecular Weight	Chemical Name and Structure
DLinDMA	616	1,2-Dilinoleyloxy-/V, /V-dimethyl-3 -ammopropanc

121

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

	2824Polydispersity index 1.01	3-N-[(to-Melhoxy polyethylene glycol)2000)carbamoyl]-l,2dimyri sty loxy-propy lam i ne0
DP PC	734	1,2 - Dipalmi toy 1- s n-gl y ceftl-3 - phosphochol incOO“zl δ o
Cholesterol	387	Chole st -5 -en-3 β-οΐ

• a alternate name: mPEGswC-DMA

The ALN TTR01 drag product is packaged in 10 mL glass vials with a fill volume of 5.5 mL (11 mg ALN-18328 per vial). The container closure system consists of a USP/EP Type 1 5 borosilicate glass vial, a teflon faced butyl rubber stopper and an aluminum flip off cap. The drug product will be stored at 5 ± 3°C.

Stability of the drag product is assayed for up to 24 months and determined using the following criteria:

Appearance: White to off-white, homogeneous opalescent liquid, no foreign particles pH: 6.8-7.8

Osmolality: 250 - 350 mOsm/kg

Lipid: siRNA Rat io :5.6 - 8.4 mg/mg

Particle Size (Z-Average):60 - 120 nm <0.15.

Example 20: In vitro reduction of human TTR mRNA expression by AD-18324 in

ARPE 19 cells

To determine the effect of TTR siRNA on TTR mRNA expression in vitro, the siRNA AD-18324 and AD-18534 were tested in human retinal pigment epithelium (ARPE-19) cells.

122

WO 2011/123468

PCT/US2011/030392

AD-18324 is a human TTR siRNA duplex and AD-18534 is a rat TTR siRNA duplex.

The sequences of the sense and antisense strands of AD-18534 and AD-18324 are reproduced below:

2017204161 20 Jun 2017

Duplex #	Strand	Oligo #	Position	Sequence 5’ to 3’	SEQIDNO:
AD-18534	s	A-32755	532	cAGuGuucuuGcucuAuAAdTdT	1411
	as	A-32756	550	UuAuAGAGcAAGAAcACUGdTdT	1412
AD-18324	s	A-32337	509	GGAuuucAuGuAAC cAAGAdTdT	1413
	as	A-32338	527	UCUUGGUuAcAUGAAAUCCdTdT	1414

A control siRNA was AD-1955 targeting a LUC gene.

ARPE-19 cells were transfected with siRNA using Lipofectamin 2000 (Invitrogen). In some embodiments of this method, other transfection agents may be used, including cholesterol or atcrocollagen. After incubation for 24 hrs, 50-60% confluent ARPE-19 cells were transiently transfected with AD-18534 or AD-18324 following manufacturer’s instruction. Total RNA was 10 isolated for real-time quantitative PCR 48 hrs after the start of transfection. ARPE-19 cells were dosed with InM, 10nM or 50nM of AD-18534 or with 1 nM, 10 nM or 50 nM of AD-18324.

TTR mRNA expression was measured by real-time quantitative PCR. Total RNA was isolated from transfected cells by using RNcasy Mini Kit (Qiagen). Total RNA (0.5 pg) was reverse-transcribed to cDNA by using ExScript RT reagent (Takara Bio inc.) according to the 15 manufacturer’s protocol. Each PCR was performed with 2 p.L of the cDNA and 0.2 prnol/L of each primer in a LightCyclcr System with SYBR Premix DimerErascr (Takara Bio Inc.). The following primers were used: human TTR (forward: 5’- CATTCTTGGCAGGATGGCTTC -3' (SEQ ID NO: 1415); reverse: 5’-CTCCCAGGTGTCATCAGCAG -3’ (SEQ ID NO: 1416). Human TTR mRNA expression was calculated relative to human GAPDI-1 expression levels in 20 the ARPE-19 cells.

Human TTR mRNA expression was markedly reduced by AD-18324 in a dose dependent manner. The results are shown in FIG. 22. Al nM dose of AD-18324 resulted in at least 10% reduction in human TTR mRNA relative expression compared to a control siRNA group. A 10 nM dose of AD-18324 resulted in at least 40% reduction in human TTR mRNA 25 relative expression compared to the control siRNA group. A 50nM dose of AD-18324 resulted in at least 60% reduction in human TTR mRNA relative expression compared to the control

123

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 siRNA group. AD-18534 did not cause a marked reduction in human TTR relative expression at each dose. There was no effect on 11-6 or TNF-alpha levels compared to controls.

These results demonstrate that AD-18324 is effective in inhibiting human TTR mRNA expression in a human retinal pigment epithelium (ARPE-19) cell in a dose dependent manner and does not produce an inflammatory response.

Example 21; In vivo reduction of endogenous rat TTR mRNA expression by AD18534 in Dark Agouti (DA) rats

To determine the effect of rat TTR siRNA on endogenous rat TTR mRNA expression, the duplex AD-18534 was tested in vivo in Dark Agouti (DA) rats.

The sequences of the sense and antisense strands of AD-18534 are described above.

DA rats were injected with AD-18534 in their vitreous cavities. Adult rats were anesthetized by diethyl ether inhalation. To dilate the pupils, 1-2 drops of 1% tropicamide were applied to the rat’s eyes. Intravitreal injections of siRNAs were made using Hamilton syringes and a 33 gauge needle. Injected volume was 5 μΐ so that vitreal volume is kept as close to normal as possible. After 24 hrs, the rat was sacrificed by diethyl ether inhalation and the eyes were harvested for subsequent dissection. The eyes were separated the cornea and lens to get the posterior cups. The RPE-choroid-sclera complexes were isolated by removing the retina from the posterior cups for analysis. Other methods may be used to optimize the siRNA delivery, including varying the amount of dose or timing of the dose. In some embodiments, the injection method may occur in another part of the eye, including the subconjunctival space or the subretina. In other embodiments, the amount of injected saline or siRNA may be increased.

Rat TTR mRNA expression was measured by real-time quantitative PCR (qPCR). Total RNA was isolated from each RPE-choroid-sclcra complexes by using RNeasy Mini Kit (Qiagen). Total RNA was reverse-transcribed to cDNA by using ExScript RT reagent (Takara

Bio Inc.), Each PCR was done in a LightCyclcr System with SYBR Premix DimcrEraser (Takara Bio Inc.). The following primers were used: rat TTR (forward: 5’TGCCTCGCTGGACTGATATTTG -3’ (SEQ ID NO: 1417); reverse: 5’TTGAACACTTTCACGGCCACA -3’ (SEQ ID NO: 1418)). Rat TTR mRNA expression was calculated relative to rat GAPDH expression levels.

FIG. 23 shows the inhibition of endogenous rat TTR mRNA expression in DA rats after injection with AD-18534, compared to DA rats that were administered a control siRNA, saline, or no treatment (p<0.01). DA rats treated with AD-18354 exhibited a reduction in endogenous

124

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017 rat TTR mRNA expression by at least 60% relative to the control siRNA group and the saline control group (p<0.01).

These results demonstrate that AD-18354 is active in suppressing endogenous rat TTR mRNA expression in the retinal pigment epithelium cells of DA rats.

Example 22: In vivo reduction of ATTR mRNA expression by AD-18324 in ATTR

V30M Transgenic (Tg) rats

To evaluate the effect of TTR siRNA AD-18324 on human mutant (V30M) ATTR mRNA expression, AD-18324 was tested in vivo in retinal pigment epithelium cells of ATTR V30M Transgenic (Tg) rats.

Transgenic rats possessing a human ATTR V30M gene were injected with AD-18324 in their vitreous cavities. Intravitreal injections of AD-18324 siRNA were made using Hamilton syringes and 33 gauge needle. After 24 hrs, the ATTR V30M Tg rats were sacrificed by diethyl ether inhalation and the eyes were harvested for subsequent dissection. The eyes were separated the cornea and lens to get the posterior cups. The RPE-choroid-sclera complexes were isolated by removing the retina from the posterior cups to evaluate the effect of AD-18324 on ATTR mRNA expression. AD-18324 siRNA was injected into the vitreous cavity using a 33 gauge needle. After 24 hours, the retinal pigment epithelium was isolated to evaluate the effect of AD18324 on ATTR mRNA expression.

ATTR mRNA expression was measured by real-time PCR. Total RNA was reverse20 transcribed to cDNA by using ExScript RT reagent (Takara Bio Inc.). Each PCR was done in a LightCycler System with Premix Ex Taq (Takara Bio Inc.). The following primers were used: human TTR (forward: 5’- GCCGTGCATGTGTTCAGA -3’ (SEQ ID NO: 1419); reverse: 5’GC'TCTCCAGACTCACTGGTTTT -3 (SEQ ID NO:1420)’). The probe was provided by Universal Probe Library (probe #66, Roche Diagnostics). ATTR mRNA expression was calculated relative to rat GAPDH expression in the ATTR V30M Tg rat.

FIG. 24 shows a significant reduction of ATTR mRNA expression in RPE cells of ATTR V30M Tg rats, compared to the control siRNA group, the saline group, and the no treatment group. ATTR mRNA expression was reduced by at least 60% compared to the no treatment group.

Western blot analysis was used to assess ATTR protein expression. Equal amounts of aqueous humor protein from rats were fractionated via 12% SDS-PAGE and transferred to nitrocellulose membranes (Bio-Rad Laboratories). Membranes were blocked with 2.5% non-fat milk and incubated overnight at 4°C with a primary antibody which was a rabbit polyclonal anti125

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

TTR (dilution 1:1000, Dako), followed by a horseradish pcroxidase-conjugatcd goat anti-rabbit immunoglobulin antibody (dilution 1:1000, Dako) as a secondary reaction for 1 hour at room temperature. The immunocomplex was visualized using the ECL western blot detection system (GE Healthcare Bio-Science).

The results are shown in FIG. 25. ATTR protein expression was significantly reduced by

AD-18324 compared to ATTR protein expression after injection of a control siRNA.

These results demonstrate that intravitreal injection of AD-18324 in ATTR V30M Tg rats significantly reduces human TTR mRNA and protein expression tn the RPE,

Example 23: In vivo reduction of endogenous rat TTR mRNA expression in Dark

Agouti (DA) rats using cholesterol conjugated AD-18534

To determine the effect of cholestcrol-conjugated rat TTR siRNA on endogenous rat TTR mRNA expression, the duplex AD-23043 was tested in vivo in Dark Agouti (DA) rats.

AD-23043 is a cholesterol conjugated siRNA with the following sequences.

Duplex #	Strand	Sequence 5’ to 3’	SEQ ID NO:
AD-23043	sense	cAGuGuucuuGcucuAuAAdTdTsL 10	1421
	antisense	UuAuAGAGcAAGAAcACUGdTdT	1422

DA rats were injected with AD-23043 in their vitreous cavities. Adult rats were anesthetized by diethyl ether inhalation. To dilate the pupils, 1-2 drops of 1% tropicamidc were applied to the rat’s eyes. Intravitreal injections of siRNAs (5 ug) were made using Hamilton syringes and a 33 gauge needle. Injected volume was 5 μΐ so that vitreal volume is kept as close 20 to normal as possible. After 14 or 21 days, the rat was sacrificed by diethyl ether inhalation and the eyes were harvested for subsequent dissection. The eyes were separated the cornea and lens to get the posterior cups. The RPE-choroid-sclcra complexes were isolated by removing the retina from the posterior cups for analysis.

Rat TTR mRNA expression was measured by real-time quantitative PCR (qPCR). Total 25 RNA was isolated from each RPE-choroid-sclcra complexes by using RNcasy Mini Kit (Qiagen). Total RNA was reverse-transcribed to cDNA by using ExScript RT reagent (Takara Bio Inc.). Each PCR was done in a LightCycler System with SYBR Premix DimerEraser (Takara Bio Inc.). The following primers were used: rat TTR (forward: 5’TGCCTCGCTGGACTGATATTTG -3’ (SEQ ID NO: 1423); reverse: 5’126

WO 2011/123468

PCT/US2011/030392

2017204161 20 Jun 2017

TTGAACACTTTCACGGCCACA -3’ (SEQ ID NO: 1424)). Rat TTR mRNA expression was calculated relative to rat GAPDH expression levels.

The results are shown in FIG. 26 and FIG. 27. Cholesterol conjugated siRNA targeting rat TTR reduced endogenous rat TTR expression by about 40% compared to a control siRNA.

Example 24: Treatment of ocular amyloidosis in human

For treatment of ocular amyloidosis in humans, the pharmaceutical compositions used in the present invention may be administered in a number of ways depending upon the invasiveness of treatment and based on whether local or systemic treatment is desired. The preferred initial treatment may be performed by ocular instillation, ointment, peroral administration or infusion.

Parenteral administration includes subcutaneous eyelid, subconjunctival injection, subtenon injection, retrobulbar injection, anterior chamber injection, intravitreous injection or ophthalmovascular injection.

127

1. A method for reducing transthyretin (TTR) expression in a retinal pigment epithelium of a subject comprising administering a sufficient amount of a dsRNA to the retina of the subject, wherein the dsRNA is AD-18324 (SEQ ID NOs: 1413 and 1414) or

AD-18534 (SEQ ID NOs: 1411 and 1412) or AD-23043 (SEQ ID NOs: 1421 and 1422);

and wherein the dsRNA is encapsulated in a lipid formulation.

2017204161 01 Jul 2019

Claims (390)

1. We claim:
2. 2. The method of claim 1, wherein the dsRNA is conjugated to a cholesterol molecule.
3. 3. The method of claim 1 or claim 2, wherein the subject is a human.
4. 4. The method of claim 3, wherein the subject is a human in need of treatment for TTR-related ocular amyloidosis.
5. 5. The method of claim 3 or claim 4, wherein the subject is a human comprising a V30M TTR gene.
6. 6. The method of any one of claims 1 to 5, wherein the dsRNA is AD-18324

   5 (SEQ ID NOs: 1413 and 1414).
7. 7. The method of any one of claims 1 to 6, wherein TTR expression is reduced in the retinal pigment epithelium (RPE).
8. 8. The method of any one of claims 1 to 7, wherein TTR mRNA expression is reduced by at least 40% or by at least 60% compared to a control.

   20 9. The method of any one of claims 1 to 8, wherein administration does not result in an inflammatory response as measured by IL-6 or TNF-alpha levels.

   128

   2017204161 01 Jul 2019

   10. The method of claim 1 or claim 2, wherein the subject is a Dark Agouti (DA) rat.

   11. The method of claim 10, wherein the dsRNA is AD-18534 (SEQ ID NOs: 1411 and 1412).

   5 12. The method of claim 10 or claim 11, wherein TTR expression is reduced in the retinal pigment epithelium (RPE).

   13. The method of any one of claims 10 to 12, wherein TTR mRNA expression is reduced by at least 60% compared to a control.

   14. The method of any one of claims 10 to 13, wherein administration does

   0 not result in an inflammatory response as measured by IL-6 or TNF-alpha levels.

   15. The method of claim 1 or claim 2, wherein the subject is a transgenic rat possessing a human ATTR V30M gene.

   16. The method of claim 15, wherein the dsRNA is AD-18324 (SEQ ID NOs: 1413 and 1414).

   5 17. The method of claim 15 or claim 16, wherein TTR expression is reduced in the retinal pigment epithelium (RPE).

   18. The method of any one of claims 15 to 17, wherein TTR mRNA expression is reduced by at least 60% compared to a control.

   19. The method of any one of claims 15 to 18, wherein administration does

   20 not result in an inflammatory response as measured by IL-6 or TNF-alpha levels.

   20. A method of treating, preventing or managing TTR-related ocular amyloidosis comprising administering to a patient in need of such treatment, prevention

   129

   2017204161 01 Jul 2019

   or management a therapeutically or prophylactically effective amount of AD-18324 (SEQ ID NOs: 1413 and 1414) encapsulated in a lipid formulation to the retina of said patient.21. A method of treating a human comprising: identifying a human diagnosedas having TTR-related ocular amyloidosis or at risk for developing TTR-related ocular5amyloidosis and administering to the human a therapeutically or prophylactically effective amount of AD-18324 (SEQ ID NOs: 1413 and 1414) encapsulated in a lipid formulation to the retina of said human.22. A method for inhibiting TTR expression in a retinal epithelium cell, themethod comprising:0(a) introducing into the retinal epithelium cell a dsRNA, wherein the dsRNA is AD18324 (SEQ ID NOs: 1413 and 1414) orAD-18534 (SEQ ID NOs: 1411 and 1412) wherein the dsRNA is encapsulated in a lipid formulation; and(b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a TTR gene, thereby inhibiting expression of the TTR gene in the5cell.23. The method of claim 22, wherein the dsRNA is AD-18324 (SEQ ID NOs: 1413 and 1414).24. The method of claim 22 or claim 23, wherein the retinal epithelium cell is a human retinal pigment epithelium transgenic cell.2025. The method of any one of claims 22 to 24, wherein TTR expression is inhibited by at least 10%, 40%, or at least 60%.26. The method of any one of claims 22 to 25, wherein introducing the dsRNA does not result in an inflammatory response as measured by IL-6 or TNF-alpha levels.

   130

   2017204161 01 Jul 2019

   27. Use of a dsRNA in the preparation of a medicament for the treatment, prevention or management of ocular amyloidosis, wherein the dsRNA is AD-18324 (SEQ IDNOs: 1413 and 1414) orAD-18534 (SEQ IDNOs: 1411 and 1412) orAD-23043 (SEQ ID NOs: 1421 and 1422); and wherein the dsRNA is encapsulated in a lipid

   5 formulation.

   28. Use of a dsRNA to treat, prevent or manage ocular amyloidosis, wherein the dsRNA is AD-18324 (SEQ IDNOs: 1413 and 1414) orAD-18534 (SEQ IDNOs: 1411 and 1412) or AD-23043 (SEQ ID NOs: 1421 and 1422); and wherein the dsRNA is encapsulated in a lipid formulation.

   131

   132

   2017204161 20 Jun 2017 ο ο ^r ω

   ro p

   Ό c [|ui/6d]

   FIG. 1

   2/32

   2017204161 20 Jun 2017

   FIG. 2A

   FIG. 2B

   3/32

   2017204161 20 Jun 2017

   FIG. 3

   4/32

   2017204161 20 Jun 2017

   HGdV9/Hll

   FIG. 4A

   5/32

   2017204161 20 Jun 2017

   FIG. 4B

   1----------1---------1----------[---------Γ----Π---------1---------i---------1

   ooo□aoooo ooCMc©a7“T“

   Qui/WJ an

   6/32

   2017204161 20 Jun 2017

   oL_c oQ00'tt—CM<NJLOCOCOLD0000CDT^-X^-□LClCL_1_1_J<<<zωωω

   FIG. 5 a E

   7/32

   2017204161 20 Jun 2017

   SR (N m (S9d Ol BAiiepj) HGdVD/ail

   FIG. 6A

   8/32

   2017204161 20 Jun 2017 (|uj/3t1) spAaquiaioj<j mruasmi i

   FIG. 6B to
9. 9/32

   2017204161 20 Jun 2017

   FIG. 7A

   N Ο d

   Φ 'ίο Ο

   HOdVD/an
10. 10/32

    2017204161 20 Jun 2017

    FIG. 7B

    oOoooooooooooooooooΦooooooco10rslrdrd

    (|iu/3ri) u i aioid luiws^jj.
11. 11/32

    2017204161 20 Jun 2017

    FIG. 8

    CO <N CO CO

    σ>σ)>»(0σι~σ>σ>Ο

    E E E

    CO T- CO o
12. 12/32

    2017204161 20 Jun 2017

    Alfsuaiui JHI ailUEBim

    FIG. 9
13. 13/32

    2017204161 20 Jun 2017 (|OJJUOO 0} 3Aj)B|9j) HOdVD'ail

    FIG. 10
14. 14/32

    2017204161 20 Jun 2017

    Μ Η

    FIG. 11A ’HK’HHWOOOOO

    5|5Λθΐ VNHLuaaAi] RadV9/HlLW8PM
15. 15/32

    2017204161 20 Jun 2017

    FIG. 11B
16. 16/32

    2017204161 20 Jun 2017

    5!ίκ1:ίοΛ;οΛ8ίϊιΓ ?£^?vw£’^:;

    ’*^L

    Ήύά'ξ'ΝίΦΐ’' >> co O tn «5

    E

    C3 cn 00 □_

    IO

    CO

    Ci>

    r*

    GO

    CS|

    CO CO

    IX

    CD

    σ) ε co

    O co

    IO40COΌΦΦCMΛ1tn otn ωΦccQ_C3ω<*·£:>·_l—I

    FIG. 11C
17. 17/32

    2017204161 20 Jun 2017 gttgactaag gtttgcagtc cctagctcag ccaggctggg actcattctt tctgctcctc atttgtgtct cggtgaatcc agttctagat catcaatgtg ggctgctgat ctctgggaaa gcatgggctc agaagggata caaatcttac cccattccat cacagccaac caccattgcc ctattccacc caaggaatga cctgaaggac accaagagta tgttttcacc ccaggcagag aaggcacttt tttttaaatt aaaaagagaa aaaggaattc cgctaggaga tgcaagcaaa gcagccatta aaaaaaaa tcaataatca agattggcag gagaagtgag agcagccatc ggcaggatgg ctctgccttg gaggctggcc aagtgtcctc gctgtccgag gccgtgcatg gacacctggg accagtgagt acaactgagg tacaaagtgg tggaaggcac gagcatgcag gactccggcc gccctgctga acggctgtcg gggacttctc gagggatggg ttccattttt tcatatgcta acaataaaac tcattccact cccttattgt tcaaaatttt tagaaagtat gatccaaatt gcacgtatta aaaagacaca {SEQ ID NO:

    gaatcagcag ggataagcag tataaaagcc acagaagtcc cttctcatcg ctggactggt ctacgggcac tgatggtcaa gcagtcctgc tgttcagaaa agccatttgc ctggagagct aggaatttgt aaatagacac ttggcatctc aggtggtatt cccgccgcta gcccctactc tcaccaatcc ctccagtgga atttcatgta actaaagcag tgttagaagt attcctgtga ttaacttgat cccttccaaa acaaagaatc ctgggcagaa tccattgtct aatatgatct ttctgtaaaa 1331)

    FIG. 12
18. 18/32

    2017204161 20 Jun 2017

    FIG. 13A

    ACAGAAGTCCACTCATTCTTGGCAGGATGGCTTCTCATCGTCTGCTCCTCCT CTGCCTTGCTGGACTGGTATTTGTGTCTGAGGCTGGCCCTACGGGCACCGGT GAATCCAAGTGTCCTCTGATGGTCAAAGTTCTAGATGCTGTCCGAGGCAGTC CTGCCATCAATGTGGCCGTGCATGTGTTCAGAAAGGCTGCTGATGACACCTG GGAGCCATTTGCCTCTGGGAAAACCAGTGAGTCTGGAGAGCTGCATGGGCTC ACAACTGAGGAGGAATTTGTAGAAGGGATATACAAAGTGGAAATAGACACCA AATCTTACTGGAAGGCACTTGGCATCTCCCCATTCCATGAGCATGCAGAGGT GGTATTCACAGCCAACGACTCCGGCCCCCGCCGCTACACCATTGCCGCCCTG CTGAGCCCCTACTCCTATTCCACCACGGCTGTCGTCACCAATCCCAAGGAAT GAGGGACTTCTCCTCCAGTGGACCTGAAGGACGAGGGATGGGATTTCATGTA ACCAAGAGTATTCCATTTTTACTAAAGCAGTGTTTTCACCTCATATGCTATG TTAGAAGTCCAGGCAGAGACAATAAAACATTCCTGTGAAAGGCACTTTTCAT TCCAAAAAAAAAAAAAAAAAAAAAAA (SEQ ID NO;1329)

    FIG. 13B

    CCTGACAGGATGGCTTCCCTTCGCCTGTTCCTCCTCTGCCTCGCTGGACTGA TATTTGCGTCTGAAGCTGGCCCTGGGGGTGCTGGAGAATCCAAGTGTCCTCT GATGGTCAAAGTCCTGGATGCTGTCCGAGGCAGCCCTGCTGTCGATGTGGCC GTGAAAGTGTTCAAAAGGACTGCAGACGGAAGCTGGGAGCCGTTTGCCTCTG GGAAGACCGCCGAGTCTGGAGAGCTGCACGGGCTCACCACAGATGAGAAGTT CACGGAAGGGGTGTACAGGGTAGAACTGGACACCAAATCATACTGGAAGGCT CTTGGCATTTCCCCATTCCATGAATACGCAGAGGTGGTTTTCACAGCCAATG ACTCTGGTCATCGCCACTACACCATCGCAGCCCTGCTCAGCCCGTACTCCTA CAGCACCACTGCTGTCGTCAGTAACCCCCAGAACTGAGGGACCCAGCCCACG AGGACCAAGATCTTGCCAAAGCAGTAGCTCCCATTTGTACTGAAACAGTGTT CTTGCTCTATAAACCGTGTTAGCAACTCGGGAAGATGCCGTGAAACGTTCTT ATTAAACCACCTTTATTTCATTC (SEQ ID NO:1330)
19. 19/32

    2017204161 20 Jun 2017 «μ 'W.m.s

    Αν>-Ϊ^ΪΖ5 .setfse

    J®i .006371.3

    7Ϊ.2

    AO-i ΐϊ.Ρΐ. sense

    NM. .OOaPS-S «M.SXP.PLZ

    AU-5i!3iiLsW«

    ΝΜ.ϋ<Χ:3?ΧΪ

    ΗΜ,ίχχλΐΖϊ.ί

    AO Ίί12·8. sense

    NM iXSiSm.'S

    KM.WO.X’iX

    Α»Ί*.ίη„$«Λ3ί

    NM,e<x;;tn.s

    A».SS.U,Ven«e «HjXFs.’,

    MM.iwsazs.a

    AO-5SJ38..s«ns^

    Ν'Μ.,νίΡΡΪ.ΐ

    ΝϊΟίχϊίϊη.ί

    AO-U528 sense

    WM.tit'SJiX.S

    NM ¢0637.1.2

    APPPOi-nsi· wMjaes3n3

    W..OOO37L2

    AtinsS,?8„st<Aie

    We 0003713

    W.iWPS i> AB-lSsiiX.ScnSij

    NM.0003 71,2

    A£J- li-faa .sa’iis

    NM .000.1'-';3

    NM,.iaXJ?7I,2

    A»· l*SZ-Me(s<e f-iSS (5063713

    AD-nisiZO.sense

    '.

    ί f i

    GrTGACTAAGTCAATAATCAGAATGAGCAGGTTTGCAGTCAGATTGGCAGGGATAAGCAGGCTAGCTC <«> l·-^·' xifi>

    ! : »

    AGGAGAAGTGAGTATAAAACCCCCACGCTCCGAGCAGCCAYCACAGAACTCCACTCATTCVTCCCACC B6

    --------------------------------------------ACACAAGTCXACTCATTCTTCGCAGG 26

    KC ;ΐΚ< i?<$ rc* ϊ > : ί

    ATGGCTTCTCATCGlCTGClCCrCCrCfGCCTTGC^GGACTGGTATTTGTGTCIGAGGClCGCCClAC 2Q4

    ATGCCTTCTCATCGTCTGCTCCT CCKTGCCTTGCTGCACTGGTATTTGTGl CrGAGGCrCGCtXTAC 34 kis 24$ Site

    GGGCACCGGTGAATCCAAGTG I XCTCTGATGGTCAA AGTTCTAGATGCTC TCCCACGCAGTCCTCCCA 272

    GGGCACCGGTGAATCCAAGTGTCCTCTGATGGTCAAACITCI AGAT GCTCTCXGAGGCACTCCTCCXA 162

    s.Xϊ i s t

    TCAATGTGCCCGTGCAT GTGTTCAGAAAGGCTGCT GATGACACCTGGGAGCCAT T TGGC 7 C TGGGAAA TCAATGTGGCXGTGGATGTGTT CAC.AAAG’GCTGCTGATCACACCTCGCAGCCATTTGCCTCTGCGAAA 23$ ί$$ Ϊ4?.- A«1

    J 1 ί

    ACGAGTGAGTCTGGAGACCTGCATGGGCTCACAACTGAGGAGGAATTTGTAGAAGCGATATACAAAGT 43$ ACCAGTGAGTCTGGAGAGCTGCATGGGCT CA^AACTCAGGAGGAATTTGTAGAAGGGATATACAaag? m

    ΪΝ· w

    S ί s

    GGAAATAGACACCAAATCTTACTCGAAGGCACTTCGeATtTGCGCATTCCATGAGCATGCAGaGSTGC 476 GGAAATAGACACCAAATCTTACTGCAAGGCACTTCGCATCTCCCCATTCCATGACCATGCAGAGGTCG jgg

    S-Gy· ><Λϊ >4i?

    ϊ ί r t

    TATTCAtAGCCAACGACrCCGGCCCCCGCCGCTACACCATTGCXGCCCrGCFCAGCCCCTAGTCCTAT 544

    TATKACAGCXAAGGACrCCGGGCGCGGCCGCTACACCATYGCCGCCCTGCTGACCCCCTACTCCTAT 474 >W?

    TCCAC€ACGCCTGTCGrCACCAAtCiXAAGGAATGAGGGA<TTerCCTCCACTGGAC<TGAAGGA<GA 612

    TGCAGcaCGGGIGTCGTCACCaatccCAaGGaatGAGGGACTTCTCCTCGaGTCGaCCTGAAGGACGA 503 ¢4½&$<?

    t i $i

    GGGATCGGATTTCATGrAACCAAGAGTATTCCATTTTTACTAAACCAGTGTTTTCACCTCATATCCTA 660

    CG«ATGGGArrrcATGrAA«AACACTATTCGATr tttactaaagcagtg rr τ tcacctcatatgcta w

    ---------------GTAACCAACACTATTCCAT............. — IS

    Jf-ttJ ί J ?

    TCTTAGAAGTCCAGGCAGAGACAATAAAACATTCCTCTGAAAGGCACTTTTCATTCCACrTTAACrTG ?4$

    TGT TAG A AG TCC 4GCC AG AC AC A ATA A AAC ATTCCTGTGAAAGGC AC T T T TC ATTCC A..........&?6 m SSS ί i ί

    A_Tr_TTT_TAAATTCCCTTAT_TGTCCC_TTCCAAAAAAAACAGAA_TCAAAA_TTTTA<'AA,AGAATCAAAGGA

    ------------------------------ΑΑΑΑΑΑΛ AAA---------------------------*--Sift

    VJ ii-la«* ί ί ίi

    ATTCTAGAAAGTATCTCGGCAGAACGCT ACCAGACATCCAAATTTCCAtTGT O' TGCAACCAAACCAC 86 4

    GTXTTAAATATGATCTGCAGCCATTAAAAAGACACATTCTGTAAAAAAAAAAAA im

    ----------------------------...................- - ......AAAAAAAAAAAA65S

    ......................................—.............--B

    FIG. 14
20. 20/32

    2017204161 20 Jun 2017

    rn>2XDiorjC□Gr<linin>XX

    CLHFlHωo d^-oOsrq<nf—1C4—-HeqinT·^>H<><o>-uq x>E-inJ5oooa soIΓΚocI-^-r^'<s©a<SCuO<r-zΉQCdiadtZ) m<aϋcz>ocTFΓΊo\CΓ]oOrqo’TF^1—1rqtFIOCri*“>\O<Ώ%©QPuωE/jIocdE—>a

    X S a

    © oΞPoΛa oXJ>>ej, “JX t or-zaVJΌx ,έ©ΌΈπ< Ο a *Xo υ co S^j cΞ oOEo.24—aο & e -£X S a g©λc.2 οo aZ? £*&G^rz;CΊ3 ΡνΧ aEOcdXo.ts©cnu<uυ >ζΪΑij ΟΛwI—1

    FIG. 15 a

    <Z)

    Z U ϊΛ © O

    E ns < <Λ z u
21. 21/32

    2017204161 20 Jun 2017 ο

    PBS SNALP-1955 SNALP-18534
22. 22/32

    2017204161 20 Jun 2017 (S9d OJ ΘΛΙΙΒΙΘ-Ο HQdVO/yil

    J?

    Έή Ε

    FIG. 17 σ> .ac

    Ε (Λ

    CQ □_

    Ε
23. 23/32

    2017204161 20 Jun 2017 co ο * ο co ό

    co ό

    ’ΤΤ CD co m m Ο)

    FIG. 18

    CM Ο 00 CO Tj- Cxi O

    F F Ο Ο Ο Ο Ο (S9d oi OAiieiey) HOdVO/dll
24. 24/32

    2017204161 20 Jun 2017 |9Α»η tfNMUi HOdVD/Hll SAiiepy

    FIG. 19
25. 25/32

    2017204161 20 Jun 2017 (S3d 01 psziieujjou) HOdVO/aU.

    FIG. 20 ο_ΛΟί cn

    I- Ji *T Ss <

    (Sad °l paziieuuou) HOdVO/ail

    CQ

    Q.
26. 26/32

    2017204161 20 Jun 2017 fe:5SS®;.'-' .v,’>·.. ; ..· .> :'· '·· ,.ν.· .

    <„. r.r.·VI ·. .:<-, :XVA

    A; '/\^;3 e|i .................

    . 7 ' , % /.^: ' < v^:v^:- . .

    ........ .....

    . Λ’ ’ '<_TT ‘ ; , : ,

    E ' ' . ί\*!|||!|ΜΜ

    ADVi-V?· ηώ xcXcToSrSf:^·^:;?^*-»^ «^'Η^ΛΪ^ίδίίΐίϊί!?:^ iiwioz-x XZ'XiOsViZ'Ni'jpiCSX'

    FIG. 21 lip 'VIM ipiW i ? - ίκ-™·5£< &^5SwS>; b r'A cW^a^~«>£s*&5¥ ϋΰ £<U£Sb& :-ULc3 iJ: b;

    (n s|9aoi anssii yii θλι)Β|θ^
27. 27/32

    Ο (Μ ttt Ο (Μ

    1^

    Ο (Μ

    FIG. 22 uoissajdxs SAiiepj VNdw HQdVO ueiunq /mi i ueuinq
28. 28/32

    2017204161 20 Jun 2017

    FIG. 23 uoissejdxe aAijeiaj VNdw HOdVO /yn ley
29. 29/32

    2017204161 20 Jun 2017

    FIG. 24 uoissajdxQ 9Aije|Qj VNdw HGdVO 1^BJ /dll ueiun|-|

    50/32

    2017204161 20 Jun 2017

    FIG. 25

    31/32

    2017204161 20 Jun 2017

    1.4

    1.21 ΐ

    0.81

    0.6i

    0.4 •“1

    CC h“ μ.

    *·*

    0.2

    21 days

    Ρ= 0.038 .1 cho control siRNA cho TTR siRNA

    1.6

    1.2 ξ

    S • S?

    ΐ ·<

    0.81

    Ρ~ G.14

    14 days

    0.61

    0.4-1

    0.2!

    0¹ cho control siRNA cho TTR siRNA

    FIG. 26

    32/32

    2017204161 20 Jun 2017

    1.4^{p= 00059} 21 days o

    cho control siRNA cho TTR siRNA

    FIG. 27

    SEQUENCE LISTING

    2017204161 20 Jun 2017 <110> ALNYLAM PHARMACEUTICALS, INC.

    KUMAMOTO UNIVERSITY <120> SIRNA THERAPY FOR TRANSTHYRETIN (TTR) RELATED OCULAR AMYLOIDOSIS <130> 26421-18452 PCT <140> PCT/US2011/030392 <141> 2011-03-29 <150> 61/318,704 <151> 2010-03-29 <150> 61/318,702 <151> 2010-03-29 <160> 1424 <170> Patentin version 3.5 <210> 1 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1 ccggugaauc caagugucc <210> 2 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 2 ggacacuugg auucaccgg <210> 3 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 3 acucauucuu ggcaggaug <210> 4 <211> 19 <212> RNA

    1 of 390

    2017204161 20 Jun 2017 <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 4 cauccugcca agaaugagu 19 <210> 5 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 5 aaguguccuc ugaugguca <210> 6 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 6 ugaccaucag aggacacuu <210> 7 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 7 ucauucuugg caggauggc <210> 8 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 8 gccauccugc caagaauga <210> 9 <211> 19

    2 of 390

    2017204161 20 Jun 2017 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 9 aaguucuaga ugcuguccg 19 <210> 10 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 10 cggacagcau cuagaacuu <210> 11 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 11 guucuagaug cuguccgag <210> 12 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 12 cucggacagc aucuagaac <210> 13 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 13 cuagaugcug uccgaggca <210> 14

    3 of 390

    2017204161 20 Jun 2017 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 14 ugccucggac agcaucuag 19 <210> 15 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 15 gaugcugucc gaggcaguc <210> 16 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 16 gacugccucg gacagcauc <210> 17 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 17 cauucuuggc aggauggcu <210> 18 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 18 agccauccug ccaagaaug

    4 Of 390

    2017204161 20 Jun 2017 <210> 19 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 19 ugcuguccga ggcaguccu 19 <210> 20 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 20 aggacugccu cggacagca <210> 21 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 21 ccgaggcagu ccugccauc <210> 22 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 22 gauggcagga cugccucgg <210> 23 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 23 caguccugcc aucaaugug

    5 of 390

    2017204161 20 Jun 2017 <210> 24 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 24 cacauugaug gcaggacug 19 <210> 25 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 25 caauguggcc gugcaugug <210> 26 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 26 cacaugcacg gccacauug <210> 27 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 27 auguguucag aaaggcugc <210> 28 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 28 gcagccuuuc ugaacacau

    6 of 390

    2017204161 20 Jun 2017 <210> 29 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 29 cagaagucca cucauucuu 19 <210> 30 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 30 aagaaugagu ggacuucug <210> 31 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 31 ggcaggaugg cuucucauc <210> 32 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 32 gaugagaagc cauccugcc <210> 33 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 33

    7 of 390 gagccauuug ccucuggga

    2017204161 20 Jun 2017 <210> 34 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 34 ucccagaggc aaauggcuc 19 <210> 35 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 35 caggauggcu ucucaucgu <210> 36 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 36 acgaugagaa gccauccug <210> 37 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 37 aggauggcuu cucaucguc <210> 38 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide

    8 of 390

    2017204161 20 Jun 2017 <400> 38 gacgaugaga agccauccu <210> 39 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 39 agagcugcau gggcucaca 19 <210> 40 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 40 ugugagccca ugcagcucu <210> 41 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 41 gcugcauggg cucacaacu <210> 42 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 42 aguugugagc ccaugcagc <210> 43 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide

    9 of 390

    2017204161 20 Jun 2017 <400> 43 ggauggcuuc ucaucgucu <210> 44 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 44 agacgaugag aagccaucc 19 <210> 45 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 45 gcaugggcuc acaacugag <210> 46 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 46 cucaguugug agcccaugc <210> 47 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 47 augggcucac aacugagga <210> 48 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic

    10 of 390 oligonucleotide

    2017204161 20 Jun 2017 <400> 48 uccucaguug ugagcccau <210> 49 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 49 ugggcucaca acugaggag <210> 50 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 50 cuccucaguu gugagccca <210> 51 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 51 gaggaauuug uagaaggga <210> 52 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 52 ucccuucuac aaauuccuc <210> 53 <211> 19 <212> RNA <213> Artificial Sequence <220>

    11 Of 390

    2017204161 20 Jun 2017 <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 53 uuuguagaag ggauauaca <210> 54 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 54 uguauauccc uucuacaaa <210> 55 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 55 uuguagaagg gauauacaa <210> 56 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 56 uuguauaucc cuucuacaa <210> 57 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 57 uguagaaggg auauacaaa <210> 58 <211> 19 <212> RNA <213> Artificial Sequence

    12 of 390

    2017204161 20 Jun 2017 <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 58 uuuguauauc ccuucuaca 19 <210> 59 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 59 agaagggaua uacaaagug <210> 60 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 60 cacuuuguau aucccuucu <210> 61 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 61 aaguggaaau agacaccaa <210> 62 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 62 uuggugucua uuuccacuu <210> 63 <211> 19 <212> RNA <213> Artificial Sequence

    13 of 390

    2017204161 20 Jun 2017 <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 63 ggaaauagac accaaaucu <210> 64 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 64 agauuuggug ucuauuucc <210> 65 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 65 gaaauagaca ccaaaucuu <210> 66 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 66 aagauuuggu gucuauuuc <210> 67 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 67 auagacacca aaucuuacu

    <210>68<211>19<212>RNA

    14 Of 390

    2017204161 20 Jun 2017 <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <4 00 > 6 8 aguaagauuu ggugucuau 19 <210> 69 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 69 uagacaccaa aucuuacug <210> 70 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 70 caguaagauu uggugucua <210> 71 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 71 agacaccaaa ucuuacugg <210> 72 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 72 ccaguaagau uuggugucu <210> 73 <211> 19

    15 of 390

    2017204161 20 Jun 2017 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 73 uuacuggaag gcacuuggc 19 <210> 74 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 74 gccaagugcc uuccaguaa <210> 75 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 75 uucucaucgu cugcuccuc <210> 76 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 76 gaggagcaga cgaugagaa <210> 77 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 77 ggaaggcacu uggcaucuc <210> 78

    16 of 390

    2017204161 20 Jun 2017 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 78 gagaugccaa gugccuucc 19 <210> 79 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 79 ggcacuuggc aucucccca <210> 80 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 80 uggggagaug ccaagugcc <210> 81 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 81 ggcaucuccc cauuccaug <210> 82 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

    17 of 390

    2017204161 20 Jun 2017 <400> 82 auggaauggg gagaugcctt <210> 83 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 83 gcaucucccc auuccauga 19 <210> 84 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 84 ucauggaaug gggagaugc <210> 85 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 85 caucucccca uuccaugag <210> 86 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <4 00 > 8 6 cucauggaau ggggagaug <210> 87 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide

    18 of 390

    2017204161 20 Jun 2017 <400> 87 aucuccccau uccaugagc <210> 88 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 88 gcucauggaa uggggagau 19 <210> 89 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 89 cuccccauuc caugagcau <210> 90 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 90 augcucaugg aauggggag <210> 91 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 91 cccauuccau gagcaugca <210> 92 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic

    19 of 390 oligonucleotide

    2017204161 20 Jun 2017 <400> 92 ugcaugcuca uggaauggg <210> 93 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 93 ccaugagcau gcagaggug 19 <210> 94 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 94 caccucugca ugcucaugg <210> 95 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 95 agcaugcaga ggugguauu <210> 96 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 96 aauaccaccu cugcaugcu <210> 97 <211> 19 <212> RNA <213> Artificial Sequence <220>

    20 Of 390

    2017204161 20 Jun 2017 <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 97 caugcagagg ugguauuca <210> 98 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 98 ugaauaccac cucugcaug <210> 99 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 99 augcagaggu gguauucac <210> 100 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 100 gugaauacca ccucugcau <210> 101 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 101 ggugguauuc acagccaac <210> 102 <211> 19 <212> RNA <213> Artificial Sequence

    21 of 390

    2017204161 20 Jun 2017 <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 102 guuggcugug aauaccacc 19 <210> 103 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 103 gugguauuca cagccaacg <210> 104 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 104 cguuggcugu gaauaccac <210> 105 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 105 ugguauucac agccaacga <210> 106 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 106 ucguuggcug ugaauacca <210> 107 <211> 19 <212> RNA <213> Artificial Sequence

    22 Of 390

    2017204161 20 Jun 2017 <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 107 gguauucaca gccaacgac 19 <210> 108 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 108 gucguuggcu gugaauacc <210> 109 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 109 guauucacag ccaacgacu <210> 110 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 110 agucguuggc ugugaauac <210> 111 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 111 uauucacagc caacgacuc <210> 112 <211> 19 <212> RNA

    23 of 390

    2017204161 20 Jun 2017 <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 112 gagucguugg cugugaaua 19 <210> 113 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 113 ucacagccaa cgacuccgg <210> 114 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 114 ccggagucgu uggcuguga <210> 115 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 115 ccccgccgcu acaccauug <210> 116 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 116 caauggugua gcggcgggg <210> 117 <211> 19

    24 of 390

    2017204161 20 Jun 2017 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 117 gaaguccacu cauucuugg 19 <210> 118 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 118 ccaagaauga guggacuuc <210> 119 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 119 cccugcugag ccccuacuc <210> 120 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 120 gaguaggggc ucagcaggg <210> 121 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 121 cugagccccu acuccuauu <210> 122

    25 Of 390

    2017204161 20 Jun 2017 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 122 aauaggagua ggggcucag 19 <210> 123 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 123 ugagccccua cuccuauuc <210> 124 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 124 gaauaggagu aggggcuca <210> 125 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 125 ccccuacucc uauuccacc <210> 126 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 126 gguggaauag gaguagggg

    26 of 390 <210> 127 <211> 19 <212> RNA <213> Artificial Sequence

    2017204161 20 Jun 2017 <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 127 cuacuccuau uccaccacg <210> 128 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 128 cgugguggaa uaggaguag <210> 129 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 129 uacuccuauu ccaccacgg <210> 130 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 130 ccguggugga auaggagua <210> 131 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 131 acuccuauuc caccacggc

    27 Of 390

    2017204161 20 Jun 2017 <210> 132 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 132 gccguggugg aauaggagu 19 <210> 133 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 133 uccuauucca ccacggcug <210> 134 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 134 cagccguggu ggaauagga <210> 135 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 135 uauuccacca cggcugucg <210> 136 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 136 cgacagccgu gguggaaua

    28 of 390

    2017204161 20 Jun 2017 <210> 137 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 137 auuccaccac ggcugucgu 19 <210> 138 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 138 acgacagccg ugguggaau <210> 139 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 139 caccacggcu gucgucacc <210> 140 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 140 ggugacgaca gccguggug <210> 141 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 141

    29 of 390 accacggcug ucgucacca

    2017204161 20 Jun 2017 <210> 142 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 142 uggugacgac agccguggu 19 <210> 143 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 143 ccacggcugu cgucaccaa <210> 144 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 144 uuggugacga cagccgugg <210> 145 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 145 acggcugucg ucaccaauc <210> 146 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide
30. 30 of 390

    2017204161 20 Jun 2017 <400> 146 gauuggugac gacagccgu <210> 147 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 147 cggcugucgu caccaaucc 19 <210> 148 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 148 ggauugguga cgacagccg <210> 149 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 149 cgucaccaau cccaaggaa <210> 150 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 150 uuccuuggga uuggugacg <210> 151 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide
31. 31 of 390

    2017204161 20 Jun 2017 <400> 151 caaucccaag gaaugaggg <210> 152 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 152 cccucauucc uugggauug 19 <210> 153 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 153 ccugaaggac gagggaugg <210> 154 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 154 ccaucccucg uccuucagg <210> 155 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 155 ggacgaggga ugggauuuc <210> 156 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic
32. 32 of 390 oligonucleotide

    2017204161 20 Jun 2017 <400> 156 gaaaucccau cccucgucc <210> 157 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 157 aaguccacuc auucuuggc 19 <210> 158 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 158 gccaagaaug aguggacuu <210> 159 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 159 gggauuucau guaaccaag <210> 160 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 160 cuugguuaca ugaaauccc <210> 161 <211> 19 <212> RNA <213> Artificial Sequence <220>
33. 33 of 390

    2017204161 20 Jun 2017 <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 161 ggauuucaug uaaccaaga <210> 162 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 162 ucuugguuac augaaaucc <210> 163 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 163 ucauguaacc aagaguauu <210> 164 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 164 aauacucuug guuacauga <210> 165 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 165 auguaaccaa gaguauucc <210> 166 <211> 19 <212> RNA <213> Artificial Sequence
34. 34 of 390

    2017204161 20 Jun 2017 <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 166 ggaauacucu ugguuacau 19 <210> 167 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 167 uguaaccaag aguauucca <210> 168 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 168 uggaauacuc uugguuaca <210> 169 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 169 guaaccaaga guauuccau <210> 170 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 170 auggaauacu cuugguuac <210> 171 <211> 19 <212> RNA <213> Artificial Sequence
35. 35 of 390

    2017204161 20 Jun 2017 <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 171 ugccuugcug gacugguau 19 <210> 172 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 172 auaccagucc agcaaggca <210> 173 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 173 uaaagcagug uuuucaccu <210> 174 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 174 aggugaaaac acugcuuua <210> 175 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 175 gccuugcugg acugguauu <210> 176 <211> 19 <212> RNA
36. 36 of 390

    2017204161 20 Jun 2017 <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 176 aauaccaguc cagcaaggc 19 <210> 177 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 177 uguuuucacc ucauaugcu <210> 178 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 178 agcauaugag gugaaaaca <210> 179 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 179 guuuucaccu cauaugcua <210> 180 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 180 uagcauauga ggugaaaac <210> 181 <211> 19
37. 37 of 390

    2017204161 20 Jun 2017 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 181 uuuucaccuc auaugcuau 19 <210> 182 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 182 auagcauaug aggugaaaa <210> 183 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 183 uucaccucau augcuaugu <210> 184 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 184 acauagcaua ugaggugaa <210> 185 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 185 caccucauau gcuauguua <210> 186
38. 38 of 390

    2017204161 20 Jun 2017 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 186 uaacauagca uaugaggug 19 <210> 187 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 187 ccuugcugga cugguauuu <210> 188 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 188 aaauaccagu ccagcaagg <210> 189 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 189 auaugcuaug uuagaaguc <210> 190 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 190 gacuucuaac auagcauau
39. 39 of 390

    2017204161 20 Jun 2017 <210> 191 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 191 uaugcuaugu uagaagucc 19 <210> 192 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 192 ggacuucuaa cauagcaua <210> 193 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 193 ugcuauguua gaaguccag <210> 194 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 194 cuggacuucu aacauagca <210> 195 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 195 cuugcuggac ugguauuug
40. 40 of 390

    2017204161 20 Jun 2017 <210> 196 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 196 caaauaccag uccagcaag 19 <210> 197 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 197 aguccaggca gagacaaua <210> 198 <211> 20 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 198 auugucucug ccuggacutt 20 <210> 199 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 199 uccaggcaga gacaauaaa 19 <210> 200 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic
41. 41 of 390 oligonucleotide

    2017204161 20 Jun 2017 <400> 200 uuuauugucu cugccugga <210> 201 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 201 gugaaaggca cuuuucauu 19 <210> 202 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 202 aaugaaaagu gccuuucac <210> 203 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 203 uggacuggua uuugugucu <210> 204 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 204 agacacaaau accagucca <210> 205 <211> 19 <212> RNA <213> Artificial Sequence <220>
42. 42 Of 390

    2017204161 20 Jun 2017 <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 205 gucugaggcu ggcccuacg <210> 206 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 206 cguagggcca gccucagac <210> 207 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 207 cugaggcugg cccuacggg <210> 208 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 208 cccguagggc cagccucag <210> 209 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 209 gaggcuggcc cuacgggca <210> 210 <211> 19 <212> RNA <213> Artificial Sequence
43. 43 of 390

    2017204161 20 Jun 2017 <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 210 ugcccguagg gccagccuc 19 <210> 211 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 211 aggcuggccc uacgggcac <210> 212 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 212 gugcccguag ggccagccu <210> 213 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 213 gcuggcccua cgggcaccg <210> 214 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 214 cggugcccgu agggccagc <210> 215 <211> 19 <212> RNA <213> Artificial Sequence
44. 44 Of 390

    2017204161 20 Jun 2017 <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 215 cuggcccuac gggcaccgg 19 <210> 216 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 216 ccggugcccg uagggccag <210> 217 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 217 ggcccuacgg gcaccggug <210> 218 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 218 caccggugcc cguagggcc <210> 219 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 219 ccacucauuc uuggcagga <210> 220 <211> 19 <212> RNA
45. 45 Of 390

    2017204161 20 Jun 2017 <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 220 uccugccaag aaugagugg 19 <210> 221 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 221 ccuacgggca ccggugaau <210> 222 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 222 auucaccggu gcccguagg <210> 223 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 223 cuacgggcac cggugaauc <210> 224 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 224 gauucaccgg ugcccguag <210> 225 <211> 19
46. 46 of 390

    2017204161 20 Jun 2017 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 225 uacgggcacc ggugaaucc 19 <210> 226 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 226 ggauucaccg gugcccgua <210> 227 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 227 acgggcaccg gugaaucca <210> 228 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 228 uggauucacc ggugcccgu <210> 229 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 229 gcaccgguga auccaagug <210> 230
47. 47 Of 390

    2017204161 20 Jun 2017 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 230 cacuuggauu caccggugc 19 <210> 231 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 231 caccggugaa uccaagugu <210> 232 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 232 acacuuggau ucaccggug <210> 233 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 233 uguggccaug cauguguuc <210> 234 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 234 gaacacaugc auggccaca
48. 48 Of 390

    2017204161 20 Jun 2017 <210> 235 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 235 guggccaugc auguguuca 19 <210> 236 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 236 ugaacacaug cauggccac <210> 237 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 237 gccaugcaug uguucagaa <210> 238 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 238 uucugaacac augcauggc <210> 239 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 239 uauuccacca cggcuguca
49. 49 of 390

    2017204161 20 Jun 2017 <210> 240 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 240 ugacagccgu gguggaaua 19 <210> 241 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 241 gucaucacca aucccaagg <210> 242 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 242 ccuugggauu ggugaugac <210> 243 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 243 guccucugau ggucaaagu <210> 244 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 244 acuuugacca ucagaggac
50. 50 of 390

    2017204161 20 Jun 2017 <210> 245 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 245 gauggucaaa guucuagau 19 <210> 246 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 246 aucuagaacu uugaccauc <210> 247 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 247 augcuguccg aggcagucc <210> 248 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 248 ggacugccuc ggacagcau <210> 249 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 249
51. 51 of 390 ccgugcaugu guucagaaa

    2017204161 20 Jun 2017 <210> 250 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 250 uuucugaaca caugcacgg 19 <210> 251 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 251 agucuggaga gcugcaugg <210> 252 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 252 ccaugcagcu cuccagacu <210> 253 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 253 caugggcuca caacugagg <210> 254 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide
52. 52 Of 390

    2017204161 20 Jun 2017 <400> 254 ccucaguugu gagcccaug <210> 255 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 255 ucucaucguc ugcuccucc 19 <210> 256 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 256 ggaggagcag acgaugaga <210> 257 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 257 ccccauucca ugagcaugc <210> 258 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 258 gcaugcucau ggaaugggg <210> 259 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide
53. 53 of 390

    2017204161 20 Jun 2017 <400> 259 gccccuacuc cuauuccac <210> 260 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 260 guggaauagg aguaggggc <210> 261 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 261 cuauuccacc acggcuguc <210> 262 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 262 gacagccgug guggaauag <210> 263 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 263 cacggcuguc gucaccaau <210> 264 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic
54. 54 Of 390 oligonucleotide

    2017204161 20 Jun 2017 <400> 264 auuggugacg acagccgug <210> 265 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 265 aggacgaggg augggauuu 19 <210> 266 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 266 aaaucccauc ccucguccu <210> 267 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 267 ucaccucaua ugcuauguu <210> 268 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 268 aacauagcau augagguga <210> 269 <211> 19 <212> RNA <213> Artificial Sequence <220>
55. 55 Of 390

    2017204161 20 Jun 2017 <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 269 ccucauaugc uauguuaga <210> 270 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 270 ucuaacauag cauaugagg <210> 271 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 271 auguuagaag uccaggcag <210> 272 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 272 cugccuggac uucuaacau <210> 273 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 273 ucugaggcug gcccuacgg <210> 274 <211> 19 <212> RNA <213> Artificial Sequence
56. 56 of 390

    2017204161 20 Jun 2017 <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 274 ccguagggcc agccucaga 19 <210> 275 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 275 ggcccuacgg gcaccggug <210> 276 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 276 caccggugcc cguagggcc <210> 277 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 277 gggcaccggu gaauccaag <210> 278 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 278 cuuggauuca ccggugccc <210> 279 <211> 19 <212> RNA <213> Artificial Sequence
57. 57 Of 390

    2017204161 20 Jun 2017 <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 279 ccaugcaugu guucagaaa 19 <210> 280 <211> 19 <212> RNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 280 uuucugaaca caugcaugg <210> 281 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 281 ccggugaauc caaguguccn n <210> 282 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other
58. 58 Of 390

    2017204161 20 Jun 2017 <400> 282 ggacacuugg auucaccggn n <210> 283 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 283 acucauucuu ggcaggaugn n <210> 284 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 284 cauccugcca agaaugagun n <210> 285 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
59. 59 of 390

    2017204161 20 Jun 2017 <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 285 aaguguccuc ugauggucan n <210> 286 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

    <220><221>modified base<222>¢20).. ¢21)<223>a, c, t, g, unknown or other<400>286ugaccaucag aggacacuun n

    <210> 287 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

    <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 287ucauucuugg caggauggcn n

    <210> 288 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide
60. 60 of 390

    2017204161 20 Jun 2017 <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 288 gccauccugc caagaaugan n <210> 289 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 289 aaguucuaga ugcuguccgn n <210> 290 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 290 cggacagcau cuagaacuun n <210> 291 <211> 21 <212> DNA <213> Artificial Sequence
61. 61 of 390

    2017204161 20 Jun 2017 <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 291 guucuagaug cuguccgagn n <210> 292 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 292 cucggacagc aucuagaacn n <210> 293 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 293 cuagaugcug uccgaggcan n
62. 62 of 390

    2017204161 20 Jun 2017 <210> 294 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 294 ugccucggac agcaucuagn n <210> 295 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 295 gaugcugucc gaggcagucn n <210> 296 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21)
63. 63 of 390 <223> a, c, t, g, unknown or other

    2017204161 20 Jun 2017 <400> 296 gacugccucg gacagcaucn n <210> 297 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 297 cauucuuggc aggauggcun n <210> 298 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 298 agccauccug ccaagaaugn n <210> 299 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
64. 64 of 390

    2017204161 20 Jun 2017 <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 299 ugcuguccga ggcaguccun n <210> 300 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 300 aggacugccu cggacagcan n <210> 301 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 301 ccgaggcagu ccugccaucn n <210> 302 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic
65. 65 of 390 oligonucleotide

    2017204161 20 Jun 2017 <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 302 gauggcagga cugccucggn n <210> 303 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 303 caguccugcc aucaaugugn n <210> 304 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

    <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 304cacauugaug gcaggacugn n

    <210> 305 <211> 21
66. 66 of 390

    2017204161 20 Jun 2017 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 305 caauguggcc gugcaugugn n <210> 306 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

    <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 306cacaugcacg gccacauugn n

    <210> 307 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

    <220><221>modified base<222>¢20) .• ¢21)<223>a, c,t, g, unknown or other<400>307
67. 67 of 390 auguguucag aaaggcugcn n

    2017204161 20 Jun 2017 <210> 308 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 308 gcagccuuuc ugaacacaun n <210> 309 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 309 cagaagucca cucauucuun n <210> 310 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>
68. 68 of 390

    2017204161 20 Jun 2017 <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 310 aagaaugagu ggacuucugn n <210> 311 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 311 ggcaggaugg cuucucaucn n <210> 312 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 312 gaugagaagc cauccugccn n <210> 313 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>
69. 69 of 390

    2017204161 20 Jun 2017 <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 313 gagccauuug ccucugggan n <210> 314 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 314 ucccagaggc aaauggcucn n <210> 315 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 315 caggauggcu ucucaucgun n <210> 316 <211> 21 <212> DNA <213> Artificial Sequence
70. 70 of 390

    2017204161 20 Jun 2017 <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 316 acgaugagaa gccauccugn n <210> 317 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 317 aggauggcuu cucaucgucn n <210> 318 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 318 gacgaugaga agccauccun n
71. 71 of 390

    2017204161 20 Jun 2017 <210> 319 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 319 agagcugcau gggcucacan n <210> 320 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 320 ugugagccca ugcagcucun n 21 <210> 321 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other
72. 72 Of 390

    2017204161 20 Jun 2017 <400> 321 gcugcauggg cucacaacun n <210> 322 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 322 aguugugagc ccaugcagcn n <210> 323 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

    <220><221>modified base<222>¢20) .. . ¢21)<223>a, c,, t, g, unknown or other<400> 323 ggauggcuucucaucgucun n

    <210> 324 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
73. 73 of 390

    2017204161 20 Jun 2017 <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 324 agacgaugag aagccauccn n <210> 325 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 325 gcaugggcuc acaacugagn n <210> 326 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 326 cucaguugug agcccaugcn n <210> 327 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide
74. 74 Of 390

    2017204161 20 Jun 2017 <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 327 augggcucac aacugaggan n <210> 328 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 328 uccucaguug ugagcccaun n <210> 329 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 329 ugggcucaca acugaggagn n <210> 330 <211> 21 <212> DNA
75. 75 Of 390

    2017204161 20 Jun 2017 <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 330 cuccucaguu gugagcccan n <210> 331 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 331 gaggaauuug uagaagggan n <210> 332 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 332 ucccuucuac aaauuccucn n
76. 76 of 390

    2017204161 20 Jun 2017 <210> 333 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 333 uuuguagaag ggauauacan n <210> 334 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 334 uguauauccc uucuacaaan n <210> 335 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base
77. 77 Of 390

    2017204161 20 Jun 2017 <222> ¢20)..¢21) <223> a, c, t, g, unknown or other <400> 335 uuguagaagg gauauacaan n <210> 336 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 336 uuguauaucc cuucuacaan n <210> 337 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 337 uguagaaggg auauacaaan n <210> 338 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic
78. 78 of 390 oligonucleotide

    2017204161 20 Jun 2017 <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 338 uuuguauauc ccuucuacan n <210> 339 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 339 agaagggaua uacaaagugn n <210> 340 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 340 cacuuuguau aucccuucun n <210> 341 <211> 21 <212> DNA <213> Artificial Sequence <220>
79. 79 of 390

    2017204161 20 Jun 2017 <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 341 aaguggaaau agacaccaan n <210> 342 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 342 uuggugucua uuuccacuun n <210> 343 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 343 ggaaauagac accaaaucun n <210> 344
80. 80 of 390

    2017204161 20 Jun 2017 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 344 agauuuggug ucuauuuccn n <210> 345 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 345 gaaauagaca ccaaaucuun n <210> 346 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other
81. 81 Of 390

    2017204161 20 Jun 2017 <400> 346 aagauuuggu gucuauuucn n <210> 347 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 347 auagacacca aaucuuacun n <210> 348 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

    <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 348aguaagauuu ggugucuaun n

    <210> 349 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
82. 82 of 390

    2017204161 20 Jun 2017 <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 349 uagacaccaa aucuuacugn n <210> 350 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

    <220><221>modified base<222>¢20) .• ¢21)<223>a, c,t, g, unknown or other<400>350

    caguaagauu uggugucuan n <210> 351 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 351 agacaccaaa ucuuacuggn n <210> 352 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide
83. 83 of 390

    2017204161 20 Jun 2017 <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 352 ccaguaagau uuggugucun n <210> 353 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

    <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 353uuacuggaag gcacuuggcn n

    <210> 354 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

    <220><221>modified base<222>¢20) .. . ¢21)<223>a, c,, t, g, unknown or other<400> 354gccaagugccuuccaguaan n

    <210> 355 <211> 21 <212> DNA <213> Artificial Sequence
84. 84 of 390

    2017204161 20 Jun 2017 <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 355 uucucaucgu cugcuccucn n <210> 356 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 356 gaggagcaga cgaugagaan n <210> 357 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 357 ggaaggcacu uggcaucucn n
85. 85 of 390

    2017204161 20 Jun 2017 <210> 358 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 358 gagaugccaa gugccuuccn n <210> 359 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 359 ggcacuuggc aucuccccan n <210> 360 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21)
86. 86 of 390 <223> a, c, t, g, unknown or other

    2017204161 20 Jun 2017 <400> 360 uggggagaug ccaagugccn n <210> 361 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 361 ggcaucuccc cauuccaugn n <210> 362 <211> 22 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢21) . . ¢22) <223> a, c, t, g, unknown or other <400> 362 auggaauggg gagaugcctt nn <210> 363 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
87. 87 of 390

    2017204161 20 Jun 2017 <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 363 gcaucucccc auuccaugan n <210> 364 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

    <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 364ucauggaaug gggsgaugcn n

    <210> 365 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 365 caucucccca uuccaugagn n <210> 366 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic
88. 88 of 390 oligonucleotide

    2017204161 20 Jun 2017 <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 366 cucauggaau ggggagaugn n <210> 367 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 367 aucuccccau uccaugagcn n <210> 368 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 368 gcucauggaa uggggagaun n <210> 369 <211> 21
89. 89 of 390

    2017204161 20 Jun 2017 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 369 cuccccauuc caugagcaun n <210> 370 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

    <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 370augcucaugg aauggggagn n

    <210> 371 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

    <220><221>modified base<222>¢20) .• ¢21)<223>a, c,t, g, unknown or other<400>371
90. 90 of 390 cccauuccau gagcaugcan n

    2017204161 20 Jun 2017 <210> 372 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 372 ugcaugcuca uggaaugggn n <210> 373 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

    <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 373ccaugagcau gcagaggugn n

    <210> 374 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>
91. 91 of 390

    2017204161 20 Jun 2017 <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 374 caccucugca ugcucauggn n <210> 375 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 375 agcaugcaga ggugguauun n <210> 376 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

    <220><221>modified base<222>¢20) .. · ¢21)<223>a, c,t, g, unknown or other<400> 376aauaccaccucugcaugcun n

    <210> 377 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>
92. 92 of 390

    2017204161 20 Jun 2017 <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 377 caugcagagg ugguauucan n <210> 378 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 378 ugaauaccac cucugcaugn n <210> 379 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 379 augcagaggu gguauucacn n <210> 380 <211> 21 <212> DNA <213> Artificial Sequence
93. 93 of 390

    2017204161 20 Jun 2017 <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 380 gugaauacca ccucugcaun n <210> 381 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 381 ggugguauuc acagccaacn n <210> 382 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 382 guuggcugug aauaccaccn n
94. 94 of 390

    2017204161 20 Jun 2017 <210> 383 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 383 gugguauuca cagccaacgn n <210> 384 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 384 cguuggcugu gaauaccacn n <210> 385 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other
95. 95 Of 390

    2017204161 20 Jun 2017 <400> 385 ugguauucac agccaacgan n <210> 386 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 386 ucguuggcug ugaauaccan n <210> 387 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 387 gguauucaca gccaacgacn n <210> 388 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
96. 96 of 390

    2017204161 20 Jun 2017 <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 388 gucguuggcu gugaauaccn n <210> 389 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 389 guauucacag ccaacgacun n <210> 390 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 390 agucguuggc ugugaauacn n <210> 391 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide
97. 97 of 390

    2017204161 20 Jun 2017 <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 391 uauucacagc caacgacucn n <210> 392 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 392 gagucguugg cugugaauan n <210> 393 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 393 ucacagccaa cgacuccggn n <210> 394 <211> 21 <212> DNA
98. 98 of 390

    2017204161 20 Jun 2017 <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 394 ccggagucgu uggcugugan n <210> 395 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 395 ccccgccgcu acaccauugn n <210> 396 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 396 caauggugua gcggcggggn n
99. 99 of 390

    2017204161 20 Jun 2017 <210> 397 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 397 gaaguccacu cauucuuggn n <210> 398 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 398 ccaagaauga guggacuucn n <210> 399 <211> 21 <212> DNA <213> Artificial Sequence <220>

    <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

    <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

    <221> modified_base
100. 100 of 390

     2017204161 20 Jun 2017 <222> ¢20)..¢21) <223> a, c, t, g, unknown or other <400> 399 cccugcugag ccccuacucn n <210> 400 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 400 gaguaggggc ucagcagggn n <210> 401 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 401 cugagccccu acuccuauun n <210> 402 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic
101. 101 of 390 oligonucleotide

     2017204161 20 Jun 2017 <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 402 aauaggagua ggggcucagn n <210> 403 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 403 ugagccccua cuccuauucn n <210> 404 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 404gaauaggagu aggggcucan n

     <210> 405 <211> 21 <212> DNA <213> Artificial Sequence <220>
102. 102 Of 390

     2017204161 20 Jun 2017 <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 405 ccccuacucc uauuccaccn n <210> 406 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 406gguggaauag gaguaggggn n

     <210> 407 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 407 cuacuccuau uccaccacgn n <210> 408
103. 103 of 390

     2017204161 20 Jun 2017 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 408 cgugguggaa uaggaguagn n <210> 409 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221>modified base<222>¢20) .. · ¢21)<223>a, c,t, g, unknown or other<400> 409uacuccuauuccaccacggn n

     <210> 410 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other
104. 104 Of 390

     2017204161 20 Jun 2017 <400> 410 ccguggugga auaggaguan n <210> 411 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 411 acuccuauuc caccacggcn n <210> 412 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 412gccguggugg aauaggagun n

     <210> 413 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
105. 105 of 390

     2017204161 20 Jun 2017 <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 413 uccuauucca ccacggcugn n <210> 414 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 414cagccguggu ggaauaggan n

     <210> 415 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221>modified base<222>¢20) .. . ¢21)<223>a, c,t, g, unknown or other<400> 415uauuccaccacggcugucgn n

     <210> 416 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
106. 106 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 416 cgacagccgu gguggaauan n <210> 417 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 417 auuccaccac ggcugucgun n <210> 418 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 418 acgacagccg ugguggaaun n <210> 419 <211> 21 <212> DNA <213> Artificial Sequence
107. 107 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 419 caccacggcu gucgucaccn n <210> 420 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 420 ggugacgaca gccguggugn n <210> 421 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 421 accacggcug ucgucaccan n
108. 108 of 390

     2017204161 20 Jun 2017 <210> 422 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 422 uggugacgac agccguggun n <210> 423 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 423 ccacggcugu cgucaccaan n <210> 424 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21)
109. 109 of 390 <223> a, c, t, g, unknown or other

     2017204161 20 Jun 2017 <400> 424 uuggugacga cagccguggn n <210> 425 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 425 acggcugucg ucaccaaucn n <210> 426 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 426 gauuggugac gacagccgun n <210> 427 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
110. 110 of 390

     2017204161 20 Jun 2017 <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 427 cggcugucgu caccaauccn n <210> 428 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 428 ggauugguga cgacagccgn n <210> 429 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 429 cgucaccaau cccaaggaan n <210> 430 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic
111. 111 of 390 oligonucleotide

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 430 uuccuuggga uuggugacgn n <210> 431 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 431caaucccaag gaaugagggn n

     <210> 432 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 432 cccucauucc uugggauugn n <210> 433 <211> 21
112. 112 of 390

     2017204161 20 Jun 2017 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 433 ccugaaggac gagggauggn n <210> 434 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 434 ccaucccucg uccuucaggn n <210> 435 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221>modified base<222>¢20) .• ¢21)<223>a, c,t, g, unknown or other<400>435
113. 113 of 390 ggacgaggga ugggauuucn n

     2017204161 20 Jun 2017 <210> 436 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 436 gaaaucccau cccucguccn n <210> 437 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 437 aaguccacuc auucuuggcn n <210> 438 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>
114. 114 Of 390

     2017204161 20 Jun 2017 <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 438 gccaagaaug aguggacuun n <210> 439 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 439 gggauuucau guaaccaagn n <210> 440 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 440 cuugguuaca ugaaaucccn n <210> 441 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>
115. 115 Of 390

     2017204161 20 Jun 2017 <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 441 ggauuucaug uaaccaagan n <210> 442 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 442 ucuugguuac augaaauccn n <210> 443 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 443 ucauguaacc aagaguauun n <210> 444 <211> 21 <212> DNA <213> Artificial Sequence
116. 116 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 444 aauacucuug guuacaugan n <210> 445 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 445 auguaaccaa gaguauuccn n <210> 446 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 446 ggaauacucu ugguuacaun n
117. 117 Of 390

     2017204161 20 Jun 2017 <210> 447 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 447 uguaaccaag aguauuccan n <210> 448 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221> modified base<222> ¢20).. ¢21)<223> a, c, t, g, unknown or other<400> 448uggaauacuc uugguuacan n

     <210> 449 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other
118. 118 Of 390

     2017204161 20 Jun 2017 <400> 449 guaaccaaga guauuccaun n <210> 450 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 450 auggaauacu cuugguuacn n <210> 451 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 451ugccuugcug gacugguaun n

     <210> 452 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
119. 119 of 390

     2017204161 20 Jun 2017 <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 452 auaccagucc agcaaggcan n <210> 453 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 453 uaaagcagug uuuucaccun n <210> 454 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 454 aggugaaaac acugcuuuan n <210> 455 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
120. 120 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 455 gccuugcugg acugguauun n <210> 456 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 456 aauaccaguc cagcaaggcn n <210> 457 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 457 uguuuucacc ucauaugcun n <210> 458 <211> 21 <212> DNA
121. 121 Of 390

     2017204161 20 Jun 2017 <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 458 agcauaugag gugaaaacan n <210> 459 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 459 guuuucaccu cauaugcuan n <210> 460 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221>modified base<222>¢20) .. ¢21)<223>a, c,t, g, unknown or other<400>460

     uagcauauga ggugaaaacn n
122. 122 Of 390

     2017204161 20 Jun 2017 <210> 461 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 461 uuuucaccuc auaugcuaun n <210> 462 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 462auagcauaug aggugaaaan n

     <210> 463 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base
123. 123 of 390

     2017204161 20 Jun 2017 <222> ¢20)..¢21) <223> a, c, t, g, unknown or other <400> 463 uucaccucau augcuaugun n <210> 464 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 464 acauagcaua ugaggugaan n <210> 465 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 465 caccucauau gcuauguuan n <210> 466 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic
124. 124 Of 390 oligonucleotide

     2017204161 20 Jun 2017 <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 466 uaacauagca uaugaggugn n <210> 467 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 467 ccuugcugga cugguauuun n <210> 468 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 468 aaauaccagu ccagcaaggn n <210> 469 <211> 21 <212> DNA <213> Artificial Sequence <220>
125. 125 Of 390

     2017204161 20 Jun 2017 <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 469 auaugcuaug uuagaagucn n <210> 470 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 470 gacuucuaac auagcauaun n <210> 471 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 471 uaugcuaugu uagaaguccn n <210> 472
126. 126 of 390

     2017204161 20 Jun 2017 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 472 ggacuucuaa cauagcauan n <210> 473 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221>modified base<222>¢20) .• ¢21)<223>a, c,t, g, unknown or other<400>473

     ugcuauguua gaaguccagn n <210> 474 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other
127. 127 Of 390

     2017204161 20 Jun 2017 <400> 474 cuggacuucu aacauagcan n <210> 475 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 475 cuugcuggac ugguauuugn n <210> 476 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 476 caaauaccag uccagcaagn n <210> 477 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
128. 128 of 390

     2017204161 20 Jun 2017 <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 477 aguccaggca gagacaauan n <210> 478 <211> 22 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢21) . . ¢22) <223> a, c, t, g, unknown or other <400> 478 auugucucug ccuggacutt nn <210> 479 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 479 uccaggcaga gacaauaaan n <210> 480 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
129. 129 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 480 uuuauugucu cugccuggan n <210> 481 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 481 gugaaaggca cuuuucauun n <210> 482 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 482aaugaaaagu gccuuucacn n

     <210> 483 <211> 21 <212> DNA <213> Artificial Sequence
130. 130 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 483 uggacuggua uuugugucun n <210> 484 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 484agacacaaau accaguccan n

     <210> 485 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 485gucugaggcu ggcccuacgn n
131. 131 of 390

     2017204161 20 Jun 2017 <210> 486 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 486 cguagggcca gccucagacn n <210> 487 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 487 cugaggcugg cccuacgggn n <210> 488 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21)
132. 132 Of 390 <223> a, c, t, g, unknown or other

     2017204161 20 Jun 2017 <400> 488 cccguagggc cagccucagn n <210> 489 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 489 gaggcuggcc cuacgggcan n <210> 490 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 490ugcccguagg gccagccucn n

     <210> 491 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
133. 133 of 390

     2017204161 20 Jun 2017 <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 491 aggcuggccc uacgggcacn n <210> 492 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 492gugcccguag ggccagccun n

     <210> 493 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 493 gcuggcccua cgggcaccgn n <210> 494 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic
134. 134 of 390 oligonucleotide

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 494 cggugcccgu agggccagcn n <210> 495 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 495 cuggcccuac gggcaccggn n <210> 496 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 496 ccggugcccg uagggccagn n <210> 497 <211> 21
135. 135 of 390

     2017204161 20 Jun 2017 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 497 ggcccuacgg gcaccggugn n <210> 498 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 498 caccggugcc cguagggccn n <210> 499 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221>modified base<222>¢20) .• ¢21)<223>a, c,t, g, unknown or other<400>499
136. 136 of 390 ccacucauuc uuggcaggan n

     2017204161 20 Jun 2017 <210> 500 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 500 uccugccaag aaugaguggn n <210> 501 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 501 ccuacgggca ccggugaaun n <210> 502 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>
137. 137 of 390

     2017204161 20 Jun 2017 <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 502 auucaccggu gcccguaggn n <210> 503 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 503 cuacgggcac cggugaaucn n <210> 504 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 504 gauucaccgg ugcccguagn n <210> 505 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>
138. 138 of 390

     2017204161 20 Jun 2017 <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 505 uacgggcacc ggugaauccn n <210> 506 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 506ggauucaccg gugcccguan n

     <210> 507 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 507Hcgggcaccg gugaauccan n

     <210> 508 <211> 21 <212> DNA <213> Artificial Sequence
139. 139 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 508 uggauucacc ggugcccgun n <210> 509 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 509 gcaccgguga auccaagugn n <210> 510 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 510 cacuuggauu caccggugcn n
140. 140 Of 390

     2017204161 20 Jun 2017 <210> 511 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 511 caccggugaa uccaagugun n <210> 512 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 512 acacuuggau ucaccggugn n <210> 513 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other
141. 141 Of 390

     2017204161 20 Jun 2017 <400> 513 uguggccaug cauguguucn n <210> 514 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 514 gaacacaugc auggccacan n <210> 515 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 515 guggccaugc auguguucan n <210> 516 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
142. 142 Of 390

     2017204161 20 Jun 2017 <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 516 ugaacacaug cauggccacn n <210> 517 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 517 gccaugcaug uguucagaan n <210> 518 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 518 uucugaacac augcauggcn n <210> 519 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
143. 143 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 519 uauuccacca cggcugucan n <210> 520 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 520ugacagccgu gguggaauan n

     <210> 521 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 521 gucaucacca aucccaaggn n <210> 522 <211> 21 <212> DNA
144. 144 of 390

     2017204161 20 Jun 2017 <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 522 ccuugggauu ggugaugacn n <210> 523 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 523 guccucugau ggucaaagun n <210> 524 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 524 acuuugacca ucagaggacn n
145. 145 Of 390

     2017204161 20 Jun 2017 <210> 525 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 525 gauggucaaa guucuagaun n <210> 526 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 526 aucuagaacu uugaccaucn n <210> 527 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base
146. 146 of 390

     2017204161 20 Jun 2017 <222> ¢20)..¢21) <223> a, c, t, g, unknown or other <400> 527 augcuguccg aggcaguccn n <210> 528 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 528 ggacugccuc ggacagcaun n <210> 529 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 529ccgugcaugu guucagaaan n

     <210> 530 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic
147. 147 Of 390 oligonucleotide

     2017204161 20 Jun 2017 <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 530 uuucugaaca caugcacggn n <210> 531 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 531 agucuggaga gcugcauggn n <210> 532 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 532 ccaugcagcu cuccagacun n <210> 533 <211> 21 <212> DNA <213> Artificial Sequence <220>
148. 148 Of 390

     2017204161 20 Jun 2017 <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 533 caugggcuca caacugaggn n <210> 534 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 534ccucaguugu gagcccaugn n

     <210> 535 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 535 ucucaucguc ugcuccuccn n <210> 536
149. 149 of 390

     2017204161 20 Jun 2017 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 536 ggaggagcag acgaugagan n <210> 537 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 537 ccccauucca ugagcaugcn n <210> 538 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other
150. 150 Of 390

     2017204161 20 Jun 2017 <400> 538 gcaugcucau ggaauggggn n <210> 539 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 539 gccccuacuc cuauuccacn n <210> 540 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 540guggaauagg aguaggggcn n

     <210> 541 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
151. 151 Of 390

     2017204161 20 Jun 2017 <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 541 cuauuccacc acggcugucn n <210> 542 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221>modified base<222>¢20).. ¢21)<223>a, c, t, g, unknown or other<400>542gacagccgug guggaauagn n

     <210> 543 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 543 cacggcuguc gucaccaaun n <210> 544 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
152. 152 Of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 544 auuggugacg acagccgugn n <210> 545 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 545 aggacgaggg augggauuun n <210> 546 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 546 aaaucccauc ccucguccun n <210> 547 <211> 21 <212> DNA <213> Artificial Sequence
153. 153 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 547 ucaccucaua ugcuauguun n <210> 548 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 548aacauagcau augaggugan n

     <210> 549 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 549 ccucauaugc uauguuagan n
154. 154 Of 390

     2017204161 20 Jun 2017 <210> 550 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 550 ucuaacauag cauaugaggn n <210> 551 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 551 auguuagaag uccaggcagn n <210> 552 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21)
155. 155 Of 390 <223> a, c, t, g, unknown or other

     2017204161 20 Jun 2017 <400> 552 cugccuggac uucuaacaun n <210> 553 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 553 ucugaggcug gcccuacggn n <210> 554 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 554 ccguagggcc agccucagan n <210> 555 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
156. 156 of 390

     2017204161 20 Jun 2017 <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 555 ggcccuacgg gcaccggugn n <210> 556 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 556 caccggugcc cguagggccn n <210> 557 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221>modified base<222>¢20).. ¢21)<223>a, c, t, g, unknown or other<400>557gggcaccggu gaauccaagn n

     <210> 558 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic
157. 157 Of 390 oligonucleotide

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 558 cuuggauuca ccggugcccn n <210> 559 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 559ccauqcaugu guucagaaan n

     <210> 560 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 560 uuucugaaca caugcauggn n <210> 561 <211> 21
158. 158 of 390

     2017204161 20 Jun 2017

     <212><213>DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>561

     ccggugaauc caagugucct t 21

     <210><211><212><213>56221DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>562

     ggacacuugg auucaccggt t 21

     <210><211><212><213>56321DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>563

     acucauucuu ggcaggaugt t 21

     <210><211><212><213>56421DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>564

     cauccugcca agaaugagut t 21
159. 159 of 390

     2017204161 20 Jun 2017

     <210><211><212><213>56521DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>565

     aaguguccuc ugauggucat t 21

     <210><211><212><213>56621DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>566

     ugaccaucag aggacacuut t 21

     <210><211><212><213>56721DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>567

     ucauucuugg caggauggct t 21

     <210><211><212><213>56821DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic
160. 160 of 390 oligonucleotide

     2017204161 20 Jun 2017 <400> 568 gccauccugc caagaaugat t <210> 569 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 569 aaguucuaga ugcuguccgt t 21 <210> 570 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 570 cggacagcau cuagaacuut t 21 <210> 571 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 571 guucuagaug cuguccgagt t 21 <210> 572 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic
161. 161 of 390 oligonucleotide

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 572 cucggacagc aucuagaact t 21 <210> 573 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 573 cuagaugcug uccgaggcat t 21 <210> 574 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 574 ugccucggac agcaucuagt t 21 <210> 575 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 575 gaugcugucc gaggcaguct t 21 <210> 576 <211> 21 <212> DNA
162. 162 Of 390

     2017204161 20 Jun 2017 <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 576 gacugccucg gacagcauct t 21 <210> 577 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 577 cauucuuggc aggauggcut t 21 <210> 578 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 578 agccauccug ccaagaaugt t 21 <210> 579 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 579 ugcuguccga ggcaguccut t 21
163. 163 of 390

     2017204161 20 Jun 2017 <210> 580 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 580 aggacugccu cggacagcat t <210> 581 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 581 ccgaggcagu ccugccauct t 21 <210> 582 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 582 gauggcagga cugccucggt t 21 <210> 583 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
164. 164 of 390

     2017204161 20 Jun 2017 <400> 583 caguccugcc aucaaugugt t <210> 584 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 584 cacauugaug gcaggacugt t 21 <210> 585 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 585 caauguggcc gugcaugugt t 21 <210> 586 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 586 cacaugcacg gccacauugt t 21 <210> 587 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
165. 165 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 587 auguguucag aaaggcugct t 21 <210> 588 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 588 gcagccuuuc ugaacacaut t 21 <210> 589 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 589 cagaagucca cucauucuut t 21 <210> 590 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 590 aagaaugagu ggacuucugt t 21 <210> 591 <211> 21 <212> DNA <213> Artificial Sequence
166. 166 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 591 ggcaggaugg cuucucauct t 21 <210> 592 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 592 gaugagaagc cauccugcct t 21 <210> 593 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 593 gagccauuug ccucugggat t 21 <210> 594 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 594 ucccagaggc aaauggcuct t 21
167. 167 of 390

     2017204161 20 Jun 2017 <210> 595 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 595 caggauggcu ucucaucgut t 21 <210> 596 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 596 acgaugagaa gccauccugt t 21 <210> 597 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 597 aggauggcuu cucaucguct t 21 <210> 598 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
168. 168 of 390 <400> 598 gacgaugaga agccauccut t 21

     2017204161 20 Jun 2017

     <210><211><212><213>59921DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>599

     agagcugcau gggcucacat t 21

     <210><211><212><213>60021DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>600

     ugugagccca ugcagcucut t 21

     <210><211><212><213>60121DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>601

     gcugcauggg cucacaacut t 21

     <210><211><212><213>60221DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide
169. 169 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 602 aguugugagc ccaugcagct t 21 <210> 603 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 603 ggauggcuuc ucaucgucut t 21 <210> 604 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 604 agacgaugag aagccaucct t 21 <210> 605 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 605 gcaugggcuc acaacugagt t 21 <210> 606 <211> 21 <212> DNA <213> Artificial Sequence
170. 170 of 390

     2017204161 20 Jun 2017

     <220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>606

     cucaguugug agcccaugct t 21

     <210><211><212><213>60721DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>607

     augggcucac aacugaggat t 21

     <210><211><212><213>60821DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>608

     uccucaguug ugagcccaut t 21

     <210><211><212><213>60921DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>609

     ugggcucaca acugaggagt t 21 <210> 610
171. 171 of 390

     2017204161 20 Jun 2017 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 610 cuccucaguu gugagcccat t 21 <210> 611 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 611 gaggaauuug uagaagggat t 21 <210> 612 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 612 ucccuucuac aaauuccuct t 21 <210> 613 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 613
172. 172 Of 390 uuuguagaag ggauauacat t

     2017204161 20 Jun 2017 <210> 614 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 614 uguauauccc uucuacaaat t 21 <210> 615 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 615 uuguagaagg gauauacaat t 21 <210> 616 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 616 uuguauaucc cuucuacaat t 21 <210> 617 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>
173. 173 of 390

     2017204161 20 Jun 2017

     <223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>617

     uguagaaggg auauacaaat t 21

     <210><211><212><213>61821DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>618

     uuuguauauc ccuucuacat t 21

     <210><211><212><213>61921DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>619

     agaagggaua uacaaagugt t 21

     <210><211><212><213>62021DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>620

     cacuuuguau aucccuucut t 21

     <210><211><212><213>62121DNAArtificial Sequence

     <220>
174. 174 Of 390

     2017204161 20 Jun 2017

     <223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>621

     aaguggaaau agacaccaat t 21

     <210><211><212><213>62221DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>622

     uuggugucua uuuccacuut t 21

     <210><211><212><213>62321DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>623

     ggaaauagac accaaaucut t 21

     <210><211><212><213>62421DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>624

     agauuuggug ucuauuucct t 21 <210> 625 <211> 21
175. 175 Of 390

     2017204161 20 Jun 2017

     <212><213>DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>625

     gaaauagaca ccaaaucuut t 21

     <210><211><212><213>62621DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>626

     aagauuuggu gucuauuuct t 21

     <210><211><212><213>62721DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>627

     auagacacca aaucuuacut t 21

     <210><211><212><213>62821DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>628

     aguaagauuu ggugucuaut t 21
176. 176 of 390

     2017204161 20 Jun 2017

     <210><211><212><213>62921DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>629

     uagacaccaa aucuuacugt t 21

     <210><211><212><213>63021DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>630

     caguaagauu uggugucuat t 21

     <210><211><212><213>63121DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>631

     agacaccaaa ucuuacuggt t 21

     <210><211><212><213>63221DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic
177. 177 Of 390 oligonucleotide

     2017204161 20 Jun 2017 <400> 632 ccaguaagau uuggugucut t <210> 633 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 633 uuacuggaag gcacuuggct t 21 <210> 634 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 634 gccaagugcc uuccaguaat t 21 <210> 635 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 635 uucucaucgu cugcuccuct t 21 <210> 636 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic
178. 178 of 390 oligonucleotide

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 636 gaggagcaga cgaugagaat t 21 <210> 637 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 637 ggaaggcacu uggcaucuct t 21 <210> 638 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 638 gagaugccaa gugccuucct t <210> 639 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 639 ggcacuuggc aucuccccat t 21 <210> 640 <211> 21 <212> DNA
179. 179 of 390

     2017204161 20 Jun 2017

     <213>Artificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>640

     uggggagaug ccaagugcct t 21

     <210><211><212><213>64121DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>641

     ggcaucuccc cauuccaugt t 21

     <210><211><212><213>64222DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>642

     auggaauggg gagaugcctt tt 22

     <210><211><212><213>64321DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>643

     gcaucucccc auuccaugat t 21
180. 180 of 390

     2017204161 20 Jun 2017 <210> 644 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 644 ucauggaaug gggagaugct t 21 <210> 645 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 645 caucucccca uuccaugagt t 21 <210> 646 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 646 cucauggaau ggggagaugt t 21 <210> 647 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
181. 181 of 390

     2017204161 20 Jun 2017 <400> 647 aucuccccau uccaugagct t <210> 648 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 648 gcucauggaa uggggagaut t 21 <210> 649 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 649 cuccccauuc caugagcaut t 21 <210> 650 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 650 augcucaugg aauggggagt t 21 <210> 651 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
182. 182 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 651 cccauuccau gagcaugcat t 21 <210> 652 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 652 ugcaugcuca uggaaugggt t 21 <210> 653 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 653 ccaugagcau gcagaggugt t 21 <210> 654 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 654 caccucugca ugcucauggt t 21 <210> 655 <211> 21 <212> DNA <213> Artificial Sequence
183. 183 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 655 agcaugcaga ggugguauut t 21 <210> 656 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 656 aauaccaccu cugcaugcut t 21 <210> 657 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 657 caugcagagg ugguauucat t 21 <210> 658 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 658 ugaauaccac cucugcaugt t 21
184. 184 of 390

     2017204161 20 Jun 2017

     <210><211><212><213>65921DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>659

     augcagaggu gguauucact t 21

     <210><211><212><213>66021DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>660

     gugaauacca ccucugcaut t 21

     <210><211><212><213>66121DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>661

     ggugguauuc acagccaact t 21

     <210><211><212><213>66221DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
185. 185 of 390 <400> 662 guuggcugug aauaccacct t 21

     2017204161 20 Jun 2017

     <210><211><212><213>66321DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>663

     gugguauuca cagccaacgt t 21

     <210><211><212><213>66421DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>664

     cguuggcugu gaauaccact t 21

     <210><211><212><213>66521DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>665

     ugguauucac agccaacgat t 21

     <210><211><212><213>66621DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide
186. 186 of 390

     2017204161 20 Jun 2017

     <220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>666

     ucguuggcug ugaauaccat t 21

     <210><211><212><213>66721DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>667

     gguauucaca gccaacgact t 21

     <210><211><212><213>66821DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>668

     gucguuggcu gugaauacct t 21

     <210><211><212><213>66921DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>669

     guauucacag ccaacgacut t 21

     <210><211><212><213>67021DNAArtificial Sequence
187. 187 of 390

     2017204161 20 Jun 2017

     <220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>670

     agucguuggc ugugaauact t 21

     <210><211><212><213>67121DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>671

     uauucacagc caacgacuct t 21

     <210><211><212><213>67221DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>672

     gagucguugg cugugaauat t 21

     <210><211><212><213>67321DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>673

     ucacagccaa cgacuccggt t 21 <210> 674
188. 188 of 390

     2017204161 20 Jun 2017 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 674 ccggagucgu uggcugugat t 21 <210> 675 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 675 ccccgccgcu acaccauugt t 21 <210> 676 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 676 caauggugua gcggcggggt t 21 <210> 677 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 677
189. 189 of 390 gaaguccacu cauucuuggt t 21

     2017204161 20 Jun 2017

     <210><211><212><213>67821DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>678

     ccaagaauga guggacuuct t 21

     <210><211><212><213>67921DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>679

     cccugcugag ccccuacuct t 21

     <210><211><212><213>68021DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>680

     gaguaggggc ucagcagggt t 21

     <210><211><212><213>68121DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide

     <220>
190. 190 Of 390 <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 681 cugagccccu acuccuauut t 21

     2017204161 20 Jun 2017 <210> 682 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 682 aauaggagua ggggcucagt t 21 <210> 683 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 683 ugagccccua cuccuauuct t 21 <210> 684 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 684 gaauaggagu aggggcucat t 21 <210> 685 <211> 21 <212> DNA <213> Artificial Sequence <220>
191. 191 Of 390

     2017204161 20 Jun 2017 <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 685 ccccuacucc uauuccacct t 21 <210> 686 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 686 gguggaauag gaguaggggt t <210> 687 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 687 cuacuccuau uccaccacgt t 21 <210> 688 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 688 cgugguggaa uaggaguagt t 21 <210> 689 <211> 21
192. 192 of 390

     2017204161 20 Jun 2017

     <212><213>DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>689

     uacuccuauu ccaccacggt t 21

     <210><211><212><213>69021DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>690

     ccguggugga auaggaguat t 21

     <210><211><212><213>69121DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>691

     acuccuauuc caccacggct t 21

     <210><211><212><213>69221DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>692

     gccguggugg aauaggagut t 21
193. 193 of 390

     2017204161 20 Jun 2017

     <210><211><212><213>69321DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>693

     uccuauucca ccacggcugt t 21

     <210><211><212><213>69421DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>694

     cagccguggu ggaauaggat t 21

     <210><211><212><213>69521DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>695

     uauuccacca cggcugucgt t 21

     <210><211><212><213>69621DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic
194. 194 of 390 oligonucleotide

     2017204161 20 Jun 2017 <400> 696 cgacagccgu gguggaauat t <210> 697 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 697 auuccaccac ggcugucgut t 21 <210> 698 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 698 acgacagccg ugguggaaut t 21 <210> 699 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 699 caccacggcu gucgucacct t 21 <210> 700 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic
195. 195 of 390 oligonucleotide

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 700 ggugacgaca gccguggugt t 21 <210> 701 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 701 accacggcug ucgucaccat t 21 <210> 702 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 702 uggugacgac agccguggut t 21 <210> 703 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 703 ccacggcugu cgucaccaat t 21 <210> 704 <211> 21 <212> DNA
196. 196 of 390

     2017204161 20 Jun 2017 <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 704 uuggugacga cagccguggt t 21 <210> 705 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 705 acggcugucg ucaccaauct t 21 <210> 706 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 706 gauuggugac gacagccgut t 21 <210> 707 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 707 cggcugucgu caccaaucct t 21
197. 197 of 390

     2017204161 20 Jun 2017 <210> 708 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 708 ggauugguga cgacagccgt t 21 <210> 709 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 709 cgucaccaau cccaaggaat t 21 <210> 710 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 710 uuccuuggga uuggugacgt t <210> 711 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
198. 198 of 390

     2017204161 20 Jun 2017 <400> 711 caaucccaag gaaugagggt t <210> 712 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 712 cccucauucc uugggauugt t 21 <210> 713 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 713 ccugaaggac gagggauggt t 21 <210> 714 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 714 ccaucccucg uccuucaggt t 21 <210> 715 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
199. 199 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 715 ggacgaggga ugggauuuct t 21 <210> 716 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 716 gaaaucccau cccucgucct t 21 <210> 717 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 717 aaguccacuc auucuuggct t 21 <210> 718 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 718 gccaagaaug aguggacuut t 21 <210> 719 <211> 21 <212> DNA <213> Artificial Sequence
200. 200 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 719 gggauuucau guaaccaagt t 21 <210> 720 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 720 cuugguuaca ugaaauccct t 21 <210> 721 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 721 ggauuucaug uaaccaagat t 21 <210> 722 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 722 ucuugguuac augaaaucct t 21
201. 201 of 390

     2017204161 20 Jun 2017

     <210><211><212><213>72321DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>723

     ucauguaacc aagaguauut t 21

     <210><211><212><213>72421DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>724

     aauacucuug guuacaugat t 21

     <210><211><212><213>72521DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>725

     auguaaccaa gaguauucct t 21

     <210><211><212><213>72621DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
202. 202 of 390

     2017204161 20 Jun 2017 <400> 726 ggaauacucu ugguuacaut t <210> 727 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 727 uguaaccaag aguauuccat t 21 <210> 728 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 728 uggaauacuc uugguuacat t 21 <210> 729 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 729 guaaccaaga guauuccaut t 21 <210> 730 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
203. 203 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 730 auggaauacu cuugguuact t 21 <210> 731 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 731 ugccuugcug gacugguaut t 21 <210> 732 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 732 auaccagucc agcaaggcat t 21 <210> 733 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 733 uaaagcagug uuuucaccut t 21 <210> 734 <211> 21 <212> DNA <213> Artificial Sequence
204. 204 of 390

     2017204161 20 Jun 2017

     <220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>734

     aggugaaaac acugcuuuat t 21

     <210><211><212><213>73521DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>735

     gccuugcugg acugguauut t 21

     <210><211><212><213>73621DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>736

     aauaccaguc cagcaaggct t 21

     <210><211><212><213>73721DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>737

     uguuuucacc ucauaugcut t 21 <210> 738
205. 205 Of 390

     2017204161 20 Jun 2017 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 738 agcauaugag gugaaaacat t 21 <210> 739 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 739 guuuucaccu cauaugcuat t 21 <210> 740 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 740 uagcauauga ggugaaaact t 21 <210> 741 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 741
206. 206 of 390 uuuucaccuc auaugcuaut t

     2017204161 20 Jun 2017 <210> 742 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 742 auagcauaug aggugaaaat t 21 <210> 743 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 743 uucaccucau augcuaugut t 21 <210> 744 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 744 acauagcaua ugaggugaat t 21 <210> 745 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>
207. 207 Of 390

     2017204161 20 Jun 2017 <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 745 caccucauau gcuauguuat t 21 <210> 746 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 746 uaacauagca uaugaggugt t 21 <210> 747 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 747 ccuugcugga cugguauuut t 21 <210> 748 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 748 aaauaccagu ccagcaaggt t <210> 749 <211> 21 <212> DNA <213> Artificial Sequence <220>
208. 208 of 390

     2017204161 20 Jun 2017 <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 749 auaugcuaug uuagaaguct t 21 <210> 750 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 750 gacuucuaac auagcauaut t 21 <210> 751 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 751 uaugcuaugu uagaagucct t 21 <210> 752 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 752 ggacuucuaa cauagcauat t 21 <211> 21 <210> 753
209. 209 of 390

     2017204161 20 Jun 2017

     <212><213>DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>753

     ugcuauguua gaaguccagt t 21

     <210><211><212><213>75421DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>754

     cuggacuucu aacauagcat t 21

     <210><211><212><213>75521DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>755

     cuugcuggac ugguauuugt t 21

     <210><211><212><213>75621DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>756

     caaauaccag uccagcaagt t 21
210. 210 of 390

     2017204161 20 Jun 2017

     <210><211><212><213>75721DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>757

     aguccaggca gagacaauat t 21

     <210><211><212><213>75822DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>758

     auugucucug ccuggacutt tt 22

     <210><211><212><213>75921DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>759

     uccaggcaga gacaauaaat t 21

     <210><211><212><213>76021DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic
211. 211 Of 390 oligonucleotide

     2017204161 20 Jun 2017 <400> 760 uuuauugucu cugccuggat t <210> 761 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 761 gugaaaggca cuuuucauut t 21 <210> 762 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 762 aaugaaaagu gccuuucact t 21 <210> 763 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 763 uggacuggua uuugugucut t 21 <210> 764 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic
212. 212 Of 390 oligonucleotide

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 764 agacacaaau accaguccat t 21 <210> 765 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 765 gucugaggcu ggcccuacgt t 21 <210> 766 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 766 cguagggcca gccucagact t 21 <210> 767 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 767 cugaggcugg cccuacgggt t 21 <210> 768 <211> 21 <212> DNA
213. 213 of 390

     2017204161 20 Jun 2017 <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 768 cccguagggc cagccucagt t 21 <210> 769 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 769 gaggcuggcc cuacgggcat t 21 <210> 770 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 770 ugcccguagg gccagccuct t 21 <210> 771 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 771 aggcuggccc uacgggcact t 21
214. 214 Of 390

     2017204161 20 Jun 2017 <210> 772 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 772 gugcccguag ggccagccut t 21 <210> 773 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 773 gcuggcccua cgggcaccgt t 21 <210> 774 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 774 cggugcccgu agggccagct t 21 <210> 775 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
215. 215 Of 390

     2017204161 20 Jun 2017 <400> 775 cuggcccuac gggcaccggt t <210> 776 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 776 ccggugcccg uagggccagt t 21 <210> 777 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 777 ggcccuacgg gcaccggugt t 21 <210> 778 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 778 caccggugcc cguagggcct t 21 <210> 779 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
216. 216 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 779 ccacucauuc uuggcaggat t 21 <210> 780 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 780 uccugccaag aaugaguggt t 21 <210> 781 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 781 ccuacgggca ccggugaaut t 21 <210> 782 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 782 auucaccggu gcccguaggt t 21 <210> 783 <211> 21 <212> DNA <213> Artificial Sequence
217. 217 Of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 783 cuacgggcac cggugaauct t 21 <210> 784 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 784 gauucaccgg ugcccguagt t 21 <210> 785 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 785 uacgggcacc ggugaaucct t 21 <210> 786 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 786 ggauucaccg gugcccguat t 21
218. 218 of 390

     2017204161 20 Jun 2017 <210> 787 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 787 acgggcaccg gugaauccat t 21 <210> 788 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 788 uggauucacc ggugcccgut t 21 <210> 789 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 789 gcaccgguga auccaagugt t 21 <210> 790 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
219. 219 of 390

     2017204161 20 Jun 2017 <400> 790 cacuuggauu caccggugct t <210> 791 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 791 caccggugaa uccaagugut t 21 <210> 792 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 792 acacuuggau ucaccggugt t 21 <210> 793 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 793 uguggccaug cauguguuct t 21 <210> 794 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
220. 220 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 794 gaacacaugc auggccacat t 21 <210> 795 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 795 guggccaugc auguguucat t 21 <210> 796 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 796 ugaacacaug cauggccact t 21 <210> 797 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 797 gccaugcaug uguucagaat t 21 <210> 798 <211> 21 <212> DNA <213> Artificial Sequence
221. 221 Of 390

     2017204161 20 Jun 2017

     <220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>798

     uucugaacac augcauggct t 21

     <210><211><212><213>79921DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>799

     uauuccacca cggcugucat t 21

     <210><211><212><213>80021DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>800

     ugacagccgu gguggaauat t 21

     <210><211><212><213>80121DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>801

     gucaucacca aucccaaggt t 21 <210> 802
222. 222 Of 390

     2017204161 20 Jun 2017 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 802 ccuugggauu ggugaugact t 21 <210> 803 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 803 guccucugau ggucaaagut t 21 <210> 804 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 804 acuuugacca ucagaggact t 21 <210> 805 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 805
223. 223 of 390 gauggucaaa guucuagaut t

     2017204161 20 Jun 2017 <210> 806 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 806 aucuagaacu uugaccauct t 21 <210> 807 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 807 augcuguccg aggcagucct t 21 <210> 808 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 808 ggacugccuc ggacagcaut t 21 <210> 809 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>
224. 224 Of 390

     2017204161 20 Jun 2017 <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 809 ccgugcaugu guucagaaat t 21 <210> 810 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 810 uuucugaaca caugcacggt t 21 <210> 811 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 811 agucuggaga gcugcauggt t 21 <210> 812 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 812 ccaugcagcu cuccagacut t <210> 813 <211> 21 <212> DNA <213> Artificial Sequence <220>
225. 225 Of 390

     2017204161 20 Jun 2017 <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 813 caugggcuca caacugaggt t 21 <210> 814 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 814 ccucaguugu gagcccaugt t <210> 815 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 815 ucucaucguc ugcuccucct t 21 <210> 816 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 816 ggaggagcag acgaugagat t 21 <210> 817 <211> 21
226. 226 of 390

     2017204161 20 Jun 2017

     <212><213>DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>817

     ccccauucca ugagcaugct t 21

     <210><211><212><213>81821DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>818

     gcaugcucau ggaauggggt t 21

     <210><211><212><213>81921DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>819

     gccccuacuc cuauuccact t 21

     <210><211><212><213>82021DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>820

     guggaauagg aguaggggct t 21
227. 227 Of 390

     2017204161 20 Jun 2017

     <210><211><212><213>82121DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>821

     cuauuccacc acggcuguct t 21

     <210><211><212><213>82221DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>822

     gacagccgug guggaauagt t 21

     <210><211><212><213>82321DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>823

     cacggcuguc gucaccaaut t 21

     <210><211><212><213>82421DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic
228. 228 of 390 oligonucleotide

     2017204161 20 Jun 2017 <400> 824 auuggugacg acagccgugt t <210> 825 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 825 aggacgaggg augggauuut t <210> 826 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 826 aaaucccauc ccucguccut t 21 <210> 827 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 827 ucaccucaua ugcuauguut t 21 <210> 828 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic
229. 229 of 390 oligonucleotide

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 828 aacauagcau augaggugat t 21 <210> 829 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 829 ccucauaugc uauguuagat t <210> 830 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 830 ucuaacauag cauaugaggt t <210> 831 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 831 auguuagaag uccaggcagt t 21 <210> 832 <211> 21 <212> DNA
230. 230 of 390

     2017204161 20 Jun 2017 <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 832 cugccuggac uucuaacaut t 21 <210> 833 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 833 ucugaggcug gcccuacggt t <210> 834 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 834 ccguagggcc agccucagat t <210> 835 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 835 ggcccuacgg gcaccggugt t 21
231. 231 of 390 <210> 836 <211> 21 <212> DNA <213> Artificial Sequence

     2017204161 20 Jun 2017 <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 836 caccggugcc cguagggcct t <210> 837 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 837 gggcaccggu gaauccaagt t 21 <210> 838 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 838 cuuggauuca ccggugccct t <210> 839 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
232. 232 of 390

     2017204161 20 Jun 2017 <400> 839 ccaugcaugu guucagaaat t <210> 840 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 840 uuucugaaca caugcauggt t 21 <210> 841 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 841 ccggugaauc caagugucct t 21 <210> 842 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 842 ggacacuugg auucaccggt t 21 <210> 843 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
233. 233 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 843 acucauucuu ggcaggaugt t 21 <210> 844 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 844 cauccugcca agaaugagut t 21 <210> 845 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 845 aaguguccuc ugauggucat t 21 <210> 846 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 846 ugaccaucag aggacacuut t 21 <210> 847 <211> 21 <212> DNA <213> Artificial Sequence
234. 234 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 847 ucauucuugg caggauggct t 21 <210> 848 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 848 gccauccugc caagaaugat t 21 <210> 849 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 849 aaguucuaga ugcuguccgt t 21 <210> 850 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 850 cggacagcau cuagaacuut t 21
235. 235 of 390

     2017204161 20 Jun 2017 <210> 851 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 851 guucuagaug cuguccgagt t 21 <210> 852 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 852 cucggacagc aucuagaact t 21 <210> 853 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 853 cuagaugcug uccgaggcat t 21 <210> 854 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
236. 236 of 390

     2017204161 20 Jun 2017 <400> 854 ugccucggac agcaucuagt t <210> 855 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 855 gaugcugucc gaggcaguct t 21 <210> 856 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 856 gacugccucg gacagcauct t 21 <210> 857 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 857 cauucuuggc aggauggcut t <210> 858 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
237. 237 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 858 agccauccug ccaagaaugt t 21 <210> 859 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 859 ugcuguccga ggcaguccut t 21 <210> 860 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 860 aggacugccu cggacagcat t 21 <210> 861 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 861 ccgaggcagu ccugccauct t 21 <210> 862 <211> 21 <212> DNA <213> Artificial Sequence
238. 238 of 390

     2017204161 20 Jun 2017

     <220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>862

     gauggcagga cugccucggt t 21

     <210><211><212><213>86321DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>863

     caguccugcc aucaaugugt t 21

     <210><211><212><213>86421DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>864

     cacauugaug gcaggacugt t 21

     <210><211><212><213>86521DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>865

     caauguggcc gugcaugugt t 21 <210> 866
239. 239 of 390

     2017204161 20 Jun 2017 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 866 cacaugcacg gccacauugt t 21 <210> 867 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 867 auguguucag aaaggcugct t <210> 868 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 868 gcagccuuuc ugaacacaut t 21 <210> 869 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 869
240. 240 of 390 cagaagucca cucauucuut t

     2017204161 20 Jun 2017 <210> 870 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 870 aagaaugagu ggacuucugt t 21 <210> 871 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 871 ggcaggaugg cuucucauct t 21 <210> 872 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 872 gaugagaagc cauccugcct t 21 <210> 873 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>
241. 241 Of 390

     2017204161 20 Jun 2017 <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 873 gagccauuug ccucugggat t 21 <210> 874 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 874 ucccagaggc aaauggcuct t 21 <210> 875 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 875 caggauggcu ucucaucgut t 21 <210> 876 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 876 acgaugagaa gccauccugt t <210> 877 <211> 21 <212> DNA <213> Artificial Sequence <220>
242. 242 Of 390

     2017204161 20 Jun 2017 <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 877 aggauggcuu cucaucguct t 21 <210> 878 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 878 gacgaugaga agccauccut t 21 <210> 879 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 879 agagcugcau gggcucacat t 21 <210> 880 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 880 ugugagccca ugcagcucut t 21 <210> 881 <211> 21
243. 243 of 390

     2017204161 20 Jun 2017

     <212><213>DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>881

     gcugcauggg cucacaacut t 21

     <210><211><212><213>88221DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>882

     aguugugagc ccaugcagct t 21

     <210><211><212><213>88321DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>883

     ggauggcuuc ucaucgucut t 21

     <210><211><212><213>88421DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>884

     agacgaugag aagccaucct t 21
244. 244 of 390

     2017204161 20 Jun 2017 <210> 885 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 885 gcaugggcuc acaacugagt t 21 <210> 886 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 886 cucaguugug agcccaugct t 21 <210> 887 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 887 augggcucac aacugaggat t <210> 888 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic
245. 245 Of 390 oligonucleotide

     2017204161 20 Jun 2017 <400> 888 uccucaguug ugagcccaut t <210> 889 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 889 ugggcucaca acugaggagt t <210> 890 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 890 cuccucaguu gugagcccat t 21 <210> 891 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 891 gaggaauuug uagaagggat t 21 <210> 892 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic
246. 246 of 390 oligonucleotide

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 892 ucccuucuac aaauuccuct t 21 <210> 893 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 893 uuuguagaag ggauauacat t <210> 894 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 894 uguauauccc uucuacaaat t <210> 895 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 895 uuguagaagg gauauacaat t 21 <210> 896 <211> 21 <212> DNA
247. 247 of 390

     2017204161 20 Jun 2017

     <213>Artificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>896

     uuguauaucc cuucuacaat t 21

     <210><211><212><213>89721DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>897

     uguagaaggg auauacaaat t 21

     <210><211><212><213>89821DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>898

     uuuguauauc ccuucuacat t 21

     <210><211><212><213>89921DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>899

     agaagggaua uacaaagugt t 21
248. 248 of 390

     2017204161 20 Jun 2017 <210> 900 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 900 cacuuuguau aucccuucut t 21 <210> 901 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 901 aaguggaaau agacaccaat t 21 <210> 902 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 902 uuggugucua uuuccacuut t <210> 903 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
249. 249 of 390

     2017204161 20 Jun 2017 <400> 903 ggaaauagac accaaaucut t <210> 904 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 904 agauuuggug ucuauuucct t 21 <210> 905 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 905 gaaauagaca ccaaaucuut t 21 <210> 906 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 906 aagauuuggu gucuauuuct t 21 <210> 907 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
250. 250 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 907 auagacacca aaucuuacut t 21 <210> 908 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 908 aguaagauuu ggugucuaut t 21 <210> 909 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 909 uagacaccaa aucuuacugt t 21 <210> 910 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 910 caguaagauu uggugucuat t 21 <210> 911 <211> 21 <212> DNA <213> Artificial Sequence
251. 251 Of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 911 agacaccaaa ucuuacuggt t 21 <210> 912 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 912 ccaguaagau uuggugucut t 21 <210> 913 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 913 uuacuggaag gcacuuggct t 21 <210> 914 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 914 gccaagugcc uuccaguaat t 21
252. 252 Of 390

     2017204161 20 Jun 2017 <210> 915 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 915 uucucaucgu cugcuccuct t 21 <210> 916 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 916 gaggagcaga cgaugagaat t 21 <210> 917 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 917 ggaaggcacu uggcaucuct t 21 <210> 918 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
253. 253 of 390

     2017204161 20 Jun 2017 <400> 918 gagaugccaa gugccuucct t <210> 919 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 919 ggcacuuggc aucuccccat t 21 <210> 920 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 920 uggggagaug ccaagugcct t 21 <210> 921 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 921 ggcaucuccc cauuccaugt t 21 <210> 922 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
254. 254 Of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 922 cauggaaugg ggagaugcct t 21 <210> 923 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 923 gcaucucccc auuccaugat t 21 <210> 924 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 924 ucauggaaug gggagaugct t 21 <210> 925 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 925 caucucccca uuccaugagt t 21 <210> 926 <211> 21 <212> DNA <213> Artificial Sequence
255. 255 Of 390

     2017204161 20 Jun 2017

     <220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>926

     cucauggaau ggggagaugt t 21

     <210><211><212><213>92721DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>927

     aucuccccau uccaugagct t 21

     <210><211><212><213>92821DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>928

     gcucauggaa uggggagaut t 21

     <210><211><212><213>92921DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>929

     cuccccauuc caugagcaut t 21 <210> 930
256. 256 of 390

     2017204161 20 Jun 2017

     <211><212><213>21DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>930

     augcucaugg aauggggagt t 21

     <210><211><212><213>93121DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>931

     cccauuccau gagcaugcat t 21

     <210><211><212><213>93221DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>932

     ugcaugcuca uggaaugggt t 21

     <210><211><212><213>93321DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>933
257. 257 Of 390 ccaugagcau gcagaggugt t

     2017204161 20 Jun 2017 <210> 934 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 934 caccucugca ugcucauggt t 21 <210> 935 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 935 agcaugcaga ggugguauut t 21 <210> 936 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 936 aauaccaccu cugcaugcut t 21 <210> 937 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>
258. 258 Of 390

     2017204161 20 Jun 2017

     <223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>937

     caugcagagg ugguauucat t 21

     <210><211><212><213>93821DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>938

     ugaauaccac cucugcaugt t 21

     <210><211><212><213>93921DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>939

     augcagaggu gguauucact t 21

     <210><211><212><213>94021DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>940

     gugaauacca ccucugcaut t 21

     <210><211><212><213>94121DNAArtificial Sequence

     <220>
259. 259 Of 390

     2017204161 20 Jun 2017

     <223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>941

     ggugguauuc acagccaact t 21

     <210><211><212><213>94221DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>942

     guuggcugug aauaccacct t 21

     <210><211><212><213>94321DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>943

     gugguauuca cagccaacgt t 21

     <210><211><212><213>94421DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>944

     cguuggcugu gaauaccact t 21 <210> 945 <211> 21
260. 260 of 390

     2017204161 20 Jun 2017

     <212><213>DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>945

     ugguauucac agccaacgat t 21

     <210><211><212><213>94621DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>946

     ucguuggcug ugaauaccat t 21

     <210><211><212><213>94721DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>947

     gguauucaca gccaacgact t 21

     <210><211><212><213>94821DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>948

     gucguuggcu gugaauacct t 21
261. 261 of 390

     2017204161 20 Jun 2017

     <210><211><212><213>94921DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>949

     guauucacag ccaacgacut t 21

     <210><211><212><213>95021DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>950

     agucguuggc ugugaauact t 21

     <210><211><212><213>95121DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>951

     uauucacagc caacgacuct t 21

     <210><211><212><213>95221DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic
262. 262 of 390 oligonucleotide

     2017204161 20 Jun 2017 <400> 952 gagucguugg cugugaauat t <210> 953 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 953 ucacagccaa cgacuccggt t 21 <210> 954 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 954 ccggagucgu uggcugugat t 21 <210> 955 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 955 ccccgccgcu acaccauugt t 21 <210> 956 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic
263. 263 of 390 oligonucleotide

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 956 caauggugua gcggcggggt t 21 <210> 957 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 957 gaaguccacu cauucuuggt t 21 <210> 958 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 958 ccaagaauga guggacuuct t 21 <210> 959 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 959 cccugcugag ccccuacuct t 21 <210> 960 <211> 21 <212> DNA
264. 264 Of 390

     2017204161 20 Jun 2017 <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 960 gaguaggggc ucagcagggt t 21 <210> 961 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 961 cugagccccu acuccuauut t 21 <210> 962 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 962 aauaggagua ggggcucagt t 21 <210> 963 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 963 ugagccccua cuccuauuct t 21
265. 265 of 390

     2017204161 20 Jun 2017 <210> 964 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 964 gaauaggagu aggggcucat t 21 <210> 965 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 965 ccccuacucc uauuccacct t 21 <210> 966 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 966 gguggaauag gaguaggggt t 21 <210> 967 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
266. 266 of 390

     2017204161 20 Jun 2017 <400> 967 cuacuccuau uccaccacgt t <210> 968 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 968 cgugguggaa uaggaguagt t 21 <210> 969 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 969 uacuccuauu ccaccacggt t 21 <210> 970 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 970 ccguggugga auaggaguat t 21 <210> 971 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
267. 267 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 971 acuccuauuc caccacggct t 21 <210> 972 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 972 gccguggugg aauaggagut t 21 <210> 973 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 973 uccuauucca ccacggcugt t 21 <210> 974 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 974 cagccguggu ggaauaggat t 21 <210> 975 <211> 21 <212> DNA <213> Artificial Sequence
268. 268 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 975 uauuccacca cggcugucgt t 21 <210> 976 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 976 cgacagccgu gguggaauat t 21 <210> 977 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 977 auuccaccac ggcugucgut t 21 <210> 978 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 978 acgacagccg ugguggaaut t 21
269. 269 of 390

     2017204161 20 Jun 2017 <210> 979 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 979 caccacggcu gucgucacct t 21 <210> 980 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 980 ggugacgaca gccguggugt t 21 <210> 981 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 981 accacggcug ucgucaccat t 21 <210> 982 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
270. 270 of 390

     2017204161 20 Jun 2017 <400> 982 uggugacgac agccguggut t <210> 983 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 983 ccacggcugu cgucaccaat t 21 <210> 984 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 984 uuggugacga cagccguggt t 21 <210> 985 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 985 acggcugucg ucaccaauct t 21 <210> 986 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
271. 271 Of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 986 gauuggugac gacagccgut t 21 <210> 987 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 987 cggcugucgu caccaaucct t 21 <210> 988 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 988 ggauugguga cgacagccgt t 21 <210> 989 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 989 cgucaccaau cccaaggaat t 21 <210> 990 <211> 21 <212> DNA <213> Artificial Sequence
272. 272 Of 390

     2017204161 20 Jun 2017

     <220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>990

     uuccuuggga uuggugacgt t 21

     <210><211><212><213>99121DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>991

     caaucccaag gaaugagggt t 21

     <210><211><212><213>99221DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>992

     cccucauucc uugggauugt t 21

     <210><211><212><213>99321DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>993

     ccugaaggac gagggauggt t 21 <210> 994
273. 273 of 390

     2017204161 20 Jun 2017 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 994 ccaucccucg uccuucaggt t 21 <210> 995 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 995 ggacgaggga ugggauuuct t 21 <210> 996 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 996 gaaaucccau cccucgucct t 21 <210> 997 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 997
274. 274 of 390 aaguccacuc auucuuggct t

     2017204161 20 Jun 2017 <210> 998 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 998 gccaagaaug aguggacuut t 21 <210> 999 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 999 gggauuucau guaaccaagt t 21 <210> 1000 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1000 cuugguuaca ugaaauccct t 21 <210> 1001 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>
275. 275 Of 390

     2017204161 20 Jun 2017 <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1001 ggauuucaug uaaccaagat t 21 <210> 1002 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1002 ucuugguuac augaaaucct t 21 <210> 1003 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1003 ucauguaacc aagaguauut t 21 <210> 1004 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1004 aauacucuug guuacaugat t 21 <210> 1005 <211> 21 <212> DNA <213> Artificial Sequence <220>
276. 276 Of 390

     2017204161 20 Jun 2017 <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1005 auguaaccaa gaguauucct t 21 <210> 1006 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1006 ggaauacucu ugguuacaut t 21 <210> 1007 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1007 uguaaccaag aguauuccat t 21 <210> 1008 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1008 uggaauacuc uugguuacat t 21 <211> 21 <210> 1009
277. 277 of 390

     2017204161 20 Jun 2017

     <212><213>DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1009

     guaaccaaga guauuccaut t 21

     <210><211><212><213>101021DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1010

     auggaauacu cuugguuact t 21

     <210><211><212><213>101121DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1011

     ugccuugcug gacugguaut t 21

     <210><211><212><213>101221DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1012

     auaccagucc agcaaggcat t 21
278. 278 of 390

     2017204161 20 Jun 2017

     <210><211><212><213>101321DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1013

     uaaagcagug uuuucaccut t 21

     <210><211><212><213>101421DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1014

     aggugaaaac acugcuuuat t 21

     <210><211><212><213>101521DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1015

     gccuugcugg acugguauut t 21

     <210><211><212><213>101621DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic
279. 279 of 390 oligonucleotide

     2017204161 20 Jun 2017 <400> 1016 aauaccaguc cagcaaggct t <210> 1017 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1017 uguuuucacc ucauaugcut t 21 <210> 1018 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1018 agcauaugag gugaaaacat t 21 <210> 1019 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1019 guuuucaccu cauaugcuat t 21 <210> 1020 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic
280. 280 of 390 oligonucleotide

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1020 uagcauauga ggugaaaact t 21 <210> 1021 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1021 uuuucaccuc auaugcuaut t 21 <210> 1022 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1022 auagcauaug aggugaaaat t 21 <210> 1023 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1023 uucaccucau augcuaugut t 21 <210> 1024 <211> 21 <212> DNA
281. 281 of 390

     2017204161 20 Jun 2017 <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1024 acauagcaua ugaggugaat t 21 <210> 1025 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1025 caccucauau gcuauguuat t 21 <210> 1026 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1026 uaacauagca uaugaggugt t 21 <210> 1027 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1027 ccuugcugga cugguauuut t 21
282. 282 of 390 <210> 1028 <211> 21 <212> DNA <213> Artificial Sequence

     2017204161 20 Jun 2017 <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1028 aaauaccagu ccagcaaggt t <210> 1029 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1029 auaugcuaug uuagaaguct t 21 <210> 1030 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1030 gacuucuaac auagcauaut t 21 <210> 1031 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
283. 283 of 390

     2017204161 20 Jun 2017 <400> 1031 uaugcuaugu uagaagucct t <210> 1032 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1032 ggacuucuaa cauagcauat t 21 <210> 1033 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1033 ugcuauguua gaaguccagt t 21 <210> 1034 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1034 cuggacuucu aacauagcat t 21 <210> 1035 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
284. 284 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1035 cuugcuggac ugguauuugt t 21 <210> 1036 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1036 caaauaccag uccagcaagt t 21 <210> 1037 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1037 aguccaggca gagacaauat t 21 <210> 1038 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1038 uauugucucu gccuggacut t 21 <210> 1039 <211> 21 <212> DNA <213> Artificial Sequence
285. 285 of 390

     2017204161 20 Jun 2017

     <220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1039

     uccaggcaga gacaauaaat t 21

     <210><211><212><213>104021DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1040

     uuuauugucu cugccuggat t 21

     <210><211><212><213>104121DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1041

     gugaaaggca cuuuucauut t 21

     <210><211><212><213>104221DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1042

     aaugaaaagu gccuuucact t 21
286. 286 of 390

     2017204161 20 Jun 2017

     <210><211><212><213>104321DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1043

     uggacuggua uuugugucut t 21

     <210><211><212><213>104421DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1044

     agacacaaau accaguccat t 21

     <210><211><212><213>104521DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1045

     gucugaggcu ggcccuacgt t 21

     <210><211><212><213>104621DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
287. 287 of 390

     2017204161 20 Jun 2017 <400> 1046 cguagggcca gccucagact t 21

     <210><211><212><213>104721DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1047

     cugaggcugg cccuacgggt t 21

     <210><211><212><213>104821DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1048

     cccguagggc cagccucagt t 21

     <210><211><212><213>104921DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1049

     gaggcuggcc cuacgggcat t 21

     <210><211><212><213>105021DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide
288. 288 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1050 ugcccguagg gccagccuct t 21 <210> 1051 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1051 aggcuggccc uacgggcact t 21 <210> 1052 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1052 gugcccguag ggccagccut t 21 <210> 1053 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1053 gcuggcccua cgggcaccgt t 21 <210> 1054 <211> 21 <212> DNA <213> Artificial Sequence
289. 289 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1054 cggugcccgu agggccagct t 21 <210> 1055 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1055 cuggcccuac gggcaccggt t 21 <210> 1056 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1056 ccggugcccg uagggccagt t 21 <210> 1057 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1057 ggcccuacgg gcaccggugt t 21 <210> 1058
290. 290 of 390

     2017204161 20 Jun 2017 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1058 caccggugcc cguagggcct t 21 <210> 1059 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1059 ccacucauuc uuggcaggat t 21 <210> 1060 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1060 uccugccaag aaugaguggt t 21 <210> 1061 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1061
291. 291 of 390 ccuacgggca ccggugaaut t

     2017204161 20 Jun 2017 <210> 1062 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1062 auucaccggu gcccguaggt t 21 <210> 1063 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1063 cuacgggcac cggugaauct t 21 <210> 1064 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1064 gauucaccgg ugcccguagt t 21 <210> 1065 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>
292. 292 Of 390

     2017204161 20 Jun 2017 <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1065 uacgggcacc ggugaaucct t 21 <210> 1066 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1066 ggauucaccg gugcccguat t 21 <210> 1067 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1067 acgggcaccg gugaauccat t 21 <210> 1068 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1068 uggauucacc ggugcccgut t <210> 1069 <211> 21 <212> DNA <213> Artificial Sequence <220>
293. 293 of 390

     2017204161 20 Jun 2017 <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1069 gcaccgguga auccaagugt t 21 <210> 1070 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1070 cacuuggauu caccggugct t 21 <210> 1071 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1071 caccggugaa uccaagugut t 21 <210> 1072 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1072 acacuuggau ucaccggugt t 21 <211> 21 <210> 1073
294. 294 of 390

     2017204161 20 Jun 2017

     <212><213>DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1073

     uguggccaug cauguguuct t 21

     <210><211><212><213>107421DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1074

     gaacacaugc auggccacat t 21

     <210><211><212><213>107521DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1075

     guggccaugc auguguucat t 21

     <210><211><212><213>107621DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1076

     ugaacacaug cauggccact t 21
295. 295 of 390

     2017204161 20 Jun 2017

     <210><211><212><213>107721DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1077

     gccaugcaug uguucagaat t 21

     <210><211><212><213>107821DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1078

     uucugaacac augcauggct t 21

     <210><211><212><213>107921DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1079

     uauuccacca cggcugucat t 21

     <210><211><212><213>108021DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic
296. 296 of 390 oligonucleotide

     2017204161 20 Jun 2017 <400> 1080 ugacagccgu gguggaauat t <210> 1081 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1081 gucaucacca aucccaaggt t 21 <210> 1082 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1082 ccuugggauu ggugaugact t 21 <210> 1083 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1083 guccucugau ggucaaagut t 21 <210> 1084 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic
297. 297 of 390 oligonucleotide

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1084 acuuugacca ucagaggact t 21 <210> 1085 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1085 gauggucaaa guucuagaut t 21 <210> 1086 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1086 aucuagaacu uugaccauct t 21 <210> 1087 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1087 augcuguccg aggcagucct t 21 <210> 1088 <211> 21 <212> DNA
298. 298 of 390

     2017204161 20 Jun 2017 <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1088 ggacugccuc ggacagcaut t 21 <210> 1089 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1089 ccgugcaugu guucagaaat t 21 <210> 1090 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1090 uuucugaaca caugcacggt t 21 <210> 1091 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1091 agucuggaga gcugcauggt t 21
299. 299 of 390

     2017204161 20 Jun 2017 <210> 1092 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1092 ccaugcagcu cuccagacut t 21 <210> 1093 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1093 caugggcuca caacugaggt t 21 <210> 1094 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1094 ccucaguugu gagcccaugt t 21 <210> 1095 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
300. 300 of 390

     2017204161 20 Jun 2017 <400> 1095 ucucaucguc ugcuccucct t <210> 1096 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1096 ggaggagcag acgaugagat t 21 <210> 1097 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1097 ccccauucca ugagcaugct t 21 <210> 1098 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1098 gcaugcucau ggaauggggt t 21 <210> 1099 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
301. 301 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1099 gccccuacuc cuauuccact t 21 <210> 1100 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1100 guggaauagg aguaggggct t 21 <210> 1101 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1101 cuauuccacc acggcuguct t 21 <210> 1102 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1102 gacagccgug guggaauagt t 21 <210> 1103 <211> 21 <212> DNA <213> Artificial Sequence
302. 302 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1103 cacggcuguc gucaccaaut t 21 <210> 1104 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1104 auuggugacg acagccgugt t 21 <210> 1105 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1105 aggacgaggg augggauuut t 21 <210> 1106 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1106 aaaucccauc ccucguccut t 21
303. 303 of 390

     2017204161 20 Jun 2017 <210> 1107 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1107 ucaccucaua ugcuauguut t 21 <210> 1108 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1108 aacauagcau augaggugat t 21 <210> 1109 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1109 ccucauaugc uauguuagat t 21 <210> 1110 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
304. 304 of 390

     2017204161 20 Jun 2017 <400> 1110 ucuaacauag cauaugaggt t <210> 1111 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1111 auguuagaag uccaggcagt t 21 <210> 1112 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1112 cugccuggac uucuaacaut t 21 <210> 1113 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1113 ucugaggcug gcccuacggt t 21 <210> 1114 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
305. 305 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1114 ccguagggcc agccucagat t 21 <210> 1115 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1115 ggcccuacgg gcaccggugt t 21 <210> 1116 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1116 caccggugcc cguagggcct t 21 <210> 1117 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1117 gggcaccggu gaauccaagt t 21 <210> 1118 <211> 21 <212> DNA <213> Artificial Sequence
306. 306 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1118 cuuggauuca ccggugccct t 21 <210> 1119 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1119 ccaugcaugu guucagaaat t 21 <210> 1120 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1120 uuucugaaca caugcauggt t 21 <210> 1121 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1121 guccucugau ggucaaagu 19 <210> 1122 <211> 19 <212> RNA <213> Artificial Sequence
307. 307 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1122 acuuugacca ucagaggac 19 <210> 1123 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1123 uucuugcucu auaaaccgu <210> 1124 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1124 acgguuuaua gagcaagaa <210> 1125 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1125 cucuauaaac cguguuagc <210> 1126 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1126 gcuaacacgg uuuauagag <210> 1127 <211> 19 <212> RNA <213> Artificial Sequence
308. 308 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1127 ucgccacuac accaucgca 19 <210> 1128 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1128 ugcgauggug uaguggcga <210> 1129 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1129 ucuugcucua uaaaccgug <210> 1130 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1130 cacgguuuau agagcaaga <210> 1131 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1131 ugcucuauaa accguguua <210> 1132 <211> 19 <212> RNA
309. 309 of 390

     2017204161 20 Jun 2017 <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1132 uaacacgguu uauagagca 19 <210> 1133 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1133 caguguucuu gcucuauaa <210> 1134 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1134 uuauagagca agaacacug <210> 1135 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1135 gcucuauaaa ccguguuag <210> 1136 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1136 cuaacacggu uuauagagc <211> 19 <210> 1137
310. 310 of 390

     2017204161 20 Jun 2017 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1137 ccuggaugcu guccgaggc 19 <210> 1138 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1138 gccucggaca gcauccagg <210> 1139 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1139 ucugaugguc aaaguccug <210> 1140 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1140 caggacuuug accaucaga <210> 1141 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1141 cuggagagcu gcacgggcu <210> 1142
311. 311 of 390

     2017204161 20 Jun 2017 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1142 agcccgugca gcucuccag 19 <210> 1143 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1143 ucuauaaacc guguuagca <210> 1144 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1144 ugcuaacacg guuuauaga <210> 1145 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1145 aacaguguuc uugcucuau <210> 1146 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1146 auagagcaag aacacuguu
312. 312 of 390

     2017204161 20 Jun 2017 <210> 1147 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1147 cucugauggu caaaguccu 19 <210> 1148 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1148 aggacuuuga ccaucagag <210> 1149 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1149 ugcuguccga ggcagcccu <210> 1150 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1150 agggcugccu cggacagca <210> 1151 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1151 gucuggagag cugcacggg
313. 313 of 390

     2017204161 20 Jun 2017 <210> 1152 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1152 cccgugcagc ucuccagac 19 <210> 1153 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1153 acaguguucu ugcucuaua <210> 1154 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1154 uauagagcaa gaacacugu <210> 1155 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1155 ccucugaugg ucaaagucc <210> 1156 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1156 ggacuuugac caucagagg
314. 314 of 390

     2017204161 20 Jun 2017 <210> 1157 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1157 aguccuggau gcuguccga 19 <210> 1158 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1158 ucggacagca uccaggacu <210> 1159 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1159 uugccucugg gaagaccgc <210> 1160 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1160 gcggucuucc cagaggcaa <210> 1161 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1161
315. 315 of 390 uggagagcug cacgggcuc

     2017204161 20 Jun 2017 <210> 1162 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1162 gagcccgugc agcucucca 19 <210> 1163 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1163 gagagcugca cgggcucac <210> 1164 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1164 gugagcccgu gcagcucuc <210> 1165 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1165 gagcugcacg ggcucacca <210> 1166 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
316. 316 of 390

     2017204161 20 Jun 2017 <400> 1166 uggugagccc gugcagcuc <210> 1167 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1167 uacaccaucg cagcccugc 19 <210> 1168 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1168 gcagggcugc gauggugua <210> 1169 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1169 guccuggaug cuguccgag <210> 1170 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1170 cucggacagc auccaggac <210> 1171 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
317. 317 of 390

     2017204161 20 Jun 2017 <400> 1171 agagcugcac gggcucacc <210> 1172 <211> 19 <212> RNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 1172 ggugagcccg ugcagcucu 19 <210> 1173 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 1173guccucugau ggucaaagun n

     <210> 1174 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1174 acuuugacca ucagaggacn n
318. 318 of 390

     2017204161 20 Jun 2017 <210> 1175 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1175 uucuugcucu auaaaccgun n <210> 1176 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1176 acgguuuaua gagcaagaan n 21 <210> 1177 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other
319. 319 Of 390

     2017204161 20 Jun 2017 <400> 1177 cucuauaaac cguguuagcn n <210> 1178 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1178 gcuaacacgg uuuauagagn n <210> 1179 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1179 ucgccacuac accaucgcan n <210> 1180 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
320. 320 of 390

     2017204161 20 Jun 2017 <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1180 ugcgauggug uaguggcgan n <210> 1181 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1181 ucuugcucua uaaaccgugn n <210> 1182 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 1182cacgguuuau agagcaagan n

     <210> 1183 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
321. 321 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1183 ugcucuauaa accguguuan n <210> 1184 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1184 uaacacgguu uauagagcan n <210> 1185 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1185 caguguucuu gcucuauaan n <210> 1186 <211> 21 <212> DNA
322. 322 of 390

     2017204161 20 Jun 2017 <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1186 uuauagagca agaacacugn n <210> 1187 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1187 gcucuauaaa ccguguuagn n 21 <210> 1188 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1188 cuaacacggu uuauagagcn n
323. 323 of 390

     2017204161 20 Jun 2017 <210> 1189 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1189 ccuggaugcu guccgaggcn n <210> 1190 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 1190gccucggaca gcauccaggn n

     <210> 1191 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base
324. 324 of 390

     2017204161 20 Jun 2017 <222> ¢20)..¢21) <223> a, c, t, g, unknown or other <400> 1191 ucugaugguc aaaguccugn n <210> 1192 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1192 caggacuuug accaucagan n <210> 1193 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221><222><223>modified base¢20).. ¢21)a, c, t, g, unknown or other<400> 1193cuggagagcu gcacgggcun n

     <210> 1194 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic
325. 325 of 390 oligonucleotide

     2017204161 20 Jun 2017 <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1194 agcccgugca gcucuccagn n <210> 1195 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1195 ucuauaaacc guguuagcan n <210> 1196 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221>modified base<222>¢20).. ¢21)<223>a, c, t, g, unknown or other<400>1196ugcuaacacg guuuauagan n

     <210> 1197 <211> 21 <212> DNA <213> Artificial Sequence <220>
326. 326 of 390

     2017204161 20 Jun 2017 <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1197 aacaguguuc uugcucuaun n <210> 1198 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221>modified base<222>¢20).. ¢21)<223>a, c, t, g, unknown or other<400>1198auagagcaag aacacuguun n

     <210> 1199 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221><222><223>modified base¢20) . . ¢21)a, c, t, g, unknown or other<400> 1199cucugauggu caaaguccun n

     <210> 1200
327. 327 of 390

     2017204161 20 Jun 2017 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1200 aggacuuuga ccaucagagn n <210> 1201 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221>modified base<222>¢20).. ¢21)<223>a, c, t, g, unknown or other<400>1201ugcuguccga ggcagcccun n

     <210> 1202 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other
328. 328 Of 390

     2017204161 20 Jun 2017 <400> 1202 agggcugccu cggacagcan n <210> 1203 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1203 gucuggagag cugcacgggn n <210> 1204 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1204 cccgugcagc ucuccagacn n <210> 1205 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
329. 329 of 390

     2017204161 20 Jun 2017 <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1205 acaguguucu ugcucuauan n <210> 1206 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221>modified base<222>¢20).. ¢21)<223>a, c, t, g, unknown or other<400>1206uauagagcaa gaacacugun n

     <210> 1207 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1207 ccucugaugg ucaaaguccn n <210> 1208 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
330. 330 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1208 ggacuuugac caucagaggn n <210> 1209 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221>modified base<222>¢20).. ¢21)<223>a, c, t, g, unknown or other<400>1209aguccuggau gcuguccgan n

     <210> 1210 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1210 ucggacagca uccaggacun n <210> 1211 <211> 21 <212> DNA <213> Artificial Sequence
331. 331 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1211 uugccucugg gaagaccgcn n <210> 1212 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1212 gcggucuucc cagaggcaan n <210> 1213 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1213 uggagagcug cacgggcucn n
332. 332 of 390

     2017204161 20 Jun 2017 <210> 1214 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1214 gagcccgugc agcucuccan n <210> 1215 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221>modified base<222>¢20).. ¢21)<223>a, c, t, g, unknown or other<400>1215gagagcugca cgggcucacn n

     <210> 1216 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21)
333. 333 of 390 <223> a, c, t, g, unknown or other

     2017204161 20 Jun 2017 <400> 1216 gugagcccgu gcagcucucn n <210> 1217 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1217 gagcugcacg ggcucaccan n <210> 1218 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1218 uggugagccc gugcagcucn n <210> 1219 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
334. 334 of 390

     2017204161 20 Jun 2017 <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1219 uacaccaucg cagcccugcn n <210> 1220 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1220 gcagggcugc gaugguguan n <210> 1221 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide

     <220><221>modified base<222>¢20).. ¢21)<223>a, c, t, g, unknown or other<400>1221guccuggaug cuguccgagn n

     <210> 1222 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic
335. 335 of 390 oligonucleotide

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1222 cucggacagc auccaggacn n <210> 1223 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1223 agagcugcac gggcucaccn n <210> 1224 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <220>

     <221> modified_base <222> ¢20).. ¢21) <223> a, c, t, g, unknown or other <400> 1224 ggugagcccg ugcagcucun n <210> 1225 <211> 21
336. 336 of 390

     2017204161 20 Jun 2017

     <212><213>DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1225

     guccucugau ggucaaagut t 21

     <210><211><212><213>122621DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1226

     acuuugacca ucagaggact t 21

     <210><211><212><213>122721DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1227

     uucuugcucu auaaaccgut t 21

     <210><211><212><213>122821DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1228

     acgguuuaua gagcaagaat t 21
337. 337 of 390

     2017204161 20 Jun 2017

     <210><211><212><213>122921DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1229

     cucuauaaac cguguuagct t 21

     <210><211><212><213>123021DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1230

     gcuaacacgg uuuauagagt t 21

     <210><211><212><213>123121DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1231

     ucgccacuac accaucgcat t 21

     <210><211><212><213>123221DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic
338. 338 of 390 oligonucleotide

     2017204161 20 Jun 2017 <400> 1232 ugcgauggug uaguggcgat t <210> 1233 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1233 ucuugcucua uaaaccgugt t 21 <210> 1234 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1234 cacgguuuau agagcaagat t 21 <210> 1235 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1235 ugcucuauaa accguguuat t 21 <210> 1236 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic
339. 339 of 390 oligonucleotide

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1236 uaacacgguu uauagagcat t 21 <210> 1237 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1237 caguguucuu gcucuauaat t 21 <210> 1238 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1238 uuauagagca agaacacugt t <210> 1239 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1239 gcucuauaaa ccguguuagt t 21 <210> 1240 <211> 21 <212> DNA
340. 340 of 390

     2017204161 20 Jun 2017

     <213>Artificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1240

     cuaacacggu uuauagagct t 21

     <210><211><212><213>124121DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1241

     ccuggaugcu guccgaggct t 21

     <210><211><212><213>124221DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1242

     gccucggaca gcauccaggt t 21

     <210><211><212><213>124321DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1243

     ucugaugguc aaaguccugt t 21
341. 341 of 390

     2017204161 20 Jun 2017 <210> 1244 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1244 caggacuuug accaucagat t 21 <210> 1245 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1245 cuggagagcu gcacgggcut t 21 <210> 1246 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1246 agcccgugca gcucuccagt t 21 <210> 1247 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
342. 342 of 390

     2017204161 20 Jun 2017 <400> 1247 ucuauaaacc guguuagcat t <210> 1248 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1248 ugcuaacacg guuuauagat t 21 <210> 1249 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1249 aacaguguuc uugcucuaut t 21 <210> 1250 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1250 auagagcaag aacacuguut t 21 <210> 1251 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
343. 343 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1251 cucugauggu caaaguccut t 21 <210> 1252 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1252 aggacuuuga ccaucagagt t 21 <210> 1253 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1253 ugcuguccga ggcagcccut t 21 <210> 1254 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1254 agggcugccu cggacagcat t 21 <210> 1255 <211> 21 <212> DNA <213> Artificial Sequence
344. 344 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1255 gucuggagag cugcacgggt t 21 <210> 1256 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1256 cccgugcagc ucuccagact t 21 <210> 1257 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1257 acaguguucu ugcucuauat t 21 <210> 1258 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1258 uauagagcaa gaacacugut t 21
345. 345 of 390

     2017204161 20 Jun 2017

     <210><211><212><213>125921DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1259

     ccucugaugg ucaaagucct t 21

     <210><211><212><213>126021DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1260

     ggacuuugac caucagaggt t 21

     <210><211><212><213>126121DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1261

     aguccuggau gcuguccgat t 21

     <210><211><212><213>126221DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
346. 346 of 390

     2017204161 20 Jun 2017 <400> 1262 ucggacagca uccaggacut t <210> 1263 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1263 uugccucugg gaagaccgct t 21 <210> 1264 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1264 gcggucuucc cagaggcaat t 21 <210> 1265 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1265 uggagagcug cacgggcuct t 21 <210> 1266 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
347. 347 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1266 gagcccgugc agcucuccat t 21 <210> 1267 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1267 gagagcugca cgggcucact t 21 <210> 1268 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1268 gugagcccgu gcagcucuct t 21 <210> 1269 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1269 gagcugcacg ggcucaccat t 21 <210> 1270 <211> 21 <212> DNA <213> Artificial Sequence
348. 348 of 390

     2017204161 20 Jun 2017

     <220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1270

     uggugagccc gugcagcuct t 21

     <210><211><212><213>127121DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1271

     uacaccaucg cagcccugct t 21

     <210><211><212><213>127221DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1272

     gcagggcugc gaugguguat t 21

     <210><211><212><213>127321DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1273

     guccuggaug cuguccgagt t 21 <210> 1274
349. 349 of 390

     2017204161 20 Jun 2017 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1274 cucggacagc auccaggact t 21 <210> 1275 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1275 agagcugcac gggcucacct t 21 <210> 1276 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1276 ggugagcccg ugcagcucut t 21 <210> 1277 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1277
350. 350 of 390 guccucugau ggucaaagut t

     2017204161 20 Jun 2017 <210> 1278 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1278 acuuugacca ucagaggact t 21 <210> 1279 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1279 uucuugcucu auaaaccgut t 21 <210> 1280 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1280 acgguuuaua gagcaagaat t 21 <210> 1281 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>
351. 351 of 390

     2017204161 20 Jun 2017

     <223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1281

     cucuauaaac cguguuagct t 21

     <210><211><212><213>128221DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1282

     gcuaacacgg uuuauagagt t 21

     <210><211><212><213>128321DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1283

     ucgccacuac accaucgcat t 21

     <210><211><212><213>128421DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1284

     ugcgauggug uaguggcgat t 21

     <210><211><212><213>128521DNAArtificial Sequence

     <220>
352. 352 Of 390

     2017204161 20 Jun 2017 <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1285 ucuugcucua uaaaccgugt t 21 <210> 1286 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1286 cacgguuuau agagcaagat t <210> 1287 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1287 ugcucuauaa accguguuat t 21 <210> 1288 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1288 uaacacgguu uauagagcat t 21 <210> 1289 <211> 21
353. 353 of 390

     2017204161 20 Jun 2017

     <212><213>DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1289

     caguguucuu gcucuauaat t 21

     <210><211><212><213>129021DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1290

     uuauagagca agaacacugt t 21

     <210><211><212><213>129121DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1291

     gcucuauaaa ccguguuagt t 21

     <210><211><212><213>129221DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1292

     cuaacacggu uuauagagct t 21
354. 354 of 390

     2017204161 20 Jun 2017

     <210><211><212><213>129321DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1293

     ccuggaugcu guccgaggct t 21

     <210><211><212><213>129421DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1294

     gccucggaca gcauccaggt t 21

     <210><211><212><213>129521DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1295

     ucugaugguc aaaguccugt t 21

     <210><211><212><213>129621DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic
355. 355 of 390 oligonucleotide

     2017204161 20 Jun 2017 <400> 1296 caggacuuug accaucagat t <210> 1297 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1297 cuggagagcu gcacgggcut t 21 <210> 1298 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1298 agcccgugca gcucuccagt t 21 <210> 1299 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1299 ucuauaaacc guguuagcat t 21 <210> 1300 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic
356. 356 of 390 oligonucleotide

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1300 ugcuaacacg guuuauagat t 21 <210> 1301 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1301 aacaguguuc uugcucuaut t <210> 1302 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1302 auagagcaag aacacuguut t 21 <210> 1303 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1303 cucugauggu caaaguccut t 21 <210> 1304 <211> 21 <212> DNA
357. 357 of 390

     2017204161 20 Jun 2017 <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1304 aggacuuuga ccaucagagt t 21 <210> 1305 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1305 ugcuguccga ggcagcccut t 21 <210> 1306 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1306 agggcugccu cggacagcat t 21 <210> 1307 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1307 gucuggagag cugcacgggt t 21
358. 358 of 390

     2017204161 20 Jun 2017 <210> 1308 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1308 cccgugcagc ucuccagact t <210> 1309 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1309 acaguguucu ugcucuauat t 21 <210> 1310 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1310 uauagagcaa gaacacugut t 21 <210> 1311 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
359. 359 of 390

     2017204161 20 Jun 2017 <400> 1311 ccucugaugg ucaaagucct t <210> 1312 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1312 ggacuuugac caucagaggt t 21 <210> 1313 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1313 aguccuggau gcuguccgat t 21 <210> 1314 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1314 ucggacagca uccaggacut t 21 <210> 1315 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
360. 360 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1315 uugccucugg gaagaccgct t 21 <210> 1316 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1316 gcggucuucc cagaggcaat t 21 <210> 1317 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1317 uggagagcug cacgggcuct t 21 <210> 1318 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1318 gagcccgugc agcucuccat t 21 <210> 1319 <211> 21 <212> DNA <213> Artificial Sequence
361. 361 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1319 gagagcugca cgggcucact t 21 <210> 1320 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1320 gugagcccgu gcagcucuct t 21 <210> 1321 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1321 gagcugcacg ggcucaccat t 21 <210> 1322 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1322 uggugagccc gugcagcuct t 21
362. 362 of 390

     2017204161 20 Jun 2017

     <210><211><212><213>132321DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1323

     uacaccaucg cagcccugct t 21

     <210><211><212><213>132421DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1324

     gcagggcugc gaugguguat t 21

     <210><211><212><213>132521DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1325

     guccuggaug cuguccgagt t 21

     <210><211><212><213>132621DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
363. 363 of 390

     2017204161 20 Jun 2017 <400> 1326 cucggacagc auccaggact t <210> 1327 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1327 agagcugcac gggcucacct t 21 <210> 1328 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1328 ggugagcccg ugcagcucut t <210> 1329 <211> 650 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic polynucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic polynucleotide <400> 1329

     acagaagtccactcattcttggcaggatggcttctcatcgtctgctcctcctctgccttg60ctggactggtatttgtgtctgaggctggccctacgggcaccggtgaatccaagtgtcctc120tgatggtcaaagttctagatgctgtccgaggcagtcctgccatcaatgtggccgtgcatg180tgttcagaaaggctgctgatgacacctgggagccatttgcctctgggaaaaccagtgagt240ctggagagctgcatgggctcacaactgaggaggaatttgtagaagggatatacaaagtgg300aaatagacaccaaatcttactggaaggcacttggcatctccccattccatgagcatgcag360
364. 364 of 390

     2017204161 20 Jun 2017

     aggtggtattcacagccaacgactccggcccccgccgctacaccattgccgccctgctga420gcccctactcctattccaccacggctgtcgtcaccaatcccaaggaatgagggacttctc480ctccagtggacctgaaggacgagggatgggatttcatgtaaccaagagtattccattttt540actaaagcagtgttttcacctcatatgctatgttagaagtccaggcagagacaataaaac600attcctgtgaaaggcacttttcattccaaaaaaaaaaaaaaaaaaaaaaa650

     <210> 1330 <211> 595 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1330

     cctgacaggatggcttcccttcgcctgttcctcctctgcctcgctggactgatatttgcg60tctgaagctggccctgggggtgctggagaatccaagtgtcctctgatggtcaaagtcctg120gatgctgtccgaggcagccctgctgtcgatgtggccgtgaaagtgttcaaaaggactgca180gacggaagctgggagccgtttgcctctgggaagaccgccgagtctggagagctgcacggg240ctcaccacagatgagaagttcacggaaggggtgtacagggtagaactggacaccaaatca300tactggaaggctcttggcatttccccattccatgaatacgcagaggtggttttcacagcc360aatgactctggtcatcgccactacaccatcgcagccctgctcagcccgtactcctacagc420accactgctgtcgtcagtaacccccagaactgagggacccagcccacgaggaccaagatc480ttgccaaagcagtagctcccatttgtactgaaacagtgttcttgctctataaaccgtgtt540agcaactcgggaagatgccgtgaaacgttcttattaaaccacctttatttcattc595

     <210> 1331 <211> 938 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic polynucleotide <400> 1331

     gttgactaagtcaataatcagaatcagcaggtttgcagtcagattggcagggataagcag60cctagctcaggagaagtgagtataaaagccccaggctgggagcagccatcacagaagtcc120actcattcttggcaggatggcttctcatcgtctgctcctcctctgccttgctggactggt180atttgtgtctgaggctggccctacgggcaccggtgaatccaagtgtcctctgatggtcaa240agttctagatgctgtccgaggcagtcctgccatcaatgtggccgtgcatgtgttcagaaa300ggctgctgatgacacctgggagccatttgcctctgggaaaaccagtgagtctggagagct360
365. 365 of 390

     2017204161 20 Jun 2017

     gcatgggctcacaactgaggaggaatttgtagaagggatatacaaagtggaaatagacac420caaatcttactggaaggcacttggcatctccccattccatgagcatgcagaggtggtatt480cacagccaacgactccggcccccgccgctacaccattgccgccctgctgagcccctactc540ctattccaccacggctgtcgtcaccaatcccaaggaatgagggacttctcctccagtgga600cctgaaggacgagggatgggatttcatgtaaccaagagtattccatttttactaaagcag660tgttttcacctcatatgctatgttagaagtccaggcagagacaataaaacattcctgtga720aaggcacttttcattccactttaacttgattttttaaattcccttattgtcccttccaaa780aaaaagagaatcaaaattttacaaagaatcaaaggaattctagaaagtatctgggcagaa840cgctaggagagatccaaatttccattgtcttgcaagcaaagcacgtattaaatatgatct900gcagccattaaaaagacacattctgtaaaaaaaaaaaa938

     <210> 1332 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1332 gggauuucau guaaccaagt t 21 <210> 1333 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1333 cuugguuaca ugaaauccct t 21 <210> 1334 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
366. 366 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1334 ggauuucaug uaaccaagat t 21 <210> 1335 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1335 ucuugguuac augaaaucct t 21 <210> 1336 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1336 gauuucaugu aaccaagagt t 21 <210> 1337 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1337 cucuugguua caugaaauct t 21 <210> 1338 <211> 21 <212> DNA <213> Artificial Sequence
367. 367 of 390

     2017204161 20 Jun 2017

     <220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1338

     auuucaugua accaagagut t 21

     <210><211><212><213>133921DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1339

     acucuugguu acaugaaaut t 21

     <210><211><212><213>134021DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1340

     uuucauguaa ccaagaguat t 21

     <210><211><212><213>134121DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1341

     uacucuuggu uacaugaaat t 21 <210> 1342
368. 368 of 390

     2017204161 20 Jun 2017 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1342 uucauguaac caagaguaut t 21 <210> 1343 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1343 auacucuugg uuacaugaat t 21 <210> 1344 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1344 ucauguaacc aagaguauut t 21 <210> 1345 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1345
369. 369 of 390 aauacucuug guuacaugat t

     2017204161 20 Jun 2017 <210> 1346 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1346 cauguaacca agaguauuct t 21 <210> 1347 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1347 gaauacucuu gguuacaugt t 21 <210> 1348 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1348 auguaaccaa gaguauucct t 21 <210> 1349 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>
370. 370 of 390

     2017204161 20 Jun 2017 <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1349 ggaauacucu ugguuacaut t 21 <210> 1350 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1350 uguaaccaag aguauuccat t 21 <210> 1351 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1351 uggaauacuc uugguuacat t 21 <210> 1352 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1352 uaaccaagag uauuccauut t 21 <210> 1353 <211> 21 <212> DNA <213> Artificial Sequence <220>
371. 371 of 390

     2017204161 20 Jun 2017 <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1353 aauggaauac ucuugguuat t 21 <210> 1354 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1354 aaccaagagu auuccauuut t 21 <210> 1355 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1355 aaauggaaua cucuugguut t 21 <210> 1356 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1356 accaagagua uuccauuuut t 21 <211> 21 <210> 1357
372. 372 of 390

     2017204161 20 Jun 2017

     <212><213>DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1357

     aaaauggaau acucuuggut t 21

     <210><211><212><213>135821DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1358

     ccaagaguau uccauuuuut t 21

     <210><211><212><213>135921DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1359

     aaaaauggaa uacucuuggt t 21

     <210><211><212><213>136021DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1360

     caagaguauu ccauuuuuat t 21
373. 373 of 390

     2017204161 20 Jun 2017

     <210><211><212><213>136121DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1361

     uaaaaaugga auacucuugt t 21

     <210><211><212><213>136221DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1362

     aagaguauuc cauuuuuact t 21

     <210><211><212><213>136321DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1363

     guaaaaaugg aauacucuut t 21

     <210><211><212><213>136421DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic
374. 374 of 390 oligonucleotide

     2017204161 20 Jun 2017 <400> 1364 agaguauucc auuuuuacut t <210> 1365 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1365 aguaaaaaug gaauacucut t 21 <210> 1366 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1366 gaguauucca uuuuuacuat t 21 <210> 1367 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1367 uaguaaaaau ggaauacuct t 21 <210> 1368 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic
375. 375 of 390 oligonucleotide

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1368 aguauuccau uuuuacuaat t 21 <210> 1369 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1369 uuaguaaaaa uggaauacut t 21 <210> 1370 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1370 guauuccauu uuuacuaaat t 21 <210> 1371 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1371 uuuaguaaaa auggaauact t 21 <210> 1372 <211> 21 <212> DNA
376. 376 of 390

     2017204161 20 Jun 2017

     <213>Artificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1372

     uauuccauuu uuacuaaagt t 21

     <210><211><212><213>137321DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1373

     cuuuaguaaa aauggaauat t 21

     <210><211><212><213>137421DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1374

     auuccauuuu uacuaaagct t 21

     <210><211><212><213>137521DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1375

     gcuuuaguaa aaauggaaut t 21
377. 377 of 390

     2017204161 20 Jun 2017 <210> 1376 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1376 uuccauuuuu acuaaagcat t 21 <210> 1377 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1377 ugcuuuagua aaaauggaat t 21 <210> 1378 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1378 uccauuuuua cuaaagcagt t <210> 1379 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
378. 378 of 390

     2017204161 20 Jun 2017 <400> 1379 cugcuuuagu aaaaauggat t <210> 1380 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1380 ccauuuuuac uaaagcagut t 21 <210> 1381 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1381 acugcuuuag uaaaaauggt t 21 <210> 1382 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1382 cauuuuuacu aaagcagugt t 21 <210> 1383 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
379. 379 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1383 cacugcuuua guaaaaaugt t 21 <210> 1384 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1384 auuuuuacua aagcagugut t 21 <210> 1385 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1385 acacugcuuu aguaaaaaut t <210> 1386 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1386 uuuuuacuaa agcaguguut t 21 <210> 1387 <211> 21 <212> DNA <213> Artificial Sequence
380. 380 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1387 aacacugcuu uaguaaaaat t 21 <210> 1388 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1388 uuuuacuaaa gcaguguuut t 21 <210> 1389 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1389 aaacacugcu uuaguaaaat t 21 <210> 1390 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1390 uuuacuaaag caguguuuut t 21
381. 381 of 390

     2017204161 20 Jun 2017 <210> 1391 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1391 aaaacacugc uuuaguaaat t 21 <210> 1392 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1392 uuacuaaagc aguguuuuct t 21 <210> 1393 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1393 gaaaacacug cuuuaguaat t 21 <210> 1394 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide
382. 382 of 390

     2017204161 20 Jun 2017 <400> 1394 uacuaaagca guguuuucat t <210> 1395 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1395 ugaaaacacu gcuuuaguat t 21 <210> 1396 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1396 acuaaagcag uguuuucact t 21 <210> 1397 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1397 gugaaaacac ugcuuuagut t 21 <210> 1398 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
383. 383 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1398 cuaaagcagu guuuucacct t 21 <210> 1399 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1399 ggugaaaaca cugcuuuagt t 21 <210> 1400 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1400 uaaagcagug uuuucaccut t 21 <210> 1401 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1401 aggugaaaac acugcuuuat t 21 <210> 1402 <211> 21 <212> DNA <213> Artificial Sequence
384. 384 of 390

     2017204161 20 Jun 2017

     <220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1402

     aaagcagugu uuucaccuct t 21

     <210><211><212><213>140321DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1403

     gaggugaaaa cacugcuuut t 21

     <210><211><212><213>140421DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1404

     aagcaguguu uucaccucat t 21

     <210><211><212><213>140521DNAArtificial Sequence<220><223>Description of Artificial Sequence: Synthetic oligonucleotide<220><223>Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide<400>1405

     ugaggugaaa acacugcuut t 21 <210> 1406
385. 385 of 390

     2017204161 20 Jun 2017 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1406 agcaguguuu ucaccucaut t 21 <210> 1407 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1407 augaggugaa aacacugcut t 21 <210> 1408 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1408 guaaccaaga guauuccaut t 21 <210> 1409 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1409
386. 386 of 390 auggaauacu cuugguuact t

     2017204161 20 Jun 2017 <210> 1410 <211> 19 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1410 gtaaccaa gagtattccat 19 <210> 1411 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1411 caguguucuu gcucuauaat t 21 <210> 1412 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1412 uuauagagca agaacacugt t 21 <210> 1413 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>
387. 387 of 390

     2017204161 20 Jun 2017 <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1413 ggauuucaug uaaccaagat t 21 <210> 1414 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1414 ucuugguuac augaaaucct t 21 <210> 1415 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic primer <400> 1415 cattcttggc aggatggctt c 21 <210> 1416 <211> 20 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic primer <400> 1416 ctcccaggtg tcatcagcag <210> 1417 <211> 22 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic primer <400> 1417 tgcctcgctg gactgatatt tg <210> 1418
388. 388 of 390

     2017204161 20 Jun 2017 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic primer <400> 1418 ttgaacactt tcacggccac a <210> 1419 <211> 18 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic primer <400> 1419 gccgtgcatg tgttcaga <210> 1420 <211> 22 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic primer <400> 1420 gctctccaga ctcactggtt tt <210> 1421 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1421 caguguucuu gcucuauaat t 21 <210> 1422 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic oligonucleotide
389. 389 of 390

     2017204161 20 Jun 2017 <220>

     <223> Description of Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 1422 uuauagagca agaacacugt t 21 <210> 1423 <211> 22 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic primer <400> 1423 tgcctcgctg gactgatatt tg 22 <210> 1424 <211> 21 <212> DNA <213> Artificial Sequence <220>

     <223> Description of Artificial Sequence: Synthetic primer <400> 1424 ttgaacactt tcacggccac a
390. 390 of 390