WO2018111327A1 - Methods and ingestible devices for the regio-specific release of jak inhibitors at the site of gastrointestinal tract disease - Google Patents

Abstract

This disclosure features methods and compositions for treating diseases of the gastrointestinal tract with a JAK inhibitor.

Description

METHODS AND INGESTIBLE DEVICES FOR THE REGIO-SPECIFIC RELEASE OF JAK INHIBITORS AT THE SITE OF GASTROINTESTINAL TRACT DISEASE

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 62/434,374, filed on December 14, 2016. The disclosure of the prior application is incorporated in its entirety into this application.

TECHNICAL FIELD

This disclosure features methods and compositions for treating diseases of the gastrointestinal tract with a JAK inhibitor.

Background

The Janus kinase (JAK) proteins are a family of non-receptor tyrosine kinases that possess a highly conserved kinase domain responsible for its enzymatic activity. Mammals have four members of this family, JAKl, JAK2, JAK3 and Tyrosine kinase 2 (TYK2). These kinases associate with the intracellular portion of cytokine or hormone receptors, and transduce signals through seven members of the STAT transcription factors - STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6 in various combinations. JAKl promotes signaling of multiple cytokines (e.g., certain type I and type II cytokines), including pro-inflammatory cytokines involved in the pathogenesis of autoimmune diseases. Single- nucleotide polymorphisms within the JAK/STAT pathway that confer susceptibility to IBD have been identified (Jostins et al., Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease, Nature 491 : 119-124, 2012). Both in vivo and in vitro studies have confirmed the role of JAK/STAT signaling in regulating immune responses (O'Shea and Plenge, JAK and STAT signaling molecules in immunoregulation and immune- mediated disease, Immunity 36:542-550, 2012). Tofacitinib, selective oral JAK inhibitor (including JAKl and JAK3) has been tested in clinical trials for both ulcerative colitis (Sandborn et al, Tofacitinib, an Oral Janus Kinase Inhibitor, in Active Ulcerative Colitis, New England J. Med 367:616-24, 2012; Panes et al, Randomized trial of tofacitinib in active ulcerative colitis: analysis of efficacy base on patient-reported outcomes, BMC

Gastroenterology 15: 14, doi: 10.1186/sl2876-015-0239-9, 2015) and Crohn's disease.

The gastrointestinal (GI) tract generally provides a therapeutic medium for an individual's body. At times, therapeutic drugs may need to be dispensed to specified locations within the small intestine or large intestine, which is more effective than oral administration of the therapeutic drugs to cure some medical conditions. For example, therapeutic drugs applied directly within the small intestine would not be contaminated, digested or otherwise compromised in the stomach, and thus allow a higher dose to be delivered at a specific location within the small intestine. However, dispensing therapeutic drugs directly within the small intestine inside a human body can be difficult, because a device or mechanism (e.g., special formulation) is needed to carry a therapeutically effective dose of drug to a desired location within the small intestine and then automatically deliver the therapeutic drug at the desired location. Such a device or mechanism also needs to be operated in a safe manner as the device or mechanism needs to enter the human body.

Provided herein in one embodiment is a novel treatment paradigm for inflammatory conditions of the gastrointestinal tract. The methods and compositions described herein allow for the regio-specific release of therapeutic drugs at or near the site of disease in the gastrointestinal tract. By releasing a therapeutic drug locally instead of systemically, the bioavailability of said drug can be increased at the site of injury and/or relative to a decrease in circulation; thereby, resulting in improved overall safety and/or efficacy and fewer side effects. Advantages may include one or more of increased drug engagement at the target, leading to new and more efficacious treatment regimens; and/or lower systemic drug levels, which means reduced toxicity and reduced immunogenicity in the case of biologies. For patients, clinicians and payors, this means an easier route of administration, fewer co- medicaments (e.g., immunomodulators), fewer side effects, and/or better outcomes.

Summary

Provided herein in one embodiment is a method of treating a disease of the gastrointestinal tract in a subject, comprising:

delivering a JAK inhibitor at a location in the gastrointestinal tract of the subject, wherein the method comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of the JAK inhibitor.

Provided herein in one embodiment is a method of treating a disease of the large intestine in a subject, comprising:

delivering a JAK inhibitor at a location in the proximal portion of the large intestine of the subject, wherein the method comprises administering endoscopically to the subject a therapeutically effective amount of the JAK inhibitor.

Provided herein in one embodiment is a method of treating a disease of the gastrointestinal tract in a subject, comprising:

releasing a JAK inhibitor at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease,

wherein the method comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of the JAK inhibitor.

Provided herein in one embodiment is a method of treating a disease of the gastrointestinal tract in a subject, comprising:

releasing a JAK inhibitor at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease,

wherein the method comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of the JAK inhibitor, wherein the

pharmaceutical composition is an ingestible device, and the method comprises administering orally to the subject the pharmaceutical composition.

Provided herein in one embodiment is a method of treating a disease of the gastrointestinal tract in a subject, comprising:

releasing a JAK inhibitor at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease, wherein the method comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of the

JAK inhibitor, wherein the method provides a concentration of the JAK inhibitor in the plasma of the subject that is less than 3 μg/ml.

Provided herein in one embodiment is a method of treating a disease of the large intestine in a subject, comprising:

releasing a JAK inhibitor at a location in the proximal portion of the large intestine of the subject that is proximate to one or more sites of disease,

wherein the method comprises administering endoscopically to the subject a therapeutically effective amount of the JAK inhibitor.

In another aspect of the present invention, there is provided a JAK inhibitor for use in a method of treating a disease of the gastrointestinal tract in a subject, wherein the method comprises orally administering to the subject an ingestible device loaded with the JAK inhibitor, wherein the JAK inhibitor is released by the device at a location in the

gastrointestinal tract of the subject that is proximate to one or more sites of disease.

In another aspect, the present invention provides a composition comprising or consisting of an ingestible device loaded with a therapeutically effective amount of a JAK inhibitor, for use in a method of treatment, wherein the method comprises orally

administering the composition to the subject, wherein the JAK inhibitor is released by the device at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease.

In another aspect, the present invention provides an ingestible device loaded with a therapeutically effective amount of a JAK inhibitor, wherein the device is controllable to release the JAK inhibitor at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease. The device may be for use in a method of treatment of the human or animal body, for example, any method as described herein.

In still another aspect, the present invention provides an ingestible device for use in a method of treating a disease of the gastrointestinal tract in a subject, wherein the method comprises orally administering to the subject the ingestible device loaded with a

therapeutically effective amount of a JAK inhibitor, wherein the JAK inhibitor is released by the device at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease.

An ingestible device as used in the present invention may comprise one or more mechanical and/or electrical mechanisms which actively control release of the JAK inhibitor. For example, in any of the above aspects and embodiments, the ingestible device as used in the present invention may comprise a release mechanism for release of the JAK inhibitor (e.g., from a reservoir comprising the JAK inhibitor) and an actuator controlling the release mechanism.

In one embodiment, the ingestible device comprises:

an ingestible housing comprising a reservoir having a therapeutically effective amount of the JAK inhibitor stored therein;

a release mechanism having a closed state which retains the JAK inhibitor in the reservoir and an open state which releases the JAK inhibitor from the reservoir to the exterior of the device; and

an actuator which changes the state of the release mechanism from the closed to the open state. In one embodiment, the ingestible device comprises

a housing defined by a first end, a second end substantially opposite from the first end;

a reservoir located within the housing and containing the JAK inhibitor wherein a first end of the reservoir is attached to the first end of the housing;

a mechanism for releasing the JAK inhibitor from the reservoir;

and

an exit valve configured to allow the JAK inhibitor to be released out of the housing from the reservoir.

Here, the exit valve can be considered as the release mechanism having a closed state which retains the JAK inhibitor in the reservoir and an open state which releases the JAK inhibitor from the reservoir to the exterior of the device, and the mechanism for releasing the JAK inhibitor from the reservoir can be considered as the actuator.

In some embodiments of methods of treatment as described herein, the one or more disease sites may have been pre-determined (e.g., determined in a step preceding the administration of the composition of the present invention). The disease site(s) may have been determined by imaging the gastrointestinal tract. For example, the disease site(s) may have been pre-determined by endoscopy (e.g., a step of colonoscopy, enteroscopy, or using a capsule endoscope). Determination that the device is proximate to the disease site may therefore comprise a determining that the device is in a location corresponding to this previously-determined disease site.

In some embodiments, the location of the device in the gut may be detected by tracking the device. For example, the device may comprise a localization mechanism which may be a communication system for transmitting localization data, e.g., by radiofrequency transmission. The device may additionally or alternatively comprise a communication system for receiving a signal remotely triggering the actuator and thus causing release of the JAK inhibitor. The signal may be sent when it is determined that the device is in the correct location in the gut.

Thus, the ingestible device may comprise:

an ingestible housing comprising a reservoir having a therapeutically effective amount of the JAK inhibitor stored therein; a release mechanism having a closed state which retains the JAK inhibitor in the reservoir and an open state which releases the JAK inhibitor from the reservoir to the exterior of the device;

a communication system for transmitting localization data to an external receiver and for receiving a signal from an external transmitter; and an actuator which changes the state of the release mechanism from the closed to the open state and which can be triggered by the signal.

In other embodiments, the ingestible device as used in the present invention may comprise an environmental sensor for detecting the location of the device in the gut and/or for detecting the presence of disease in the GI tract. For example, the environment sensor may be an image sensor for obtaining images in vivo.

Detecting the presence of disease may comprise, for example, detecting the presence of inflamed tissue, and/or lesions such as ulceration e.g., aphthoid ulcerations, "punched-out ulcers" and/or superficial ulcers of the mucosa, cobblestoning, stenosis, granulomas, crypt abscesses, fissures, e.g., extensive linear fissures, villous atrophy, fibrosis, and/or bleeding.

Detecting the presence of disease may also comprise molecular sensing, such as detecting the amount of an inflammatory cytokine or other marker of inflammation. Such a marker can be measured locally from a biopsy or systemically in the serum.

Where the ingestible device comprises an environmental sensor, actuation of the release mechanism may be triggered by a processor or controller communicably coupled to the environmental sensor. Thus, in some embodiments, the device may not require any external signal or control in order to release the drug.

In one embodiment, the ingestible device may comprise:

an ingestible housing comprising a reservoir having a therapeutically effective amount of the JAK inhibitor stored therein;

a release mechanism having a closed state which retains the JAK inhibitor in the reservoir and an open state which releases the JAK inhibitor from the reservoir to the exterior of the device;

an actuator which controls the transition of the release mechanism from the closed to the open state;

a detector for detecting the location of the device in the gut and/or the presence of diseased tissue; and a processor or controller which is coupled to the detector and to the actuator and which triggers the actuator to cause the release mechanism to transition from its closed state to its open state when it is determined that the device is in the presence of diseased tissue and/or in a location in the gut that has been predetermined to be proximal to diseased tissue.

In another embodiment, there is provided:

an ingestible housing comprising a reservoir having a therapeutically effective amount of the JAK inhibitor stored therein;

a detector coupled to the ingestible housing, the detector configured to detect when the ingestible housing is proximate to a respective disease site of the one of the one or more sites of disease;

a valve system in fluid communication with the reservoir system; and a controller communicably coupled to the valve system and the detector, the controller configured to cause the valve system to open in response to the detector detecting that the ingestible housing is proximate to the respective disease site so as to release the therapeutically effective amount of the JAK inhibitor at the respective disease site.

As above, detection that the ingestible housing is proximate to the respective disease site may be based on environmental data indicating the location of the device in the GI tract (and reference to a pre-determined disease site) or on environmental data directly indicating the presence of diseased tissue.

Additionaly or alternatively, the device may further comprise a communication system adapted to transmit the environment data to an external receiver (e.g., outside of the body). This data may be used, for example, for diagnostic purposes. The external receiver may comprise means for displaying the data.

In some embodiments, this data may be analyzed externally to the device and used to determine when the drug should be released: an external signal may then be sent to the device to trigger release of the drug. Thus, the communication system may further be adapted to receive a signal remotely triggering the actuator and thus causing release of the JAK inhibitor. The signal may be sent from an extemal transmitter in response to receipt/analysis and/or assessment of the environmental data, e.g., data indicating that the device has reached the desired location of the gut (where the location of the diseased tissue has been pre- determined) and/or data indicating the presence of diseased tissue. "External" may be "outside of the body".

Thus, in another embodiment, the ingestible device may comprise:

an ingestible housing comprising a reservoir having a a therapeutically effective amount of the JAK inhibitor stored therein;

a release mechanism having a closed state which retains the JAK inhibitor in the reservoir and an open state which releases the JAK inhibitor from the reservoir to the exterior of the device;

an environmental detector for detecting environmental data indicating the location of the device in the gut and/or the presence of diseased tissue;

a communication system for transmitting the environmental data to an external receiver and for receiving a signal from an external transmitter; and an actuator which controls the transition of the release mechanism from the closed to the open state in response to the signal.

It will be understood from the above that when the device comprises one or more environmental detectors, e.g., comprises an image detector, the compositions may be used both for disease detection and for disease treatment.

Accordingly, in a further embodiment, there is provided a JAK inhibitor for use in a method of detecting and treating a disease of the gastrointestinal tract in a subject, wherein the method comprises orally administering to the subject an ingestible device loaded with the JAK inhibitor, wherein the ingestible device comprises an environmental sensor for determining the presence of diseased tissue in the GI tract, and wherein the JAK inhibitor is released by the device at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease, as detected by the environmental sensor. The device may be according to any of the embodiments described herein.

In another embodiment, there is provided a composition for use in a method of detecting and treating a disease of the gastrointestinal tract in a subject, wherein the composition comprises or consists of an ingestible device loaded with a therapeutically effective amount of a JAK inhibitor, wherein the ingestible device comprises an

environmental sensor for determining the presence of diseased tissue in the GI tract, and wherein the JAK inhibitor is released by the device at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease, as detected by the environmental sensor. Again, the device may be according to any of the embodiments described herein. In some embodiments, where the ingestible device as used in the present invention comprises an environmental sensor for detecting the presence of disease in the GI tract and a communication system as described above, the method of treatment may comprise:

i) receiving at an external receiver from the ingestible device a signal transmitting the environmental data;

ii) assessing the environmental data to confirm the presence of the disease; and iii) when the presence of the disease is confirmed, sending from an external transmitter to the ingestible device a signal triggering release of the JAK inhibitor.

For example, the presence of disease may be confirmed based on the presence of inflamed tissue and/or lesions associated with any of the disease states referred to herein. For example, the presence of disease may be confirmed based on the presence of inflammation, ulceration e.g., aphthoid ulcerations, "punched-out ulcers" and/or superficial ulcers of the mucosa, cobblestoning, stenosis, granulomas, crypt abscesses, fissures, e.g., extensive linear fissures, villous atrophy, fibrosis, and/or bleeding.

In some embodiments, the present invention may relate to a system comprising:

an ingestible device loaded with a therapeutically effective amount of a JAK inhibitor, a release mechanism for release of the JAK inhibitor (e.g., from a reservoir comprising the JAK inhibitor), an actuator controlling the release mechanism, an environmental sensor for determining the location of the device in the gut and/or for detecting the presence of diseased tissue and a communication system adapted to transmit the environment data and receive a signal triggering the actuator;

a receiver and display module for receiving and displaying outside of the body the environment data from the ingestible device;

a transmitter for sending to the ingestible device a signal triggering the actuator. In any of the above embodiments, the ingestible device may further comprise an anchoring system for anchoring the device or a portion thereof in a location and an actuator for the anchoring system. This may be triggered in response to a determination that the device is at a location in the gastrointestinal tract of the subject proximate to one or more sites of disease. For instance, this may be detected by the environmental sensor. The triggering may be controlled by a processor in the device, that is, autonomously. A device where the triggering is controlled by a processor in the device is said to be an autonomous device. Alternatively, it may be controlled by a signal sent from outside of the body, as described above. In any of the above aspects and embodiments, disease of the GI tract may be an inflammatory bowel disease.

In some embodiments, the disease of the GI tract is ulcerative colitis.

In some embodiments, the disease of the GI tract is Crohn's disease.

In general, apparatuses, compositions, and methods disclosed herein are useful in the treatment of diseases of the gastrointestinal tract. Exemplary gastrointestinal tract diseases that can be treated include, without limitation, inflammatory bowel disease (IBD), Crohn's disease (e.g., active Crohn's disease, refractory Crohn's disease, or fistulizing Crohn's disease), ulcerative colitis, indeterminate colitis, microscopic colitis, infectious colitis, drug or chemical-induced colitis, diverticulitis, and ischemic colitis, gastritis, peptic ulcers, stress ulcers, bleeding ulcers, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, short-bowel (anastomosis) syndrome, a hypersecretory state associated with systemic mastocytosis or basophilic leukemia or hyperhistaminemia, Celiac disease (e.g., nontropical Sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic

gastroenteritis, colitis associated with radiotherapy or chemotherapy, colitis associated with disorders of innate immunity as in leukocyte adhesion deficiency-1, chronic granulomatous disease, food allergies, gastritis, infectious gastritis or enterocolitis (e.g., Helicobacter pylori- infected chronic active gastritis), other forms of gastrointestinal inflammation caused by an infectious agent, pseudomembranous colitis, hemorrhagic colitis, hemolytic-uremic syndrome colitis, diversion colitis, irritable bowel syndrome, irritable colon syndrome, and pouchitis. In some embodiments, apparatuses, compositions, and methods disclosed herein are used to treat one gastrointestinal disease. In some embodiments, apparatuses, compositions, and methods disclosed herein are used to treat more than one gastrointestinal disease. In some embodiments, apparatuses, compositions, and methods disclosed herein are used to treat multiple gastrointestinal diseases that occur in the same area of the gastrointestinal tract (e.g., each disease can occur in the small intestine, large intestine, colon, or any sub-region thereof). In some embodiments, apparatuses, compositions, and methods disclosed herein are used to treat multiple gastrointestinal diseases that occur in different areas of the

gastrointestinal tract. In some embodiments, administration (e.g., local administration to the gastrointestinal tract) of JAK inhibitor is useful in the treatment of gastrointestinal diseases including, but not limited to, inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, or any of the other gastrointestinal diseases described herein. Aspects and embodiments as described herein are intended to be freely combinable. For example, any details or embodiments described herein for methods of treatment apply equally to a JAK inhibitor, composition or ingestible device for use in said treatment. Any details or embodiments described for a device apply equally to methods of treatment using the device, or to a JAK inhibitor or composition for use in a method of treatment involving the device.

Brief Description of the Drawings

FIG. 1 provides an exemplary structural diagram illustrating aspects of an ingestible device 100 having a piston to push for drug delivery, according to some embodiments described herein.

FIG. 2 provides another exemplary structural diagram illustrating aspects of an ingestible device 100 having a piston to push for drug delivery, according to some embodiments described herein.

Detailed description Definitions:

By "ingestible", it is meant that the device can be swallowed whole.

"Gastrointestinal inflammatory disorders" are a group of chronic disorders that cause inflammation and/or ulceration in the mucous membrane. These disorders include, for example, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, indeterminate colitis and infectious colitis), mucositis (e.g., oral mucositis, gastrointestinal mucositis, nasal mucositis and proctitis), necrotizing enterocolitis and esophagitis.

"Inflammatory Bowel Disease" or "IBD" is a chronic inflammatory autoimmune condition of the gastrointestinal (GI) tract. The GI tract can be divided into four main different sections, the oesophagus, stomach, small intestine and large intestine or colon. The small intestine possesses three main subcompartments: the duodenum, jejunum and ileum. Similarly, the large intestine consists of six sections: the cecum, ascending colon, transverse colon, ascending colon, sigmoid colon, and the rectum. The small intestine is about 6 m long, its diameter is 2.5 to 3 cm and the transit time through it is typically 3 hours. The duodenum has a C-shape, and is 30 cm long. Due to its direct connection with the stomach, it is physically more stable than the jejunum and ileum, which are sections that can freely move. The jejunum is 2.4 m in length and the ileum is 3.6 m in length and their surface areas are 180 m² and 280 m² respectively. The large intestine is 1.5 m long, its diameter is between 6.3 and 6.5 cm, the transit time though this section is 20 hours and has a reduced surface area of approximately 150 m². The higher surface area of the small intestine enhances its capacity for systemic drug absorption.

The etiology of IBD is complex, and many aspects of the pathogenesis remain unclear. The treatment of moderate to severe IBD poses

significant challenges to treating physicians, because conventional therapy with

corticosteroids and immunomodulator therapy (e.g., azathioprine, 6 mercaptopurine, and methotrexate administered via traditional routes such as tablet form, oral suspension, or intravenously) is associated with side effects and intolerance and has not shown proven benefit in maintenance therapy (steroids). Monoclonal antibodies targeting tumor necrosis factor alpha (TNF-a), such as infliximab (a chimeric antibody) and adalimumab (a fully human antibody), are currently used in the management of CD. Infliximab has also shown efficacy and has been approved for use in UC. However, approximately 10%-20% of patients with CD are primary nonresponders to anti TNF therapy, and another ~20%-30% of CD patients lose response over time (Schnitzler et al., Gut 58:492-500 (2009)). Other adverse events (AEs) associated with anti TNFs include elevated rates of bacterial infection, including tuberculosis, and, more rarely, lymphoma and demyelination (Chang et al., Nat Clin Pract Gastroenterol Hepatology 3 :220 (2006); Hoentjen et al, World J. Gastroenterol. 15(17):2067 (2009)). No currently available therapy achieves sustained remission in more than 20%-30% of IBD patients with chronic disease (Hanauer et al, Lancet 359: 1541-49 (2002); Sandborn et al, N Engl J Med 353 : 1912-25 (2005)). In addition, most patients do not achieve sustained steroid-free remission and mucosal healing, clinical outcomes that correlate with true disease modification.

Although the cause of IBD remains unknown, several factors such as genetic, infectious and immunologic susceptibility have been implicated. IBD is much more common in Caucasians, especially those of Jewish descent. The chronic inflammatory nature of the condition has prompted an intense search for a possible infectious cause. Although agents have been found which stimulate acute inflammation, none has been found to cause the chronic inflammation associated with IBD. The hypothesis that IBD is an autoimmune disease is supported by the previously mentioned extraintestinal manifestation of IBD as joint arthritis, and the known positive response to IBD by treatment with therapeutic agents such as adrenal glucocorticoids, cyclosporine and azathioprine, which are known to suppress immune response. In addition, the GI tract, more than any other organ of the body, is continuously exposed to potential antigenic substances such as proteins from food, bacterial byproducts (LPS), etc.

A chronic inflammatory autoimmune condition of the gastrointestinal (GI) tract presents clinically as either ulcerative colitis (UC) or Crohn's disease (CD). Both IBD conditions are associated with an increased risk for malignancy of the GI tract.

"Crohn's disease" ("CD") is a chronic transmural inflammatory disease with the potential to affect any part of the entire GI tract, and UC is a mucosal inflammation of the colon. Both conditions are characterized clinically by frequent bowel motions, malnutrition, and dehydration, with disruption in the activities of daily living.

CD is frequently complicated by the development of malabsorption, strictures, and fistulae and may require repeated surgery. UC, less frequently, may be complicated by severe bloody diarrhea and toxic megacolon, also requiring surgery. The most prominent feature

Crohn's disease is the granular, reddish-purple edematous thickening of the bowel wall. With the development of inflammation, these granulomas often lose their circumscribed borders and integrate with the surrounding tissue. Diarrhea and obstruction of the bowel are the predominant clinical features. As with ulcerative colitis, the course of Crohn's disease may be continuous or relapsing, mild or severe, but unlike ulcerative colitis, Crohn's disease is not curable by resection of the involved segment of bowel. Most patients with Crohn's disease require surgery at some point, but subsequent relapse is common and continuous medical treatment is usual. Crohn's disease may involve any part of the alimentary tract from the mouth to the anus, although typically it appears in the ileocolic, small-intestinal or colonic- anorectal regions. Histopathologically, the disease manifests by discontinuous

granulomatomas, crypt abscesses, fissures and aphthous ulcers. The inflammatory infiltrate is mixed, consisting of lymphocytes (both T and B cells), plasma cells, macrophages, and neutrophils. There is a disproportionate increase in IgM- and IgG-secreting plasma cells, macrophages and neutrophils.

To date, the primary outcome measure in Crohn's Disease clinical trials is the Crohn's

Disease Activity Index (CDAI), which has served as the basis for approval of multiple drug treatments, including for example, vedolizumab and natalizumab. The CDAI was developed by regressing clinician global assessment of disease activity on eighteen potential items representing patient reported outcomes (PROs) (i.e. abdominal pain, pain awakening patient from sleep, appetite), physical signs (i.e. average daily temperature, abdominal mass), medication use (i.e. loperamide or opiate use for diarrhea) and a laboratory test (i.e.

hematocrit). Backward stepwise regression analysis identified eight independent predictors which are the number of liquid or soft stools, severity of abdominal pain, general well-being, occurrence of extra-intestinal symptoms, need for anti diarrheal drugs, presence of an abdominal mass, hematocrit, and body weight. The final score is a composite of these eight items, adjusted using regression coefficients and standardization to construct an overall CDAI score, ranging from 0 to 600 with higher score indicating greater disease activity. Widely used benchmarks are: CDAI <150 is defined as clinical remission, 150 to 219 is defined as mildly active disease, 220 to 450 is defined as moderately active disease, and above 450 is defined as very severe disease (Best WR, et al, Gastroenterology 77:843-6, 1979).

Vedolizumab and natalizumab have been approved on the basis of demonstrated clinical remission, i.e. CDAI < 150.

Although the CDAI has been in use for over 40 years, and has served as the basis for drug approval, it has several limitations as an outcome measure for clinical trials. For example, most of the overall score comes from the patient diary card items (pain, number of liquid bowel movements, and general well-being), which are vaguely defined and not standardized terms (Sandler et al, J. Clin. Epidemiol 41 :451-8, 1988; Thia et al., Inflamm Bowel Dis 17: 105-11, 2011). In addition, measurement of pain is based on a four- point scale rather than an updated seven-point scale. The remaining 5 index items contribute very little to identifying an efficacy signal and may be a source of measurement noise.

Furthermore, concerns have been raised about poor criterion validity for the CDAI, a reported lack of correlation between the CDAI and endoscopic measures of inflammation (which may render the CDAI as a poor discriminator of active CD and irritable bowel syndrome) and high reported placebo rates (Korzenik et al, N Engl J Med. 352:2193-201, 2005; Sandborn WJ, et al, N Engl J Med 353 : 1912-25, 2005; Sandborn WJ, et al, Ann Intern 19; 146:829-38, 2007, Epub 2007 Apr 30; Kim et al, Gastroenterology 146: (5 supplement 1) S-368, 2014).

It is, thus, generally recognized that additional or alternative measures of CD symptoms are needed, such as new PRO tools or adaptations of the CDAI to derive a new PRO. The PR02 and PR03 tools are such adaptations of the CDAI and have been recently described in Khanna et al., Aliment Pharmacol. Ther. 41 :77-86, 2015. The PR02

evaluates the frequency of loose/liquid stools and abdominal pain {Id). These items are derived and weighted accordingly from the CDAI and are the CDAI diary card items, along with general well-being, that contribute most to the observed clinical benefit measured by CDAI (Sandler et al, J. Clin. Epidemiol 41 : 451-8, 1988; Thia et al, Inflamm Bowel Dis 17: 105-11, 2011 ; Kim et al, Gastroenterology 146: (5 supplement 1) S-368,

2014). The remission score of < 11 is the CDAI-weighted sum of the average stool frequency and pain scores in a 7-day period, which yielded optimum sensitivity and specificity for identification of CDAI remission (score of < 150) in a retrospective data

analysis of ustekinumab induction treatment for moderate to severe CD in a Phase II clinical study (Gasink C, et al, abstract, ACG Annual Meeting 2014). The PR02 was shown to be sensitive and responsive when used as a continuous outcome measure in a retrospective data analysis of MTX treatment in active CD (Khanna R, et al, Inflamm Bowel Dis 20: 1850-61, 2014) measured by CDAI. Additional outcome measures include the Mayo Clinic Score, the Crohn disease endoscopic index of severity (CDEIS), and the Ulcerative colitis endoscopic index of severity (UCEIS). Additional outcome measures include Clinical remission, Mucosal healing, Histological healing (transmural), MRI or ultrasound for measurement or evaluation of bowel wall thickness, abscesses, fistula and histology.

An additional means of assessing the extent and severity of Crohn's Disease is endoscopy. Endoscopic lesions typical of Crohn's disease have been described in numerous studies and include, e.g., aphthoid ulcerations, "punched-out ulcers," cobblestoning and stenosis. Endoscopic evaluation of such lesions was used to develop the first validated endoscopic score, the Crohn's Disease Endoscopic Index of Severity (CDEIS) (Mary et al, Gut 39:983-9, 1989). More recently, because the CDEIS is time-consuming, complicated and impractical for routine use, a Simplified Endoscopic Activity Score for Crohn's Disease (SES- CD) was developed and validated (Dapemo et al, Gastrointest. Endosc. 60(4):505-12, 2004). The SES-CD consists of four endoscopic variables (size of ulcers,

proportion of surface covered by ulcers, proportion of surface with any other lesions (e.g., inflammation), and presence of narrowings [stenosis]) that are scored in five ileocolonic segments, with each variable, or assessment, rated from 0 to 3.

To date, there is no cure for CD. Accordingly, the current treatment goals for CD are to induce and maintain symptom improvement, induce mucosal healing, avoid surgery, and improve quality of life (Lichtenstein GR, et al., Am J Gastroenterol 104:465-83, 2009; Van Assche G, et al., J Crohns Colitis. 4:63-101, 2010). The current therapy of IBD usually involves the administration of antiinflammatory or immunosuppressive agents, such as sulfasalazine, corticosteroids, 6- mercaptopurine/azathioprine, or cyclosporine, all of which are not typically delivered by localized release of a drug at the site or location of disease. More recently, biologies like TNF-alpha inhibitors and IL-12/IL-23 blockers, are used to treat IBD. If anti-inflammatory/immunosuppressive/biologic therapies fail, colectomies are the last line of defense. The typical operation for CD not involving the rectum is resection (removal of a diseased segment of bowel) and anastomosis (reconnection) without an ostomy. Sections of the small or large intestine may be removed. About 30% of CD patients will need surgery within the first year after diagnosis. In the subsequent years, the rate is about 5% per year. Unfortunately, CD is characterized by a high rate of recurrence; about 5% of patients need a second surgery each year after initial surgery.

Refining a diagnosis of inflammatory bowel disease involves evaluating the progression status of the diseases using standard classification criteria. The classification systems used in IBD include the Truelove and Witts Index (Truelove S. C. and Witts, L.J. Br Med J. 1955;2: 1041-1048), which classifies colitis as mild, moderate, or severe, as well as Lennard- Jones. (Lennard- Jones JE. Scand J Gastroenterol Suppl 1989; 170:2-6) and the simple clinical colitis activity index (SCCAI). (Walmsley et. al. Gut. 1998;43:29-32) These systems track such variables as daily bowel movements, rectal bleeding, temperature, heart rate, hemoglobin levels, erythrocyte sedimentation rate, weight, hematocrit score, and the level of serum albumin.

There is sufficient overlap in the diagnostic criteria for UC and CD that it is sometimes impossible to say which a given patient has; however, the type of lesion typically seen is different, as is the localization. UC mostly appears in the colon, proximal to the rectum, and the characteristic lesion is a superficial ulcer of the mucosa; CD can appear anywhere in the bowel, with occasional involvement of stomach, esophagus and duodenum, and the lesions are usually described as extensive linear fissures.

In approximately 10-15% of cases, a definitive diagnosis of ulcerative colitis or Crohn's disease cannot be made and such cases are often referred to as "indeterminate colitis." Two antibody detection tests are available that can help the diagnosis, each of which assays for antibodies in the blood. The antibodies are "perinuclear anti-neutrophil antibody" (pANCA) and "anti-Saccharomyces cervisiae antibody" (ASCA). Most patients with ulcerative colitis have the pANCA antibody but not the ASCA antibody, while most patients with Crohn's disease have the ASCA antibody but not the pANCA antibody. However, these two tests have shortcomings as some patients have neither antibody and some Crohn's disease patients may have only the pANCA antibody. A third test, which measures the presence and accumulation of circulating anti-microbial antibodies - particularly flagellin antibodies, has proven to be useful for detecting susceptibility to Crohn's Disease before disease

development. See Choung, R. S., et al. "Serologic microbial associated markers can predict Crohn's disease behaviour years before disease diagnosis." Alimentary pharmacology & therapeutics 43.12 (2016): 1300-1310.

"Ulcerative colitis (UC)" afflicts the large intestine. The course of the disease may be continuous or relapsing, mild or severe. The earliest lesion is an inflammatory infiltration with abscess formation at the base of the crypts of Lieberkuhn. Coalescence of these distended and ruptured crypts tends to separate the overlying mucosa from its blood supply, leading to ulceration. Symptoms of the disease include cramping, lower abdominal pain, rectal bleeding, and frequent, loose discharges consisting mainly of blood, pus and mucus with scanty fecal particles. A total colectomy may be required for acute, severe or chronic, unremitting ulcerative colitis.

The clinical features of UC are highly variable, and the onset may be insidious or abrupt, and may include diarrhea, tenesmus and relapsing rectal bleeding. With fulminant involvement of the entire colon, toxic megacolon, a life-threatening emergency, may occur. Extraintestinal manifestations include arthritis, pyoderma gangrenoum, uveitis, and erythema nodosum.

The terms "antibody" and "immunoglobulin" are used interchangeably in the broadest sense and include monoclonal antibodies (for example, full length or intact monoclonal antibodies), polyclonal antibodies, multivalent antibodies, multispecific antibodies (e.g., bispecific, trispecific etc. antibodies so long as they exhibit the desired biological activity) and may also include certain antibody fragments (as described in greater detail herein). An antibody can be human, humanized and/or affinity matured.

"Antibody fragments" comprise only a portion of an intact antibody, where in certain embodiments, the portion retains at least one, and typically most or all, of the functions normally associated with that portion when present in an intact antibody. In one embodiment, an antibody fragment comprises an antigen binding site of the intact antibody and thus retains the ability to bind antigen. In another embodiment, an antibody fragment, for example one that comprises the Fc region, retains at least one of the biological functions normally associated with the Fc region when present in an intact antibody, such as FcRn binding, antibody half-life modulation, ADCC function and complement binding. In one embodiment, an antibody fragment is a monovalent antibody that has an in vivo half-life substantially similar to an intact antibody. For example, such an antibody fragment may comprise on antigen binding arm linked to an Fc sequence capable of conferring in vivo stability to the fragment.

The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigen. Furthermore, in contrast to polyclonal antibody preparations that typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.

The monoclonal antibodies herein specifically include "chimeric" antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U. S. Patent No. 4,816,567; and Morrison et al, Proc. Natl. Acad. Sci. USA 81 :6851 -6855 (1984)).

"Treatment regimen" refers to a combination of dosage, frequency of administration, or duration of treatment, with or without addition of a second medication.

"Effective treatment regimen" refers to a treatment regimen that will offer beneficial response to a patient receiving the treatment.

"Patient response" or "patient responsiveness" can be assessed using any endpoint indicating a benefit to the patient, including, without limitation, (1) inhibition, to some extent, of disease progression, including slowing down and complete arrest; (2) reduction in the number of disease episodes and/or symptoms; (3) reduction in lesional size; (4) inhibition (i.e., reduction, slowing down or complete stopping) of disease cell infiltration into adjacent peripheral organs and/or tissues; (5) inhibition (i.e., reduction, slowing down or complete stopping) of disease spread; (6) decrease of auto-immune response, which may, but does not have to, result in the regression or ablation of the disease lesion; (7) relief, to some extent, of one or more symptoms associated with the disorder; (8) increase in the length of disease-free presentation following treatment; and/or (9) decreased mortality at a given point of time following treatment. The term "responsiveness" refers to a measurable response, including complete response (CR) and partial response (PR).

As used herein, "complete response" or "CR" means the disappearance of all signs of inflammation or remission in response to treatment. This does not necessarily mean the disease has been cured.

"Partial response" or "PR" refers to a decrease of at least 50% in the severity of inflammation, in response to treatment.

A "beneficial response" of a patient to treatment with a therapeutic agent and similar wording refers to the clinical or therapeutic benefit imparted to a patient at risk for or suffering from a gastrointestinal inflammatory disorder from or as a result of the treatment with the agent. Such benefit includes cellular or biological responses, a complete response, a partial response, a stable disease (without progression or relapse), or a response with a later relapse of the patient from or as a result of the treatment with the agent.

As used herein, "non-response" or "lack of response" or similar wording means an absence of a complete response, a partial response, or a beneficial response to treatment with a therapeutic agent.

"A patient maintains responsiveness to a treatment" when the patient's responsiveness does not decrease with time during the course of a treatment.

A "symptom" of a disease or disorder (e.g., inflammatory bowel disease, e.g., ulcerative colitis or Crohn's disease) is any morbid phenomenon or departure from the normal in structure, function, or sensation, experienced by a subject and indicative of disease.

Inhibitory Agents of Janus Kinase (JAK) Activity and/or Expression

The term "JAK inhibitor" refers to an agent which decreases the expression of Janus kinase 1 (JAKl), JAK2, JAK3, or non-receptor protein tyrosine kinase 2 (TYK-2) and/or the kinase activity of at least one of JAKl, JAK2, JAK3, and TYK-2. In some embodiments, the JAK inhibitor decreases the expression of JAKl. In some embodiments, the JAK inhibitor decreases the expression of JAK2. In some embodiments, the JAK inhibitor decreases the expression of JAK3. In some embodiments, the JAK inhibitor decreases the expression of TYK-2.

In some embodiments, the JAK inhibitor decreases the kinase activity of JAKl . In some embodiments, the JAK inhibitor decreases the kinase activity of JAK2. In some embodiments, the JAK inhibitor decreases the kinase activity of JAK3. In some embodiments, the JAK inhibitor decreases the kinase activity of TYK-2. In some embodiments, the JAK inhibitor is a decreases the kinase activity of JAKl, JAK2, JAK3, and TYK2. In some embodiments, the JAK inhibitor decreases the kinase activity of two or more (e.g., 3 or 4) of: JAKl, JAK2, JAK3 and TYK2. In some embodiments, the JAK inhibitor decreases the kinase activity of a single JAK isoform (e.g., JAKl, JAK2, JAK3, or TYK2).

In some embodiments, the JAK inhibitor decreases the kinase activity of JAKl and JAK2. In some embodiments, the JAK inhibitor decreases the kinase activity of JAKl and JAK3. In some embodiments, the JAK inhibitor decreases the kinase activity of JAK2 and JAK3. In some embodiments, the JAK inhibitor decreases the kinase activity of JAKl, JAK2 and JAK3.

In some embodiments, a JAK inhibitory agent is an inhibitory nucleic acid or a small molecule. In some embodiments, the inhibitory nucleic acid is an antisense nucleic acid, a ribozyme, a small interfering RNA, a small hairpin RNA, or a microRNA. Examples of aspects of these different inhibitory nucleic acids are described below. Any of the examples of inhibitory nucleic acids that can decrease expression of a JAKl, JAK2, JAK3, or TYK2 mRNA in a mammalian cell can be synthesized in vitro.

Inhibitory nucleic acids that can decrease the expression of JAKl, JAK2, JAK3, or TYK2 mRNA expression in a mammalian cell include antisense nucleic acid molecules, i.e., nucleic acid molecules whose nucleotide sequence is complementary to all or part of a JAKl, JAK2, JAK3, or TYK2 mRNA (e.g., complementary to all or a part of any one of SEQ ID NOs: 1-15).

Human JAKl mRNA Variant 1 (SEQ ID NO: 1)

1 ggggcgggac gggaggcggt gcgtcgctga gcgcaggccg cggcggccgc ggagtatcct

61 ggagctgcag acagtgcggg cctgcgccca gtcccggctg tcctcgccgc gacccctcct

121 cagccctggg cgcgcgcacg ctggggcccc gcggggctgg ccgcctagcg agcctgccgg

181 tcgaccccag ccagcgcagc gacggggcgc tgcctggccc aggcgcacac ggaagtgcgc

241 ttctctgaag tagctttgga aagtagagaa gaaaatccag tttgcttctt ggagaacact

301 ggacagctga ataaatgcag tatctaaata taaaagagga ctgcaatgcc atggctttct

361 gtgctaaaat gaggagctcc aagaagactg aggtgaacct ggaggcccct gagccagggg

421 tggaagtgat cttctatctg tcggacaggg agcccctccg gctgggcagt ggagagtaca

481 cagcagagga actgtgcatc agggctgcac aggcatgccg tatctctcct ctttgtcaca

541 acctctttgc cctgtatgac gagaacacca agctctggta tgctccaaat cgcaccatca

601 ccgttgatga caagatgtcc ctccggctcc actaccggat gaggttctat ttcaccaatt

661 ggcatggaac caacgacaat gagcagtcag tgtggcgtca ttctccaaag aagcagaaaa

721 atggctacga gaaaaaaaag attccagatg caacccctct ccttgatgcc agctcactgg

781 agtatctgtt tgctcaggga cagtatgatt tggtgaaatg cctggctcct attcgagacc

841 ccaagaccga gcaggatgga catgatattg agaacgagtg tctagggatg gctgtcctgg 901 ccatctcaca ctatgccatg atgaagaaga tgcagttgcc agaactgccc aaggacatca 961 gctacaagcg atatattcca gaaacattga ataagtccat cagacagagg aaccttctca 1021 ccaggatgcg gataaataat gttttcaagg atttcctaaa ggaatttaac aacaagacca 1081 tttgtgacag cagcgtgtcc acgcatgacc tgaaggtgaa atacttggct accttggaaa 1141 ctttgacaaa acattacggt gctgaaatat ttgagacttc catgttactg atttcatcag

1201 aaaatgagat gaattggttt cattcgaatg acggtggaaa cgttctctac tacgaagtga 1261 tggtgactgg gaatcttgga atccagtgga ggcataaacc aaatgttgtt tctgttgaaa 1321 aggaaaaaaa taaactgaag cggaaaaaac tggaaaataa acacaagaag gatgaggaga 1381 aaaacaagat ccgggaagag tggaacaatt tttcttactt ccctgaaatc actcacattg 1441 taataaagga gtctgtggtc agcattaaca agcaggacaa caagaaaatg gaactgaagc

1501 tctcttccca cgaggaggcc ttgtcctttg tgtccctggt agatggctac ttccggctca 1561 cagcagatgc ccatcattac ctctgcaccg acgtggcccc cccgttgatc gtccacaaca 1621 tacagaatgg ctgtcatggt ccaatctgta cagaatacgc catcaataaa ttgcggcaag 1681 aaggaagcga ggaggggatg tacgtgctga ggtggagctg caccgacttt gacaacatcc 1741 tcatgaccgt cacctgcttt gagaagtctg agcaggtgca gggtgcccag aagcagttca

1801 agaactttca gatcgaggtg cagaagggcc gctacagtct gcacggttcg gaccgcagct 1861 tccccagctt gggagacctc atgagccacc tcaagaagca gatcctgcgc acggataaca 1921 tcagcttcat gctaaaacgc tgctgccagc ccaagccccg agaaatctcc aacctgctgg 1981 tggctactaa gaaagcccag gagtggcagc ccgtctaccc catgagccag ctgagtttcg 2041 atcggatcct caagaaggat ctggtgcagg gcgagcacct tgggagaggc acgagaacac

2101 acatctattc tgggaccctg atggattaca aggatgacga aggaacttct gaagagaaga 2161 agataaaagt gatcctcaaa gtcttagacc ccagccacag ggatatttcc ctggccttct 2221 tcgaggcagc cagcatgatg agacaggtct cccacaaaca catcgtgtac ctctatggcg 2281 tctgtgtccg cgacgtggag aatatcatgg tggaagagtt tgtggaaggg ggtcctctgg 2341 atctcttcat gcaccggaaa agcgatgtcc ttaccacacc atggaaattc aaagttgcca

2401 aacagctggc cagtgccctg agctacttgg aggataaaga cctggtccat ggaaatgtgt 2461 gtactaaaaa cctcctcctg gcccgtgagg gcatcgacag tgagtgtggc ccattcatca 2521 agctcagtga ccccggcatc cccattacgg tgctgtctag gcaagaatgc attgaacgaa 2581 tcccatggat tgctcctgag tgtgttgagg actccaagaa cctgagtgtg gctgctgaca 2641 agtggagctt tggaaccacg ctctgggaaa tctgctacaa tggcgagatc cccttgaaag

2701 acaagacgct gattgagaaa gagagattct atgaaagccg gtgcaggcca gtgacaccat 2761 catgtaagga gctggctgac ctcatgaccc gctgcatgaa ctatgacccc aatcagaggc 2821 ctttcttccg agccatcatg agagacatta ataagcttga agagcagaat ccagatattg 2881 tttcagaaaa aaaaccagca actgaagtgg accccacaca ttttgaaaag cgcttcctaa 2941 agaggatccg tgacttggga gagggccact ttgggaaggt tgagctctgc aggtatgacc

3001 ccgaagggga caatacaggg gagcaggtgg ctgttaaatc tctgaagcct gagagtggag 3061 gtaaccacat agctgatctg aaaaaggaaa tcgagatctt aaggaacctc tatcatgaga 3121 acattgtgaa gtacaaagga atctgcacag aagacggagg aaatggtatt aagctcatca 3181 tggaatttct gccttcggga agccttaagg aatatcttcc aaagaataag aacaaaataa 3241 acctcaaaca gcagctaaaa tatgccgttc agatttgtaa ggggatggac tatttgggtt

3301 ctcggcaata cgttcaccgg gacttggcag caagaaatgt ccttgttgag agtgaacacc 3361 aagtgaaaat tggagacttc ggtttaacca aagcaattga aaccgataag gagtattaca 3421 ccgtcaagga tgaccgggac agccctgtgt tttggtatgc tccagaatgt ttaatgcaat 3481 ctaaatttta tattgcctct gacgtctggt cttttggagt cactctgcat gagctgctga 3541 cttactgtga ttcagattct agtcccatgg ctttgttcct gaaaatgata ggcccaaccc 3601 atggccagat gacagtcaca agacttgtga atacgttaaa agaaggaaaa cgcctgccgt 3661 gcccacctaa ctgtccagat gaggtttatc aacttatgag gaaatgctgg gaattccaac 3721 catccaatcg gacaagcttt cagaacctta ttgaaggatt tgaagcactt ttaaaataag 3781 aagcatgaat aacatttaaa ttccacagat tatcaagtcc ttctcctgca acaaatgccc

3841 aagtcatttt ttaaaaattt ctaatgaaag aagtttgtgt tctgtccaaa aagtcactga 3901 actcatactt cagtacatat acatgtataa ggcacactgt agtgcttaat atgtgtaagg 3961 acttcctctt taaatttggt accagtaact tagtgacaca taatgacaac caaaatattt 4021 gaaagcactt aagcactcct ccttgtggaa agaatatacc accatttcat ctggctagtt 4081 caccatcaca actgcattac caaaagggga tttttgaaaa cgaggagttg accaaaataa

4141 tatctgaaga tgattgcttt tccctgctgc cagctgatct gaaatgtttt gctggcacat 4201 taatcataga taaagaaaga ttgatggact tagccctcaa atttcagtat ctatacagta 4261 ctagaccatg cattcttaaa atattagata ccaggtagta tatattgttt ctgtacaaaa 4321 atgactgtat tctctcacca gtaggactta aactttgttt ctccagtggc ttagctcctg 4381 ttcctttggg tgatcactag cacccatttt tgagaaagct ggttctacat ggggggatag

4441 ctgtggaata gataatttgc tgcatgttaa ttctcaagaa ctaagcctgt gccagtgctt 4501 tcctaagcag tataccttta atcagaactc attcccagaa cctggatgct attacacatg 4561 cttttaagaa acgtcaatgt atatcctttt ataactctac cactttgggg caagctattc 4621 cagcactggt tttgaatgct gtatgcaacc agtctgaata ccacatacgc tgcactgttc 4681 ttagagggtt tccatactta ccaccgatct acaagggttg atccctgttt ttaccatcaa

4741 tcatcaccct gtggtgcaac acttgaaaga cccggctaga ggcactatgg acttcaggat 4801 ccactagaca gttttcagtt tgcttggagg tagctgggta atcaaaaatg tttagtcatt 4861 gattcaatgt gaacgattac ggtctttatg accaagagtc tgaaaatctt tttgttatgc 4921 tgtttagtat tcgtttgata ttgttacttt tcacctgttg agcccaaatt caggattggt 4981 tcagtggcag caatgaagtt gccatttaaa tttgttcata gcctacatca ccaaggtctc

5041 tgtgtcaaac ctgtggccac tctatatgca ctttgtttac tctttataca aataaatata 5101 ctaaagactt tacatgca

Human JAK1 mRNA Variant 2 (SEQ ID NO: 2)

1 agaagcggag cgtatacgga ggaggcggga tgcatttctg catcgagcgc acaaagttat

61 ctaaaacagt tcatgctgct gaaaacctcc ttcctggcag atgtccctca accctactgg 121 tgcctggctt ctgagacaca cgcttctctg aagtagcttt ggaaagtaga gaagaaaatc 181 cagtttgctt cttggagaac actggacagc tgaataaatg cagtatctaa atataaaaga 241 ggactgcaat gccatggctt tctgtgctaa aatgaggagc tccaagaaga ctgaggtgaa 301 cctggaggcc cctgagccag gggtggaagt gatcttctat ctgtcggaca gggagcccct

361 ccggctgggc agtggagagt acacagcaga ggaactgtgc atcagggctg cacaggcatg 421 ccgtatctct cctctttgtc acaacctctt tgccctgtat gacgagaaca ccaagctctg 481 gtatgctcca aatcgcacca tcaccgttga tgacaagatg tccctccggc tccactaccg 541 gatgaggttc tatttcacca attggcatgg aaccaacgac aatgagcagt cagtgtggcg 601 tcattctcca aagaagcaga aaaatggcta cgagaaaaaa aagattccag atgcaacccc

661 tctccttgat gccagctcac tggagtatct gtttgctcag ggacagtatg atttggtgaa 721 atgcctggct cctattcgag accccaagac cgagcaggat ggacatgata ttgagaacga 781 gtgtctaggg atggctgtcc tggccatctc acactatgcc atgatgaaga agatgcagtt 841 gccagaactg cccaaggaca tcagctacaa gcgatatatt ccagaaacat tgaataagtc 901 catcagacag aggaaccttc tcaccaggat gcggataaat aatgttttca aggatttcct 961 aaaggaattt aacaacaaga ccatttgtga cagcagcgtg tccacgcatg acctgaaggt 1021 gaaatacttg gctaccttgg aaactttgac aaaacattac ggtgctgaaa tatttgagac 1081 ttccatgtta ctgatttcat cagaaaatga gatgaattgg tttcattcga atgacggtgg

1141 aaacgttctc tactacgaag tgatggtgac tgggaatctt ggaatccagt ggaggcataa 1201 accaaatgtt gtttctgttg aaaaggaaaa aaataaactg aagcggaaaa aactggaaaa 1261 taaacacaag aaggatgagg agaaaaacaa gatccgggaa gagtggaaca atttttctta 1321 cttccctgaa atcactcaca ttgtaataaa ggagtctgtg gtcagcatta acaagcagga 1381 caacaagaaa atggaactga agctctcttc ccacgaggag gccttgtcct ttgtgtccct

1441 ggtagatggc tacttccggc tcacagcaga tgcccatcat tacctctgca ccgacgtggc 1501 ccccccgttg atcgtccaca acatacagaa tggctgtcat ggtccaatct gtacagaata 1561 cgccatcaat aaattgcggc aagaaggaag cgaggagggg atgtacgtgc tgaggtggag 1621 ctgcaccgac tttgacaaca tcctcatgac cgtcacctgc tttgagaagt ctgagcaggt 1681 gcagggtgcc cagaagcagt tcaagaactt tcagatcgag gtgcagaagg gccgctacag

1741 tctgcacggt tcggaccgca gcttccccag cttgggagac ctcatgagcc acctcaagaa 1801 gcagatcctg cgcacggata acatcagctt catgctaaaa cgctgctgcc agcccaagcc 1861 ccgagaaatc tccaacctgc tggtggctac taagaaagcc caggagtggc agcccgtcta 1921 ccccatgagc cagctgagtt tcgatcggat cctcaagaag gatctggtgc agggcgagca 1981 ccttgggaga ggcacgagaa cacacatcta ttctgggacc ctgatggatt acaaggatga

2041 cgaaggaact tctgaagaga agaagataaa agtgatcctc aaagtcttag accccagcca 2101 cagggatatt tccctggcct tcttcgaggc agccagcatg atgagacagg tctcccacaa 2161 acacatcgtg tacctctatg gcgtctgtgt ccgcgacgtg gagaatatca tggtggaaga 2221 gtttgtggaa gggggtcctc tggatctctt catgcaccgg aaaagcgatg tccttaccac 2281 accatggaaa ttcaaagttg ccaaacagct ggccagtgcc ctgagctact tggaggataa

2341 agacctggtc catggaaatg tgtgtactaa aaacctcctc ctggcccgtg agggcatcga 2401 cagtgagtgt ggcccattca tcaagctcag tgaccccggc atccccatta cggtgctgtc 2461 taggcaagaa tgcattgaac gaatcccatg gattgctcct gagtgtgttg aggactccaa 2521 gaacctgagt gtggctgctg acaagtggag ctttggaacc acgctctggg aaatctgcta 2581 caatggcgag atccccttga aagacaagac gctgattgag aaagagagat tctatgaaag

2641 ccggtgcagg ccagtgacac catcatgtaa ggagctggct gacctcatga cccgctgcat 2701 gaactatgac cccaatcaga ggcctttctt ccgagccatc atgagagaca ttaataagct 2761 tgaagagcag aatccagata ttgtttcaga aaaaaaacca gcaactgaag tggaccccac 2821 acattttgaa aagcgcttcc taaagaggat ccgtgacttg ggagagggcc actttgggaa 2881 ggttgagctc tgcaggtatg accccgaagg ggacaataca ggggagcagg tggctgttaa

2941 atctctgaag cctgagagtg gaggtaacca catagctgat ctgaaaaagg aaatcgagat 3001 cttaaggaac ctctatcatg agaacattgt gaagtacaaa ggaatctgca cagaagacgg 3061 aggaaatggt attaagctca tcatggaatt tctgccttcg ggaagcctta aggaatatct 3121 tccaaagaat aagaacaaaa taaacctcaa acagcagcta aaatatgccg ttcagatttg 3181 taaggggatg gactatttgg gttctcggca atacgttcac cgggacttgg cagcaagaaa

3241 tgtccttgtt gagagtgaac accaagtgaa aattggagac ttcggtttaa ccaaagcaat 3301 tgaaaccgat aaggagtatt acaccgtcaa ggatgaccgg gacagccctg tgttttggta 3361 tgctccagaa tgtttaatgc aatctaaatt ttatattgcc tctgacgtct ggtcttttgg 3421 agtcactctg catgagctgc tgacttactg tgattcagat tctagtccca tggctttgtt 3481 cctgaaaatg ataggcccaa cccatggcca gatgacagtc acaagacttg tgaatacgtt 3541 aaaagaagga aaacgcctgc cgtgcccacc taactgtcca gatgaggttt atcaacttat 3601 gaggaaatgc tgggaattcc aaccatccaa tcggacaagc tttcagaacc ttattgaagg 3661 atttgaagca cttttaaaat aagaagcatg aataacattt aaattccaca gattatcaag 3721 tccttctcct gcaacaaatg cccaagtcat tttttaaaaa tttctaatga aagaagtttg

3781 tgttctgtcc aaaaagtcac tgaactcata cttcagtaca tatacatgta taaggcacac 3841 tgtagtgctt aatatgtgta aggacttcct ctttaaattt ggtaccagta acttagtgac 3901 acataatgac aaccaaaata tttgaaagca cttaagcact cctccttgtg gaaagaatat 3961 accaccattt catctggcta gttcaccatc acaactgcat taccaaaagg ggatttttga 4021 aaacgaggag ttgaccaaaa taatatctga agatgattgc ttttccctgc tgccagctga

4081 tctgaaatgt tttgctggca cattaatcat agataaagaa agattgatgg acttagccct 4141 caaatttcag tatctataca gtactagacc atgcattctt aaaatattag ataccaggta 4201 gtatatattg tttctgtaca aaaatgactg tattctctca ccagtaggac ttaaactttg 4261 tttctccagt ggcttagctc ctgttccttt gggtgatcac tagcacccat ttttgagaaa 4321 gctggttcta catgggggga tagctgtgga atagataatt tgctgcatgt taattctcaa

4381 gaactaagcc tgtgccagtg ctttcctaag cagtatacct ttaatcagaa ctcattccca 4441 gaacctggat gctattacac atgcttttaa gaaacgtcaa tgtatatcct tttataactc 4501 taccactttg gggcaagcta ttccagcact ggttttgaat gctgtatgca accagtctga 4561 ataccacata cgctgcactg ttcttagagg gtttccatac ttaccaccga tctacaaggg 4621 ttgatccctg tttttaccat caatcatcac cctgtggtgc aacacttgaa agacccggct

4681 agaggcacta tggacttcag gatccactag acagttttca gtttgcttgg aggtagctgg 4741 gtaatcaaaa atgtttagtc attgattcaa tgtgaacgat tacggtcttt atgaccaaga 4801 gtctgaaaat ctttttgtta tgctgtttag tattcgtttg atattgttac ttttcacctg

4861 ttgagcccaa attcaggatt ggttcagtgg cagcaatgaa gttgccattt aaatttgttc 4921 atagcctaca tcaccaaggt ctctgtgtca aacctgtggc cactctatat gcactttgtt

4981 tactctttat acaaataaat atactaaaga ctttacatgc a

Human JAK1 mRNA Variant 3 (SEQ ID NO: 3)

1 atctatcaca tggcagagat agaataaaaa cagaaaaatg gcgacggtca cgttgtggcg 61 agccttgctg cgtcattaga taatcctcat gcaaatagcg ggaagaacaa aggaagggga

121 gcccgggacc cccgggggcg cagcgcttct ctgaagtagc tttggaaagt agagaagaaa 181 atccagtttg cttcttggag aacactggac agctgaataa atgcagtatc taaatataaa 241 agaggactgc aatgccatgg ctttctgtgc taaaatgagg agctccaaga agactgaggt 301 gaacctggag gcccctgagc caggggtgga agtgatcttc tatctgtcgg acagggagcc 361 cctccggctg ggcagtggag agtacacagc agaggaactg tgcatcaggg ctgcacaggc

421 atgccgtatc tctcctcttt gtcacaacct ctttgccctg tatgacgaga acaccaagct 481 ctggtatgct ccaaatcgca ccatcaccgt tgatgacaag atgtccctcc ggctccacta 541 ccggatgagg ttctatttca ccaattggca tggaaccaac gacaatgagc agtcagtgtg 601 gcgtcattct ccaaagaagc agaaaaatgg ctacgagaaa aaaaagattc cagatgcaac 661 ccctctcctt gatgccagct cactggagta tctgtttgct cagggacagt atgatttggt

721 gaaatgcctg gctcctattc gagaccccaa gaccgagcag gatggacatg atattgagaa 781 cgagtgtcta gggatggctg tcctggccat ctcacactat gccatgatga agaagatgca 841 gttgccagaa ctgcccaagg acatcagcta caagcgatat attccagaaa cattgaataa 901 gtccatcaga cagaggaacc ttctcaccag gatgcggata aataatgttt tcaaggattt 961 cctaaaggaa tttaacaaca agaccatttg tgacagcagc gtgtccacgc atgacctgaa 1021 ggtgaaatac ttggctacct tggaaacttt gacaaaacat tacggtgctg aaatatttga 1081 gacttccatg ttactgattt catcagaaaa tgagatgaat tggtttcatt cgaatgacgg 1141 tggaaacgtt ctctactacg aagtgatggt gactgggaat cttggaatcc agtggaggca

1201 taaaccaaat gttgtttctg ttgaaaagga aaaaaataaa ctgaagcgga aaaaactgga 1261 aaataaacac aagaaggatg aggagaaaaa caagatccgg gaagagtgga acaatttttc 1321 ttacttccct gaaatcactc acattgtaat aaaggagtct gtggtcagca ttaacaagca 1381 ggacaacaag aaaatggaac tgaagctctc ttcccacgag gaggccttgt cctttgtgtc 1441 cctggtagat ggctacttcc ggctcacagc agatgcccat cattacctct gcaccgacgt

1501 ggcccccccg ttgatcgtcc acaacataca gaatggctgt catggtccaa tctgtacaga 1561 atacgccatc aataaattgc ggcaagaagg aagcgaggag gggatgtacg tgctgaggtg 1621 gagctgcacc gactttgaca acatcctcat gaccgtcacc tgctttgaga agtctgagca 1681 ggtgcagggt gcccagaagc agttcaagaa ctttcagatc gaggtgcaga agggccgcta 1741 cagtctgcac ggttcggacc gcagcttccc cagcttggga gacctcatga gccacctcaa

1801 gaagcagatc ctgcgcacgg ataacatcag cttcatgcta aaacgctgct gccagcccaa 1861 gccccgagaa atctccaacc tgctggtggc tactaagaaa gcccaggagt ggcagcccgt 1921 ctaccccatg agccagctga gtttcgatcg gatcctcaag aaggatctgg tgcagggcga 1981 gcaccttggg agaggcacga gaacacacat ctattctggg accctgatgg attacaagga 2041 tgacgaagga acttctgaag agaagaagat aaaagtgatc ctcaaagtct tagaccccag

2101 ccacagggat atttccctgg ccttcttcga ggcagccagc atgatgagac aggtctccca 2161 caaacacatc gtgtacctct atggcgtctg tgtccgcgac gtggagaata tcatggtgga 2221 agagtttgtg gaagggggtc ctctggatct cttcatgcac cggaaaagcg atgtccttac 2281 cacaccatgg aaattcaaag ttgccaaaca gctggccagt gccctgagct acttggagga 2341 taaagacctg gtccatggaa atgtgtgtac taaaaacctc ctcctggccc gtgagggcat

2401 cgacagtgag tgtggcccat tcatcaagct cagtgacccc ggcatcccca ttacggtgct 2461 gtctaggcaa gaatgcattg aacgaatccc atggattgct cctgagtgtg ttgaggactc 2521 caagaacctg agtgtggctg ctgacaagtg gagctttgga accacgctct gggaaatctg 2581 ctacaatggc gagatcccct tgaaagacaa gacgctgatt gagaaagaga gattctatga 2641 aagccggtgc aggccagtga caccatcatg taaggagctg gctgacctca tgacccgctg

2701 catgaactat gaccccaatc agaggccttt cttccgagcc atcatgagag acattaataa 2761 gcttgaagag cagaatccag atattgtttc agaaaaaaaa ccagcaactg aagtggaccc 2821 cacacatttt gaaaagcgct tcctaaagag gatccgtgac ttgggagagg gccactttgg 2881 gaaggttgag ctctgcaggt atgaccccga aggggacaat acaggggagc aggtggctgt 2941 taaatctctg aagcctgaga gtggaggtaa ccacatagct gatctgaaaa aggaaatcga

3001 gatcttaagg aacctctatc atgagaacat tgtgaagtac aaaggaatct gcacagaaga 3061 cggaggaaat ggtattaagc tcatcatgga atttctgcct tcgggaagcc ttaaggaata 3121 tcttccaaag aataagaaca aaataaacct caaacagcag ctaaaatatg ccgttcagat 3181 ttgtaagggg atggactatt tgggttctcg gcaatacgtt caccgggact tggcagcaag 3241 aaatgtcctt gttgagagtg aacaccaagt gaaaattgga gacttcggtt taaccaaagc

3301 aattgaaacc gataaggagt attacaccgt caaggatgac cgggacagcc ctgtgttttg 3361 gtatgctcca gaatgtttaa tgcaatctaa attttatatt gcctctgacg tctggtcttt 3421 tggagtcact ctgcatgagc tgctgactta ctgtgattca gattctagtc ccatggcttt 3481 gttcctgaaa atgataggcc caacccatgg ccagatgaca gtcacaagac ttgtgaatac 3541 gttaaaagaa ggaaaacgcc tgccgtgccc acctaactgt ccagatgagg tttatcaact 3601 tatgaggaaa tgctgggaat tccaaccatc caatcggaca agctttcaga accttattga 3661 aggatttgaa gcacttttaa aataagaagc atgaataaca tttaaattcc acagattatc 3721 aagtccttct cctgcaacaa atgcccaagt cattttttaa aaatttctaa tgaaagaagt 3781 ttgtgttctg tccaaaaagt cactgaactc atacttcagt acatatacat gtataaggca 3841 cactgtagtg cttaatatgt gtaaggactt cctctttaaa tttggtacca gtaacttagt

3901 gacacataat gacaaccaaa atatttgaaa gcacttaagc actcctcctt gtggaaagaa 3961 tataccacca tttcatctgg ctagttcacc atcacaactg cattaccaaa aggggatttt 4021 tgaaaacgag gagttgacca aaataatatc tgaagatgat tgcttttccc tgctgccagc 4081 tgatctgaaa tgttttgctg gcacattaat catagataaa gaaagattga tggacttagc 4141 cctcaaattt cagtatctat acagtactag accatgcatt cttaaaatat tagataccag

4201 gtagtatata ttgtttctgt acaaaaatga ctgtattctc tcaccagtag gacttaaact

4261 ttgtttctcc agtggcttag ctcctgttcc tttgggtgat cactagcacc catttttgag

4321 aaagctggtt ctacatgggg ggatagctgt ggaatagata atttgctgca tgttaattct 4381 caagaactaa gcctgtgcca gtgctttcct aagcagtata cctttaatca gaactcattc 4441 ccagaacctg gatgctatta cacatgcttt taagaaacgt caatgtatat ccttttataa

4501 ctctaccact ttggggcaag ctattccagc actggttttg aatgctgtat gcaaccagtc 4561 tgaataccac atacgctgca ctgttcttag agggtttcca tacttaccac cgatctacaa 4621 gggttgatcc ctgtttttac catcaatcat caccctgtgg tgcaacactt gaaagacccg 4681 gctagaggca ctatggactt caggatccac tagacagttt tcagtttgct tggaggtagc 4741 tgggtaatca aaaatgttta gtcattgatt caatgtgaac gattacggtc tttatgacca

4801 agagtctgaa aatctttttg ttatgctgtt tagtattcgt ttgatattgt tacttttcac

4861 ctgttgagcc caaattcagg attggttcag tggcagcaat gaagttgcca tttaaatttg 4921 ttcatagcct acatcaccaa ggtctctgtg tcaaacctgt ggccactcta tatgcacttt 4981 gtttactctt tatacaaata aatatactaa agactttaca tgca

Human JAK1 mRNA Variant 4 (SEQ ID NO: 4)

1 atctatcaca tggcagagat agaataaaaa cagaaaaatg gcgacggtca cgttgtggcg 61 agccttgctg cgtcattaga taatcctcat gcaaatagcg ggaagaacaa aggaagggga 121 gcccgggacc cccgggggcg caggatccgg cgggaggagt ctaagaggag gaggcggcgg

181 tgccggagga ggaggaggag ggagggagaa gagaggaaga ccggagtccc cgcggcggcg 241 gcggtccgga gagagggcga gccccgcgcg gcgccgggga ccgggcgcta ccacgaggcc 301 gggacgctgg agtctgggtt atctaaaaca gttcatgctg ctgaaaacct ccttcctggc 361 agatgtccct caaccctact ggtgcctggc ttctgagaca cacgcttctc tgaagtagct 421 ttggaaagta gagaagaaaa tccagtttgc ttcttggaga acactggaca gctgaataaa

481 tgcagtatct aaatataaaa gaggactgca atgccatggc tttctgtgct aaaatgagga 541 gctccaagaa gactgaggtg aacctggagg cccctgagcc aggggtggaa gtgatcttct 601 atctgtcgga cagggagccc ctccggctgg gcagtggaga gtacacagca gaggaactgt 661 gcatcagggc tgcacaggca tgccgtatct ctcctctttg tcacaacctc tttgccctgt 721 atgacgagaa caccaagctc tggtatgctc caaatcgcac catcaccgtt gatgacaaga

781 tgtccctccg gctccactac cggatgaggt tctatttcac caattggcat ggaaccaacg 841 acaatgagca gtcagtgtgg cgtcattctc caaagaagca gaaaaatggc tacgagaaaa 901 aaaagattcc agatgcaacc cctctccttg atgccagctc actggagtat ctgtttgctc 961 agggacagta tgatttggtg aaatgcctgg ctcctattcg agaccccaag accgagcagg 1021 atggacatga tattgagaac gagtgtctag ggatggctgt cctggccatc tcacactatg 1081 ccatgatgaa gaagatgcag ttgccagaac tgcccaagga catcagctac aagcgatata 1141 ttccagaaac attgaataag tccatcagac agaggaacct tctcaccagg atgcggataa 1201 ataatgtttt caaggatttc ctaaaggaat ttaacaacaa gaccatttgt gacagcagcg

1261 tgtccacgca tgacctgaag gtgaaatact tggctacctt ggaaactttg acaaaacatt 1321 acggtgctga aatatttgag acttccatgt tactgatttc atcagaaaat gagatgaatt 1381 ggtttcattc gaatgacggt ggaaacgttc tctactacga agtgatggtg actgggaatc 1441 ttggaatcca gtggaggcat aaaccaaatg ttgtttctgt tgaaaaggaa aaaaataaac 1501 tgaagcggaa aaaactggaa aataaacaca agaaggatga ggagaaaaac aagatccggg

1561 aagagtggaa caatttttct tacttccctg aaatcactca cattgtaata aaggagtctg 1621 tggtcagcat taacaagcag gacaacaaga aaatggaact gaagctctct tcccacgagg 1681 aggccttgtc ctttgtgtcc ctggtagatg gctacttccg gctcacagca gatgcccatc 1741 attacctctg caccgacgtg gcccccccgt tgatcgtcca caacatacag aatggctgtc 1801 atggtccaat ctgtacagaa tacgccatca ataaattgcg gcaagaagga agcgaggagg

1861 ggatgtacgt gctgaggtgg agctgcaccg actttgacaa catcctcatg accgtcacct 1921 gctttgagaa gtctgagcag gtgcagggtg cccagaagca gttcaagaac tttcagatcg 1981 aggtgcagaa gggccgctac agtctgcacg gttcggaccg cagcttcccc agcttgggag 2041 acctcatgag ccacctcaag aagcagatcc tgcgcacgga taacatcagc ttcatgctaa 2101 aacgctgctg ccagcccaag ccccgagaaa tctccaacct gctggtggct actaagaaag

2161 cccaggagtg gcagcccgtc taccccatga gccagctgag tttcgatcgg atcctcaaga 2221 aggatctggt gcagggcgag caccttggga gaggcacgag aacacacatc tattctggga 2281 ccctgatgga ttacaaggat gacgaaggaa cttctgaaga gaagaagata aaagtgatcc 2341 tcaaagtctt agaccccagc cacagggata tttccctggc cttcttcgag gcagccagca 2401 tgatgagaca ggtctcccac aaacacatcg tgtacctcta tggcgtctgt gtccgcgacg

2461 tggagaatat catggtggaa gagtttgtgg aagggggtcc tctggatctc ttcatgcacc 2521 ggaaaagcga tgtccttacc acaccatgga aattcaaagt tgccaaacag ctggccagtg 2581 ccctgagcta cttggaggat aaagacctgg tccatggaaa tgtgtgtact aaaaacctcc 2641 tcctggcccg tgagggcatc gacagtgagt gtggcccatt catcaagctc agtgaccccg 2701 gcatccccat tacggtgctg tctaggcaag aatgcattga acgaatccca tggattgctc

2761 ctgagtgtgt tgaggactcc aagaacctga gtgtggctgc tgacaagtgg agctttggaa 2821 ccacgctctg ggaaatctgc tacaatggcg agatcccctt gaaagacaag acgctgattg 2881 agaaagagag attctatgaa agccggtgca ggccagtgac accatcatgt aaggagctgg 2941 ctgacctcat gacccgctgc atgaactatg accccaatca gaggcctttc ttccgagcca 3001 tcatgagaga cattaataag cttgaagagc agaatccaga tattgtttca gaaaaaaaac

3061 cagcaactga agtggacccc acacattttg aaaagcgctt cctaaagagg atccgtgact 3121 tgggagaggg ccactttggg aaggttgagc tctgcaggta tgaccccgaa ggggacaata 3181 caggggagca ggtggctgtt aaatctctga agcctgagag tggaggtaac cacatagctg 3241 atctgaaaaa ggaaatcgag atcttaagga acctctatca tgagaacatt gtgaagtaca 3301 aaggaatctg cacagaagac ggaggaaatg gtattaagct catcatggaa tttctgcctt

3361 cgggaagcct taaggaatat cttccaaaga ataagaacaa aataaacctc aaacagcagc 3421 taaaatatgc cgttcagatt tgtaagggga tggactattt gggttctcgg caatacgttc 3481 accgggactt ggcagcaaga aatgtccttg ttgagagtga acaccaagtg aaaattggag 3541 acttcggttt aaccaaagca attgaaaccg ataaggagta ttacaccgtc aaggatgacc 3601 gggacagccc tgtgttttgg tatgctccag aatgtttaat gcaatctaaa ttttatattg

3661 cctctgacgt ctggtctttt ggagtcactc tgcatgagct gctgacttac tgtgattcag

3721 attctagtcc catggctttg ttcctgaaaa tgataggccc aacccatggc cagatgacag 3781 tcacaagact tgtgaatacg ttaaaagaag gaaaacgcct gccgtgccca cctaactgtc 3841 cagatgaggt ttatcaactt atgaggaaat gctgggaatt ccaaccatcc aatcggacaa 3901 gctttcagaa ccttattgaa ggatttgaag cacttttaaa ataagaagca tgaataacat 3961 ttaaattcca cagattatca agtccttctc ctgcaacaaa tgcccaagtc attttttaaa

4021 aatttctaat gaaagaagtt tgtgttctgt ccaaaaagtc actgaactca tacttcagta

4081 catatacatg tataaggcac actgtagtgc ttaatatgtg taaggacttc ctctttaaat

4141 ttggtaccag taacttagtg acacataatg acaaccaaaa tatttgaaag cacttaagca 4201 ctcctccttg tggaaagaat ataccaccat ttcatctggc tagttcacca tcacaactgc 4261 attaccaaaa ggggattttt gaaaacgagg agttgaccaa aataatatct gaagatgatt 4321 gcttttccct gctgccagct gatctgaaat gttttgctgg cacattaatc atagataaag

4381 aaagattgat ggacttagcc ctcaaatttc agtatctata cagtactaga ccatgcattc 4441 ttaaaatatt agataccagg tagtatatat tgtttctgta caaaaatgac tgtattctct

4501 caccagtagg acttaaactt tgtttctcca gtggcttagc tcctgttcct ttgggtgatc

4561 actagcaccc atttttgaga aagctggttc tacatggggg gatagctgtg gaatagataa 4621 tttgctgcat gttaattctc aagaactaag cctgtgccag tgctttccta agcagtatac

4681 ctttaatcag aactcattcc cagaacctgg atgctattac acatgctttt aagaaacgtc 4741 aatgtatatc cttttataac tctaccactt tggggcaagc tattccagca ctggttttga

4801 atgctgtatg caaccagtct gaataccaca tacgctgcac tgttcttaga gggtttccat 4861 acttaccacc gatctacaag ggttgatccc tgtttttacc atcaatcatc accctgtggt 4921 gcaacacttg aaagacccgg ctagaggcac tatggacttc aggatccact agacagtttt 4981 cagtttgctt ggaggtagct gggtaatcaa aaatgtttag tcattgattc aatgtgaacg 5041 attacggtct ttatgaccaa gagtctgaaa atctttttgt tatgctgttt agtattcgtt

5101 tgatattgtt acttttcacc tgttgagccc aaattcagga ttggttcagt ggcagcaatg

5161 aagttgccat ttaaatttgt tcatagccta catcaccaag gtctctgtgt caaacctgtg

5221 gccactctat atgcactttg tttactcttt atacaaataa atatactaaa gactttacat

5281 gca

Human JAK1 mRNA Variant 5 (SEQ ID NO: 5)

1 atctatcaca tggcagagat agaataaaaa cagaaaaatg gcgacggtca cgttgtggcg 61 agccttgctg cgtcattaga taatcctcat gcaaatagcg ggaagaacaa aggaagggga 121 gcccgggacc cccgggggcg caggatccgg cgggaggagt ctaagaggag gaggcggcgg 181 tgccggagga ggaggaggag ggagggagaa gagaggaaga ccggagtccc cgcggcggcg 241 gcggtccgga gagagggcga gccccgcgcg gcgccgggga ccgggcgcta ccacgaggcc 301 gggacgctgg agtctgggcg cttctctgaa gtagctttgg aaagtagaga agaaaatcca 361 gtttgcttct tggagaacac tggacagctg aataaatgca gtatctaaat ataaaagagg 421 actgcaatgc catggctttc tgtgctaaaa tgaggagctc caagaagact gaggtgaacc 481 tggaggcccc tgagccaggg gtggaagtga tcttctatct gtcggacagg gagcccctcc 541 ggctgggcag tggagagtac acagcagagg aactgtgcat cagggctgca caggcatgcc 601 gtatctctcc tctttgtcac aacctctttg ccctgtatga cgagaacacc aagctctggt

661 atgctccaaa tcgcaccatc accgttgatg acaagatgtc cctccggctc cactaccgga 721 tgaggttcta tttcaccaat tggcatggaa ccaacgacaa tgagcagtca gtgtggcgtc 781 attctccaaa gaagcagaaa aatggctacg agaaaaaaaa gattccagat gcaacccctc 841 tccttgatgc cagctcactg gagtatctgt ttgctcaggg acagtatgat ttggtgaaat 901 gcctggctcc tattcgagac cccaagaccg agcaggatgg acatgatatt gagaacgagt 961 gtctagggat ggctgtcctg gccatctcac actatgccat gatgaagaag atgcagttgc

1021 cagaactgcc caaggacatc agctacaagc gatatattcc agaaacattg aataagtcca 1081 tcagacagag gaaccttctc accaggatgc ggataaataa tgttttcaag gatttcctaa 1141 aggaatttaa caacaagacc atttgtgaca gcagcgtgtc cacgcatgac ctgaaggtga 1201 aatacttggc taccttggaa actttgacaa aacattacgg tgctgaaata tttgagactt 1261 ccatgttact gatttcatca gaaaatgaga tgaattggtt tcattcgaat gacggtggaa

1321 acgttctcta ctacgaagtg atggtgactg ggaatcttgg aatccagtgg aggcataaac 1381 caaatgttgt ttctgttgaa aaggaaaaaa ataaactgaa gcggaaaaaa ctggaaaata 1441 aacacaagaa ggatgaggag aaaaacaaga tccgggaaga gtggaacaat ttttcttact 1501 tccctgaaat cactcacatt gtaataaagg agtctgtggt cagcattaac aagcaggaca 1561 acaagaaaat ggaactgaag ctctcttccc acgaggaggc cttgtccttt gtgtccctgg

1621 tagatggcta cttccggctc acagcagatg cccatcatta cctctgcacc gacgtggccc 1681 ccccgttgat cgtccacaac atacagaatg gctgtcatgg tccaatctgt acagaatacg 1741 ccatcaataa attgcggcaa gaaggaagcg aggaggggat gtacgtgctg aggtggagct 1801 gcaccgactt tgacaacatc ctcatgaccg tcacctgctt tgagaagtct gagcaggtgc 1861 agggtgccca gaagcagttc aagaactttc agatcgaggt gcagaagggc cgctacagtc

1921 tgcacggttc ggaccgcagc ttccccagct tgggagacct catgagccac ctcaagaagc 1981 agatcctgcg cacggataac atcagcttca tgctaaaacg ctgctgccag cccaagcccc 2041 gagaaatctc caacctgctg gtggctacta agaaagccca ggagtggcag cccgtctacc 2101 ccatgagcca gctgagtttc gatcggatcc tcaagaagga tctggtgcag ggcgagcacc 2161 ttgggagagg cacgagaaca cacatctatt ctgggaccct gatggattac aaggatgacg

2221 aaggaacttc tgaagagaag aagataaaag tgatcctcaa agtcttagac cccagccaca 2281 gggatatttc cctggccttc ttcgaggcag ccagcatgat gagacaggtc tcccacaaac 2341 acatcgtgta cctctatggc gtctgtgtcc gcgacgtgga gaatatcatg gtggaagagt 2401 ttgtggaagg gggtcctctg gatctcttca tgcaccggaa aagcgatgtc cttaccacac 2461 catggaaatt caaagttgcc aaacagctgg ccagtgccct gagctacttg gaggataaag

2521 acctggtcca tggaaatgtg tgtactaaaa acctcctcct ggcccgtgag ggcatcgaca 2581 gtgagtgtgg cccattcatc aagctcagtg accccggcat ccccattacg gtgctgtcta 2641 ggcaagaatg cattgaacga atcccatgga ttgctcctga gtgtgttgag gactccaaga 2701 acctgagtgt ggctgctgac aagtggagct ttggaaccac gctctgggaa atctgctaca 2761 atggcgagat ccccttgaaa gacaagacgc tgattgagaa agagagattc tatgaaagcc

2821 ggtgcaggcc agtgacacca tcatgtaagg agctggctga cctcatgacc cgctgcatga 2881 actatgaccc caatcagagg cctttcttcc gagccatcat gagagacatt aataagcttg 2941 aagagcagaa tccagatatt gtttcagaaa aaaaaccagc aactgaagtg gaccccacac 3001 attttgaaaa gcgcttccta aagaggatcc gtgacttggg agagggccac tttgggaagg 3061 ttgagctctg caggtatgac cccgaagggg acaatacagg ggagcaggtg gctgttaaat

3121 ctctgaagcc tgagagtgga ggtaaccaca tagctgatct gaaaaaggaa atcgagatct 3181 taaggaacct ctatcatgag aacattgtga agtacaaagg aatctgcaca gaagacggag 3241 gaaatggtat taagctcatc atggaatttc tgccttcggg aagccttaag gaatatcttc 3301 caaagaataa gaacaaaata aacctcaaac agcagctaaa atatgccgtt cagatttgta 3361 aggggatgga ctatttgggt tctcggcaat acgttcaccg ggacttggca gcaagaaatg 3421 tccttgttga gagtgaacac caagtgaaaa ttggagactt cggtttaacc aaagcaattg 3481 aaaccgataa ggagtattac accgtcaagg atgaccggga cagccctgtg ttttggtatg 3541 ctccagaatg tttaatgcaa tctaaatttt atattgcctc tgacgtctgg tcttttggag 3601 tcactctgca tgagctgctg acttactgtg attcagattc tagtcccatg gctttgttcc

3661 tgaaaatgat aggcccaacc catggccaga tgacagtcac aagacttgtg aatacgttaa 3721 aagaaggaaa acgcctgccg tgcccaccta actgtccaga tgaggtttat caacttatga 3781 ggaaatgctg ggaattccaa ccatccaatc ggacaagctt tcagaacctt attgaaggat 3841 ttgaagcact tttaaaataa gaagcatgaa taacatttaa attccacaga ttatcaagtc 3901 cttctcctgc aacaaatgcc caagtcattt tttaaaaatt tctaatgaaa gaagtttgtg

3961 ttctgtccaa aaagtcactg aactcatact tcagtacata tacatgtata aggcacactg 4021 tagtgcttaa tatgtgtaag gacttcctct ttaaatttgg taccagtaac ttagtgacac 4081 ataatgacaa ccaaaatatt tgaaagcact taagcactcc tccttgtgga aagaatatac 4141 caccatttca tctggctagt tcaccatcac aactgcatta ccaaaagggg atttttgaaa 4201 acgaggagtt gaccaaaata atatctgaag atgattgctt ttccctgctg ccagctgatc

4261 tgaaatgttt tgctggcaca ttaatcatag ataaagaaag attgatggac ttagccctca 4321 aatttcagta tctatacagt actagaccat gcattcttaa aatattagat accaggtagt 4381 atatattgtt tctgtacaaa aatgactgta ttctctcacc agtaggactt aaactttgtt 4441 tctccagtgg cttagctcct gttcctttgg gtgatcacta gcacccattt ttgagaaagc 4501 tggttctaca tggggggata gctgtggaat agataatttg ctgcatgtta attctcaaga

4561 actaagcctg tgccagtgct ttcctaagca gtataccttt aatcagaact cattcccaga 4621 acctggatgc tattacacat gcttttaaga aacgtcaatg tatatccttt tataactcta 4681 ccactttggg gcaagctatt ccagcactgg ttttgaatgc tgtatgcaac cagtctgaat 4741 accacatacg ctgcactgtt cttagagggt ttccatactt accaccgatc tacaagggtt 4801 gatccctgtt tttaccatca atcatcaccc tgtggtgcaa cacttgaaag acccggctag

4861 aggcactatg gacttcagga tccactagac agttttcagt ttgcttggag gtagctgggt 4921 aatcaaaaat gtttagtcat tgattcaatg tgaacgatta cggtctttat gaccaagagt 4981 ctgaaaatct ttttgttatg ctgtttagta ttcgtttgat attgttactt ttcacctgtt

5041 gagcccaaat tcaggattgg ttcagtggca gcaatgaagt tgccatttaa atttgttcat 5101 agcctacatc accaaggtct ctgtgtcaaa cctgtggcca ctctatatgc actttgttta

5161 ctctttatac aaataaatat actaaagact ttacatgca

Human JAK1 mRNA Variant 6 (SEQ ID NO: 6)

1 ggggcgggac gggaggcggt gcgtcgctga gcgcaggccg cggcggccgc ggagtatcct 61 ggagctgcag acagtgcggg cctgcgccca gtcccggctg tcctcgccgc gacccctcct

121 cagccctggg cgcgcgcacg ctggggcccc gcggggctgg ccgcctagcg agcctgccgg 181 tcgaccccag ccagcgcagc gacggggcgc tgcctggccc aggcgcacac ggaagtgtta 241 tctaaaacag ttcatgctgc tgaaaacctc cttcctggca gatgtccctc aaccctactg 301 gtgcctggct tctgagacac acgcttctct gaagtagctt tggaaagtag agaagaaaat 361 ccagtttgct tcttggagaa cactggacag ctgaataaat gcagtatcta aatataaaag

421 aggactgcaa tgccatggct ttctgtgcta aaatgaggag ctccaagaag actgaggtga 481 acctggaggc ccctgagcca ggggtggaag tgatcttcta tctgtcggac agggagcccc 541 tccggctggg cagtggagag tacacagcag aggaactgtg catcagggct gcacaggcat 601 gccgtatctc tcctctttgt cacaacctct ttgccctgta tgacgagaac accaagctct 661 ggtatgctcc aaatcgcacc atcaccgttg atgacaagat gtccctccgg ctccactacc 721 ggatgaggtt ctatttcacc aattggcatg gaaccaacga caatgagcag tcagtgtggc 781 gtcattctcc aaagaagcag aaaaatggct acgagaaaaa aaagattcca gatgcaaccc 841 ctctccttga tgccagctca ctggagtatc tgtttgctca gggacagtat gatttggtga

901 aatgcctggc tcctattcga gaccccaaga ccgagcagga tggacatgat attgagaacg 961 agtgtctagg gatggctgtc ctggccatct cacactatgc catgatgaag aagatgcagt 1021 tgccagaact gcccaaggac atcagctaca agcgatatat tccagaaaca ttgaataagt 1081 ccatcagaca gaggaacctt ctcaccagga tgcggataaa taatgttttc aaggatttcc 1141 taaaggaatt taacaacaag accatttgtg acagcagcgt gtccacgcat gacctgaagg

1201 tgaaatactt ggctaccttg gaaactttga caaaacatta cggtgctgaa atatttgaga 1261 cttccatgtt actgatttca tcagaaaatg agatgaattg gtttcattcg aatgacggtg 1321 gaaacgttct ctactacgaa gtgatggtga ctgggaatct tggaatccag tggaggcata 1381 aaccaaatgt tgtttctgtt gaaaaggaaa aaaataaact gaagcggaaa aaactggaaa 1441 ataaacacaa gaaggatgag gagaaaaaca agatccggga agagtggaac aatttttctt

1501 acttccctga aatcactcac attgtaataa aggagtctgt ggtcagcatt aacaagcagg 1561 acaacaagaa aatggaactg aagctctctt cccacgagga ggccttgtcc tttgtgtccc 1621 tggtagatgg ctacttccgg ctcacagcag atgcccatca ttacctctgc accgacgtgg 1681 cccccccgtt gatcgtccac aacatacaga atggctgtca tggtccaatc tgtacagaat 1741 acgccatcaa taaattgcgg caagaaggaa gcgaggaggg gatgtacgtg ctgaggtgga

1801 gctgcaccga ctttgacaac atcctcatga ccgtcacctg ctttgagaag tctgagcagg 1861 tgcagggtgc ccagaagcag ttcaagaact ttcagatcga ggtgcagaag ggccgctaca 1921 gtctgcacgg ttcggaccgc agcttcccca gcttgggaga cctcatgagc cacctcaaga 1981 agcagatcct gcgcacggat aacatcagct tcatgctaaa acgctgctgc cagcccaagc 2041 cccgagaaat ctccaacctg ctggtggcta ctaagaaagc ccaggagtgg cagcccgtct

2101 accccatgag ccagctgagt ttcgatcgga tcctcaagaa ggatctggtg cagggcgagc 2161 accttgggag aggcacgaga acacacatct attctgggac cctgatggat tacaaggatg 2221 acgaaggaac ttctgaagag aagaagataa aagtgatcct caaagtctta gaccccagcc 2281 acagggatat ttccctggcc ttcttcgagg cagccagcat gatgagacag gtctcccaca 2341 aacacatcgt gtacctctat ggcgtctgtg tccgcgacgt ggagaatatc atggtggaag

2401 agtttgtgga agggggtcct ctggatctct tcatgcaccg gaaaagcgat gtccttacca 2461 caccatggaa attcaaagtt gccaaacagc tggccagtgc cctgagctac ttggaggata 2521 aagacctggt ccatggaaat gtgtgtacta aaaacctcct cctggcccgt gagggcatcg 2581 acagtgagtg tggcccattc atcaagctca gtgaccccgg catccccatt acggtgctgt 2641 ctaggcaaga atgcattgaa cgaatcccat ggattgctcc tgagtgtgtt gaggactcca

2701 agaacctgag tgtggctgct gacaagtgga gctttggaac cacgctctgg gaaatctgct 2761 acaatggcga gatccccttg aaagacaaga cgctgattga gaaagagaga ttctatgaaa 2821 gccggtgcag gccagtgaca ccatcatgta aggagctggc tgacctcatg acccgctgca 2881 tgaactatga ccccaatcag aggcctttct tccgagccat catgagagac attaataagc 2941 ttgaagagca gaatccagat attgtttcag aaaaaaaacc agcaactgaa gtggacccca

3001 cacattttga aaagcgcttc ctaaagagga tccgtgactt gggagagggc cactttggga 3061 aggttgagct ctgcaggtat gaccccgaag gggacaatac aggggagcag gtggctgtta 3121 aatctctgaa gcctgagagt ggaggtaacc acatagctga tctgaaaaag gaaatcgaga 3181 tcttaaggaa cctctatcat gagaacattg tgaagtacaa aggaatctgc acagaagacg 324 gaggaaatgg tattaagctc atcatggaat ttctgccttc gggaagcctt aaggaatatc 330 ttccaaagaa taagaacaaa ataaacctca aacagcagct aaaatatgcc gttcagattt 336 gtaaggggat ggactatttg ggttctcggc aatacgttca ccgggacttg gcagcaagaa 342 atgtccttgt tgagagtgaa caccaagtga aaattggaga cttcggttta accaaagcaa 348 ttgaaaccga taaggagtat tacaccgtca aggatgaccg ggacagccct gtgttttggt 354 atgctccaga atgtttaatg caatctaaat tttatattgc ctctgacgtc tggtcttttg 360 gagtcactct gcatgagctg ctgacttact gtgattcaga ttctagtccc atggctttgt 366 tcctgaaaat gataggccca acccatggcc agatgacagt cacaagactt gtgaatacgt 372 taaaagaagg aaaacgcctg ccgtgcccac ctaactgtcc agatgaggtt tatcaactta 378 tgaggaaatg ctgggaattc caaccatcca atcggacaag ctttcagaac cttattgaag 384 gatttgaagc acttttaaaa taagaagcat gaataacatt taaattccac agattatcaa 390 gtccttctcc tgcaacaaat gcccaagtca ttttttaaaa atttctaatg aaagaagttt 396 gtgttctgtc caaaaagtca ctgaactcat acttcagtac atatacatgt ataaggcaca 402 ctgtagtgct taatatgtgt aaggacttcc tctttaaatt tggtaccagt aacttagtga 408 cacataatga caaccaaaat atttgaaagc acttaagcac tcctccttgt ggaaagaata 414 taccaccatt tcatctggct agttcaccat cacaactgca ttaccaaaag gggatttttg 420 aaaacgagga gttgaccaaa ataatatctg aagatgattg cttttccctg ctgccagctg 426 atctgaaatg ttttgctggc acattaatca tagataaaga aagattgatg gacttagccc 432 tcaaatttca gtatctatac agtactagac catgcattct taaaatatta gataccaggt 438 agtatatatt gtttctgtac aaaaatgact gtattctctc accagtagga cttaaacttt 444 gtttctccag tggcttagct cctgttcctt tgggtgatca ctagcaccca tttttgagaa 450 agctggttct acatgggggg atagctgtgg aatagataat ttgctgcatg ttaattctca 456 agaactaagc ctgtgccagt gctttcctaa gcagtatacc tttaatcaga actcattccc 462 agaacctgga tgctattaca catgctttta agaaacgtca atgtatatcc ttttataact 468 ctaccacttt ggggcaagct attccagcac tggttttgaa tgctgtatgc aaccagtctg 474 aataccacat acgctgcact gttcttagag ggtttccata cttaccaccg atctacaagg 480 gttgatccct gtttttacca tcaatcatca ccctgtggtg caacacttga aagacccggc 486 tagaggcact atggacttca ggatccacta gacagttttc agtttgcttg gaggtagctg 492 ggtaatcaaa aatgtttagt cattgattca atgtgaacga ttacggtctt tatgaccaag 498 agtctgaaaa tctttttgtt atgctgttta gtattcgttt gatattgtta cttttcacct

504 gttgagccca aattcaggat tggttcagtg gcagcaatga agttgccatt taaatttgtt 510 catagcctac atcaccaagg tctctgtgtc aaacctgtgg ccactctata tgcactttgt 516 ttactcttta tacaaataaa tatactaaag actttacatg ca Human JAK1 mRNA Variant 7 (SEQ ID NO: 7)

1 agaagcggag cgtatacgga ggaggcggga tgcatttctg catcgagcgc acaaagcgct 61 tctctgaagt agctttggaa agtagagaag aaaatccagt ttgcttcttg gagaacactg 121 gacagctgaa taaatgcagt atctaaatat aaaagaggac tgcaatgcca tggctttctg 181 tgctaaaatg aggagctcca agaagactga ggtgaacctg gaggcccctg agccaggggt 241 ggaagtgatc ttctatctgt cggacaggga gcccctccgg ctgggcagtg gagagtacac

301 agcagaggaa ctgtgcatca gggctgcaca ggcatgccgt atctctcctc tttgtcacaa 361 cctctttgcc ctgtatgacg agaacaccaa gctctggtat gctccaaatc gcaccatcac 421 cgttgatgac aagatgtccc tccggctcca ctaccggatg aggttctatt tcaccaattg 481 gcatggaacc aacgacaatg agcagtcagt gtggcgtcat tctccaaaga agcagaaaaa 541 tggctacgag aaaaaaaaga ttccagatgc aacccctctc cttgatgcca gctcactgga 601 gtatctgttt gctcagggac agtatgattt ggtgaaatgc ctggctccta ttcgagaccc 661 caagaccgag caggatggac atgatattga gaacgagtgt ctagggatgg ctgtcctggc 721 catctcacac tatgccatga tgaagaagat gcagttgcca gaactgccca aggacatcag 781 ctacaagcga tatattccag aaacattgaa taagtccatc agacagagga accttctcac

841 caggatgcgg ataaataatg ttttcaagga tttcctaaag gaatttaaca acaagaccat 901 ttgtgacagc agcgtgtcca cgcatgacct gaaggtgaaa tacttggcta ccttggaaac 961 tttgacaaaa cattacggtg ctgaaatatt tgagacttcc atgttactga tttcatcaga 1021 aaatgagatg aattggtttc attcgaatga cggtggaaac gttctctact acgaagtgat 1081 ggtgactggg aatcttggaa tccagtggag gcataaacca aatgttgttt ctgttgaaaa

1141 ggaaaaaaat aaactgaagc ggaaaaaact ggaaaataaa cacaagaagg atgaggagaa 1201 aaacaagatc cgggaagagt ggaacaattt ttcttacttc cctgaaatca ctcacattgt 1261 aataaaggag tctgtggtca gcattaacaa gcaggacaac aagaaaatgg aactgaagct 1321 ctcttcccac gaggaggcct tgtcctttgt gtccctggta gatggctact tccggctcac 1381 agcagatgcc catcattacc tctgcaccga cgtggccccc ccgttgatcg tccacaacat

1441 acagaatggc tgtcatggtc caatctgtac agaatacgcc atcaataaat tgcggcaaga 1501 aggaagcgag gaggggatgt acgtgctgag gtggagctgc accgactttg acaacatcct 1561 catgaccgtc acctgctttg agaagtctga gcaggtgcag ggtgcccaga agcagttcaa 1621 gaactttcag atcgaggtgc agaagggccg ctacagtctg cacggttcgg accgcagctt 1681 ccccagcttg ggagacctca tgagccacct caagaagcag atcctgcgca cggataacat

1741 cagcttcatg ctaaaacgct gctgccagcc caagccccga gaaatctcca acctgctggt 1801 ggctactaag aaagcccagg agtggcagcc cgtctacccc atgagccagc tgagtttcga 1861 tcggatcctc aagaaggatc tggtgcaggg cgagcacctt gggagaggca cgagaacaca 1921 catctattct gggaccctga tggattacaa ggatgacgaa ggaacttctg aagagaagaa 1981 gataaaagtg atcctcaaag tcttagaccc cagccacagg gatatttccc tggccttctt

2041 cgaggcagcc agcatgatga gacaggtctc ccacaaacac atcgtgtacc tctatggcgt 2101 ctgtgtccgc gacgtggaga atatcatggt ggaagagttt gtggaagggg gtcctctgga 2161 tctcttcatg caccggaaaa gcgatgtcct taccacacca tggaaattca aagttgccaa 2221 acagctggcc agtgccctga gctacttgga ggataaagac ctggtccatg gaaatgtgtg 2281 tactaaaaac ctcctcctgg cccgtgaggg catcgacagt gagtgtggcc cattcatcaa

2341 gctcagtgac cccggcatcc ccattacggt gctgtctagg caagaatgca ttgaacgaat 2401 cccatggatt gctcctgagt gtgttgagga ctccaagaac ctgagtgtgg ctgctgacaa 2461 gtggagcttt ggaaccacgc tctgggaaat ctgctacaat ggcgagatcc ccttgaaaga 2521 caagacgctg attgagaaag agagattcta tgaaagccgg tgcaggccag tgacaccatc 2581 atgtaaggag ctggctgacc tcatgacccg ctgcatgaac tatgacccca atcagaggcc

2641 tttcttccga gccatcatga gagacattaa taagcttgaa gagcagaatc cagatattgt 2701 ttcagaaaaa aaaccagcaa ctgaagtgga ccccacacat tttgaaaagc gcttcctaaa 2761 gaggatccgt gacttgggag agggccactt tgggaaggtt gagctctgca ggtatgaccc 2821 cgaaggggac aatacagggg agcaggtggc tgttaaatct ctgaagcctg agagtggagg 2881 taaccacata gctgatctga aaaaggaaat cgagatctta aggaacctct atcatgagaa

2941 cattgtgaag tacaaaggaa tctgcacaga agacggagga aatggtatta agctcatcat 3001 ggaatttctg ccttcgggaa gccttaagga atatcttcca aagaataaga acaaaataaa 3061 cctcaaacag cagctaaaat atgccgttca gatttgtaag gggatggact atttgggttc 3121 tcggcaatac gttcaccggg acttggcagc aagaaatgtc cttgttgaga gtgaacacca 3181 agtgaaaatt ggagacttcg gtttaaccaa agcaattgaa accgataagg agtattacac 3241 cgtcaaggat gaccgggaca gccctgtgtt ttggtatgct ccagaatgtt taatgcaatc 3301 taaattttat attgcctctg acgtctggtc ttttggagtc actctgcatg agctgctgac 3361 ttactgtgat tcagattcta gtcccatggc tttgttcctg aaaatgatag gcccaaccca 3421 tggccagatg acagtcacaa gacttgtgaa tacgttaaaa gaaggaaaac gcctgccgtg

3481 cccacctaac tgtccagatg aggtttatca acttatgagg aaatgctggg aattccaacc 3541 atccaatcgg acaagctttc agaaccttat tgaaggattt gaagcacttt taaaataaga 3601 agcatgaata acatttaaat tccacagatt atcaagtcct tctcctgcaa caaatgccca 3661 agtcattttt taaaaatttc taatgaaaga agtttgtgtt ctgtccaaaa agtcactgaa 3721 ctcatacttc agtacatata catgtataag gcacactgta gtgcttaata tgtgtaagga

3781 cttcctcttt aaatttggta ccagtaactt agtgacacat aatgacaacc aaaatatttg 3841 aaagcactta agcactcctc cttgtggaaa gaatatacca ccatttcatc tggctagttc 3901 accatcacaa ctgcattacc aaaaggggat ttttgaaaac gaggagttga ccaaaataat 3961 atctgaagat gattgctttt ccctgctgcc agctgatctg aaatgttttg ctggcacatt 4021 aatcatagat aaagaaagat tgatggactt agccctcaaa tttcagtatc tatacagtac

4081 tagaccatgc attcttaaaa tattagatac caggtagtat atattgtttc tgtacaaaaa 4141 tgactgtatt ctctcaccag taggacttaa actttgtttc tccagtggct tagctcctgt 4201 tcctttgggt gatcactagc acccattttt gagaaagctg gttctacatg gggggatagc 4261 tgtggaatag ataatttgct gcatgttaat tctcaagaac taagcctgtg ccagtgcttt 4321 cctaagcagt atacctttaa tcagaactca ttcccagaac ctggatgcta ttacacatgc

4381 ttttaagaaa cgtcaatgta tatcctttta taactctacc actttggggc aagctattcc 4441 agcactggtt ttgaatgctg tatgcaacca gtctgaatac cacatacgct gcactgttct 4501 tagagggttt ccatacttac caccgatcta caagggttga tccctgtttt taccatcaat 4561 catcaccctg tggtgcaaca cttgaaagac ccggctagag gcactatgga cttcaggatc 4621 cactagacag ttttcagttt gcttggaggt agctgggtaa tcaaaaatgt ttagtcattg

4681 attcaatgtg aacgattacg gtctttatga ccaagagtct gaaaatcttt ttgttatgct 4741 gtttagtatt cgtttgatat tgttactttt cacctgttga gcccaaattc aggattggtt

4801 cagtggcagc aatgaagttg ccatttaaat ttgttcatag cctacatcac caaggtctct 4861 gtgtcaaacc tgtggccact ctatatgcac tttgtttact ctttatacaa ataaatatac 4921 taaagacttt acatgca

Human JAK1 mRNA Variant 8 (SEQ ID NO: 8)

1 ggggcgggac gggaggcggt gcgtcgctga gcgcaggccg cggcggccgc ggagtatcct 61 ggagctgcag acagtgcggg cctgcgccca gtcccggctg tcctcgccgc gacccctcct 121 cagccctggg cgcgcgcacg ctggggcccc gcggggctgg ccgcctagcg agcctgccgg

181 tcgaccccag ccagcgcagc gacggggcgc tgcctggccc aggcgcacac ggaagtgcgc 241 ttctctgaag tagctttgga aagtagagaa gaaaatccag tttgcttctt ggagaacact 301 ggacagctga ataaatgcag tatctaaata taaaagagga ctgcaatgcc atggctttct 361 gtgctaaaat gaggagctcc aagaagactg aggtgaacct ggaggcccct gagccagggg 421 tggaagtgat cttctatctg tcggacaggg agcccctccg gctgggcagt ggagagtaca

481 cagcagagga actgtgcatc agggctgcac aggcatgccg tatctctcct ctttgtcaca 541 acctctttgc cctgtatgac gagaacacca agctctggta tgctccaaat cgcaccatca 601 ccgttgatga caagatgtcc ctccggctcc actaccggat gaggttctat ttcaccaatt 661 ggcatggaac caacgacaat gagcagtcag tgtggcgtca ttctccaaag aagcagaaaa 721 atggctacga gaaaaaaaag attccagatg caacccctct ccttgatgcc agctcactgg 781 agtatctgtt tgctcaggga cagtatgatt tggtgaaatg cctggctcct attcgagacc 841 ccaagaccga gcaggatgga catgatattg agaacgagtg tctagggatg gctgtcctgg 901 ccatctcaca ctatgccatg atgaagaaga tgcagttgcc agaactgccc aaggacatca

961 gctacaagcg atatattcca gaaacattga ataagtccat cagacagagg aaccttctca 1021 ccaggatgcg gataaataat gttttcaagg atttcctaaa ggaatttaac aacaagacca 1081 tttgtgacag cagcgtgtcc acgcatgacc tgaaggtgaa atacttggct accttggaaa 1141 ctttgacaaa acattacggt gctgaaatat ttgagacttc catgttactg atttcatcag 1201 aaaatgagat gaattggttt cattcgaatg acggtggaaa cgttctctac tacgaagtga

1261 tggtgactgg gaatcttgga atccagtgga ggcataaacc aaatgttgtt tctgttgaaa 1321 aggaaaaaaa taaactgaag cggaaaaaac tggaaaataa acacaagaag gatgaggaga 1381 aaaacaagat ccgggaagag tggaacaatt tttcttactt ccctgaaatc actcacattg 1441 taataaagga gtctgtggtc agcattaaca agcaggacaa caagaaaatg gaactgaagc 1501 tctcttccca cgaggaggcc ttgtcctttg tgtccctggt agatggctac ttccggctca

1561 cagcagatgc ccatcattac ctctgcaccg acgtggcccc cccgttgatc gtccacaaca 1621 tacagaatgg ctgtcatggt ccaatctgta cagaatacgc catcaataaa ttgcggcaag 1681 aaggaagcga ggaggggatg tacgtgctga ggtggagctg caccgacttt gacaacatcc 1741 tcatgaccgt cacctgcttt gagaagtctg aggtgcaggg tgcccagaag cagttcaaga 1801 actttcagat cgaggtgcag aagggccgct acagtctgca cggttcggac cgcagcttcc

1861 ccagcttggg agacctcatg agccacctca agaagcagat cctgcgcacg gataacatca 1921 gcttcatgct aaaacgctgc tgccagccca agccccgaga aatctccaac ctgctggtgg 1981 ctactaagaa agcccaggag tggcagcccg tctaccccat gagccagctg agtttcgatc 2041 ggatcctcaa gaaggatctg gtgcagggcg agcaccttgg gagaggcacg agaacacaca 2101 tctattctgg gaccctgatg gattacaagg atgacgaagg aacttctgaa gagaagaaga

2161 taaaagtgat cctcaaagtc ttagacccca gccacaggga tatttccctg gccttcttcg 2221 aggcagccag catgatgaga caggtctccc acaaacacat cgtgtacctc tatggcgtct 2281 gtgtccgcga cgtggagaat atcatggtgg aagagtttgt ggaagggggt cctctggatc 2341 tcttcatgca ccggaaaagc gatgtcctta ccacaccatg gaaattcaaa gttgccaaac 2401 agctggccag tgccctgagc tacttggagg ataaagacct ggtccatgga aatgtgtgta

2461 ctaaaaacct cctcctggcc cgtgagggca tcgacagtga gtgtggccca ttcatcaagc 2521 tcagtgaccc cggcatcccc attacggtgc tgtctaggca agaatgcatt gaacgaatcc 2581 catggattgc tcctgagtgt gttgaggact ccaagaacct gagtgtggct gctgacaagt 2641 ggagctttgg aaccacgctc tgggaaatct gctacaatgg cgagatcccc ttgaaagaca 2701 agacgctgat tgagaaagag agattctatg aaagccggtg caggccagtg acaccatcat

2761 gtaaggagct ggctgacctc atgacccgct gcatgaacta tgaccccaat cagaggcctt 2821 tcttccgagc catcatgaga gacattaata agcttgaaga gcagaatcca gatattgttt 2881 cagaaaaaaa accagcaact gaagtggacc ccacacattt tgaaaagcgc ttcctaaaga 2941 ggatccgtga cttgggagag ggccactttg ggaaggttga gctctgcagg tatgaccccg 3001 aaggggacaa tacaggggag caggtggctg ttaaatctct gaagcctgag agtggaggta

3061 accacatagc tgatctgaaa aaggaaatcg agatcttaag gaacctctat catgagaaca 3121 ttgtgaagta caaaggaatc tgcacagaag acggaggaaa tggtattaag ctcatcatgg 3181 aatttctgcc ttcgggaagc cttaaggaat atcttccaaa gaataagaac aaaataaacc 3241 tcaaacagca gctaaaatat gccgttcaga tttgtaaggg gatggactat ttgggttctc 3301 ggcaatacgt tcaccgggac ttggcagcaa gaaatgtcct tgttgagagt gaacaccaag 3361 tgaaaattgg agacttcggt ttaaccaaag caattgaaac cgataaggag tattacaccg 3421 tcaaggatga ccgggacagc cctgtgtttt ggtatgctcc agaatgttta atgcaatcta 3481 aattttatat tgcctctgac gtctggtctt ttggagtcac tctgcatgag ctgctgactt 3541 actgtgattc agattctagt cccatggctt tgttcctgaa aatgataggc ccaacccatg

3601 gccagatgac agtcacaaga cttgtgaata cgttaaaaga aggaaaacgc ctgccgtgcc 3661 cacctaactg tccagatgag gtttatcaac ttatgaggaa atgctgggaa ttccaaccat 3721 ccaatcggac aagctttcag aaccttattg aaggatttga agcactttta aaataagaag 3781 catgaataac atttaaattc cacagattat caagtccttc tcctgcaaca aatgcccaag 3841 tcatttttta aaaatttcta atgaaagaag tttgtgttct gtccaaaaag tcactgaact

3901 catacttcag tacatataca tgtataaggc acactgtagt gcttaatatg tgtaaggact 3961 tcctctttaa atttggtacc agtaacttag tgacacataa tgacaaccaa aatatttgaa 4021 agcacttaag cactcctcct tgtggaaaga atataccacc atttcatctg gctagttcac 4081 catcacaact gcattaccaa aaggggattt ttgaaaacga ggagttgacc aaaataatat 4141 ctgaagatga ttgcttttcc ctgctgccag ctgatctgaa atgttttgct ggcacattaa

4201 tcatagataa agaaagattg atggacttag ccctcaaatt tcagtatcta tacagtacta 4261 gaccatgcat tcttaaaata ttagatacca ggtagtatat attgtttctg tacaaaaatg 4321 actgtattct ctcaccagta ggacttaaac tttgtttctc cagtggctta gctcctgttc 4381 ctttgggtga tcactagcac ccatttttga gaaagctggt tctacatggg gggatagctg 4441 tggaatagat aatttgctgc atgttaattc tcaagaacta agcctgtgcc agtgctttcc

4501 taagcagtat acctttaatc agaactcatt cccagaacct ggatgctatt acacatgctt 4561 ttaagaaacg tcaatgtata tccttttata actctaccac tttggggcaa gctattccag 4621 cactggtttt gaatgctgta tgcaaccagt ctgaatacca catacgctgc actgttctta 4681 gagggtttcc atacttacca ccgatctaca agggttgatc cctgttttta ccatcaatca 4741 tcaccctgtg gtgcaacact tgaaagaccc ggctagaggc actatggact tcaggatcca

4801 ctagacagtt ttcagtttgc ttggaggtag ctgggtaatc aaaaatgttt agtcattgat 4861 tcaatgtgaa cgattacggt ctttatgacc aagagtctga aaatcttttt gttatgctgt 4921 ttagtattcg tttgatattg ttacttttca cctgttgagc ccaaattcag gattggttca

4981 gtggcagcaa tgaagttgcc atttaaattt gttcatagcc tacatcacca aggtctctgt 5041 gtcaaacctg tggccactct atatgcactt tgtttactct ttatacaaat aaatatacta

5101 aagactttac atgca

Human JAK2 mRNA Variant 1 (SEQ ID NO: 9)

1 ctgcaggaag gagagaggaa gaggagcaga agggggcagc agcggacgcc gctaacggcc 61 tccctcggcg ctgacaggct gggccggcgc ccggctcgct tgggtgttcg cgtcgccact

121 tcggcttctc ggccggtcgg gcccctcggc ccgggcttgc ggcgcgcgtc ggggctgagg 181 gctgctgcgg cgcagggaga ggcctggtcc tcgctgccga gggatgtgag tgggagctga 241 gcccacactg gagggccccc gagggcccag cctggaggtc gttcagagcc gtgcccgtcc 301 cggggcttcg cagaccttga cccgccgggt aggagccgcc cctgcgggct cgagggcgcg 361 ctctggtcgc ccgatctgtg tagccggttt cagaagcagg caacaggaac aagatgtgaa

421 ctgtttctct tctgcagaaa aagaggctct tcctcctcct cccgcgacgg caaatgttct 481 gaaaaagact ctgcatggga atggcctgcc ttacgatgac agaaatggag ggaacatcca 541 cctcttctat atatcagaat ggtgatattt ctggaaatgc caattctatg aagcaaatag 601 atccagttct tcaggtgtat ctttaccatt cccttgggaa atctgaggca gattatctga 661 cctttccatc tggggagtat gttgcagaag aaatctgtat tgctgcttct aaagcttgtg 721 gtatcacacc tgtgtatcat aatatgtttg ctttaatgag tgaaacagaa aggatctggt 781 atccacccaa ccatgtcttc catatagatg agtcaaccag gcataatgta ctctacagaa 841 taagatttta ctttcctcgt tggtattgca gtggcagcaa cagagcctat cggcatggaa

901 tatctcgagg tgctgaagct cctcttcttg atgactttgt catgtcttac ctctttgctc 961 agtggcggca tgattttgtg cacggatgga taaaagtacc tgtgactcat gaaacacagg 1021 aagaatgtct tgggatggca gtgttagata tgatgagaat agccaaagaa aacgatcaaa 1081 ccccactggc catctataac tctatcagct acaagacatt cttaccaaaa tgtattcgag 1141 caaagatcca agactatcat attttgacaa ggaagcgaat aaggtacaga tttcgcagat

1201 ttattcagca attcagccaa tgcaaagcca ctgccagaaa cttgaaactt aagtatctta 1261 taaatctgga aactctgcag tctgccttct acacagagaa atttgaagta aaagaacctg 1321 gaagtggtcc ttcaggtgag gagatttttg caaccattat aataactgga aacggtggaa 1381 ttcagtggtc aagagggaaa cataaagaaa gtgagacact gacagaacag gatttacagt 1441 tatattgcga ttttcctaat attattgatg tcagtattaa gcaagcaaac caagagggtt

1501 caaatgaaag ccgagttgta actatccata agcaagatgg taaaaatctg gaaattgaac 1561 ttagctcatt aagggaagct ttgtctttcg tgtcattaat tgatggatat tatagattaa 1621 ctgcagatgc acatcattac ctctgtaaag aagtagcacc tccagccgtg cttgaaaata 1681 tacaaagcaa ctgtcatggc ccaatttcga tggattttgc cattagtaaa ctgaagaaag 1741 caggtaatca gactggactg tatgtacttc gatgcagtcc taaggacttt aataaatatt

1801 ttttgacttt tgctgtcgag cgagaaaatg tcattgaata taaacactgt ttgattacaa 1861 aaaatgagaa tgaagagtac aacctcagtg ggacaaagaa gaacttcagc agtcttaaag 1921 atcttttgaa ttgttaccag atggaaactg ttcgctcaga caatataatt ttccagttta 1981 ctaaatgctg tcccccaaag ccaaaagata aatcaaacct tctagtcttc agaacgaatg 2041 gtgtttctga tgtaccaacc tcaccaacat tacagaggcc tactcatatg aaccaaatgg

2101 tgtttcacaa aatcagaaat gaagatttga tatttaatga aagccttggc caaggcactt 2161 ttacaaagat ttttaaaggc gtacgaagag aagtaggaga ctacggtcaa ctgcatgaaa 2221 cagaagttct tttaaaagtt ctggataaag cacacagaaa ctattcagag tctttctttg 2281 aagcagcaag tatgatgagc aagctttctc acaagcattt ggttttaaat tatggagtat 2341 gtgtctgtgg agacgagaat attctggttc aggagtttgt aaaatttgga tcactagata

2401 catatctgaa aaagaataaa aattgtataa atatattatg gaaacttgaa gttgctaaac 2461 agttggcatg ggccatgcat tttctagaag aaaacaccct tattcatggg aatgtatgtg 2521 ccaaaaatat tctgcttatc agagaagaag acaggaagac aggaaatcct cctttcatca 2581 aacttagtga tcctggcatt agtattacag ttttgccaaa ggacattctt caggagagaa 2641 taccatgggt accacctgaa tgcattgaaa atcctaaaaa tttaaatttg gcaacagaca

2701 aatggagttt tggtaccact ttgtgggaaa tctgcagtgg aggagataaa cctctaagtg 2761 ctctggattc tcaaagaaag ctacaatttt atgaagatag gcatcagctt cctgcaccaa 2821 agtgggcaga attagcaaac cttataaata attgtatgga ttatgaacca gatttcaggc 2881 cttctttcag agccatcata cgagatctta acagtttgtt tactccagat tatgaactat 2941 taacagaaaa tgacatgtta ccaaatatga ggataggtgc cctggggttt tctggtgcct

3001 ttgaagaccg ggatcctaca cagtttgaag agagacattt gaaatttcta cagcaacttg 3061 gcaagggtaa ttttgggagt gtggagatgt gccggtatga ccctctacag gacaacactg 3121 gggaggtggt cgctgtaaaa aagcttcagc atagtactga agagcaccta agagactttg 3181 aaagggaaat tgaaatcctg aaatccctac agcatgacaa cattgtaaag tacaagggag 3241 tgtgctacag tgctggtcgg cgtaatctaa aattaattat ggaatattta ccatatggaa 3301 gtttacgaga ctatcttcaa aaacataaag aacggataga tcacataaaa cttctgcagt 3361 acacatctca gatatgcaag ggtatggagt atcttggtac aaaaaggtat atccacaggg 3421 atctggcaac gagaaatata ttggtggaga acgagaacag agttaaaatt ggagattttg 3481 ggttaaccaa agtcttgcca caagacaaag aatactataa agtaaaagaa cctggtgaaa 3541 gtcccatatt ctggtatgct ccagaatcac tgacagagag caagttttct gtggcctcag 3601 atgtttggag ctttggagtg gttctgtatg aacttttcac atacattgag aagagtaaaa 3661 gtccaccagc ggaatttatg cgtatgattg gcaatgacaa acaaggacag atgatcgtgt 3721 tccatttgat agaacttttg aagaataatg gaagattacc aagaccagat ggatgcccag 3781 atgagatcta tatgatcatg acagaatgct ggaacaataa tgtaaatcaa cgcccctcct 3841 ttagggatct agctcttcga gtggatcaaa taagggataa catggctgga tgaaagaaat 3901 gaccttcatt ctgagaccaa agtagattta cagaacaaag ttttatattt cacattgctg 3961 tggactatta ttacatatat cattattata taaatcatga tgctagccag caaagatgtg 4021 aaaatatctg ctcaaaactt tcaaagttta gtaagttttt cttcatgagg ccaccagtaa 4081 aagacattaa tgagaattcc ttagcaagga ttttgtaaga agtttcttaa acattgtcag 4141 ttaacatcac tcttgtctgg caaaagaaaa aaaatagact ttttcaactc agctttttga 4201 gacctgaaaa aattattatg taaattttgc aatgttaaag atgcacagaa tatgtatgta 4261 tagtttttac cacagtggat gtataatacc ttggcatctt gtgtgatgtt ttacacacat 4321 gagggctggt gttcattaat actgttttct aatttttcca tagttaatct ataattaatt

4381 acttcactat acaaacaaat taagatgttc agataattga ataagtacct ttgtgtcctt 4441 gttcatttat atcgctggcc agcattataa gcaggtgtat acttttagct tgtagttcca 4501 tgtactgtaa atatttttca cataaaggga acaaatgtct agttttattt gtataggaaa 4561 tttccctgac cctaaataat acattttgaa atgaaacaag cttacaaaga tataatctat 4621 tttattatgg tttcccttgt atctatttgt ggtgaatgtg ttttttaaat ggaactatct

4681 ccaaattttt ctaagactac tatgaacagt tttcttttaa aattttgaga ttaagaatgc 4741 caggaatatt gtcatccttt gagctgctga ctgccaataa cattcttcga tctctgggat 4801 ttatgctcat gaactaaatt taagcttaag ccataaaata gattagattg ttttttaaaa 4861 atggatagct cattaagaag tgcagcaggt taagaatttt ttcctaaaga ctgtatattt 4921 gaggggtttc agaattttgc attgcagtca tagaagagat ttatttcctt tttagagggg 4981 aaatgaggta aataagtaaa aaagtatgct tgttaatttt attcaagaat gccagtagaa 5041 aattcataac gtgtatcttt aagaaaaatg agcatacatc ttaaatcttt tcaattaagt 5101 ataaggggtt gttcgttgtt gtcatttgtt atagtgctac tccactttag acaccatagc 5161 taaaataaaa tatggtgggt tttgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg 5221 tgttatttat acaaaactta aaatacttgc tgttttgatt aaaaagaaaa tagtttctta

5281 cttta

Human JAK2 mRNA Variant 2 (SEQ ID NO: 10)

1 attcggggag actgcaggcc aaccgggagg ctgagttcga agctagcagg gcggcgaagc 61 cagtgtcgcc cgcggcgttg agaagacggt gtggccccgg agagggtgga gacaactgtg 121 acgggcttcc cggctgcccg aagtgggagt ggtgtggggc tgcaggaagg agagaggaag 181 aggagcagaa gggggcagca gcggacgccg ctaacggcct ccctcggcgc tgacaggctg 241 ggccggcgcc cggctcgctt gggtgttcgc gtcgccactt cggcttctcg gccggtcggg 301 cccctcggcc cgggcttgcg gcgcgcgtcg gggctgaggg ctgctgcggc gcagggagag 361 gcctggtcct cgctgccgag ggatgtgagt gggagctgag cccacactgg agggcccccg 421 agggcccagc ctggaggtcg ttcagagccg tgcccgtccc ggggcttcgc agaccttgac 481 ccgccgggtt tcagaagcag gcaacaggaa caagatgtga actgtttctc ttctgcagaa 541 aaagaggctc ttcctcctcc tcccgcgacg gcaaatgttc tgaaaaagac tctgcatggg 601 aatggcctgc cttacgatga cagaaatgga gggaacatcc acctcttcta tatatcagaa

661 tggtgatatt tctggaaatg ccaattctat gaagcaaata gatccagttc ttcaggtgta 721 tctttaccat tcccttggga aatctgaggc agattatctg acctttccat ctggggagta 781 tgttgcagaa gaaatctgta ttgctgcttc taaagcttgt ggtatcacac ctgtgtatca 841 taatatgttt gctttaatga gtgaaacaga aaggatctgg tatccaccca accatgtctt 901 ccatatagat gagtcaacca ggcataatgt actctacaga ataagatttt actttcctcg

961 ttggtattgc agtggcagca acagagccta tcggcatgga atatctcgag gtgctgaagc 1021 tcctcttctt gatgactttg tcatgtctta cctctttgct cagtggcggc atgattttgt 1081 gcacggatgg ataaaagtac ctgtgactca tgaaacacag gaagaatgtc ttgggatggc 1141 agtgttagat atgatgagaa tagccaaaga aaacgatcaa accccactgg ccatctataa 1201 ctctatcagc tacaagacat tcttaccaaa atgtattcga gcaaagatcc aagactatca

1261 tattttgaca aggaagcgaa taaggtacag atttcgcaga tttattcagc aattcagcca 1321 atgcaaagcc actgccagaa acttgaaact taagtatctt ataaatctgg aaactctgca 1381 gtctgccttc tacacagaga aatttgaagt aaaagaacct ggaagtggtc cttcaggtga 1441 ggagattttt gcaaccatta taataactgg aaacggtgga attcagtggt caagagggaa 1501 acataaagaa agtgagacac tgacagaaca ggatttacag ttatattgcg attttcctaa

1561 tattattgat gtcagtatta agcaagcaaa ccaagagggt tcaaatgaaa gccgagttgt 1621 aactatccat aagcaagatg gtaaaaatct ggaaattgaa cttagctcat taagggaagc 1681 tttgtctttc gtgtcattaa ttgatggata ttatagatta actgcagatg cacatcatta 1741 cctctgtaaa gaagtagcac ctccagccgt gcttgaaaat atacaaagca actgtcatgg 1801 cccaatttcg atggattttg ccattagtaa actgaagaaa gcaggtaatc agactggact

1861 gtatgtactt cgatgcagtc ctaaggactt taataaatat tttttgactt ttgctgtcga 1921 gcgagaaaat gtcattgaat ataaacactg tttgattaca aaaaatgaga atgaagagta 1981 caacctcagt gggacaaaga agaacttcag cagtcttaaa gatcttttga attgttacca 2041 gatggaaact gttcgctcag acaatataat tttccagttt actaaatgct gtcccccaaa 2101 gccaaaagat aaatcaaacc ttctagtctt cagaacgaat ggtgtttctg atgtaccaac

2161 ctcaccaaca ttacagaggc ctactcatat gaaccaaatg gtgtttcaca aaatcagaaa 2221 tgaagatttg atatttaatg aaagccttgg ccaaggcact tttacaaaga tttttaaagg 2281 cgtacgaaga gaagtaggag actacggtca actgcatgaa acagaagttc ttttaaaagt 2341 tctggataaa gcacacagaa actattcaga gtctttcttt gaagcagcaa gtatgatgag 2401 caagctttct cacaagcatt tggttttaaa ttatggagta tgtgtctgtg gagacgagaa

2461 tattctggtt caggagtttg taaaatttgg atcactagat acatatctga aaaagaataa 2521 aaattgtata aatatattat ggaaacttga agttgctaaa cagttggcat gggccatgca 2581 ttttctagaa gaaaacaccc ttattcatgg gaatgtatgt gccaaaaata ttctgcttat 2641 cagagaagaa gacaggaaga caggaaatcc tcctttcatc aaacttagtg atcctggcat 2701 tagtattaca gttttgccaa aggacattct tcaggagaga ataccatggg taccacctga

2761 atgcattgaa aatcctaaaa atttaaattt ggcaacagac aaatggagtt ttggtaccac 2821 tttgtgggaa atctgcagtg gaggagataa acctctaagt gctctggatt ctcaaagaaa 2881 gctacaattt tatgaagata ggcatcagct tcctgcacca aagtgggcag aattagcaaa 2941 ccttataaat aattgtatgg attatgaacc agatttcagg ccttctttca gagccatcat 300 acgagatctt aacagtttgt ttactccaga ttatgaacta ttaacagaaa atgacatgtt 306 accaaatatg aggataggtg ccctggggtt ttctggtgcc tttgaagacc gggatcctac 312 acagtttgaa gagagacatt tgaaatttct acagcaactt ggcaagggta attttgggag 318 tgtggagatg tgccggtatg accctctaca ggacaacact ggggaggtgg tcgctgtaaa 324 aaagcttcag catagtactg aagagcacct aagagacttt gaaagggaaa ttgaaatcct 330 gaaatcccta cagcatgaca acattgtaaa gtacaaggga gtgtgctaca gtgctggtcg 336 gcgtaatcta aaattaatta tggaatattt accatatgga agtttacgag actatcttca 342 aaaacataaa gaacggatag atcacataaa acttctgcag tacacatctc agatatgcaa 348 gggtatggag tatcttggta caaaaaggta tatccacagg gatctggcaa cgagaaatat 354 attggtggag aacgagaaca gagttaaaat tggagatttt gggttaacca aagtcttgcc 360 acaagacaaa gaatactata aagtaaaaga acctggtgaa agtcccatat tctggtatgc 366 tccagaatca ctgacagaga gcaagttttc tgtggcctca gatgtttgga gctttggagt 372 ggttctgtat gaacttttca catacattga gaagagtaaa agtccaccag cggaatttat 378 gcgtatgatt ggcaatgaca aacaaggaca gatgatcgtg ttccatttga tagaactttt 384 gaagaataat ggaagattac caagaccaga tggatgccca gatgagatct atatgatcat 390 gacagaatgc tggaacaata atgtaaatca acgcccctcc tttagggatc tagctcttcg 396 agtggatcaa ataagggata acatggctgg atgaaagaaa tgaccttcat tctgagacca 402 aagtagattt acagaacaaa gttttatatt tcacattgct gtggactatt attacatata 408 tcattattat ataaatcatg atgctagcca gcaaagatgt gaaaatatct gctcaaaact 414 ttcaaagttt agtaagtttt tcttcatgag gccaccagta aaagacatta atgagaattc 420 cttagcaagg attttgtaag aagtttctta aacattgtca gttaacatca ctcttgtctg 426 gcaaaagaaa aaaaatagac tttttcaact cagctttttg agacctgaaa aaattattat 432 gtaaattttg caatgttaaa gatgcacaga atatgtatgt atagttttta ccacagtgga 438 tgtataatac cttggcatct tgtgtgatgt tttacacaca tgagggctgg tgttcattaa 444 tactgttttc taatttttcc atagttaatc tataattaat tacttcacta tacaaacaaa 450 ttaagatgtt cagataattg aataagtacc tttgtgtcct tgttcattta tatcgctggc 456 cagcattata agcaggtgta tacttttagc ttgtagttcc atgtactgta aatatttttc 462 acataaaggg aacaaatgtc tagttttatt tgtataggaa atttccctga ccctaaataa 468 tacattttga aatgaaacaa gcttacaaag atataatcta ttttattatg gtttcccttg 474 tatctatttg tggtgaatgt gttttttaaa tggaactatc tccaaatttt tctaagacta 480 ctatgaacag ttttctttta aaattttgag attaagaatg ccaggaatat tgtcatcctt 486 tgagctgctg actgccaata acattcttcg atctctggga tttatgctca tgaactaaat 492 ttaagcttaa gccataaaat agattagatt gttttttaaa aatggatagc tcattaagaa 498 gtgcagcagg ttaagaattt tttcctaaag actgtatatt tgaggggttt cagaattttg 504 cattgcagtc atagaagaga tttatttcct ttttagaggg gaaatgaggt aaataagtaa 510 aaaagtatgc ttgttaattt tattcaagaa tgccagtaga aaattcataa cgtgtatctt 516 taagaaaaat gagcatacat cttaaatctt ttcaattaag tataaggggt tgttcgttgt 522 tgtcatttgt tatagtgcta ctccacttta gacaccatag ctaaaataaa atatggtggg 528 ttttgtgtgt gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtgttattta tacaaaactt 534 aaaatacttg ctgttttgat taaaaagaaa atagtttctt acttta

Human JAK2 mRNA Variant 3 (SEQ ID NO: 11)

1 attcggggag actgcaggcc aaccgggagg ctgagttcga agctagcagg gcggcgaagc 61 cagtgtcgcc cgcggcgttg agaagacggc aaatgttctg aaaaagactc tgcatgggaa 121 tggcctgcct tacgatgaca gaaatggagg gaacatccac ctcttctata tatcagaatg 181 gtgatatttc tggaaatgcc aattctatga agcaaataga tccagttctt caggtgtatc 241 tttaccattc ccttgggaaa tctgaggcag attatctgac ctttccatct ggggagtatg 301 ttgcagaaga aatctgtatt gctgcttcta aagcttgtgg tatcacacct gtgtatcata

361 atatgtttgc tttaatgagt gaaacagaaa ggatctggta tccacccaac catgtcttcc 421 atatagatga gtcaaccagg cataatgtac tctacagaat aagattttac tttcctcgtt 481 ggtattgcag tggcagcaac agagcctatc ggcatggaat atctcgaggt gctgaagctc 541 ctcttcttga tgactttgtc atgtcttacc tctttgctca gtggcggcat gattttgtgc 601 acggatggat aaaagtacct gtgactcatg aaacacagga agaatgtctt gggatggcag

661 tgttagatat gatgagaata gccaaagaaa acgatcaaac cccactggcc atctataact 721 ctatcagcta caagacattc ttaccaaaat gtattcgagc aaagatccaa gactatcata 781 ttttgacaag gaagcgaata aggtacagat ttcgcagatt tattcagcaa ttcagccaat 841 gcaaagccac tgccagaaac ttgaaactta agtatcttat aaatctggaa actctgcagt 901 ctgccttcta cacagagaaa tttgaagtaa aagaacctgg aagtggtcct tcaggtgagg

961 agatttttgc aaccattata ataactggaa acggtggaat tcagtggtca agagggaaac 1021 ataaagaaag tgagacactg acagaacagg atttacagtt atattgcgat tttcctaata 1081 ttattgatgt cagtattaag caagcaaacc aagagggttc aaatgaaagc cgagttgtaa 1141 ctatccataa gcaagatggt aaaaatctgg aaattgaact tagctcatta agggaagctt 1201 tgtctttcgt gtcattaatt gatggatatt atagattaac tgcagatgca catcattacc

1261 tctgtaaaga agtagcacct ccagccgtgc ttgaaaatat acaaagcaac tgtcatggcc 1321 caatttcgat ggattttgcc attagtaaac tgaagaaagc aggtaatcag actggactgt 1381 atgtacttcg atgcagtcct aaggacttta ataaatattt tttgactttt gctgtcgagc 1441 gagaaaatgt cattgaatat aaacactgtt tgattacaaa aaatgagaat gaagagtaca 1501 acctcagtgg gacaaagaag aacttcagca gtcttaaaga tcttttgaat tgttaccaga

1561 tggaaactgt tcgctcagac aatataattt tccagtttac taaatgctgt cccccaaagc 1621 caaaagataa atcaaacctt ctagtcttca gaacgaatgg tgtttctgat gtaccaacct 1681 caccaacatt acagaggcct actcatatga accaaatggt gtttcacaaa atcagaaatg 1741 aagatttgat atttaatgaa agccttggcc aaggcacttt tacaaagatt tttaaaggcg 1801 tacgaagaga agtaggagac tacggtcaac tgcatgaaac agaagttctt ttaaaagttc

1861 tggataaagc acacagaaac tattcagagt ctttctttga agcagcaagt atgatgagca 1921 agctttctca caagcatttg gttttaaatt atggagtatg tgtctgtgga gacgagaata 1981 ttctggttca ggagtttgta aaatttggat cactagatac atatctgaaa aagaataaaa 2041 attgtataaa tatattatgg aaacttgaag ttgctaaaca gttggcatgg gccatgcatt 2101 ttctagaaga aaacaccctt attcatggga atgtatgtgc caaaaatatt ctgcttatca

2161 gagaagaaga caggaagaca ggaaatcctc ctttcatcaa acttagtgat cctggcatta 2221 gtattacagt tttgccaaag gacattcttc aggagagaat accatgggta ccacctgaat 2281 gcattgaaaa tcctaaaaat ttaaatttgg caacagacaa atggagtttt ggtaccactt 2341 tgtgggaaat ctgcagtgga ggagataaac ctctaagtgc tctggattct caaagaaagc 2401 tacaatttta tgaagatagg catcagcttc ctgcaccaaa gtgggcagaa ttagcaaacc

2461 ttataaataa ttgtatggat tatgaaccag atttcaggcc ttctttcaga gccatcatac 2521 gagatcttaa cagtttgttt actccagatt atgaactatt aacagaaaat gacatgttac 2581 caaatatgag gataggtgcc ctggggtttt ctggtgcctt tgaagaccgg gatcctacac 2641 agtttgaaga gagacatttg aaatttctac agcaacttgg caagggtaat tttgggagtg 2701 tggagatgtg ccggtatgac cctctacagg acaacactgg ggaggtggtc gctgtaaaaa 2761 agcttcagca tagtactgaa gagcacctaa gagactttga aagggaaatt gaaatcctga 2821 aatccctaca gcatgacaac attgtaaagt acaagggagt gtgctacagt gctggtcggc 2881 gtaatctaaa attaattatg gaatatttac catatggaag tttacgagac tatcttcaaa 2941 aacataaaga acggatagat cacataaaac ttctgcagta cacatctcag atatgcaagg 3001 gtatggagta tcttggtaca aaaaggtata tccacaggga tctggcaacg agaaatatat 3061 tggtggagaa cgagaacaga gttaaaattg gagattttgg gttaaccaaa gtcttgccac 3121 aagacaaaga atactataaa gtaaaagaac ctggtgaaag tcccatattc tggtatgctc 3181 cagaatcact gacagagagc aagttttctg tggcctcaga tgtttggagc tttggagtgg 3241 ttctgtatga acttttcaca tacattgaga agagtaaaag tccaccagcg gaatttatgc 3301 gtatgattgg caatgacaaa caaggacaga tgatcgtgtt ccatttgata gaacttttga 3361 agaataatgg aagattacca agaccagatg gatgcccaga tgagatctat atgatcatga 3421 cagaatgctg gaacaataat gtaaatcaac gcccctcctt tagggatcta gctcttcgag 3481 tggatcaaat aagggataac atggctggat gaaagaaatg accttcattc tgagaccaaa 3541 gtagatttac agaacaaagt tttatatttc acattgctgt ggactattat tacatatatc

3601 attattatat aaatcatgat gctagccagc aaagatgtga aaatatctgc tcaaaacttt 3661 caaagtttag taagtttttc ttcatgaggc caccagtaaa agacattaat gagaattcct 3721 tagcaaggat tttgtaagaa gtttcttaaa cattgtcagt taacatcact cttgtctggc 3781 aaaagaaaaa aaatagactt tttcaactca gctttttgag acctgaaaaa attattatgt 3841 aaattttgca atgttaaaga tgcacagaat atgtatgtat agtttttacc acagtggatg 3901 tataatacct tggcatcttg tgtgatgttt tacacacatg agggctggtg ttcattaata 3961 ctgttttcta atttttccat agttaatcta taattaatta cttcactata caaacaaatt

4021 aagatgttca gataattgaa taagtacctt tgtgtccttg ttcatttata tcgctggcca 4081 gcattataag caggtgtata cttttagctt gtagttccat gtactgtaaa tatttttcac

4141 ataaagggaa caaatgtcta gttttatttg tataggaaat ttccctgacc ctaaataata 4201 cattttgaaa tgaaacaagc ttacaaagat ataatctatt ttattatggt ttcccttgta

4261 tctatttgtg gtgaatgtgt tttttaaatg gaactatctc caaatttttc taagactact

4321 atgaacagtt ttcttttaaa attttgagat taagaatgcc aggaatattg tcatcctttg

4381 agctgctgac tgccaataac attcttcgat ctctgggatt tatgctcatg aactaaattt 4441 aagcttaagc cataaaatag attagattgt tttttaaaaa tggatagctc attaagaagt 4501 gcagcaggtt aagaattttt tcctaaagac tgtatatttg aggggtttca gaattttgca 4561 ttgcagtcat agaagagatt tatttccttt ttagagggga aatgaggtaa ataagtaaaa 4621 aagtatgctt gttaatttta ttcaagaatg ccagtagaaa attcataacg tgtatcttta 4681 agaaaaatga gcatacatct taaatctttt caattaagta taaggggttg ttcgttgttg 4741 tcatttgtta tagtgctact ccactttaga caccatagct aaaataaaat atggtgggtt 4801 ttgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gttatttata caaaacttaa

4861 aatacttgct gttttgatta aaaagaaaat agtttcttac ttta

Human JAK2 mRNA Variant 4 (SEQ ID NO: 12)

1 gggagtggtg tggggctgca ggaaggagag aggaagagga gcagaagggg gcagcagcgg

61 acgccgctaa cggcctccct cggcgctgac aggctgggcc ggcgcccggc tcgcttgggt 121 gttcgcgtcg ccacttcggc ttctcggccg gtcgggcccc tcggcccggg cttgcggcgc 181 gcgtcggggc tgagggctgc tgcggcgcag ggagaggcct ggtcctcgct gccgagggat 241 gtgagtggga gctgagccca cactggaggg cccccgaggg cccagcctgg aggtcgttca 301 gagccgtgcc cgtcccgggg cttcgcagac cttgacccgc cgggtaggag ccgcccctgc 361 gggctcgagg gcgcgctctg gtcgcccgat ctgtgtagcc ggcaaatgtt ctgaaaaaga 421 ctctgcatgg gaatggcctg ccttacgatg acagaaatgg agggaacatc cacctcttct 481 atatatcaga atggtgatat ttctggaaat gccaattcta tgaagcaaat agatccagtt

541 cttcaggtgt atctttacca ttcccttggg aaatctgagg cagattatct gacctttcca 601 tctggggagt atgttgcaga agaaatctgt attgctgctt ctaaagcttg tggtatcaca 661 cctgtgtatc ataatatgtt tgctttaatg agtgaaacag aaaggatctg gtatccaccc 721 aaccatgtct tccatataga tgagtcaacc aggcataatg tactctacag aataagattt 781 tactttcctc gttggtattg cagtggcagc aacagagcct atcggcatgg aatatctcga

841 ggtgctgaag ctcctcttct tgatgacttt gtcatgtctt acctctttgc tcagtggcgg 901 catgattttg tgcacggatg gataaaagta cctgtgactc atgaaacaca ggaagaatgt 961 cttgggatgg cagtgttaga tatgatgaga atagccaaag aaaacgatca aaccccactg 1021 gccatctata actctatcag ctacaagaca ttcttaccaa aatgtattcg agcaaagatc 1081 caagactatc atattttgac aaggaagcga ataaggtaca gatttcgcag atttattcag

1141 caattcagcc aatgcaaagc cactgccaga aacttgaaac ttaagtatct tataaatctg 1201 gaaactctgc agtctgcctt ctacacagag aaatttgaag taaaagaacc tggaagtggt 1261 ccttcaggtg aggagatttt tgcaaccatt ataataactg gaaacggtgg aattcagtgg 1321 tcaagaggga aacataaaga aagtgagaca ctgacagaac aggatttaca gttatattgc 1381 gattttccta atattattga tgtcagtatt aagcaagcaa accaagaggg ttcaaatgaa

1441 agccgagttg taactatcca taagcaagat ggtaaaaatc tggaaattga acttagctca 1501 ttaagggaag ctttgtcttt cgtgtcatta attgatggat attatagatt aactgcagat 1561 gcacatcatt acctctgtaa agaagtagca cctccagccg tgcttgaaaa tatacaaagc 1621 aactgtcatg gcccaatttc gatggatttt gccattagta aactgaagaa agcaggtaat 1681 cagactggac tgtatgtact tcgatgcagt cctaaggact ttaataaata ttttttgact

1741 tttgctgtcg agcgagaaaa tgtcattgaa tataaacact gtttgattac aaaaaatgag 1801 aatgaagagt acaacctcag tgggacaaag aagaacttca gcagtcttaa agatcttttg 1861 aattgttacc agatggaaac tgttcgctca gacaatataa ttttccagtt tactaaatgc 1921 tgtcccccaa agccaaaaga taaatcaaac cttctagtct tcagaacgaa tggtgtttct 1981 gatgtaccaa cctcaccaac attacagagg cctactcata tgaaccaaat ggtgtttcac

2041 aaaatcagaa atgaagattt gatatttaat gaaagccttg gccaaggcac ttttacaaag 2101 atttttaaag gcgtacgaag agaagtagga gactacggtc aactgcatga aacagaagtt 2161 cttttaaaag ttctggataa agcacacaga aactattcag agtctttctt tgaagcagca 2221 agtatgatga gcaagctttc tcacaagcat ttggttttaa attatggagt atgtgtctgt 2281 ggagacgaga atattctggt tcaggagttt gtaaaatttg gatcactaga tacatatctg

2341 aaaaagaata aaaattgtat aaatatatta tggaaacttg aagttgctaa acagttggca 2401 tgggccatgc attttctaga agaaaacacc cttattcatg ggaatgtatg tgccaaaaat 2461 attctgctta tcagagaaga agacaggaag acaggaaatc ctcctttcat caaacttagt 2521 gatcctggca ttagtattac agttttgcca aaggacattc ttcaggagag aataccatgg 2581 gtaccacctg aatgcattga aaatcctaaa aatttaaatt tggcaacaga caaatggagt

2641 tttggtacca ctttgtggga aatctgcagt ggaggagata aacctctaag tgctctggat 2701 tctcaaagaa agctacaatt ttatgaagat aggcatcagc ttcctgcacc aaagtgggca 2761 gaattagcaa accttataaa taattgtatg gattatgaac cagatttcag gccttctttc 2821 agagccatca tacgagatct taacagtttg tttactccag attatgaact attaacagaa 2881 aatgacatgt taccaaatat gaggataggt gccctggggt tttctggtgc ctttgaagac 2941 cgggatccta cacagtttga agagagacat ttgaaatttc tacagcaact tggcaagggt 3001 aattttggga gtgtggagat gtgccggtat gaccctctac aggacaacac tggggaggtg 3061 gtcgctgtaa aaaagcttca gcatagtact gaagagcacc taagagactt tgaaagggaa 3121 attgaaatcc tgaaatccct acagcatgac aacattgtaa agtacaaggg agtgtgctac

3181 agtgctggtc ggcgtaatct aaaattaatt atggaatatt taccatatgg aagtttacga 3241 gactatcttc aaaaacataa agaacggata gatcacataa aacttctgca gtacacatct 3301 cagatatgca agggtatgga gtatcttggt acaaaaaggt atatccacag ggatctggca 3361 acgagaaata tattggtgga gaacgagaac agagttaaaa ttggagattt tgggttaacc 3421 aaagtcttgc cacaagacaa agaatactat aaagtaaaag aacctggtga aagtcccata

3481 ttctggtatg ctccagaatc actgacagag agcaagtttt ctgtggcctc agatgtttgg 3541 agctttggag tggttctgta tgaacttttc acatacattg agaagagtaa aagtccacca 3601 gcggaattta tgcgtatgat tggcaatgac aaacaaggac agatgatcgt gttccatttg 3661 atagaacttt tgaagaataa tggaagatta ccaagaccag atggatgccc agatgagatc 3721 tatatgatca tgacagaatg ctggaacaat aatgtaaatc aacgcccctc ctttagggat

3781 ctagctcttc gagtggatca aataagggat aacatggctg gatgaaagaa atgaccttca 3841 ttctgagacc aaagtagatt tacagaacaa agttttatat ttcacattgc tgtggactat 3901 tattacatat atcattatta tataaatcat gatgctagcc agcaaagatg tgaaaatatc 3961 tgctcaaaac tttcaaagtt tagtaagttt ttcttcatga ggccaccagt aaaagacatt 4021 aatgagaatt ccttagcaag gattttgtaa gaagtttctt aaacattgtc agttaacatc

4081 actcttgtct ggcaaaagaa aaaaaataga ctttttcaac tcagcttttt gagacctgaa 4141 aaaattatta tgtaaatttt gcaatgttaa agatgcacag aatatgtatg tatagttttt 4201 accacagtgg atgtataata ccttggcatc ttgtgtgatg ttttacacac atgagggctg 4261 gtgttcatta atactgtttt ctaatttttc catagttaat ctataattaa ttacttcact 4321 atacaaacaa attaagatgt tcagataatt gaataagtac ctttgtgtcc ttgttcattt

4381 atatcgctgg ccagcattat aagcaggtgt atacttttag cttgtagttc catgtactgt 4441 aaatattttt cacataaagg gaacaaatgt ctagttttat ttgtatagga aatttccctg 4501 accctaaata atacattttg aaatgaaaca agcttacaaa gatataatct attttattat 4561 ggtttccctt gtatctattt gtggtgaatg tgttttttaa atggaactat ctccaaattt 4621 ttctaagact actatgaaca gttttctttt aaaattttga gattaagaat gccaggaata

4681 ttgtcatcct ttgagctgct gactgccaat aacattcttc gatctctggg atttatgctc 4741 atgaactaaa tttaagctta agccataaaa tagattagat tgttttttaa aaatggatag 4801 ctcattaaga agtgcagcag gttaagaatt ttttcctaaa gactgtatat ttgaggggtt 4861 tcagaatttt gcattgcagt catagaagag atttatttcc tttttagagg ggaaatgagg 4921 taaataagta aaaaagtatg cttgttaatt ttattcaaga atgccagtag aaaattcata

4981 acgtgtatct ttaagaaaaa tgagcataca tcttaaatct tttcaattaa gtataagggg 5041 ttgttcgttg ttgtcatttg ttatagtgct actccacttt agacaccata gctaaaataa 5101 aatatggtgg gttttgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgttattt 5161 atacaaaact taaaatactt gctgttttga ttaaaaagaa aatagtttct tacttta

Human JAK3 mRNA (SEQ ID NO: 13)

1 cacacaggaa ggagccgagt gggactttcc tctcgctgcc tcccggctct gcccgccctt 61 cgaaagtcca gggtccctgc ccgctaggca agttgcactc atggcacctc caagtgaaga 121 gacgcccctg atccctcagc gttcatgcag cctcttgtcc acggaggctg gtgccctgca 181 tgtgctgctg cccgctcggg gccccgggcc cccccagcgc ctatctttct cctttgggga 241 ccacttggct gaggacctgt gcgtgcaggc tgccaaggcc agcggcatcc tgcctgtgta 301 ccactccctc tttgctctgg ccacggagga cctgtcctgc tggttccccc cgagccacat 361 cttctccgtg gaggatgcca gcacccaagt cctgctgtac aggattcgct tttacttccc 421 caattggttt gggctggaga agtgccaccg cttcgggcta cgcaaggatt tggccagtgc

481 tatccttgac ctgccagtcc tggagcacct ctttgcccag caccgcagtg acctggtgag 541 tgggcgcctc cccgtgggcc tcagtctcaa ggagcagggt gagtgtctca gcctggccgt 601 gttggacctg gcccggatgg cgcgagagca ggcccagcgg ccgggagagc tgctgaagac 661 tgtcagctac aaggcctgcc tacccccaag cctgcgcgac ctgatccagg gcctgagctt 721 cgtgacgcgg aggcgtattc ggaggacggt gcgcagagcc ctgcgccgcg tggccgcctg

781 ccaggcagac cggcactcgc tcatggccaa gtacatcatg gacctggagc ggctggatcc 841 agccggggcc gccgagacct tccacgtggg cctccctggg gcccttggtg gccacgacgg 901 gctggggctg ctccgcgtgg ctggtgacgg cggcatcgcc tggacccagg gagaacagga 961 ggtcctccag cccttctgcg actttccaga aatcgtagac attagcatca agcaggcccc 1021 gcgcgttggc ccggccggag agcaccgcct ggtcactgtt accaggacag acaaccagat

1081 tttagaggcc gagttcccag ggctgcccga ggctctgtcg ttcgtggcgc tcgtggacgg 1141 ctacttccgg ctgaccacgg actcccagca cttcttctgc aaggaggtgg caccgccgag 1201 gctgctggag gaagtggccg agcagtgcca cggccccatc actctggact ttgccatcaa 1261 caagctcaag actgggggct cacgtcctgg ctcctatgtt ctccgccgca gcccccagga 1321 ctttgacagc ttcctcctca ctgtctgtgt ccagaacccc cttggtcctg attataaggg

1381 ctgcctcatc cggcgcagcc ccacaggaac cttccttctg gttggcctca gccgacccca 1441 cagcagtctt cgagagctcc tggcaacctg ctgggatggg gggctgcacg tagatggggt 1501 ggcagtgacc ctcacttcct gctgtatccc cagacccaaa gaaaagtcca acctgatcgt 1561 ggtccagaga ggtcacagcc cacccacatc atccttggtt cagccccaat cccaatacca 1621 gctgagtcag atgacatttc acaagatccc tgctgacagc ctggagtggc atgagaacct

1681 gggccatggg tccttcacca agatttaccg gggctgtcgc catgaggtgg tggatgggga 1741 ggcccgaaag acagaggtgc tgctgaaggt catggatgcc aagcacaaga actgcatgga 1801 gtcattcctg gaagcagcga gcttgatgag ccaagtgtcg taccggcatc tcgtgctgct 1861 ccacggcgtg tgcatggctg gagacagcac catggtgcag gaatttgtac acctgggggc 1921 catagacatg tatctgcgaa aacgtggcca cctggtgcca gccagctgga agctgcaggt

1981 ggtcaaacag ctggcctacg ccctcaacta tctggaggac aaaggcctgc cccatggcaa 2041 tgtctctgcc cggaaggtgc tcctggctcg ggagggggct gatgggagcc cgcccttcat 2101 caagctgagt gaccctgggg tcagccccgc tgtgttaagc ctggagatgc tcaccgacag 2161 gatcccctgg gtggcccccg agtgtctccg ggaggcgcag acacttagct tggaagctga 2221 caagtggggc ttcggcgcca cggtctggga agtgtttagt ggcgtcacca tgcccatcag

2281 tgccctggat cctgctaaga aactccaatt ttatgaggac cggcagcagc tgccggcccc 2341 caagtggaca gagctggccc tgctgattca acagtgcatg gcctatgagc cggtccagag 2401 gccctccttc cgagccgtca ttcgtgacct caatagcctc atctcttcag actatgagct 2461 cctctcagac cccacacctg gtgccctggc acctcgtgat gggctgtgga atggtgccca 2521 gctctatgcc tgccaagacc ccacgatctt cgaggagaga cacctcaagt acatctcaca

2581 gctgggcaag ggcaactttg gcagcgtgga gctgtgccgc tatgacccgc taggcgacaa 2641 tacaggtgcc ctggtggccg tgaaacagct gcagcacagc gggccagacc agcagaggga 2701 ctttcagcgg gagattcaga tcctcaaagc actgcacagt gatttcattg tcaagtatcg 2761 tggtgtcagc tatggcccgg gccgccagag cctgcggctg gtcatggagt acctgcccag 2821 cggctgcttg cgcgacttcc tgcagcggca ccgcgcgcgc ctcgatgcca gccgcctcct 2881 tctctattcc tcgcagatct gcaagggcat ggagtacctg ggctcccgcc gctgcgtgca 2941 ccgcgacctg gccgcccgaa acatcctcgt ggagagcgag gcacacgtca agatcgctga 3001 cttcggccta gctaagctgc tgccgcttga caaagactac tacgtggtcc gcgagccagg 3061 ccagagcccc attttctggt atgcccccga atccctctcg gacaacatct tctctcgcca 3121 gtcagacgtc tggagcttcg gggtcgtcct gtacgagctc ttcacctact gcgacaaaag 3181 ctgcagcccc tcggccgagt tcctgcggat gatgggatgt gagcgggatg tccccgccct 3241 ctgccgcctc ttggaactgc tggaggaggg ccagaggctg ccggcgcctc ctgcctgccc 3301 tgctgaggtt cacgagctca tgaagctgtg ctgggcccct agcccacagg accggccatc 3361 attcagcgcc ctgggccccc agctggacat gctgtggagc ggaagccggg ggtgtgagac 3421 tcatgccttc actgctcacc cagagggcaa acaccactcc ctgtcctttt catagctcct 3481 gcccgcagac ctctggatta ggtctctgtt gactggctgt gtgaccttag gcccggagct 3541 gcccctctct gggcctcaga ggccttatga gggtcctcta cttcaggaac acccccatga 3601 cattgcattt gggggggctc ccgtggcctg tagaatagcc tgtggccttt gcaatttgtt 3661 aaggttcaag acagatgggc atatgtgtca gtggggctct ctgagtcctg gcccaaagaa 3721 gcaaggaacc aaatttaaga ctctcgcatc ttcccaaccc cttaagccct ggccccctga 3781 gtttcctttt ctgtctctct ctttttattt tttttatttt tatttttatt tttgagacag

3841 agcctcgctc tgttacccag ggtggagtgc agtggtgcga tctcggctca gtgcaacctc 3901 tgcttcccag gttcaagcga ttctcctgcc tcagcctccc gagtagctgg gattacaggt 3961 gtgcaccacc acacccggct aatttttttt atttttaata gagatgaggt ttcaccatga 4021 tggccaggct gatctcgaac tcctaacctc aagtgatcct cccacctcag cctcccaaag 4081 tgttggaata ataggcatga gccactgcac ccaggctttt ttttttttaa atttattatt 4141 attattttta agagacagga tcttgctacg ttgcccaggc tggtcttgaa ctcctgggct 4201 acagtgatcc tcctgcctta tcctcctaaa tagctgggac tacagcacct agttttgagt 4261 ttcctgtctt atttccaatg gggacattca tgtagctttt tttttttttt tttttttgag

4321 acggagtctc gctctgtcgc ccaggctgga gtacagtggc gcaatctagg ctcactgcaa 4381 gctccgcctc ctgggttcac accattctct cgcctcagcc tcccaagtag ctgggactac 4441 aggcgcccgc caccacaccc ggctaatttt ttgtattttt agtagagacg gggtttcacc 4501 ttgttagcca ggatggtttc catctcctga cctcgtgatc tgcccgtctc ggcctcccaa 4561 agtgctggga ttacaggcat gagccactgc gcccggccct catgtagctt taaatgtatg 4621 atctgacttc tgctccccga tctctgtttc tctggaggaa gccaaggaca agagcagttg 4681 ctgtggctgg gactctgcct tttaggggag cccgtgtatc tctttgggat cctgaaaggg 4741 ggcaggaaag gctggggtcc cagtccaccc taatggtatc tgagtgtcct agggcttcag 4801 ttttcccacc tgtccaatgg gaccctttct gtcctcaccc tacaaggggc acaaagggat 4861 gacaccaaac ctggcaggaa cttttcacgc aatcaaggga aggaaaggca ttcctggcag 4921 agggaacagc atgccaagcg tgagaaggct cagagtaagg aggttaagag cccaagtatt 4981 ggagcctaca gttttgcccc ttccatgcag tgtgacagtg ggcaagttcc tttccctctc 5041 tgggtctcag ttctgtcccc tgcaaaatgg tcagagctta ccccttggct gtgcagggtc 5101 aactttctga ctggtgagag ggattctcat gcaggttaag cttctgctgc tcctcctcac 5161 ctgcaaagct tttctgccac ttttgcctcc ttggaaaact cttatccatc tctcaaaact 5221 ccagctacca catccttgca gccttccctc atataccccc actactactg tagccctgtc 5281 cttccctcca gccccactct ggccctgggg ctggggaagt gtctgtgtcc agctgtctcc 5341 cctgacctca gggttccttg ggggctgggc tgaggcctca gtacagaggg ggctctggaa 5401 atgtttgttg actgaataaa ggaattcagt ggaaaaaaaa aaaaaaaaa Human JAK3 mRNA (SEQ ID NO: 14)

1 ccctctgacc aggactgagg ggctttttct ctctgtgccc caggcaagtt gcactcatta 61 tggaattccg gcggcccgct aggcaagttg cactcatggc acctccaagt gaagagacgc 121 ccctgatccc tcagcgttca tgcagcctct tgtccacgga ggctggtgcc ctgcatgtgc

181 tgctgcccgc tcgggccccg gggccccccc agcgcctatc tttctccttt ggggaccact 241 tggctgagga cctgtgcgtg caggctgcca aggccagcgg catcctgcct gtgtaccact 301 ccctctttgc tctggccacg gaggacctgt cctgctggtt ccccccgagc cacatcttct 361 ccgtggagga tgccagcacc caagtcctgc tgtacaggat tcgcttttac ttccccaatt 421 ggtttgggct ggagaagtgc caccgcttcg ggctacgcaa ggatttggcc agtgctatcc

481 ttgacctgcc agtcctggag cacctctttg cccagcaccg cagtgacctg gtgagtgggc 541 gcctccccgt gggcctcagt ctcaaggagc agggtgagtg tctcagcctg gccgtgttgg 601 acctggcccg gatggcgcga gagcaggccc agcggccggg agagctgctg aagactgtca 661 gctacaaggc ctgcctaccc ccaagcctgc gcgacctgat ccagggcctg agcttcgtga 721 cgcggagggc tattcggagg acggtgcgca gagccctgcc gcgcgtggcc gcctgccagg

781 cagaccggca ctcgctcatg gccaagtaca tcatggacct ggagcggctg gatccagccg 841 gggccgccga gaccttccac gtgggcctcc ctggggccct tggtggccac gacgggctgg 901 ggctgctccg cgtggctggt gacggcggca tcgcctggac ccagggagaa caggaggtcc 961 tccagccctt ctgcgacttt ccagaaatcg tagacattag catcaagcag gccccgcgcg 1021 ttggcccggc cggagagcac cgcctggtca ctgttaccag gacagacaac cagattttag

1081 aggccgagtt cccagggctg cccgaggctc tgtcgttcgt ggcgctcgtg gacggctact 1141 tccggctgac cacggactcc cagcacttct tctgcaagga ggtggcaccg ccgaggctgc 1201 tggaggaagt ggccgagcag tgccacggcc ccatcactct ggactttgcc atcaacaagc 1261 tcaagactgg gggctcacgt cctggctcct atgttctccg ccgcagcccc caggactttg 1321 acagcttcct cctcactgtc tgtgtccaga acccccttgg tcctgattat aagggctgcc

1381 tcatccggcg cagccccaca ggaaccttcc ttctggttgg cctcagccga ccccacagca 1441 gtcttcgaga gctcctggca acctgctggg atggggggct gcacgtagat ggggtggcag 1501 tgaccctcac ttcctgctgt atccccagac ccaaagaaaa gtccaacctg atcgtggtcc 1561 agagaggtca cagcccaccc acatcatcct tggttcagcc ccaatcccaa taccagctga 1621 gtcagatgac atttcacaag atccctgctg acagcctgga gtggcatgag aacctgggcc

1681 atgggtcctt caccaagatt taccggggct gtcgccatga ggtggtggat ggggaggccc 1741 gaaagacaga ggtgctgctg aaggtcatgg atgccaagca caagaactgc atggagtcat 1801 tcctggaagc agcgagcttg atgagccaag tgtcgtaccg gcatctcgtg ctgctccacg 1861 gcgtgtgcat ggctggagac agcaccatgg tgcaggaatt tgtacacctg ggggccatag 1921 acatgtatct gcgaaaacgt ggccacctgg tgccagccag ctggaagctg caggtggtca

1981 aacagctggc ctacgccctc aactatctgg aggacaaagg cctgccccat ggcaatgtct 2041 ctgcccggaa ggtgctcctg gctcgggagg gggctgatgg gagcccgccc ttcatcaagc 2101 tgagtgaccc tggggtcagc cccgctgtgt taagcctgga gatgctcacc gacaggatcc 2161 cctgggtggc ccccgagtgt ctccgggagg cgcagacact tagcttggaa gctgacaagt 2221 ggggcttcgg cgccacggtc tgggaagtgt ttagtggcgt caccatgccc atcagtgccc

2281 tggatcctgc taagaaactc caattttatg aggaccggca gcagctgccg gcccccaagt 2341 ggacagagct ggccctgctg attcaacagt gcatggccta tgagccggtc cagaggccct 2401 ccttccgagc cgtcattcgt gacctcaata gcctcatctc ttcagactat gagctcctct 2461 cagaccccac acctggtgcc ctggcacctc gtgatgggct gtggaatggt gcccagctct 2521 atgcctgcca agaccccacg atcttcgagg agagacacct caagtacatc tcacagctgg 2581 gcaagggcaa ctttggcagc gtggagctgt gccgctatga cccgctagcc cacaatacag 2641 gtgccctggt ggccgtgaaa cagctgcagc acagcgggcc agaccagcag agggactttc 2701 agcgggagat tcagatcctc aaagcactgc acagtgattt cattgtcaag tatcgtggtg 2761 tcagctatgg cccgggccgg ccagagctgc ggctggtcat ggagtacctg cccagcggct 2821 gcttgcgcga cttcctgcag cggcaccgcg cgcgcctcga tgccagccgc ctccttctct 2881 attcctcgca gatctgcaag ggcatggagt acctgggctc ccgccgctgc gtgcaccgcg 2941 acctggccgc ccgaaacatc ctcgtggaga gcgaggcaca cgtcaagatc gctgacttcg 3001 gcctagctaa gctgctgccg cttgacaaag actactacgt ggtccgcgag ccaggccaga 3061 gccccatttt ctggtatgcc cccgaatccc tctcggacaa catcttctct cgccagtcag 3121 acgtctggag cttcggggtc gtcctgtacg agctcttcac ctactgcgac aaaagctgca 3181 gcccctcggc cgagttcctg cggatgatgg gatgtgagcg ggatgtcccc gccctctgcc 3241 gcctcttgga actgctggag gagggccaga ggctgccggc gcctcctgcc tgccctgctg 3301 aggttcacga gctcatgaag ctgtgctggg cccctagccc acaggaccgg ccatcattca 3361 gcgccctggg cccccagctg gacatgctgt ggagcggaag ccgggggtgt gagactcatg 3421 ccttcactgc tcacccagag ggcaaacacc actccctgtc cttttcatag ctcctgcccg 3481 cagacctctg gattaggtct ctgttgactg gctgtgtgac cttaggcccg gagctgcccc 3541 tctctgggcc tcagaggcct tatgagggtc ctctacttca ggaacacccc catgacattg 3601 catttggggg ggctcccgtg gcctgtagaa tagcctgtgg cctttgcaat ttgttaaggt 3661 tcaagacaga tgggcatatg tgtcagtggg gctctctgag tcctggccca aagaagcaag 3721 gaaccaaatt taagactctc gcatcttccc aaccccttaa gccctggccc cctgagtttc 3781 cttttctcgt ctctctcttt ttattttttt tatttttatt tttatttttg agacagagcc

3841 tcgctcgtta cccagggtgg agtgcagtgg tagcgatctc ggctcacagt gcaacctctg 3901 cttcccaggt tcaagcgatt ctcctgcctc agcctcccga gtagctggga ttacaggtgt 3961 gcaccaccac acccggctaa ttttttttat ttttaataga gatgaggttt caccatgatg 4021 gccaggctga tctcgaactc ctaacctcaa gtgatcctcc cacc

Human TYK2 mRNA (SEQ ID NO: 15)

1 aagcagtagc tacccgcggg agcggggagg ggtccgggtt cgagcttgtg ttcccccgga

61 agggtgagtc tggacgcggg cgcggaagga gcgcggccgg aggtcctcag gaagaagccg 121 cggggactgg ctgcgcttga caggctgcac ttggatggga gcacctggtg cctcgggact 181 gctccgatgc ccgggtctgt gctgaatgtg taatatgcgg aactatattg aaacattaca 241 accatctttt gatggcaaca ccctgaggac ctcccttttc cagatgggga aactgaggcc 301 cagaattgct aagtggcttg cttgagttga cacagggagc tccaggactc accctcagct

361 gagccacctg ccgggagcat gcctctgcgc cactggggga tggccagggg cagtaagccc 421 gttggggatg gagcccagcc catggctgcc atgggaggcc tgaaggtgct tctgcactgg 481 gctggtccag gcggcgggga gccctgggtc actttcagtg agtcatcgct gacagctgag 541 gaagtctgca tccacattgc acataaagtt ggtatcactc ctccttgctt caatctcttt 601 gccctcttcg atgctcaggc ccaagtctgg ttgcccccaa accacatcct agagatcccc

661 agagatgcaa gcctgatgct atatttccgc ataaggtttt atttccggaa ctggcatggc 721 atgaatcctc gggaaccggc tgtgtaccgt tgtgggcccc caggaaccga ggcatcctca 781 gatcagacag cacaggggat gcaactcctg gacccagcct catttgagta cctctttgag 841 cagggcaagc atgagtttgt gaatgacgtg gcatcactgt gggagctgtc gaccgaggag 901 gagatccacc actttaagaa tgagagcctg ggcatggcct ttctgcacct ctgtcacctc 961 gctctccgcc atggcatccc cctggaggag gtggccaaga agaccagctt caaggactgc 1021 atcccgcgct ccttccgccg gcatatccgg cagcacagcg ccctgacccg gctgcgcctt 1081 cggaacgtct tccgcaggtt cctgcgggac ttccagccgg gccgactctc ccagcagatg

1141 gtcatggtca aatacctagc cacactcgag cggctggcac cccgcttcgg cacagagcgt 1201 gtgcccgtgt gccacctgag gctgctggcc caggccgagg gggagccctg ctacatccgg 1261 gacagtgggg tggcccctac agaccctggc cctgagtctg ctgctgggcc cccaacccac 1321 gaggtgctgg tgacaggcac tggtggcatc cagtggtggc cagtagagga ggaggtgaac 1381 aaggaggagg gttctagtgg cagcagtggc aggaaccccc aagccagcct gtttgggaag

1441 aaggccaagg ctcacaaggc agtcggccag ccggcagaca ggccgcggga gccactgtgg 1501 gcctacttct gtgacttccg ggacatcacc cacgtggtgc tgaaagagca ctgtgtcagc 1561 atccaccggc aggacaacaa gtgcctggag ctgagcttgc cttcccgggc tgcggcgctg 1621 tccttcgtgt cgctggtgga cggctatttc cgcctgacgg ccgactccag ccactacctg 1681 tgccacgagg tggctccccc acggctggtg atgagcatcc gggatgggat ccacggaccc

1741 ctgctggagc catttgtgca ggccaagctg cggcccgagg acggcctgta cctcattcac 1801 tggagcacca gccaccccta ccgcctgatc ctcacagtgg cccagcgtag ccaggcacca 1861 gacggcatgc agagcttgcg gctccgaaag ttccccattg agcagcagga cggggccttc 1921 gtgctggagg gctggggccg gtccttcccc agcgttcggg aacttggggc tgccttgcag 1981 ggctgcttgc tgagggccgg ggatgactgc ttctctctgc gtcgctgttg cctgccccaa

2041 ccaggagaaa cctccaatct catcatcatg cggggggctc gggccagccc caggacactc 2101 aacctcagcc agctcagctt ccaccgggtt gaccagaagg agatcaccca gctgtcccac 2161 ttgggccagg gcacaaggac caacgtgtat gagggccgcc tgcgagtgga gggcagcggg 2221 gaccctgagg agggcaagat ggatgacgag gaccccctcg tgcctggcag ggaccgtggg 2281 caggagctac gagtggtgct caaagtgctg gaccctagtc accatgacat cgccctggcc

2341 ttctacgaga cagccagcct catgagccag gtctcccaca cgcacctggc cttcgtgcat 2401 ggcgtctgtg tgcgcggccc tgaaaatatc atggtgacag agtacgtgga gcacggaccc 2461 ctggatgtgt ggctgcggag ggagcggggc catgtgccca tggcttggaa gatggtggtg 2521 gcccagcagc tggccagcgc cctcagctac ctggagaaca agaacctggt tcatggtaat 2581 gtgtgtggcc ggaacatcct gctggcccgg ctggggttgg cagagggcac cagccccttc

2641 atcaagctga gtgatcctgg cgtgggcctg ggcgccctct ccagggagga gcgggtggag 2701 aggatcccct ggctggcccc cgaatgccta ccaggtgggg ccaacagcct aagcaccgcc 2761 atggacaagt gggggtttgg cgccaccctc ctggagatct gctttgacgg agaggcccct 2821 ctgcagagcc gcagtccctc cgagaaggag catttctacc agaggcagca ccggctgccc 2881 gagccctcct gcccacagct ggccacactc accagccagt gtctgaccta tgagccaacc

2941 cagaggccat cattccgcac catcctgcgt gacctcaccc ggctgcagcc ccacaatctt 3001 gctgacgtct tgactgtgaa cccggactca ccggcgtcgg accctacggt tttccacaag 3061 cgctatttga aaaagatccg agatctgggc gagggtcact tcggcaaggt cagcttgtac 3121 tgctacgatc cgaccaacga cggcactggc gagatggtgg cggtgaaagc cctcaaggca 3181 gactgcggcc cccagcaccg ctcgggctgg aagcaggaga ttgacattct gcgcacgctc

3241 taccacgagc acatcatcaa gtacaagggc tgctgcgagg accaaggcga gaagtcgctg 3301 cagctggtca tggagtacgt gcccctgggc agcctccgag actacctgcc ccggcacagc 3361 atcgggctgg cccagctgct gctcttcgcc cagcagatct gcgagggcat ggcctatctg 3421 cacgcgcagc actacatcca ccgagaccta gccgcgcgca acgtgctgct ggacaacgac 3481 aggctggtca agatcgggga ctttggccta gccaaggccg tgcccgaagg ccacgagtac 3541 taccgcgtgc gcgaggatgg ggacagcccc gtgttctggt atgccccaga gtgcctgaag

3601 gagtataagt tctactatgc gtcagatgtc tggtccttcg gggtgaccct gtatgagctg

3661 ctgacgcact gtgactccag ccagagcccc cccacgaaat tccttgagct cataggcatt

3721 gctcagggtc agatgacagt tctgagactc actgagttgc tggaacgagg ggagaggctg

3781 ccacggcccg acaaatgtcc ctgtgaggtc tatcatctca tgaagaactg ctgggagaca

3841 gaggcgtcct ttcgcccaac cttcgagaac ctcataccca ttctgaagac agtccatgag

3901 aagtaccaag gccaggcccc ttcagtgttc agcgtgtgct gaggcacaat ggcagccctg

3961 cctgggagga ctggaccagg cagtggctgc agagggagcc tcctgctccc tgctccagga

4021 tgaaaccaag agggggatgt cagcctcacc cacaccgtgt gccttactcc tgtctagaga

4081 ccccacctct gtgaacttat ttttctttct tggccgtgag cctaaccatg atcttgaggg

4141 acccaacatt tgtaggggca ctaatccagc ccttaaatcc cccagcttcc aaacttgagg

4201 cccaccatct ccaccatctg gtaataaact catgttttct ctgctggaaa aaaaaaaaaa

4261 aa

Inhibitory Nucleic Acids

An antisense nucleic acid molecule can be complementary to all or part of a non- coding region of the coding strand of a nucleotide sequence encoding a JAK1, JAK2, JAK3, or TYK2 protein. Non-coding regions (5' and 3' untranslated regions) are the 5' and 3' sequences that flank the coding region in a gene and are not translated into amino acids.

Based upon the sequences disclosed herein, one of skill in the art can easily choose and synthesize any of a number of appropriate antisense nucleic acids to target a nucleic acid encoding a JAK1, JAK2, JAK3, or TYK2 protein described herein. Antisense nucleic acids targeting a nucleic acid encoding a JAK1 , JAK2, JAK3, or TYK2 protein can be designed using the software available at the Integrated DNA Technologies website.

An antisense nucleic acid can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides or more in length. An antisense oligonucleotide can be constructed using chemical synthesis and enzymatic ligation reactions using procedures known in the art. For example, an antisense nucleic acid can be chemically synthesized using naturally occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used.

Examples of modified nucleotides which can be used to generate an antisense nucleic acid include 5-fiuorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl- 2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1 -methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2- methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7- methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D- mannosylqueosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6- isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2- thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5- oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3- N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest).

The antisense nucleic acid molecules described herein can be prepared in vitro and administered to a mammal, e.g., a human. Alternatively, they can be generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding a JAK1, JAK2, JAK3, or TYK2 protein to thereby inhibit expression, e.g., by inhibiting transcription and/or translation. The hybridization can be by conventional nucleotide complementarities to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes, through specific interactions in the major groove of the double helix. The antisense nucleic acid molecules can be delivered to a mammalian cell using a vector (e.g., a lentivirus, a retrovirus, or an adenovirus vector).

An antisense nucleic acid can be an a-anomeric nucleic acid molecule. An a- anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual, β-units, the strands run parallel to each other (Gaultier et al, Nucleic Acids Res. 15:6625-6641, 1987). The antisense nucleic acid can also comprise a 2'-0-methylribonucleotide (Inoue et al, Nucleic Acids Res. 15:6131-6148, 1987) or a chimeric RNA-DNA analog (Inoue et al, FEBS Lett. 215:327-330, 1987).

Another example of an inhibitory nucleic acid is a ribozyme that has specificity for a nucleic acid encoding a JAK1, JAK2, JAK3, or TYK2 protein (e.g., specificity for a JAK1, JAK2, JAK3, or TYK2 mRNA, e.g., specificity for any one of SEQ ID NOs: 1-15).

Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a

complementary region. Thus, ribozymes (e.g., hammerhead ribozymes (described in Haselhoff and Gerlach, Nature 334:585-591, 1988)) can be used to catalytically cleave mRNA transcripts to thereby inhibit translation of the protein encoded by the mRNA. A ribozyme having specificity for a JAK1, JAK2, JAK3, or TYK2 mRNA can be designed based upon the nucleotide sequence of any of the JAK1, JAK2, JAK3, or TYK2 mRNA sequences disclosed herein. For example, a derivative of a Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in a JAK1, JAK2, JAK3, or TYK2 mRNA (see, e.g., U.S. Patent. Nos. 4,987,071 and 5,116,742). Alternatively, a JAK1, JAK2, JAK3, or TYK2 mRNA can be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules. See, e.g., Bartel et al, Science 261 : 1411-1418, 1993.

An inhibitory nucleic acid can also be a nucleic acid molecule that forms triple helical structures. For example, expression of a JAK1, JAK2, JAK3, or JAK4 polypeptide can be inhibited by targeting nucleotide sequences complementary to the regulatory region of the gene encoding the JAK1, JAK2, JAK3, or TYK2 polypeptide (e.g., the promoter and/or enhancer, e.g., a sequence that is at least 1 kb, 2 kb, 3 kb, 4 kb, or 5 kb upstream of the transcription initiation start state) to form triple helical structures that prevent transcription of the gene in target cells. See generally Helene, Anticancer Drug Des. 6(6):569-84, 1991 ; Helens, Ann. N. Y. Acad. Sci. 660:27-36, 1992; and Maher, Bioassays 14(12):807-15, 1992.

In various embodiments, inhibitory nucleic acids can be modified at the base moiety, sugar moiety, or phosphate backbone to improve, e.g., the stability, hybridization, or solubility of the molecule. For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids (see, e.g., Hyrup et al, Bioorganic Medicinal Chem. 4(l):5-23, 1996). Peptide nucleic acids (PNAs) are nucleic acid mimics, e.g., DNA mimics, in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of PNAs allows for specific hybridization to DNA and RNA under conditions of low ionic strength. The synthesis of PNA oligomers can be performed using standard solid phase peptide synthesis protocols (see, e.g., Perry-O'Keefe et al, Proc. Natl. Acad. Sci.

U.S.A. 93: 14670-675, 1996). PNAs can be used as antisense or antigene agents for sequence- specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication.

PNAs can be modified, e.g., to enhance their stability or cellular uptake, by attaching lipophilic or other helper groups to PNA, by the formation of PNA-DNA chimeras, or by the use of liposomes or other techniques of drug delivery known in the art. For example, PNA- DNA chimeras can be generated which may combine the advantageous properties of PNA and DNA. Such chimeras allow DNA recognition enzymes, e.g., RNAse H and DNA polymerases, to interact with the DNA portion while the PNA portion would provide high binding affinity and specificity. PNA-DNA chimeras can be linked using linkers of appropriate lengths selected in terms of base stacking, number of bonds between the nucleobases, and orientation.

The synthesis of PNA-DNA chimeras can be performed as described in Finn et al, Nucleic Acids Res. 24:3357-63, 1996. For example, a DNA chain can be synthesized on a solid support using standard phosphoramidite coupling chemistry and modified nucleoside analogs. Compounds such as 5'-(4-methoxytrityl)amino-5'-deoxy -thymidine phosphoramidite can be used as a link between the PNA and the 5' end of DNA (Mag et al., Nucleic Acids Res. 17:5973-88, 1989). PNA monomers are then coupled in a stepwise manner to produce a chimeric molecule with a 5' PNA segment and a 3' DNA segment (Finn et al, Nucleic Acids Res. 24:3357-63, 1996). Alternatively, chimeric molecules can be synthesized with a 5' DNA segment and a 3' PNA segment (Peterser et al, Bioorganic Med. Chem. Lett. 5 : 11 19-1 1 124, 1975).

In some embodiments, the inhibitory nucleic acids can include other appended groups such as peptides, or agents facilitating transport across the cell membrane (see, Letsinger et al, Proc. Natl. Acad. Sci. U.S.A. 86:6553-6556, 1989; Lemaitre et al., Proc. Natl. Acad. Sci. U.S.A. 84:648-652, 1989; and WO 88/09810). In addition, the inhibitory nucleic acids can be modified with hybridization-triggered cleavage agents (see, e.g., Krol et al, Bio/Techniques 6:958-976, 1988) or intercalating agents (see, e.g., Zon, Pharm. Res., 5 :539-549, 1988). To this end, the oligonucleotide may be conjugated to another molecule, e.g., a peptide, hybridization triggered cross-linking agent, transport agent, hybridization-triggered cleavage agent, etc.

Another means by which expression of a JAKl, JAK2, JAK3, or TYK2 mRNA can be decreased in a mammalian cell is by RNA interference (RNAi). RNAi is a process in which mRNA is degraded in host cells. To inhibit an mRNA, double-stranded RNA

(dsRNA) corresponding to a portion of the gene to be silenced (e.g., a gene encoding a JAKl , JAK2, JAK3, or TYK2 polypeptide) is introduced into a mammalian cell. The dsRNA is digested into 21 -23 nucleotide-long duplexes called short interfering RNAs (or siRNAs), which bind to a nuclease complex to form what is known as the RNA-induced silencing complex (or RISC). The RISC targets the homologous transcript by base pairing interactions between one of the siRNA strands and the endogenous mRNA. It then cleaves the mRNA about 12 nucleotides from the 3' terminus of the siRNA (see Sharp et al, Genes Dev. 15 :485- 490, 2001, and Hammond et al, Nature Rev. Gen. 2: 110-119, 2001).

RNA-mediated gene silencing can be induced in a mammalian cell in many ways, e.g., by enforcing endogenous expression of RNA hairpins (see, Paddison et al, Proc. Natl. Acad. Sci. U.S.A. 99: 1443-1448, 2002) or, as noted above, by transfection of small (21-23 nt) dsRNA (reviewed in Caplen, Trends Biotech. 20:49-51, 2002). Methods for modulating gene expression with RNAi are described, e.g., in U. S. Patent No. 6,506,559 and US

2003/0056235, which are hereby incorporated by reference.

Standard molecular biology techniques can be used to generate siRNAs. Short interfering RNAs can be chemically synthesized, recombinantly produced, e.g., by expressing RNA from a template DNA, such as a plasmid, or obtained from commercial vendors, such as Dharmacon. The RNA used to mediate RNAi can include synthetic or modified nucleotides, such as phosphorothioate nucleotides. Methods of transfecting cells with siRNA or with plasmids engineered to make siRNA are routine in the art.

The siRNA molecules used to decrease expression of a JAK1 , JAK2, JAK3, or TYK2 mRNA can vary in a number of ways. For example, they can include a 3' hydroxyl group and strands of 21 , 22, or 23 consecutive nucleotides. They can be blunt ended or include an overhanging end at either the 3' end, the 5' end, or both ends. For example, at least one strand of the RNA molecule can have a 3' overhang from about 1 to about 6 nucleotides (e.g., 1-5, 1 - 3, 2-4, or 3-5 nucleotides (whether pyrimidine or purine nucleotides) in length. Where both strands include an overhang, the length of the overhangs may be the same or different for each strand.

To further enhance the stability of the RNA duplexes, the 3' overhangs can be stabilized against degradation (by, e.g., including purine nucleotides, such as adenosine or guanosine nucleotides or replacing pyrimidine nucleotides by modified analogues (e.g., substitution of uridine 2-nucleotide 3' overhangs by 2'-deoxythymidine is tolerated and does not affect the efficiency of RNAi). Any siRNA can be used in the methods of decreasing a JAK1 , JAK2, JAK3, or TYK2 mRNA, provided it has sufficient homology to the target of interest (e.g., a sequence present in any one of SEQ ID NOs: 1-15, e.g., a target sequence encompassing the translation start site or the first exon of the mRNA). There is no upper limit on the length of the siRNA that can be used (e.g., the siRNA can range from about 21 base pairs of the gene to the full length of the gene or more (e.g., about 20 to about 30 base pairs, about 50 to about 60 base pairs, about 60 to about 70 base pairs, about 70 to about 80 base pairs, about 80 to about 90 base pairs, or about 90 to about 100 base pairs).

Non-limiting examples of JAK inhibitors that are short interfering RNAs (siRNAs) are described in Cook et al, Blood 123:2826-2837, 2014. Non-limiting examples of JAK inhibitors that are short hairpin RNAs (shRNAs) are described in Koppikar et al., Nature 489(7414): 155-159, 2012).

In certain embodiments, a therapeutically effective amount of an inhibitory nucleic acid targeting a nucleic acid encoding a JAK1, JAK2, JAK3, or TYK2 protein can be administered to a subject (e.g., a human subject) in need thereof.

In some embodiments, the inhibitory nucleic acid can be about 10 nucleotides to about 40 nucleotides (e.g., about 10 to about 30 nucleotides, about 10 to about 25 nucleotides, about 10 to about 20 nucleotides, about 10 to about 15 nucleotides, 10 nucleotides, 11 nucleotides, 12 nucleotides, 13 nucleotides, 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, 25 nucleotides, 26 nucleotides, 27 nucleotides, 28 nucleotides, 29 nucleotides, 30 nucleotides, 31 nucleotides, 32 nucleotides, 33 nucleotides, 34 nucleotides, 35 nucleotides, 36 nucleotides, 37 nucleotides, 38 nucleotides, 39 nucleotides, or 40 nucleotides) in length. One skilled in the art will appreciate that inhibitory nucleic acids may comprise at least one modified nucleic acid at either the 5' or 3 'end of DNA or RNA.

As is known in the art, the term "thermal melting point (Tm)" refers to the temperature, under defined ionic strength, pH, and inhibitory nucleic acid concentration, at which 50% of the inhibitory nucleic acids complementary to the target sequence hybridize to the target sequence at equilibrium. In some embodiments, an inhibitory nucleic acid can bind specifically to a target nucleic acid under stingent conditions, e.g., those in which the salt concentration is at least about 0.01 to 1.0 M Na ion concentration (or other salts) at pH 7.0 to 8.3 and the temperature is at least about 30 °C. for short oligonucleotides (e.g., 10 to 50 nucleotide). Stringent conditions can also be achieved with the addition of destabilizing agents such as formamide.

In some embodiments of any of the inhibitory nucleic acids described herein, the inhibitory nucleic acid binds to a target nucleic acid (e.g., a nucleic acid encoding JAK1,

JAK2, JAK3, or TYK2) with a Tm of greater than 20 °C, greater than 22 °C, greater than 24 °C, greater than 26 °C, greater than 28 °C, greater than 30 °C, greater than 32 °C, greater than 34 °C, greater than 36 °C, greater than 38 °C, greater than 40 °C, greater than 42 °C, greater than 44 °C, greater than 46 °C, greater than 48 °C, greater than 50 °C, greater than 52 °C, greater than 54 °C, greater than 56 °C, greater than 58 °C, greater than 60 °C, greater than 62 °C, greater than 64 °C, greater than 66 °C, greater than 68 °C, greater than 70 °C, greater than 72 °C, greater than 74 °C, greater than 76 °C, greater than 78 °C, or greater than 80 °C, e.g., as measured in phosphate buffered saline using a UV spectrophotometer.

In some embodiments of any of the inhibitor nucleic acids described herein, the inhibitory nucleic acid binds to a target nucleic acid (e.g., a nucleic acid encoding a JAK1, JAK2, JAK3, or TYK2) with a T_m of about 20 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, about 46 °C, about 44 °C, about 42 °C, about 40 °C, about 38 °C, about 36 °C, about 34 °C, about 32 °C, about 30 °C, about 28 °C, about 26 °C, about 24 °C, or about 22 °C (inclusive); about 22 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, about 46 °C, about 44 °C, about 42 °C, about 40 °C, about 38 °C, about 36 °C, about 34 °C, about 32 °C, about 30 °C, about 28 °C, about 26 °C, or about 24 °C (inclusive); about 24 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, about 46 °C, about 44 °C, about 42 °C, about 40 °C, about 38 °C, about 36 °C, about 34 °C, about 32 °C, about 30 °C, about 28 °C, or about 26 °C (inclusive); about 26 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, about 46 °C, about 44 °C, about 42 °C, about 40 °C, about 38 °C, about 36 °C, about 34 °C, about 32 °C, about 30 °C, or about 28 °C (inclusive); about 28 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, about 46 °C, about 44 °C, about 42 °C, about 40 °C, about 38 °C, about 36 °C, about 34 °C, about 32 °C, or about 30 °C (inclusive); about 30 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, about 46 °C, about 44 °C, about 42 °C, about 40 °C, about 38 °C, about 36 °C, about 34 °C, or about 32 °C (inclusive); about 32 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, about 46 °C, about 44 °C, about 42 °C, about 40 °C, about 38 °C, about 36 °C, or about 34 °C (inclusive); about 34 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, about 46 °C, about 44 °C, about 42 °C, about 40 °C, about 38 °C, or about 36 °C (inclusive); about 36 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, about 46 °C, about 44 °C, about 42 °C, about 40 °C, or about 38 °C (inclusive); about 38 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, about 46 °C, about 44 °C, about 42 °C, or about 40 °C (inclusive); about 40 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, about 46 °C, about 44 °C, or about 42 °C (inclusive); about 42 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, about 46 °C, or about 44 °C (inclusive); about 44 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, about 48 °C, or about 46 °C (inclusive); about 46 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, about 50 °C, or about 48 °C (inclusive); about 48 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, about 52 °C, or about 50 °C (inclusive); about 50 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, about 54 °C, or about 52 °C (inclusive); about 52 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, about 56 °C, or about 54 °C (inclusive); about 54 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, about 58 °C, or about 56 °C (inclusive); about 56 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, about 60 °C, or about 58 °C (inclusive); about 58 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, about 62 °C, or about 60 °C (inclusive); about 60 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, about 64 °C, or about 62 °C (inclusive); about 62 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, about 66 °C, or about 64 °C (inclusive); about 64 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, about 68 °C, or about 66 °C

(inclusive); about 66 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, about 70 °C, or about 68 °C (inclusive); about 68 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, about 72 °C, or about 70 °C (inclusive); about 70 °C to about 80 °C, about 78 °C, about 76 °C, about 74 °C, or about 72 °C (inclusive); about 72 °C to about 80 °C, about 78 °C, about 76 °C, or about 74 °C (inclusive); about 74 °C to about 80 °C, about 78 °C, or about 76 °C (inclusive); about 76 °C to about 80 °C or about 78 °C (inclusive); or about 78 °C to about 80 °C (inclusive),

In some embodiments, the inhibitory nucleic acid can be formulated in a nanoparticle (e.g., a nanoparticle including one or more synthetic polymers, e.g., Patil et al.,

Pharmaceutical Nanotechnol. 367: 195-203, 2009; Yang et al, ACSAppl. Mater. Interfaces, doi: 10.1021/acsami.6bl6556, 2017; Perepelyuk et al, Mol. Ther. Nucleic Acids 6:259-268, 2017). In some embodiments, the nanoparticle can be a mucoadhesive particle (e.g., nanoparticles having a positively-charged exterior surface) (Andersen et al, Methods Mol. Biol. 555:77-86, 2009). In some embodiments, the nanoparticle can have a neutrally -charged exterior surface.

In some embodiments, the inhibitory nucleic acid can be formulated, e.g., as a liposome (Buyens et al, J. Control Release 158(3): 362-370, 2012; Scarabel et al, Expert Opin. Drug Deliv. 17: 1 -14, 2017), a micelle (e.g., a mixed micelle) (Tangs angasaksri et al, BioMacromolecules 17:246-255, 2016; Wu et al, Nanotechnology, doi: 10.1088/1361 - 6528/aa6519, 2017), a microemulsion (WO 1 1/004395), a nanoemulsion, or a solid lipid nanoparticle (Sahay et al, Nature Biotechnol. 31 :653-658, 2013; and Lin et al,

Nanomedicine 9(1): 105-120, 2014). Additional exemplary structural features of inhibitory nucleic acids and formulations of inhibitory nucleic acids are described in US 2016/0090598.

In some embodiments, a pharmaceutical composition can include a sterile saline solution and one or more inhibitory nucleic acid (e.g., any of the inhibitory nucleic acids described herein). In some examples, a pharmaceutical composition consists of a sterile saline solution and one or more inhibitory nucleic acid (e.g., any of the inhibitory nucleic acids described herein). In certain embodiments, the sterile saline is a pharmaceutical grade saline. In certain embodiments, a pharmaceutical composition can include one or more inhibitory nucleic acid (e.g., any of the inhibitory nucleic acids described herein) and sterile water. In certain embodiments, a pharmaceutical composition consists of one or more inhibitory nucleic acid (e.g., any of the inhibitory nucleic acids described herein) and sterile water. In certain embodiments, a pharmaceutical composition includes one or more inhibitory nucleic acid (e.g., any of the inhibitory nucleic acids described herein) and phosphate-buffered saline (PBS). In certain embodiments, a pharmaceutical composition consists of one or more inhibitory nucleic acids (e.g., any of the inhibitory nucleic acids described herein) and sterile phosphate-buffered saline (PBS). In some examples, the sterile saline is a pharmaceutical grade PBS.

In certain embodiments, one or more inhibitory nucleic acids (e.g., any of the inhibitory nucleic acids described herein) may be admixed with pharmaceutically acceptable active and/or inert substances for the preparation of pharmaceutical compositions or formulations. Compositions and methods for the formulation of pharmaceutical compositions depend on a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered.

Pharmaceutical compositions including one or more inhibitory nucleic acids encompass any pharmaceutically acceptable salts, esters, or salts of such esters. Non-limiting examples of pharmaceutical compositions include pharmaceutically acceptable salts of inhibitory nucleic acids. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts. Also provided herein are prodrugs that can include additional nucleosides at one or both ends of an inhibitory nucleic acid which are cleaved by endogenous nucleases within the body, to form the active inhibitory nucleic acid.

Lipid moieties can be used to formulate an inhibitory nucleic acid. In certain such methods, the inhibitory nucleic acid is introduced into preformed liposomes or lipoplexes made of mixtures of cationic lipids and neutral lipids. In certain methods, inhibitory nucleic acid complexes with mono- or poly-cationic lipids are formed without the presence of a neutral lipid. In certain embodiments, a lipid moiety is selected to increase distribution of an inhibitory nucleic acid to a particular cell or tissue in a mammal. In some examples, a lipid moiety is selected to increase distribution of an inhibitory nucleic acid to fat tissue in a mammal. In certain embodiments, a lipid moiety is selected to increase distribution of an inhibitory nucleic acid to muscle tissue.

In certain embodiments, pharmaceutical compositions provided herein comprise one or more inhibitory nucleic acid and one or more excipients. In certain such embodiments, excipients are selected from water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin,

hydroxymethylcellulose and polyvinylpyrrolidone.

In some examples, a pharmaceutical composition provided herein includes liposomes and emulsions. Liposomes and emulsions can be used to formulate hydrophobic compounds. In some examples, certain organic solvents such as dimethylsulfoxide are used.

In some examples, a pharmaceutical composition provided herein includes one or more tissue-specific delivery molecules designed to deliver one or more inhibitory nucleic acids to specific tissues or cell types in a mammal. For example, a pharmaceutical composition can include liposomes coated with a tissue-specific antibody.

In some embodiments, a pharmaceutical composition provided herein can include a co-solvent system. Examples of such co-solvent systems include benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. A non-limiting example of such a co-solvent system is the VPD co-solvent system, which is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80™ and 65% w/v polyethylene glycol 300. As can be appreciated, other surfactants may be used instead of Polysorbate 80™; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose. In some examples, a pharmaceutical composition can be formulated for oral administration. In some examples, pharmaceutical compositions are formulated for buccal administration.

In some examples, a pharmaceutical composition is formulated for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.). In some of these

embodiments, a pharmaceutical composition includes a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. In some examples, other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives). In some examples, injectable suspensions are prepared using appropriate liquid carriers, suspending agents, and the like. Some pharmaceutical compositions for injection are formulated in unit dosage form, e.g., in ampoules or in multi-dose containers. Some pharmaceutical compositions for injection are suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, and/or dispersing agents.

Solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes.

Small Molecules

In some embodiments, the JAK inhibitor is a small molecule. In some embodiments, the JAK inhibitory agent is a pan- JAK inhibitor (e.g., 3-O-methylthespesilactam (Li et al., Biochem. Pharmacol. 86(10): 1411-8, 2013)).

In some embodiments, the JAK inhibitor is a JAK1 and JAK2 inhibitor. In some embodiments, the JAK1 and JAK2 inhibitor is ruxolitinib (Jakafi®, Jakavi®, INCBO 18424) (Harrison et al, N. Engl. J. Med. 366:787-798, 2012; Pieri et al, Am. J. Hematol. 92(2): 187- 195, 2017; Mackay-Wiggan et al., JCI Insight l(15):e89790, 2016; Rudolph et al, Leukemia 30(10):2119-2123, 2016; Furqan et al., BiomarkRes. 1(1):5, 2013), baricitinib (INCB028050, LY3009104) (Gras, Drugs Today (Bare) 52(10):543-550, 2016; Smolen et al, Ann. Rheum. Dis. 76(4):694-700, 2016; Kubo et al, Expert. Rev. Clin. Immunol. 12(9):911-919, 2016; Fridman et al, J. Immunol. 84(9):5298-5307, 2010), AZD1480 (Guschin et al., EMBO J. 14: 1421-1429, 1995; Ioannidis et al., J. Med. Chem. 54: 262-276, 2011; Moisan et al, Nat. Cell Biol. 17(l):57-67, 2015; Qin et al., J. Neurosci. 36(18):5144059, 2016; Jiang et al., Biochem. Biophys. Res. Commun. 458(4):908-912, 2015; Verstovsek et al, Leuk. Res. 39(2): 157-163, 2015; Plimack et al., Oncologist 18(7): 819-820, 2013; Yan et al, Oncotarget 4(3):433-445, 2013), filgotinib (GLPG0634, G146034) (Vermeire et al, Lancet

389(10066):266-275, 2017; Menet et al., J. Med. Chem. 57(22):9323-9342, 2014; Van Rompaey et al, J. Immunol. 191(7):3568-3577, 2013; Namour et al, Clin. Pharmacokinet. 54(8):859-874, 2015), momelotinib (GS-0387, CYT387) (Pardanani et al, Leukemia 23: 1441-1445, 2009; Gupta et al., Haematologica 102(1):94-102, 2017; Hu et al, Mol. Pharm. 13(2):689-697, 2016; Abubaker et al, BMC Cancer 14: 317, 2014; Durmus et al,

Pharmacol. Res. 76:9-16, 2013; Pardanani et al, Leukemia 27(6): 1322-1327, 2013;

Monaghan et al., Leukemia 25(12): 1891-1899, 2011; Tyner et al, Blood 115(25): 5232-5240, 2010).

In some embodiments, the JAK inhibitory agent is a JAK1 inhibitor (e.g.,

GSK2586184 (Kahl et al, Lupus 25(13): 1420-1430, 2016; Ludbrook et al, Br. J. Dermatol. 174(5):985-995, 2016; van Vollenhoven et al., Lupus 24(6): 648-649, 2015), oclacitinib (PF03394197, Apoquel®) (Gonzales et al, J. Vet. Pharmacol. Ther. 37(4):317-324, 2014; Collard et al, J. Vet. Pharmacol. Ther. 37(3):279-285, 2014; Cosgrove et al, Vet. Dermatol. 24(6):587-597, 2013), upadacitinib (ABT494) (Kremer et al, Arthritis Rheumatol.

68(12):2867-2877, 2016; Mohamed et al, Clin. Pharmaco. 55(12): 1547-1558, 2016), GLG0778 (O'Shea et al, Ann. Rev. Med. 66(1):311-28, 2015; Schwartz et al, Nat. Rev. Rheum. 12: 25-36, 2016), INCB039110 (Mascarenhas et al, Haematologica 102(2):327-335, 2017; Bissonnette et al, J. Dermatolog. Treat. 27(4):332-338, 2016; Rosenthal et al, Exp. Opin. Pharmacother. 15(9): 1265-1276, 2014), PF04965842 (Gadina et al., Curr. Opin. Rheumatol. 26(2):237-243, 2014; Degryset et al, J. Hematol. Oncol. 8:91, 2015); SAR- 20347 (Works et al, J. Immunol. 193(7):3278-3287, 2014)).

In some embodiments, the JAK inhibitory agent is a JAK2 inhibitor (e.g., CEP-33779 (Dugan et al, J. Med. Chem. 55(11):5243-5254, 2012; Seavey et al., Mol. Cancer Ther. l l(4):984-993, 2012; Stump et al, Arthritis Res. Ther. 13(2):R68, 2011), fedratinib

(TG101348, SAR302503) (Pardanani et al, J. Clin. Oncol. 29:789-796, 2011; Jamieson et al, J. Transl. Med. 13:294, 2015; Zhang et al, Oncotarget 6(16): 14329-14343, 2015; Wemig et al, Blood 105:4508-4515, 2008); lestaurtinib (CEP-701) (Hexnet et al, Blood 111 :5663- 5671, 2008; Santos et al., Blood 115: 1131-1136, 2010; Smith et al, Blood 103: 3669-3676, 2004; Hexner et al., Leuk. Lymphoma. 56(9):2543, 2015; Geyer et al, Hematology

17(Suppll):S129-132, 2012; Diaz et al, PLoS One 6(4):el 8856, 2011 ; Mintum et al, Cancer Chemother. Pharmacol. 68(4): 1057-1065, 2011), AC -430 (O'Shea et al, Immunity 36(4):542-550, 2012; Patterson et al., Clin. Exp. Immunol. 176: 1-10, 2014), pacritinib (SB1518) (Deeg et al, J. Clin. Oncol. 29: Abstract 6515, 2011; Verstovsek et al, J. Hematol. Oncol. 9(1): 137, 2016; Chow et al., Onco Targets. Ther. 9:2655-2665, 2016; Komrokji et al., Blood 125(17):2649-2655, 2015; Jayaraman et al, DrugMetab. Lett. 9(l):28-47, 2015), BMS-911543 (Mace et al, Oncotarget 6(42):44509-44522, 2015; Wan et al, ACS Med. Chem. Lett. 6(8):850-855, 2015; Purandare et al, Leukemia 26(2):280-288, 2012), XL019 (Verstovsek et al, Leuk. Res. 38(3):316-322, 2014; Forsyth et al, Bioorg. Med. Chem. Lett. 22(24):7653-7658, 2012), INCB039110 (Mascarenhas et al, Haematologica 102(2):327-335, 2017; Bissonnette et al, J. Dermatol. Treat. 27(4):332-338, 2016), gandotinib® (LY- 2784544) (Ma et al, Blood Cancer J. 3:el09, 2013; Verstovsek et al., Blood 122: 665, 2013; Mitchell et al, Org. Process Res. Dev. 16(1):70-81. 2012); R723 (Shide et al, Blood 111 '(25): 6866-6875, 2011)); Z3 (S ayy ah et al., Mol. Cancer. Ther. 7(8):2308-2318, 2008)) or a variant thereof.

In some embodiments, the JAK inhibitory agent is a JAK3 inhibitor (e.g.,

decemotinib (VX-509) (Elwood et al., J. Pharmacol. Exp. Ther. 2017; Genovese et al, Ann Rheum Dis. 75(11): 1979-1983, 2016; Gadina et al., Arthritis Rheumatol. 68(l):31-34, 2016; Farmer et al, J. Med. Chem. 58(18):7195-7216, 2015; Fleischmann et al, Arthritis

Rheumatol. 67(2):334-343, 2015; Mahajan et al., J. Pharmacol. 353(2):405-414, 2015), R348 or a variant thereof (Velotta et al., Transplantation 87(5): 653-659, 2009; Deuse et al, Transplantation 85(6): 885-892, 2008)). In some embodiments, the small molecule is R256 or a variant thereof (Ashino et al, J. Allergy Clin. Immunol. 133(4): 1162-1174, 2014). In some embodiments, the small molecule is R333 or a variant thereof. In some embodiments, the small molecule is INCB047986 or a variant thereof (Norman, Exp. Opin. Investig. Drugs 23(8): 1067-1077, 2014). In some embodiments, the small molecule is INCB16562 or a variant thereof (Koppikar et al, Blood 115(4):2919-2927, 2010; Li et al., Neoplasia 12(1):28- 38, 2010). In some embodiments, the small molecule is NVP-BSK805 or a variant thereof (Ringel Q\ &\., Acta Haematol. 132(l):75-86, 2014; Baffert et al, Mol. Cancer. Ther.

9(7): 1945-1955, 2010). In some embodiments, the small molecule is peficitinib (ASP015K, JNJ-54781532) or a variant thereof (Genovese et al, Arthritis Rheumatol , 2017; Ito et al, J. Pharmacol. Sci. 133(l):25-33, 2017; Cao et al. (2016) Clin. Pharmacol. Drug Dev. 5(6):435- 449, 2016; Takeuchi et ύ., Αηη. Rheum. Dis. 75(6): 1057-1064, 2016). In some

embodiments, the small molecule is tofacitinib (Xeljanz®, Jakvinus®, CP-690, 500) or a variant thereof (Ghoreschi et al., J. Immunol. 186(7):4234-4243, 2011 ; Yoshida et al, Biochem. Biophys. Res. Commun 418(2):234-240, 2012; Calama et al., Pulm. Pharmacol.

Ther. S 1094-5539(16):30060-30068, 2017; Cutolo et al., J. Inflamm. Res. 6: 129-137, 2013).

In some embodiments, the small molecule is cucurbitacin I (JSI-124) or a variant thereof (Oi et al, Int. J. Oncol. 49(6):2275-2284, 2016; Qi et al., Am. J. Chin. Med. 43(2):337-347, 2015; Seo et al, Food Chem. Toxicol. 64:217-224, 2014). In some embodiments, the small molecule is CHZ868 or a variant thereof (Wu et al., Cancer Cell 28(1):29-41, 2015; Meyer et al, Cancer Cell 28(1): 15-28, 2015).

In some embodiments, the small molecule is a TYK2 inhibitor (e.g., Masse et al, J.

Immunol. 194(1):67, 2015; Menet, Pharm. Pat. Anal. 3(4):449-466, 2014; Liang et al, Euro. J. Med. Chem. 67: 175-187, 2013; Jang et al., Bioorg. Med. Chem. Lett. 25(18):3947-3952,

2015); U.S. Patent Nos. 9,296,725 and 9,309,240; US 2013/0231340; and US

2016/0251376). In some embodiments, the TYK2 inhibitor is Ndi-031301 (Akahane et al.,

Blood 128: 1596, 2016); BMS-986165 (Gillooly et al, 2016 ACR/ARHP Annual Meeting,

Abstract 11L, 2016); SAR-20347 (Works et al., J. Immunol. 193(7):3278-3287, 2014);

tyrphostin Al (Ishizaki et al, Int. Immunol. 26(5):257-267, 2014); a triazolopyridine (US

2013/0143915); or a variant thereof.

Additional examples of JAK inhibitors that are small molecules are described in, e.g.,

Furomoto et al., BioDrugs 27(5):431-438, 2013; O' Shea et εά., Αηη. Rheum. Dis.

72(2):iil l l-ii-115, 2013; Sonbol et al, Ther. Adv. Hematol. 4(1): 15-35, 2013; and Tanaka et al. (2015) J. Biochem. 158(3): 173-179, 2015.

Exemplary embodiments:

The following exemplary embodiments 1) - 94) are provided herein:

1) A method of treating a disease of the gastro-intestinal tract in a subject, comprising: delivering a JAK inhibitor at a location in the gastrointestinal tract of the subject, wherein the method comprises administering orally to the subject a pharmaceutical composition comprising a therapeutically effective amount of the JAK inhibitor.

2) The method of exemplary embodiment 1, wherein the disease of the GI tract is an inflammatory bowel disease.

3) The method of exemplary embodiment 1, wherein the disease of the GI tract is

ulcerative colitis.

4) The method of exemplary embodiment 1, wherein the disease of the GI tract is

Crohn's disease. 5) The method of any one of exemplary embodiments 1, 2, or 3, 4, wherein the JAK inhibitor is delivered at a location in the large intestine of the subject.

6) The method of exemplary embodiment 5, wherein the location is in the proximal portion of the large intestine.

7) The method of exemplary embodiment 5, wherein the location is in the distal portion of the large intestine.

8) The method of any one of exemplary embodiments 1, 2, or 3, 4, wherein the JAK inhibitor is delivered at a location in the ascending colon of the subject.

9) The method of exemplary embodiment 8, wherein the location is in the proximal portion of the ascending colon.

10) The method of exemplary embodiment 8, wherein the location is in the distal portion of the ascending colon.

11) The method of any one of exemplary embodiments 1, 2, or 3, 4, wherein the JAK inhibitor is delivered at a location in the cecum of the subject.

12) The method of exemplary embodiment 11, wherein the location is in the proximal portion of the cecum.

13) The method of exemplary embodiment 11, wherein the location is in the distal portion of the cecum.

14) The method of any one of exemplary embodiments 1, 2, or 3, 4, wherein the JAK inhibitor is delivered at a location in the sigmoid colon of the subject.

15) The method of exemplary embodiment 14, wherein the location is in the proximal portion of the sigmoid colon.

16) The method of exemplary embodiment 14, wherein the location is in the distal portion of the sigmoid colon.

17) The method of any one of exemplary embodiments 1, 2, or 3, 4, wherein the JAK inhibitor is delivered at a location in the transverse colon of the subject.

18) The method of exemplary embodiment 17, wherein the location is in the proximal portion of the transverse colon.

19) The method of exemplary embodiment 17, wherein the location is in the distal portion of the transverse colon.

20) The method of any one of exemplary embodiments 1, 2, or 3, 4, wherein the JAK inhibitor is delivered at a location in the descending colon of the subject. 21) The method of exemplary embodiment 20, wherein the location is in the proximal portion of the descending colon.

22) The method of exemplary embodiment 20, wherein the location is in the distal portion of the descending colon.

23) The method of any one of exemplary embodiments 1, 2, or 3, 4, wherein the JAK inhibitor is delivered at a location in the small intestine of the subject.

24) The method of exemplary embodiment 23, wherein the location is in the proximal portion of the small intestine.

25) The method of exemplary embodiment 23, wherein the location is in the distal portion of the small intestine.

26) The method of any one of exemplary embodiments 1, 2, or 3, 4, wherein the JAK inhibitor is delivered at a location in the duodenum of the subject.

27) The method of exemplary embodiment 26, wherein the location is in the proximal portion of the duodenum.

28) The method of exemplary embodiment 26, wherein the location is in the distal portion of the duodenum.

29) The method of any one of exemplary embodiments 1, 2, or 3, 4, wherein the JAK inhibitor is delivered at a location in the jejunum of the subject.

30) The method of exemplary embodiment 29, wherein the location is in the proximal portion of the j ej unum.

31) The method of exemplary embodiment 29, wherein the location is in the distal portion of the jejunum.

32) The method of any one of exemplary embodiments 1, 2, or 3, 4, wherein the JAK inhibitor is delivered at a location in the ileum of the subject.

33) The method of exemplary embodiment 32, wherein the location is in the proximal portion of the ileum.

34) The method of exemplary embodiment 32, wherein the location is in the distal portion of the ileum.

35) The method of any one of the preceding exemplary embodiments, wherein the

location is proximate to one or more sites of disease.

36) The method of exemplary embodiment 35, further comprising identifying the one or more sites of disease by a method comprising imaging of the gastrointestinal tract. 37) The method of any one of the preceding exemplary embodiments, wherein the JAK inhibitor is delivered to the location by mucosal contact.

38) The method of any one of the preceding exemplary embodiments, wherein the JAK inhibitor is delivered to the location by a process that does not comprise systemic transport of the JAK inhibitor.

39) The method of any one of the preceding exemplary embodiments, wherein the amount of the JAK inhibitor that is administered is from about 1 mg to about 300 mg.

40) The method of exemplary embodiment 39, wherein the amount of the JAK inhibitor that is administered is from about 1 mg to about 100 mg.

41) The method of exemplary embodiment 40, wherein the amount of the JAK inhibitor that is administered is from about 5 mg to about 40 mg.

42) The method of any one of exemplary embodiments 1 to 41, wherein the amount of the

JAK inhibitor is less than an amount that is effective when the JAK inhibitor is administered systemically.

43) The method of any one of the preceding exemplary embodiments, comprising

administering (i) an amount of the JAK inhibitor that is an induction dose.

44) The method of exemplary embodiment 43, further comprising (ii) administering an amount of the JAK inhibitor that is a maintenance dose following the administration of the induction dose.

45) The method of exemplary embodiment 43 or 44, wherein the induction dose is

administered once a day.

46) The method of exemplary embodiment 43 or 44, wherein the induction dose is

administered once every three days.

47) The method of exemplary embodiment 43 or 44, wherein the induction dose is

administered once a week.

48) The method of exemplary embodiment 44, wherein step (ii) is repeated one or more times.

49) The method of exemplary embodiment 44, wherein the induction dose is equal to the maintenance dose.

50) The method of exemplary embodiment 44, wherein the induction dose is greater than the maintenance dose.

51) The method of exemplary embodiment 44, wherein the induction dose is 5 greater than the maintenance dose. 52) The method of exemplary embodiment 44, wherein the induction dose is 2 greater than the maintenance dose.

53) The method of any one of the preceding exemplary embodiments, wherein the method comprises delivering the JAK inhibitor at the location in the gastrointestinal tract as a single bolus.

54) The method of any one of exemplary embodiments 1 to 52, wherein the method

comprises delivering the JAK inhibitor at the location in the gastrointestinal tract as more than one bolus.

55) The method of any one of exemplary embodiments 1 to 52, wherein the method

comprises delivering the JAK inhibitor at the location in the gastrointestinal tract in a continuous manner.

56) The method of exemplary embodiment 55, wherein the method comprises delivering the JAK inhibitor at the location in the gastrointestinal tract over a time period of 20 or more minutes.

57) The method of any one of the preceding exemplary embodiments, wherein the method provides a concentration of the JAK inhibitor in the plasma of the subject that is less than 3 μg/ml.

58) The method of exemplary embodiment 57, wherein the method provides a

concentration of the JAK inhibitor in the plasma of the subject that is less than 0.3 μg/ml.

59) The method of exemplary embodiment 58, wherein the method provides a

concentration of the JAK inhibitor in the plasma of the subject that is less than 0.01

60) The method of any one of exemplary embodiments 1 to 59, wherein the method does not comprise delivering a JAK inhibitor rectally to the subject.

61) The method of any one of exemplary embodiments 1 to 59, wherein the method does not comprise delivering a JAK inhibitor via an enema to the subject.

62) The method of any one of exemplary embodiments 1 to 59, wherein the method does not comprise delivering a JAK inhibitor via suppository to the subject.

63) The method of any one of exemplary embodiments 1 to 59, wherein the method does not comprise delivering a JAK inhibitor via instillation to the rectum of the subject. 64) The method of exemplary embodiment 63, wherein the JAK inhibitor is a JAK1 inhibitor. 65) The method of exemplary embodiment 63, wherein the JAK inhibitor is selected from tofacitinib (Xeljanz®), filgotinib (GLPG0634, Galapagos NV); TD-1473 (Theravance Biopharma, Inc.); ruxolitinib; and generic equivalents thereof.

66) The method of any one of the preceding exemplary embodiments, wherein the

pharmaceutical composition is an ingestible device, comprising:

a housing defined by a first end, a second end substantially opposite from the first end, and a wall extending longitudinally from the first end to the second end;

a storage reservoir located within the housing and containing the JAK inhibitor, wherein a first end of the storage reservoir is connected to the first end of the housing; a mechanism for releasing the JAK inhibitor from the storage reservoir;

and;

an exit valve configured to allow the JAK inhibitor to be released out of the housing from the storage reservoir.

67) The method of exemplary embodiment 66, wherein the ingestible device further comprises:

an electronic component located within the housing; and

a gas generating cell located within the housing and adjacent to the electronic component,

wherein the electronic component is configured to activate the gas generating cell to generate gas.

68) The method of exemplary embodiment 66 or 67, wherein the ingestible device further comprises:

a safety device placed within or attached to the housing,

wherein the safety device is configured to relieve an internal pressure within the housing when the internal pressure exceeds a threshold level.

69) The method of exemplary embodiment 66, wherein the pharmaceutical composition is an ingestible device, comprising:

a housing defined by a first end, a second end substantially opposite from the first end, and a wall extending longitudinally from the first end to the second end;

an electronic component located within the housing;

a gas generating cell located within the housing and adjacent to the electronic component, wherein the electronic component is configured to activate the gas generating cell to generate gas;

a storage reservoir located within the housing,

wherein the storage reservoir stores a dispensable substance and a first end of the storage reservoir is connected to the first end of the housing;

an exit valve located at the first end of the housing,

wherein the exit valve is configured to allow the dispensable substance to be released out of the first end of the housing from the storage reservoir; and

a safety device placed within or attached to the housing,

wherein the safety device is configured to relieve an internal pressure within the housing when the internal pressure exceeds a threshold level.

70) The method of exemplary embodiment 66, wherein the pharmaceutical composition is an ingestible device, comprising:

a housing defined by a first end, a second end substantially opposite from the first end, and a wall extending longitudinally from the first end to the second end;

an electronic component located within the housing,

a gas generating cell located within the housing and adjacent to the electronic component,

wherein the electronic component is configured to activate the gas generating cell to generate gas;

a storage reservoir located within the housing,

wherein the storage reservoir stores a dispensable substance and a first end of the storage reservoir is connected to the first end of the housing;

an injection device located at the first end of the housing,

wherein the jet injection device is configured to inject the dispensable substance out of the housing from the storage reservoir; and

a safety device placed within or attached to the housing,

wherein the safety device is configured to relieve an internal pressure within the housing.

71) The method of exemplary embodiment 66, wherein the pharmaceutical composition is an ingestible device, comprising:

a housing defined by a first end, a second end substantially opposite from the first end, and a wall extending longitudinally from the first end to the second end; an optical sensing unit located on a side of the housing,

wherein the optical sensing unit is configured to detect a reflectance from an environment external to the housing;

an electronic component located within the housing;

a gas generating cell located within the housing and adjacent to the electronic component,

wherein the electronic component is configured to activate the gas generating cell to generate gas in response to identifying a location of the ingestible device based on the reflectance;

a storage reservoir located within the housing,

wherein the storage reservoir stores a dispensable substance and a first end of the storage reservoir is connected to the first end of the housing;

a membrane in contact with the gas generating cell and configured to move or deform into the storage reservoir by a pressure generated by the gas generating cell; and

a dispensing outlet placed at the first end of the housing,

wherein the dispensing outlet is configured to deliver the dispensable substance out of the housing from the storage reservoir.

72) The method of any one of exemplary embodiments 1-71, wherein the pharmaceutical composition is an ingestible device as disclosed in US Patent Application Ser. No. 62/385,553, incorporated by reference herein in its entirety.

73) The method of any one of exemplary embodiments 1-71, wherein the pharmaceutical composition is an ingestible device comprising a localization mechanism as disclosed in international patent application PCT/US2015/052500, incorporated by reference herein in its entirety.

74) The method of any one of exemplary embodiments 1-73, wherein the pharmaceutical composition is not a dart-like dosage form.

75) A method of treating a disease of the large intestine of a subject, comprising:

delivering of a JAK inhibitor at a location in the proximal portion of the large intestine of the subject,

wherein the method comprises administering endoscopically to the subject a therapeutically effective amount of the JAK inhibitor.

76) The method of exemplary embodiment 75, wherein the disease of the large intestine is an inflammatory bowel disease. 77) The method of exemplary embodiment 75, wherein the disease of the large intestine is ulcerative colitis.

78) The method of exemplary embodiment 75, wherein the disease the large intestine is Crohn's disease.

79) The method of any one of exemplary embodiments 75 to 78, wherein the JAK

inhibitor is delivered at a location in the proximal portion of the ascending colon.

80) The method of any one of exemplary embodiments 75 to 78, wherein the JAK

inhibitor is delivered at a location in the proximal portion of the cecum.

81) The method of any one of exemplary embodiments 75 to 78, wherein the JAK

inhibitor is delivered at a location in the proximal portion of the sigmoid colon.

82) The method of any one of exemplary embodiments 75 to 78, wherein the JAK

inhibitor is delivered at a location in the proximal portion of the transverse colon.

83) The method of any one of exemplary embodiments 75 to 78, wherein the JAK

inhibitor is delivered at a location in the proximal portion of the descending colon.

84) The method of any one of the preceding exemplary embodiments, further comprising administering a second agent orally, intravenously or subcutaneously, wherein the second agent is the same JAK inhibitor as in exemplary embodiment 1 or 75; a different JAK inhibitor; or an agent having a different biological target from JAK.

85) The method of any one of the preceding exemplary embodiments, further comprising administering a second agent orally, intravenously or subcutaneously, wherein the second agent is an agent suitable for treating an inflammatory bowel disease.

86) The method of exemplary embodiment 84 or 85, wherein the JAK inhibitor is

administered prior to the second agent.

87) The method of exemplary embodiment 84 or 85, wherein the JAK inhibitor is

administered after the second agent.

88) The method of exemplary embodiment 84 or 85, wherein the JAK inhibitor and the second agent are administered substantially at the same time.

89) The method of any one of exemplary embodiments 84 to 88, wherein the second agent is administered intravenously.

90) The method of any one of exemplary embodiments 84 to 88, wherein the second agent is administered subcutaneously. 91) The method of any one of exemplary embodiments 84 to 90, wherein the amount of the second agent is less than the amount of the second agent when the JAK inhibitor and the second agent are both administered systemically.

92) The method of exemplary embodiment 91, wherein the second agent is an

immunosuppressant.

93) In some aspects of these embodiments, the second agent is methotrexate.

94) The method of any one of exemplary embodiments 1 to 83, wherein the method does not comprise.

Endoscopes. Ingestible Devices, and Reservoirs containing the drug

Direct visualization of the GI mucosa is useful to detect subtle mucosal alterations, as in inflammatory bowel diseases, as well as any flat or sessile lesions. The GI tract can be imaged using endoscopes, or more recently ingestible devices that are swallowed.

The technology behind standard colonoscopy consists of a long, semi-rigid insertion tube with a steerable tip (stiff if compared to the colon), which is pushed by the physician from the outside. However, invasiveness, patient discomfort, fear of pain, and -more often than not- the need for conscious sedation limit the take-up of screening colonoscopy.

Diagnosis and treatment in the GI tract are dominated by the use of flexible endoscopes. A few large companies, namely Olympus Medical Systems Co. (Tokyo, Japan), Pentax Medical Co. (Montvale, NJ, USA), Fujinon, Inc. (Wayne, NJ, USA) and Karl Storz GmbH & Co. KG (Tuttlingen, Germany), cover the majority of the market in flexible GI endoscopy.

In a review of robotic endoscopic capsules, Journal of Micro-Bio Robotics 11.1-4 (2016): 1-18, Ciuti et al. state that progress in micro-electromechanical systems (MEMS) technologies have led to the development of new endoscopic capsules with enhanced diagnostic capabilities, in addition to traditional visualization of mucosa (embedding, e.g. pressure, pH, blood detection and temperature sensors).

Endoscopes may comprise a catheter. As an example, the catheter may be a spray catheter. As an example, a spray catheter may be used to deliver dyes for diagnostic purposes. As an example, a spray catheter may be used to deliver a therapeutic agent at the site of disease in the GI tract. For example, the Olypmus PW-205V is a ready-to-use spray catheter that enables efficient spraying for maximal differentiation of tissue structures during endoscopy, but may also be used to deliver drugs diseased tissue.

FIG. 1, disclosed in US Provisional Application No. 62/385,553, incorporated by reference herein in its entirety, illustrates an example of an ingestible device for localized delivery of pharmaceutical compositions disclosed herein, in accordance with particular implementations. The ingestible device 100 includes a piston or drive element 134 to push for drug delivery, in accordance with particular implementations described herein. The ingestible device 100 may have one or more batteries 131 placed at one end 102a of a housing 101 to provide power for the ingestible device 100. A printed circuit board (PCB) 132 may be placed adjacent to a battery or other power source 131, and a gas generating cell 103 may be mounted on or above the PCB 132. The gas generating cell 103 may be sealed from the bottom chamber (e.g., space including 131 and 132) of the ingestible device 100. A movable piston 134 may be placed adjacent to the gas generating cell 103. In this way, gas generation from the gas generating cell 103 may propel a piston 134 to move towards another end 102b of the housing 101 such that the dispensable substance in a reservoir compartment 135 can be pushed out of the housing through a dispensing outlet 107, e.g., the movement is shown at 136, with the piston 134 at a position after dispensing the substance. The dispensing outlet 107 may comprise a plug. The reservoir compartment 135 can store the dispensable substance (e.g., drug substance), or alternatively the reservoir compartment can house a storage reservoir 161 which comprises the dispensable substance. The reservoir

compartment 135 or storage reservoir 161 may have a volume of approximately 600μί or even more dispensable substance, which may be dispensed in a single bolus, or gradually over a period of time.

The battery cells 131 may have a height of 1.65 mm each, and one to three batteries may be used. The height of the piston may be reduced with custom molded part for around 1.5mm to save space. If the gas generating cell 103 is integrated with the piston 134, the overall height of the PCB, batteries and gas generating cell in total can be reduced to around 5 mm, thus providing more space for drug storage. For example, for an ingestible device of 7.8 mm in length (e.g., from end 102a to the other end 102b), a reservoir compartment 135 or a storage reservoir 161 of approximately 600μί may be used for drug delivery. For another example, for an ingestible device of 17.5 mm in length, a reservoir compartment 135 or a storage reservoir 161 of approximately 1300μί may be used for drug release.

In some implementations, at the reservoir 135 or 161 for storing a therapeutically effective amount of the JAK inhibitor forms at least a portion of the device housing 101. The therapeutically effective amount of the JAK inhibitor can be stored in the reservoir 135 or 161 at a particular pressure, for example, determined to be higher than a pressure inside the GI tract so that once the reservoir 135 or 161 is in fluid communication with the GI tract, the JAK inhibitor is automatically released. In certain implementations, the reservoir compartment 135 includes a plurality of chambers, and each of the plurality of the chambers stores a different dispensable substance or a different storage reservoir 161.

In certain embodiments, the storage reservoir 161 is a compressible component or has compressible side walls. In particular embodiments, the compressible component can be composed, at least in part, or coated (e.g., internally) with polyvinyl chloride (PVC), silicone, DEHP (di-2-ethylhexyl phthalate), Tyvek, polyester film, poly olefin, polyethylene, polyurethane, or other materials that inhibit the JAK inhibitor from sticking to the reservoir and provide a sterile reservoir environment for the JAK inhibitor. The storage reservoir 161 can be hermetically sealed. The reservoir compartment 135 or storage reservoir 161 can be configured to store JAK inhibitor in quantities in the range of 0.01 mL - 2 mL, such as 0.05 mL - 2 mL, such as 0.05 mL - 2 mL, such as 0.6mL - 2 mL. In some embodiments, the storage reservoir 161 is attachable to the device housing 101 , for example, in the reservoir compartment. Accordingly, the storage reservoir 135 can be loaded with the JAK inhibitor prior to being positioned in and/or coupled to the ingestible device housing 101. The ingestible device housing 101 includes one or more openings configured as a loading port to load the dispensable substance into the reservoir compartment. In another embodiment, the ingestible device housing 101 includes one or more openings configured as a vent.

In certain embodiments, the ingestible device housing 101 includes one or more actuation systems (e.g., gas generating cell 103) for pumping the JAK inhibitor from the reservoir 135. In some embodiments, the actuation system can include a mechanical, electrical, electromechanical, hydraulic, and/or fluid actuation system. For example, a chemical actuation means may use chemical reaction of mixing one or more reagents to generate a sufficient volume of gas to propel the piston or drive element 134 for drug release. The actuation system can be integrated into the reservoir compartment 135 or can be an auxiliary system acting on or outside of the reservoir compartment 135. For example, the actuation system can include pumping system for pushing/pulling the JAK inhibitor out of the reservoir compartment 135 or the actuation system can be configured to cause the reservoir compartment 135 to change structurally so that the volume inside of the reservoir compartment 135 changes, thereby dispensing the JAK inhibitor from the reservoir compartment 135. The actuation system can include an energy storage component such as a battery or a capacitor for powering the actuation system. The actuation system can be actuated via gas pressure or a system storing potential energy, such as energy from an elastic reservoir component being expanded during loading of the reservoir and after being positioned in the ingestible device housing 101 being subsequently released from the expanded state when the ingestible device housing is at the location for release within the GI tract. In certain embodiments, the reservoir compartment 135 can include a membrane portion, whereby the JAK inhibitor is dispensed from the reservoir compartment 135 or storage reservoir 161 via osmotic pressure.

In particular embodiments the storage reservoir 161 is in a form of a bellow that is configured to be compressed via a pressure from the gas generating cell. The JAK inhibitor may be loaded into the bellow, which may be compressed by gas generation from the gas generating cell or other actuation means to dispense the dispensable substance through the dispensing outlet 107 and out of the housing 101. In some embodiments, the ingestible device includes a capillary plate placed between the gas generating cell and the first end of the housing, and a wax seal between the gas generating cell and the reservoir, wherein the wax seal is configured to melt and the dispensable substance is pushed through the capillary plate by a pressure from the gas generating cell. The shape of the bellow may aid in controlled delivery. The reservoir compartment 135 includes a dispensing outlet, such as a valve or dome slit 162 extending out of an end of the housing 101, in accordance with particular implementations. Thus when the bellow is being compressed, the dispensable substance may be propelled out of the bellow through the valve or the dome slit.

In certain embodiments, the reservoir compartment 135 includes one or more valves

(e.g. a valve in the dispensing outlet 107) that are configured to move or open to fluidly couple the reservoir compartment 135 to the GI tract. In certain embodiments, a housing wall of the housing 101 can form a portion of the reservoir compartment 135. In certain embodiments, the housing walls of the reservoir serve as a gasket. One or more of the one or more valves are positioned in the housing wall of the device housing 101 , in accordance with particular implementations. One or more conduits may extend from the reservoir 135 to the one or more valves, in certain implementations.

In certain embodiments, a housing wall of the housing 101 can be formed of a material that is configured to dissolve, for example, in response to contact at the disease site. In certain embodiments, a housing wall of the housing 101 can be configured to dissolve in response to a chemical reaction or an electrical signal. The one or more valves and/or the signals for causing the housing wall of the housing 101 to dissolve or dissipate can be controlled by one or more processors or controllers positioned on PCB 132 in the device housing 101. The controller is communicably coupled to one or more sensors or detectors configured to determine when the device housing 101 is proximate to a disease site. The sensors or detectors comprise a plurality of electrodes comprising a coating, in certain implementations. Releasing of the JAK inhibitor from the reservoir compartment 135 is triggered by an electric signal from the electrodes resulting from the interaction of the coating with the one or more sites of disease site. The one or more sensors can include a chemical sensor, an electrical sensor, an optical sensor, an electromagnetic sensor, a light sensor, and/or a radiofrequency sensor.

In particular embodiments, the device housing 101 can include one or more pumps configured to pump the therapeutically effective amount of the JAK inhibitor from the reservoir compartment 135. The pump is communicably coupled to the one or more controllers. The controller is configured to activate the pump in response to detection by the one or more detectors of the disease site and activation of the valves to allow the reservoir 135 to be in fluid communication with the GI tract. The pump can include a fluid actuated pump, an electrical pump, or a mechanical pump.

In certain embodiments, the device housing 101 comprises one or more anchor systems for anchoring the device housing 101 or a portion thereof at a particular location in the GI tract adjacent the disease site. In some embodiments, a storage reservoir comprises an anchor system, and the storage reservoir comprising a releasable substance is anchored to the GI tract. The anchor system can be activated by the controller in response to detection by the one or more detectors of the disease site. In certain implementations, the anchor system includes legs or spikes configured to extend from the housing wall(s) of the device housing 101. The spikes can be configured to retract and/or can be configured to dissolve over time. An example of an attachable device that becomes fixed to the interior surface of the GI tract is described in PCT Patent Application PCT/US2015/012209, "Gastrointestinal Sensor Implantation System", filed January 21, 2015, which is hereby incorporated by reference herein in its entirety.

In certain embodiments, the reservoir is an anchorable reservoir, which is a reservoir comprising one or more anchor systems for anchoring the reservoir at a particular location in the GI tract adjacent the disease site. In certain embodiments, the anchor system includes legs or spikes or other securing means such as a piercing element, a gripping element, a magnetic-flux-guiding element, or an adhesive material, configured to extend from the anchorable reservoir of the device housing. The spikes can be configured to retract and/or can be configured to dissolve over time. In some embodiments, the anchorable reservoir is suitable for localizing, positioning and/or anchoring. In some embodiments, the anchorable reservoir is suitable for localizing, and positioning and/or anchoring by an endoscope. In some embodiments, the anchorable reservoir is connected to the endoscope. In some embodiments, the anchorable reservoir is connected to the endoscope in a manner suitable for oral administration. In some embodiments, the anchorable reservoir is connected to the endoscope in a manner suitable for rectal administration. Accordingly, provided herein in some embodiments is an anchorable reservoir is connected to an endoscope wherein the anchorable reservoir comprises a therapeutically effective amount of the JAK inhibitor. In some embodiments the endoscope is fitted with a spray catheter.

Exemplary embodiments of anchorable reservoirs are as follows. In more particular examples of the following exemplary embodiments the reservoir is connected to an endoscope.

In one embodiment, the anchorable reservoir comprises an implant capsule for insertion into a body canal to apply radiation treatment to a selected portion of the body canal. The reservoir includes a body member defining at least one therapeutic treatment material receiving chamber and at least one resilient arm member associated with the body member for removably engaging the body canal when the device is positioned therein.

In one embodiment the anchorable reservoir has multiple suction ports and permits multiple folds of tissue to be captured in the suction ports with a single positioning of the device and attached together by a tissue securement mechanism such as a suture, staple or other form of tissue bonding. The suction ports may be arranged in a variety of configurations on the reservoir to best suit the desired resulting tissue orientation.

In some embodiments an anchorable reservoir comprises a tract stimulator and/or monitor IMD comprising a housing enclosing electrical stimulation and/or monitoring circuitry and a power source and an elongated flexible member extending from the housing to an active fixation mechanism adapted to be fixed into the GI tract wall is disclosed. After fixation is effected, the elongated flexible member bends into a preformed shape that presses the housing against the mucosa so that forces that would tend to dislodge the fixation mechanism are minimized. The IMD is fitted into an esophageal catheter lumen with the fixation mechanism aimed toward the catheter distal end opening whereby the bend in the flexible member is straightened. The catheter body is inserted through the esophagus into the GI tract cavity to direct the catheter distal end to the site of implantation and fix the fixation mechanism to the GI tract wall. The IMD is ejected from the lumen, and the flexible member assumes its bent configuration and lodges the hermetically sealed housing against the mucosa. A first stimulation/sense electrode is preferably an exposed conductive portion of the housing that is aligned with the bend of the flexible member so that it is pressed against the mucosa. A second stimulation/sense electrode is located at the fixation site.

In some embodiments a reservoir for sensing one or more parameters of a patient is anchored to a tissue at a specific site and is released from a device, using a single actuator operated during a single motion. As an example, a delivery device may anchor the capsule to the tissue site and release the reservoir from the delivery device during a single motion of the actuator.

In some embodiments a device is provided comprising: a reservoir configured to contain a fluid, the reservoir having at least one outlet through which the fluid may exit the reservoir; a fluid contained within the reservoir; a primary material contained within the reservoir and having a controllable effective concentration in the fluid; and at least one electromagnetically responsive control element located in the reservoir or in a wall of the reservoir and adapted for modifying the distribution of the primary material between a first active form carried in the fluid and a second form within the reservoir in response to an incident electromagnetic control signal, the effective concentration being the concentration of the first active form in the fluid, whereby fluid exiting the reservoir carries the primary material in the first active form at the effective concentration.

In some embodiments systems and methods are provided for implementing or deploying medical or veterinary devices or reservoirs (a) operable for anchoring at least partly within a digestive tract, (b) small enough to pass through the tract per vias natural es and including a wireless-control component, (c) having one or more protrusions positionable adjacent to a mucous membrane, (d) configured to facilitate redundant modes of anchoring, (e) facilitating a "primary" material supply deployable within a stomach for an extended and/or controllable period, (f) anchored by one or more adaptable extender modules supported by a subject's head or neck, and/or (g) configured to facilitate supporting at least a sensor within a subj ect's body lumen for up to a day or more.

In certain embodiments, the reservoir is attachable to an ingestible device. In certain embodiments, the ingestible device comprises a housing and the reservoir is attachable to the housing. In certain embodiments, the attachable reservoir is also an anchorable reservoir, such as an anchorable reservoir comprising one or more anchor systems for anchoring the reservoir at a particular location in the GI tract as disclosed hereinabove.

Accordingly, in certain embodiments, provided herein is a JAK inhibitor for use in a method of treating a disease of the gastrointestinal tract as disclosed herein, wherein the JAK inhibitor is contained in a reservoir suitable for attachment to a device housing, and wherein the method comprises attaching the reservoir to the device housing to form the ingestible device, prior to orally administering the ingestible device to the subject.

In certain embodiments, provided herein is an attachable reservoir containing a JAK inhibitor for use in a method of treating a disease of the gastrointestinal tract, wherein the method comprises attaching the reservoir to a device housing to form an ingestible device and orally administering the ingestible device to a subject, wherein the JAK inhibitor is released by device at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease.

In certain embodiments, provided herein is an attachable reservoir containing a JAK inhibitor, wherein the reservoir is attachable to a device housing to form an ingestible device that is suitable for oral administration to a subject and that is capable of releasing the JAK inhibitor at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease.

In particular implementation the ingestible device includes cameras (e.g., video cameras) that affords inspection of the entire GI tract without discomfort or the need for sedation, thus avoiding many of the potential risks of conventional endoscopy. Video imaging can be used to help determine one or more characteristics of the GI tract, including the location of disease (e.g., presence or location of inflamed tissue and/or lesions associated with inflammatory bowel disease). In some embodiments, the ingestible device 101 may comprise a camera for generating video imaging data of the GI tract which can be used to determine, among other things, the location of the device. Examples of video imaging capsules include Medtronic's PillCam™, Olympus' Endocapsule®, and IntroMedic's MicroCam™. For a review of imaging capsules, see Basar et al. "Ingestible Wireless Capsule Technology: A Review of Development and Future Indication" International Journal of Antennas and Propagation (2012); 1-14). Other imaging technologies implemented with the device 101 can include thermal imaging cameras, and those that employ ultrasound or Doppler principles to generate different images (see Chinese patent application

CN104473611 : "Capsule endoscope system having ultrasonic positioning function". Ingestible devices can be equipped with sources for generating reflected light, including light in the Ultraviolet, Visible, Near-infrared and/or Mid-infrared spectrum, and the corresponding detectors for spectroscopy and hyperspectral imaging. Likewise, autofluorescense may be used to characterize GI tissue (e.g., subsurface vessel information), or low-dose radiation (see Check-Cap™) can be used to obtain 3D reconstructed images.

Device Components

An ingestible device in accordance with particular embodiments of the present invention may comprise a component made of a non-digestible material and containing the JAK inhibitor. In some embodiments, the material is plastic.

It is envisaged that the device is single-use. The device is loaded with a drug prior to the time of administration. In some embodiments, it may be preferred that there is provided a medicinal product comprising the device pre-filled with the drug. Localization components

Various implementations may be used for localization of ingestible devices within the GI tract. For example, certain implementations can include one or more electromagnetic sensor coils, magnetic fields, electromagnetic waves, electric potential values, ultrasound positioning systems, gamma scintigraphy techniques or other radio-tracker technology have been described by others. Alternatively, imaging can be used to localize, for example, using anatomical landmarks or more complex algorithms for 3D reconstruction based on multiple images. Other technologies rely on radio frequency, which relies on sensors placed externally on the body to receive the strength of signals emitted by the capsule. Ingestible devices may also be localized based on reflected light in the medium surrounding the device; pH;

temperature; time following ingestion; and/or acoustic signals.

Anchoring components

Several systems may actively actuate and control the capsule position and orientation in different sections of the GI tract. Examples include leg-like or anchor-like mechanisms that can be deployed by an ingestible device to resist peristaltic forces in narrowed sections of the GI tract, such as the intestine, and anchor the device to a location. Other systems employ magnetic shields of different shapes that can interact with external magnetic fields to move the device. These mechanisms may be particularly useful in areas outside of the small intestine, like the cecum and large intestine.

An anchoring mechanism may be a mechanical mechanism. For example, a device may be a capsule comprising a plurality of legs configured to steer the capsule. The number of legs in the capsule may be, for example, two, four, six, eight, ten or twelve. The aperture between the legs of the device may be up to about 35 mm; about 30 to about 35 mm; about 35 to about 75 mm; or about 70 to about 75 mm. The contact area of each leg may be varied to reduce impact on the tissue. One or more motors in the capsule may each actuate a set of legs independently from the other. The motors may be battery-powered motors.

An anchoring mechanism may be a non-mechanical mechanism. For example, a device may be a capsule comprising a permanent magnet located inside the capsule. The capsule may be anchored at the desired location of the GI tract by an external magnetic field.

An anchoring mechanism may comprise a non-mechanical mechanism and a mechanical mechanism. For example, a device may be a capsule comprising one or more legs, one or more of which are coated with an adhesive material.

Locomotion components

Ingestible devices can be active or passive, depending on whether they have controlled or non-controlled locomotion. Passive (non-controlled) locomotion is more commonly used among ingestible devices given the challenges of implementing a locomotion module. Active (controlled) locomotion is more common in endoscopic ingestible capsules. For example, a capsule may comprise a miniaturized locomotion system (internal locomotion). Internal locomotion mechanisms may employ independent miniaturized propellers actuated by DC brushed motors, or the use of water jets. As an example, a mechanism may comprise flagellar or flap-based swimming mechanisms. As an example, a mechanism may comprise cyclic compression/extension shape-memory alloy (SMA) spring actuators and anchoring systems based on directional micro-needles. As an example, a mechanism may comprise six SMA actuated units, each provided with two SMA actuators for enabling bidirectional motion. As an example, a mechanism may comprise a motor adapted to electrically stimulating the GI muscles to generate a temporary restriction in the bowel.

As an example, a capsule may comprise a magnet and motion of the capsule is caused by an external magnetic field. For example, a locomotion system may comprise an ingestible capsule and an external magnetic field source. For example, the system may comprise an ingestible capsule and magnetic guidance equipment such as, for example, magnetic resonance imaging and computer tomography, coupled to a dedicated control interface. In some embodiments drug release mechanisms may also be triggered by an external condition, such as temperature, pH, movement, acoustics, or combinations thereof.

Use of an endoscope or an ingestible device in biopsy and surgery

Ingestible devices may comprise a mechanism adapted to permit the collection of tissue samples. In some examples, this is achieved using electro-mechanical solutions to collect and store the sample inside an ingestible device. As an example, a biopsy mechanism may include a rotational tissue cutting razor fixed to a torsional spring or the use of microgrippers to fold and collect small biopsies. As an example, Over-the-scope clips (OTSC®) may be used to perform endoscopic surgery and/or biopsy. As an example of the methods disclosed herein, the method may comprise releasing a JAK inhibitor and collecting a sample inside the device. As an example, the method may comprise releasing a JAK inhibitor and collecting a sample inside the device in a single procedure.

Communication systems

An ingestible device may be equipped with a communication system adapted to transmit and/or receive data, including imaging and/or localization data. As an example, a communication system may employ radiofrequency transmission. Ingestible devices using radiofrequency communication are attractive because of their efficient transmission through the layers of the skin. This is especially true for low frequency transmission (UHF-433 ISM and lower, including the Medical Device Radio Communication Service band (MDRS) band 402-406MHz). In another embodiment, acoustics are used for communications, including the transmission of data. For example, an ingestible capsule may be able to transmit information by applying one or more base voltages to an electromechanical transducer or piezoelectric (e.g., PZT, PVDF, etc.) device to cause the piezoelectric device to ring at particular frequencies, resulting in an acoustic transmission. A multi-sensor array for receiving the acoustic transmission may include a plurality of acoustic transducers that receive the acoustic transmission from a movable device such as an ingestible capsule as described in US Patent Application No. 11/851214 filed September 6, 2007, incorporated by reference herein in its entirety. As an example, a communication system may employ human body communication technology. Human body communication technology uses the human body as a conductive medium, which generally requires a large number of sensor electrodes on the skin. As an example, a communication system may integrate a data storage system.

Environmental Sensors

In some embodiments the device may comprise environmental sensors to measure pH, temperature, transit times, or combinations thereof. Other examples of environmental sensors include, but are not limited to a capacitance sensor, an impedance sensor, a heart rate sensor, acoustic sensor such as a microphone or hydrophone, image sensor, and/or a movement sensor. In one embodiment, the ingestible device comprises a plurality of different environmental sensors for generating different kinds of environmental data.

In order to avoid the problem of capsule retention, a thorough past medical and surgical history should be undertaken. In addition, several other steps have been proposed, including performing investigations such as barium follow-through. In cases where it is suspected that there is a high risk of retention, the patient is given a patency capsule a few days before swallowing an ingestible device. Any dissolvable non-endoscopic capsule may be used to determine the patency of the GI tract. The patency capsule is usually the same size as the ingestible device and can be made of cellophane. In some embodiments, the patency capsule contains a mixture of barium and lactose, which allows visualization by x-ray.

The patency capsule may also include a radiotag or other label, which allows for it to be detected by radio-scanner externally. The patency capsule may comprise wax plugs, which allow for intestinal fluid to enter and dissolve the content, thereby dividing the capsule into small particles.

Accordingly, in some embodiments, the methods herein comprise (a) identifying a subject having a disease of the gastrointestinal tract and (b) evaluating the subject for suitability to treatment. In some embodiments, the methods herein comprise evaluating for suitability to treatment a subject identified as having a disease of the gastrointestinal tract. In some embodiments, evaluating the subject for suitability to treatment comprises determining the patency of the subject's GI tract.

In some embodiments, an ingestible device comprises a tissue anchoring mechanism for anchoring the ingestible device to a subject's tissue. For example, an ingestible device could be administered to a subject and once it reaches the desired location, the tissue attachment mechanism can be activated or deployed such that the ingestible device, or a portion thereof, is anchored to the desired location. In some embodiments, the tissue anchoring mechanism is reversible such that after initial anchoring, the tissue attachment device is retracted, dissolved, detached, inactivated or otherwise rendered incapable of anchoring the ingestible device to the subject's tissue. In some embodiments the attachment mechanism is placed endoscopically.

In some embodiments, a tissue anchoring mechanism comprises an osmotically- driven sucker. In some embodiments, the osmotically-driven sucker comprises a first valve on the near side of the osmotically-driven sucker (e.g., near the subject's tissue) and a second one-way valve that is opened by osmotic pressure on the far side of the osmotically-driven sucker, and an internal osmotic pump system comprising salt crystals and semi-permeable membranes positioned between the two valves. In such embodiments, osmotic pressure is used to adhere the ingestible device to the subject's tissue without generating a vacuum within the ingestible capsule. After the osmotic system is activated by opening the first valve, fluid is drawn in through the sucker and expelled through the second burst valve.

Fluid continues to flow until all the salt contained in the sucker is dissolved or until tissue is drawn into the sucker. As liminal fluid is drawn through the osmotic pump system, solutes build up between the tissue and the first valve, reducing osmotic pressure. In some embodiments, the solute buildup stalls the pump before the tissue contacts the valve, preventing tissue damage. In some embodiments, a burst valve is used on the far side of the osmotically-driven sucker rather than a one-way valve, such that luminal fluid eventually clears the saline chamber and the osmotic flow reverses, actively pushing the subject's tissue out of the sucker. In some embodiments, the ingestible device may be anchored to the interior surface of tissues forming the GI tract of a subject. In one embodiment, the ingestible device comprises a connector for anchoring the device to the interior surface of the GI tract. The connector may be operable to ingestible device to the interior surface of the GI tract using an adhesive, negative pressure and/or fastener.

In some embodiments a device comprises a tract stimulator and/or monitor IMD comprising a housing enclosing electrical stimulation and/or monitoring circuitry and a power source and an elongated flexible member extending from the housing to an active fixation mechanism adapted to be fixed into the GI tract wall is disclosed. After fixation is effected, the elongated flexible member bends into a preformed shape that presses the housing against the mucosa so that forces that would tend to dislodge the fixation mechanism are minimized. The IMD is fitted into an esophageal catheter lumen with the fixation mechanism aimed toward the catheter distal end opening whereby the bend in the flexible member is straightened. The catheter body is inserted through the esophagus into the GI tract cavity to direct the catheter distal end to the site of implantation and fix the fixation mechanism to the GI tract wall. The IMD is ejected from the lumen, and the flexible member assumes its bent configuration and lodges the hermetically sealed housing against the mucosa. A first stimulation/sense electrode is preferably an exposed conductive portion of the housing that is aligned with the bend of the flexible member so that it is pressed against the mucosa. A second stimulation/sense electrode is located at the fixation site.

In some embodiments a device includes a fixation mechanism to anchor the device to tissue within a body lumen, and a mechanism to permit selective de-anchoring of the device from the tissue anchoring site without the need for endoscopic or surgical intervention. An electromagnetic device may be provided to mechanically actuate the de-anchoring mechanism. Alternatively, a fuse link may be electrically blown to de-anchor the device. As a further alternative, a rapidly degradable bonding agent may be exposed to a degradation agent to de-anchor the device from a bonding surface within the body lumen.

In some embodiments a device is as disclosed in patent publication

WO2015112575A1, incorporated by reference herein in its entirety. The patent publication is directed to a gastrointestinal sensor implantation system. In some embodiments an orally - administrable capsule comprises a tissue capture device or reservoir removably coupled to the orally-administrable capsule, where the tissue capture device including a plurality of fasteners for anchoring the tissue capture device to gastrointestinal tissue within a body

In some embodiments, the ingestible device contains an electric energy emitting means, a radio signal transmitting means, a medicament storage means and a remote actuatable medicament releasing means. The capsule signals a remote receiver as it progresses through the alimentary tract in a previously mapped route and upon reaching a specified site is remotely triggered to release a dosage of medicament. Accordingly, in some embodiments, releasing the JAK inhibitor is triggered by a remote electromagnetic signal.

In some embodiments, the ingestible device includes a housing introducible into a body cavity and of a material insoluble in the body cavity fluids, but formed with an opening covered by a material which is soluble in body cavity fluids. A diaphragm divides the interior of the housing into a medication chamber including the opening, and a control chamber. An electrolytic cell in the control chamber generates a gas when electrical current is passed therethrough to deliver medication from the medication chamber through the opening into the body cavity at a rate controlled by the electrical current. Accordingly, in some embodiments, releasing the JAK inhibitor is triggered by generation in the composition of a gas in an amount sufficient to expel the JAK inhibitor.

In some embodiments, the ingestible device includes an oral drug delivery device having a housing with walls of water permeable material and having at least two chambers separated by a displaceable membrane. The first chamber receives drug and has an orifice through which the drug is expelled under pressure. The second chamber contains at least one of two spaced apart electrodes forming part of an electric circuit which is closed by the ingress of an aqueous ionic solution into the second chamber. When current flows through the circuit, gas is generated and acts on the displaceable membrane to compress the first chamber and expel the active ingredient through the orifice for progressive delivery to the gastrointestinal tract.

In some embodiments, the ingestible device includes an ingestible device for delivering a substance to a chosen location in the GI tract of a mammal includes a receiver of electromagnetic radiation for powering an openable part of the device to an opened position for dispensing of the substance. The receiver includes a coiled wire that couples the energy field, the wire having an air or ferrite core. In a further embodiment the invention includes an apparatus for generating the electromagnetic radiation, the apparatus including one or more pairs of field coils supported in a housing. The device optionally includes a latch defined by a heating resistor and a fusible restraint. The device may also include a flexible member that may serve one or both the functions of activating a transmitter circuit to indicate dispensing of the substance; and restraining of a piston used for expelling the substance.

In some embodiments, the ingestible device includes an ingestible device for delivering a substance to a chosen location in the GI tract of a mammal includes a receiver of electromagnetic radiation for powering an openable part of the device to an opened position for dispensing of the substance. The receiver includes a coiled wire that couples the energy field, the wire having an air or ferrite core. In a further embodiment the invention includes an apparatus for generating the electromagnetic radiation, the apparatus including one or more pairs of field coils supported in a housing. The device optionally includes a latch defined by a heating resistor and a fusible restraint. The device may also include a flexible member that may serve one or both the functions of activating a transmitter circuit to indicate dispensing of the substance; and restraining of a piston used for expelling the substance. In some embodiments, the ingestible device is a device a swallowable capsule. A sensing module is disposed in the capsule. A bioactive substance dispenser is disposed in the capsule. A memory and logic component is disposed in the capsule and in communication with the sensing module and the dispenser.

In some embodiments, localized administration is implemented via an electronic probe which is introduced into the intestinal tract of a living organism and which operates autonomously therein, adapted to deliver one or more therapy agents. In one embodiment, the method includes loading the probe with one or more therapy agents, and selectively releasing the agents from the probe at a desired location of the intestinal tract in order to provide increased efficacy over traditional oral ingestion or intravenous introduction of the agent(s).

In some embodiments, the ingestible device includes electronic control means for dispensing the drug substantially to the diseased tissue sites of the GI tract, according to a pre-determined drug release profile obtained prior to administration from the specific mammal. Accordingly, in some embodiments, releasing the JAK inhibitor is triggered by an electromagnetic signal generated within the device. The releasing may occur according to a pre-determined drug release profile.

In some embodiments, the ingestible device can include at least one guide tube, one or more tissue penetrating members positioned in the guide tube, a delivery member, an actuating mechanism and a release element. The release element degrades upon exposure to various conditions in the intestine so as to release and actuate the actuating mechanism. Embodiments of the invention are particularly useful for the delivery of drugs which are poorly absorbed, tolerated and/or degraded within the GI tract.

In some embodiments, the ingestible device includes an electronic pill comprising at least one reservoir with a solid powder or granulate medicament or formulation, a discharge opening and an actuator responsive to control circuitry for displacing medicine from the reservoir to the discharge opening. The medicament or formulation comprises a dispersion of one or more active ingredients—e.g., solids in powder or granulate form-in an inert carrier matrix. Optionally, the active ingredients are dispersed using intestinal moisture absorbed into the pill via a semi-permeable wall section.

In some embodiments, the ingestible device includes a sensor comprising a plurality of electrodes having a miniature size and a lower power consumption and a coating exterior to the electrodes, wherein the coating interacts with a target condition thereby producing a change in an electrical property of the electrodes, wherein the change is transduced into an electrical signal by the electrodes. Accordingly, in some embodiments, releasing the JAK inhibitor is triggered by an electric signal by the electrodes resulting from the interaction of the coating with the one or more sites of disease. Further provided herein is a system for medication delivery comprising such sensor and a pill.

In some embodiments, the ingestible device includes an electronic pill comprising a plurality of reservoirs, each of the reservoirs comprising a discharge opening covered by a removable cover. The pill comprises at least one actuator responsive to control circuitry for removing the cover from the discharge opening. The actuator can for example be a spring loaded piston breaking a foil cover when dispensing the medicament. Alternatively, the cover can be a rotatable disk or cylinder with an opening which can be brought in line with the discharge opening of a reservoir under the action of the actuator.

In some embodiments, the ingestible device includes an electronically and remotely controlled pill or medicament delivery system. The pill includes a housing; a reservoir for storing a medicament; an electronically controlled release valve or hatch for dispensing one or more medicaments stored in the reservoir while traversing the gastrointestinal tract; control and timing circuitry for opening and closing the valve; and a battery. The control and timing circuitry opens and closes the valve throughout a dispensing time period in accordance with a preset dispensing timing pattern which is programmed within the control and timing circuitry. RF communication circuitry receives control signals for remotely overriding the preset dispensing timing pattern, reprogramming the control and timing circuitry or terminating the dispensing of the medicament within the body. The pill includes an RFID tag for tracking, identification, inventory and other purposes.

In some embodiments, the ingestible device includes an electronic capsule which has a discrete drive element comprising: a housing, electronics for making the electronic capsule operable, a pumping mechanism for dosing and displacing a substance, a power source for powering the electronic capsule and enabling the electronics and the pumping mechanism to operate, and a locking mechanism; and a discrete payload element comprising: a housing, a reservoir for storing the substance, one or more openings in the housing for releasing the substance from the reservoir and a locking mechanism for engaging the drive element locking mechanism. Engagement of the drive element locking mechanism with the payload element locking mechanism secures the drive element to the payload element, thereby making the electronic capsule operable and specific. In some embodiments, the ingestible device may be a mucoadhesive device configured for release of an active agent.

In some embodiments, the ingestible device includes an apparatus that includes an ingestible medical treatment device, which is configured to initially assume a contracted state having a volume of less than 4 cm³. The device includes a gastric anchor, which initially assumes a contracted size, and which is configured to, upon coming in contact with a liquid, expand sufficiently to prevent passage of the anchor through a round opening having a diameter of between 1 cm and 3 cm. The device also includes a duodenal unit, which is configured to pass through the opening, and which is coupled to the gastric anchor such that the duodenal unit is held between 1 cm and 20 cm from the gastric anchor.

In some embodiments, the ingestible device includes a medical robotic system and method of operating such comprises taking intraoperative external image data of a patient anatomy, and using that image data to generate a modeling adjustment for a control system of the medical robotic system (e.g., updating anatomic model and/or refining instrument registration), and/or adjust a procedure control aspect (e.g., regulating substance or therapy delivery, improving targeting, and/or tracking performance).

In one embodiment the ingestible device may also include one or more environmental sensors. Environmental sensor may be used to generate environmental data for the environment external to device in the gastrointestinal (GI) tract of the subject. In some embodiments, environmental data is generated at or near the location within the GI tract of the subject where a drug is delivered. Examples of environmental sensor include, but are not limited to a capacitance sensor, a temperature sensor, an impedance sensor, a pH sensor, a heart rate sensor, acoustic sensor, image sensor (e.g., a hydrophone), and/or a movement sensor (e.g., an accelerometer). In one embodiment, the ingestible device comprises a plurality of different environmental sensors for generating different kinds of environmental data.

In one embodiment, the image sensor is a video camera suitable for obtaining images in vivo of the tissues forming the GI tract of the subject. In one embodiment, the

environmental data is used to help determine one or more characteristics of the GI tract, including the location of disease (e.g., presence or location of inflamed tissue and/or lesions associated with inflammatory bowel disease). In some embodiments, the ingestible device may comprise a camera for generating video imaging data of the GI tract which can be used to determine, among other things, the location of the device. In another embodiment, the ingestible device described herein may be localized using a gamma scintigraphy technique or other radio-tracker technology as employed by Phaeton Research's Enterion™ capsule (See Teng, Renli, and Juan Maya. "Absolute bioavailability and regional absorption of ticagrelor in healthy volunteers. " Journal of Drug Assessment 3.1 (2014): 43-50), or monitoring the magnetic field strength of permanent magnet in the ingestible device (see T. D. Than, et al, "A review of localization systems for robotic endoscopic capsules," IEEE Trans. Biomed. Eng., vol. 59, no. 9, pp. 2387-2399, Sep. 2012).

In one embodiment, drug delivery is triggered when it encounters the site of disease in the GI tract.

In one embodiment, the one or more environmental sensors measure pH, temperature, transit times, or combinations thereof.

In some embodiments, releasing the JAK inhibitor is dependent on the pH at or in the vicinity of the location. In some embodiments the pH in the jejunum is from 6.1 to 7.2, such as 6.6. In some embodiments the pH in the mid small bowel is from 7.0 to 7.8, such as 7.4. In some embodiments the pH in the ileum is from 7.0 to 8.0, such as 7.5. In some embodiments the pH in the right colon is from 5.7 to 7.0, such as 6.4. In some embodiments the pH in the mid colon is from 5.7 to 7.4, such as 6.6. In some embodiments the pH in the left colon is from 6.3 to 7.7, such as 7.0. In some embodiments, the gastric pH in fasting subjects is from about 1.1 to 2.1 , such as from 1.4 to 2.1, such as from 1.1 to 1.6, such as from 1.4 to 1.6. In some embodiments, the gastric pH in fed subjects is from 3.9 to 7.0, such as from 3.9 to 6.7, such as from 3.9 to 6.4, such as from 3.9 to 5.8, such as from 3.9 to 5.5, such as from 3.9 to 5.4, such as from 4.3 to 7.0, such as from 4.3 to 6.7, such as from 4.3 to

6.4, such as from 4.3 to 5.8, such as from 4.3 to 5.5, such as from 4.3 to 5.4. In some embodiments, the pH in the duodenum is from 5.8 to 6.8, such as from 6.0 to 6.8, such as from 6.1 to 6.8, such as from 6.2 to 6.8, such as from 5.8 to 6.7, such as from 6.0 to 6.7, such as from 6.1 to 6.7, such as from 6.2 to 6.7, such as from 5.8 to 6.6, such as from 6.0 to 6.6, such as from 6.1 to 6.6, such as from 6.2 to 6.6, such as from 5.8 to 6.5, such as from 6.0 to

6.5, such as from 6.1 to 6.5, such as from 6.2 to 6.5.

In some embodiments, releasing the JAK inhibitor is not dependent on the pH at or in the vicinity of the location. In some embodiments, releasing the JAK inhibitor is triggered by degradation of a release component located in the capsule. In some embodiments, the JAK inhibitor is not triggered by degradation of a release component located in the capsule. In some embodiments, wherein releasing the JAK inhibitor is not dependent on enzymatic activity at or in the vicinity of the location. In some embodiments, releasing the JAK inhibitor is not dependent on bacterial activity at or in the vicinity of the location.

In some embodiments, the pharmaceutical composition is an ingestible device, comprising:

a housing defined by a first end, a second end substantially opposite from the first end, and a wall extending longitudinally from the first end to the second end;

a reservoir located within the housing and containing the JAK inhibitor, wherein a first end of the reservoir is attached to the first end of the housing;

a mechanism for releasing the JAK inhibitor from the reservoir;

and;

an exit valve configured to allow the JAK inhibitor to be released out of the housing from the reservoir.

In some embodiments, the ingestible device further comprises:

an electronic component located within the housing; and

a gas generating cell located within the housing and adjacent to the electronic component,

wherein the electronic component is configured to activate the gas generating cell to generate gas.

In some embodiments, the ingestible device further comprises:

a safety device placed within or attached to the housing,

wherein the safety device is configured to relieve an internal pressure within the housing when the internal pressure exceeds a threshold level.

In some embodiments, the pharmaceutical composition is an ingestible device, comprising:

a housing defined by a first end, a second end substantially opposite from the first end, and a wall extending longitudinally from the first end to the second end;

an electronic component located within the housing;

a gas generating cell located within the housing and adjacent to the electronic component,

wherein the electronic component is configured to activate the gas generating cell to generate gas;

a reservoir located within the housing, wherein the reservoir stores a dispensable substance and a first end of the reservoir is attached to the first end of the housing;

an exit valve located at the first end of the housing,

wherein the exit valve is configured to allow the dispensable substance to be released out of the first end of the housing from the reservoir; and

a safety device placed within or attached to the housing,

wherein the safety device is configured to relieve an internal pressure within the housing when the internal pressure exceeds a threshold level.

In some embodiments, the pharmaceutical composition is an ingestible device, comprising: a housing defined by a first end, a second end substantially opposite from the first end, and a wall extending longitudinally from the first end to the second end;

an electronic component located within the housing,

a gas generating cell located within the housing and adjacent to the electronic component,

wherein the electronic component is configured to activate the gas generating cell to generate gas;

a reservoir located within the housing,

wherein the reservoir stores a dispensable substance and a first end of the reservoir is attached to the first end of the housing;

an injection device located at the first end of the housing,

wherein the jet injection device is configured to inject the dispensable substance out of the housing from the reservoir; and

a safety device placed within or attached to the housing,

wherein the safety device is configured to relieve an internal pressure within the housing.

In some embodiments, the pharmaceutical composition is an ingestible device, comprising:

a housing defined by a first end, a second end substantially opposite from the first end, and a wall extending longitudinally from the first end to the second end;

an optical sensing unit located on a side of the housing,

wherein the optical sensing unit is configured to detect a reflectance from an environment external to the housing; an electronic component located within the housing;

a gas generating cell located within the housing and adjacent to the electronic component,

wherein the electronic component is configured to activate the gas generating cell to generate gas in response to identifying a location of the ingestible device based on the reflectance;

a reservoir located within the housing,

wherein the reservoir stores a dispensable substance and a first end of the reservoir is attached to the first end of the housing;

a membrane in contact with the gas generating cell and configured to move or deform into the reservoir by a pressure generated by the gas generating cell; and

a dispensing outlet placed at the first end of the housing,

wherein the dispensing outlet is configured to deliver the dispensable substance out of the housing from the reservoir.

In some embodiments, the pharmaceutical composition is an ingestible device as disclosed in US Patent Application Ser. No. 62/385,553, incorporated by reference herein in its entirety.

In some embodiments, the pharmaceutical composition is an ingestible device comprising a localization mechanism as disclosed in international patent application

PCT/US2015/052500, incorporated by reference herein in its entirety.

In some embodiments, the pharmaceutical composition is not a dart-like dosage form. In case of conflict between the present specification and any subject matter incorporated by reference herein, the present specification, including definitions, will control. Locations of treatment

In some embodiments, the JAK inhibitor is delivered at a location in the large intestine of the subj ect. In some embodiments, the location is in the proximal portion of the large intestine. In some embodiments, the location is in the distal portion of the large intestine.

In some embodiments, the JAK inhibitor is delivered at a location in the ascending colon of the subject. In some embodiments, the location is in the proximal portion of the ascending colon. In some embodiments, the location is in the distal portion of the ascending colon. In some embodiments, the JAK inhibitor is delivered at a location in the cecum of the subject. In some embodiments, the location is in the proximal portion of the cecum. In some embodiments, the location is in the distal portion of the cecum.

In some embodiments, the JAK inhibitor is delivered at a location in the sigmoid colon of the subject. In some embodiments, the location is in the proximal portion of the sigmoid colon. In some embodiments, the location is in the distal portion of the sigmoid colon.

In some embodiments, the JAK inhibitor is delivered at a location in the transverse colon of the subject. In some embodiments, the location is in the proximal portion of the transverse colon. In some embodiments, the location is in the distal portion of the transverse colon.

In some embodiments, the JAK inhibitor is delivered at a location in the descending colon of the subject. In some embodiments, the location is in the proximal portion of the descending colon. In some embodiments, the location is in the distal portion of the descending colon.

In some embodiments, the JAK inhibitor is delivered at a location in the small intestine of the subj ect. In some embodiments, the location is in the proximal portion of the small intestine. In some embodiments, the location is in the distal portion of the small intestine.

In some embodiments, the JAK inhibitor is delivered at a location in the duodenum of the subject. In some embodiments, the location is in the proximal portion of the duodenum. In some embodiments, the location is in the distal portion of the duodenum.

In some embodiments, the JAK inhibitor is delivered at a location in the jejunum of the subject. In some embodiments, the location is in the proximal portion of the jejunum. In some embodiments, the location is in the distal portion of the jejunum.

In some embodiments, the JAK inhibitor is delivered at a location in the duodenum of the subject and is not delivered at other locations in the gastrointestinal tract. In some embodiments, the JAK inhibitor is delivered at a location in the duodenum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a site of disease is in the duodenum and no site of disease is present at other locations in the gastrointestinal tract. In some embodiments, the JAK inhibitor is delivered at a location in the duodenum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a first site of disease is in the duodenum and a second site of disease is in the stomach and no site of disease is present at other locations in the gastrointestinal tract.

In some embodiments, the JAK inhibitor is delivered at a location in the proximal duodenum of the subject and is not delivered at other locations in the gastrointestinal tract. In some embodiments, the JAK inhibitor is delivered at a location in the proximal duodenum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a site of disease is in the duodenum and no site of disease is present at other locations in the gastrointestinal tract. In some embodiments, the JAK inhibitor is delivered at a location in the proximal duodenum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a first site of disease is in the duodenum and a second site of disease is in the stomach and no site of disease is present at other locations in the gastrointestinal tract.

In some embodiments, the JAK inhibitor is delivered at a location in the jejunum of the subject and is not delivered at other locations in the gastrointestinal tract. In some embodiments, the JAK inhibitor is delivered at a location in the jejunum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a site of disease is in the jejunum and no site of disease is present at other locations in the gastrointestinal tract. In some embodiments, the JAK inhibitor is delivered at a location in the jejunum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a first site of disease is in the jejunum and a second site of disease is in the ileum and no site of disease is present at other locations in the gastrointestinal tract.

In some embodiments, the JAK inhibitor is delivered at a location in the proximal portion of the jejunum of the subject and is not delivered at other locations in the gastrointestinal tract. In some embodiments, the JAK inhibitor is delivered at a location in the proximal portion of the jejunum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a site of disease is in the j ejunum and no site of disease is present at other locations in the gastrointestinal tract. In some embodiments, the JAK inhibitor is delivered at a location in the proximal portion of the jejunum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a first site of disease is in the jejunum and a second site of disease is in the ileum and no site of disease is present at other locations in the gastrointestinal tract.

In some embodiments, the JAK inhibitor is delivered at a location in the distal portion of the jejunum of the subject and is not delivered at other locations in the gastrointestinal tract. In some embodiments, the JAK inhibitor is delivered at a location in the distal portion of the jejunum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a site of disease is in the jejunum and no site of disease is present at other locations in the gastrointestinal tract. In some embodiments, the JAK inhibitor is delivered at a location in the distal portion of the jejunum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a first site of disease is in the jejunum and a second site of disease is in the ileum and no site of disease is present at other locations in the gastrointestinal tract.

In some embodiments, the JAK inhibitor is delivered at a location in the ileum of the subject. In some embodiments, the location is in the proximal portion of the ileum. In some embodiments, the location is in the distal portion of the ileum.

In some embodiments, the JAK inhibitor is delivered at a location in the ileum of the subject and is not delivered at other locations in the gastrointestinal tract. In some embodiments, the JAK inhibitor is delivered at a location in the ileum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a site of disease is in the ileum and no site of disease is present at other locations in the gastrointestinal tract. In some embodiments, the JAK inhibitor is delivered at a location in the ileum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a first site of disease is in the ileum and a second site of disease is in the cecum and no site of disease is present at other locations in the gastrointestinal tract. In some embodiments, the JAK inhibitor is delivered at a location in the ileum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a first site of disease is in the ileum and a second site of disease is in the cecum and/or ascending colon, and no site of disease is present at other locations in the

gastrointestinal tract.

In some embodiments, the JAK inhibitor is delivered at a location in the proximal portion of the ileum of the subject and is not delivered at other locations in the gastrointestinal tract. In some embodiments, the JAK inhibitor is delivered at a location in the proximal portion of the ileum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a site of disease is in the ileum and no site of disease is present at other locations in the gastrointestinal tract. In some embodiments, the JAK inhibitor is delivered at a location in the proximal portion of the ileum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a first site of disease is in the ileum and a second site of disease is in the cecum and no site of disease is present at other locations in the gastrointestinal tract. In some embodiments, the JAK inhibitor is delivered at a location in the proximal portion of the ileum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a first site of disease is in the ileum and a second site of disease is in the cecum and/or ascending colon, and no site of disease is present at other locations in the gastrointestinal tract.

In some embodiments, the JAK inhibitor is delivered at a location in the distal portion of the ileum of the subject and is not delivered at other locations in the gastrointestinal tract. In some embodiments, the JAK inhibitor is delivered at a location in the distal portion of the ileum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a site of disease is in the ileum and no site of disease is present at other locations in the gastrointestinal tract. In some embodiments, the JAK inhibitor is delivered at a location in the distal portion of the ileum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a first site of disease is in the ileum and a second site of disease is in the cecum and no site of disease is present at other locations in the gastrointestinal tract. In some embodiments, the JAK inhibitor is delivered at a location in the distal portion of the ileum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a first site of disease is in the ileum and a second site of disease is in the cecum and/or ascending colon, and no site of disease is present at other locations in the

gastrointestinal tract.

In some embodiments, the JAK inhibitor is delivered at a location in the cecum of the subject and is not delivered at other locations in the gastrointestinal tract. In some embodiments, the JAK inhibitor is delivered at a location in the distal portion of the cecum of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a site of disease is in the cecum and/or ascending colon, and no site of disease is present at other locations in the gastrointestinal tract. In some embodiments, the JAK inhibitor is delivered at a location in the distal portion of the ileum or the proximal portion of the ascending colon of the subject and is not delivered at other locations in the gastrointestinal tract, wherein a first site of disease is in the cecum and a second site of disease is in the ascending colon, and no site of disease is present at other locations in the gastrointestinal tract.

In some embodiments, the location at which the JAK inhibitor is delivered is proximate to a site of disease. The site of disease may be, for example, an injury, inflamed tissue, or one or more lesions. In some embodiments, the location at which the JAK inhibitor is delivered is proximate to one or more sites of disease. In some embodiments, the JAK inhibitor is delivered 50 cm or less from the one or more sites of disease. In some embodiments, the JAK inhibitor is delivered 40 cm or less from the one or more sites of disease. In some embodiments, the JAK inhibitor is delivered 30 cm or less from the one or more sites of disease. In some embodiments, the JAK inhibitor is delivered 20 cm or less from the one or more sites of disease. In some embodiments, the JAK inhibitor is delivered 10 cm or less from the one or more sites of disease. In some embodiments, the JAK inhibitor is delivered 5 cm or less from the one or more sites of disease. In some embodiments, the JAK inhibitor is delivered 2 cm or less from the one or more sites of disease. In some embodiments, the method further comprises identifying the one or more sites of disease by a method comprising imaging of the gastrointestinal tract. In some embodiments, imaging of the gastrointestinal tract comprises video imaging. In some embodiments, imaging of the gastrointestinal tract comprises thermal imaging. In some embodiments, imaging of the gastrointestinal tract comprises ultrasound imaging. In some embodiments, imaging of the gastrointestinal tract comprises Doppler imaging.

In some embodiments the method does not comprise releasing more than 20 % of the

JAK inhibitor at a location that is not proximate to a site of disease. In some embodiments the method does not comprise releasing more than 10 % of the JAK inhibitor at a location that is not proximate to a site of disease. In some embodiments the method does not comprise releasing more than 5 % of the JAK inhibitor at a location that is not proximate to a site of disease. In some embodiments the method does not comprise releasing more than 4 % of the JAK inhibitor at a location that is not proximate to a site of disease. In some embodiments the method does not comprise releasing more than 3 % of the JAK inhibitor at a location that is not proximate to a site of disease. In some embodiments the method does not comprise releasing more than 2 % of the JAK inhibitor at a location that is not proximate to a site of disease.

In some embodiments the method comprises releasing the JAK inhibitor at a location that is proximate to a site of disease, wherein the JAK inhibitor and, if applicable, any carriers, excipients or stabilizers admixed with the JAK inhibitor, are substantially unchanged, at the time of release of the JAK inhibitor at the location, relatively to the time of administration of the composition to the subject.

In some embodiments the method comprises releasing the JAK inhibitor at a location that is proximate to a site of disease, wherein the JAK inhibitor and, if applicable, any carriers, excipients or stabilizers admixed with the JAK inhibitor, are substantially unchanged by any physiological process (such as, but not limited to, degradation in the stomach), at the time of release of the JAK inhibitor at the location, relatively to the time of administration of the composition to the subject.

In some embodiments, the JAK inhibitor is delivered to the location by mucosal contact.

In some embodiments, the JAK inhibitor is delivered to the location by a process that does not comprise systemic transport of the JAK inhibitor.

In some embodiments, the amount of the JAK inhibitor that is administered is from about 1 mg to about 500 mg. In some embodiments, the amount of the JAK inhibitor that is administered is from about 1 mg to about 100 mg. In some embodiments, the amount of the JAK inhibitor that is administered is from about 5 mg to about 40 mg.

In some embodiments, the amount of the JAK inhibitor that is administered is less than an amount that is effective when the JAK inhibitor is delivered systemically.

In some embodiments, the amount of the JAK inhibitor that is administered is an induction dose. In some embodiments, such induction dose is effective to induce remission of the TNF and cytokine storm and healing of acute inflammation and lesions. In some embodiments, the induction dose is administered once a day. In some embodiments, the induction dose is administered once every three days. In some embodiments, the induction dose is administered once a week. In some embodiments, the induction dose is administered once a day, once every three days, or once a week, over a period of about 6-8 weeks.

In some embodiments, the method comprises administering (i) an amount of the JAK inhibitor that is an induction dose, and (ii) an amount of the JAK inhibitor that is a maintenance dose, in this order. In some embodiments, step (ii) is repeated one or more times. In some embodiments, the induction dose is equal to the maintenance dose. In some embodiments, the induction dose is greater than the maintenance dose. In some

embodiments, the induction dose is five times greater than the maintenance dose. In some embodiments, the induction dose is two times greater than the maintenance dose.

In some embodiments an induction dose of JAK inhibitor and a maintenance dose of JAK inhibitor are each administered to the subject by administering a pharmaceutical composition comprising a therapeutically effective amount of the JAK inhibitor, wherein the pharmaceutical composition is a device. In some embodiments an induction dose of JAK inhibitor is administered to the subject in a different manner from the maintenance dose. As an example, the induction dose may be administered systemically. In some embodiments, the induction dose may be administered other than orally. As an example, the induction dose may be administered rectally. As an example, the induction dose may be administered intravenously. As an example, the induction dose may be administered subcutaneously. In some embodiments, the induction dose may be administered by spray catheter.

In some embodiments, the concentration of the JAK inhibitor delivered at the location in the gastrointestinal tract is 10%, 25%, 50%, 75%, 100%, 200%, 300%, 400%, 500%, 1000%, 2000% greater than the concentration of JAK inhibitor in plasma.

In some embodiments, the method provides a concentration of the JAK inhibitor at a location that is a site of disease or proximate to a site of disease that is 2-100 times greater than at a location that is not a site of disease or proximate to a site of disease.

In some embodiments, the method comprises delivering the JAK inhibitor at the location in the gastrointestinal tract as a single bolus.

In some embodiments, the method comprises delivering the JAK inhibitor at the location in the gastrointestinal tract as more than one bolus.

In some embodiments, the method comprises delivering the JAK inhibitor at the location in the gastrointestinal tract in a continuous manner.

In some embodiments, the method comprises delivering the JAK inhibitor at the location in the gastrointestinal tract over a time period of 20 or more minutes.

In some embodiments, the method provides a concentration of the JAK inhibitor in the plasma of the subject that is less than 10 μg/ml. In some embodiments, the method provides a concentration of the JAK inhibitor in the plasma of the subject that is less than 3 μg/ml. In some embodiments, the method provides a concentration of the JAK inhibitor in the plasma of the subject that is less than 1 μg/ml. In some embodiments, the method provides a concentration of the JAK inhibitor in the plasma of the subject that is less than 0.3 μg/ml. In some embodiments, the method provides a concentration of the JAK inhibitor in the plasma of the subject that is less than 0.1 μg/ml. In some embodiments, the method provides a concentration of the JAK inhibitor in the plasma of the subject that is less than 0.01 μg/ml. In some embodiments, the values of the concentration of the JAK inhibitor in the plasma of the subject provided herein refer to Ctrough, that is, the lowest value of the concentration prior to administration of the next dose.

In some embodiments, the method does not comprise delivering a JAK inhibitor rectally to the subject. In some embodiments, the method does not comprise delivering a JAK inhibitor via an enema to the subject.

In some embodiments, the method does not comprise delivering a JAK inhibitor via suppository to the subject.

In some embodiments, the method does not comprise delivering a JAK inhibitor via instillation to the rectum of a subject.

In some embodiments, the methods disclosed herein comprise producing a therapeutically effective degradation product of the JAK inhibitor in the gastrointestinal tract. In some embodiments, the degradation product is a therapeutic antibody fragment. In some embodiments, a therapeutically effective amount of the degradation product is produced.

In some embodiments, the methods comprising administering the JAK inhibitor in the manner disclosed herein disclosed herein result in a reduced immunosuppressive properties relative to methods of administration of the JAK inhibitor systemically.

In some embodiments, the methods comprising administering the JAK inhibitor in the manner disclosed herein disclosed herein result in reduced immunogenicity relative to methods of administration of the JAK inhibitor systemically.

Markers

In some embodiments, the methods provided herein comprise monitoring the progress of the disease. In some embodiments, monitoring the progress of the disease comprises measuring the levels of IBD serological markers. In some embodiments, monitoring the progress of the disease comprises determining mucosal healing at the location of release. In some embodiments, monitoring the progress of the disease comprises determining the Crohn's Disease Activity Index (CDAI) over a period of about 6-8 weeks, or over a period of about 52 weeks, following administration of the JAK inhibitor. In some embodiments, monitoring the progress of the disease comprises determining the Harvey-Bradshaw Index (HBI) following administration of the JAK inhibitor. Possible markers may include the following: anti-glycan antibodies: anti-Saccharomices cerevisiae (ASCA); anti- laminaribioside (ALCA); anti-chitobioside (ACCA); anti-mannobioside (AMCA); anti- laminarin (anti-L); anti-chitin (anti-C) antibodies: anti-outer membrane porin C (anti-OmpC), anti-Cbirl flagellin; anti-12 antibody; autoantibodies targeting the exocrine pancreas (PAB); perinuclear anti-neutrophil antibody (pANCA). In some embodiments, monitoring the progress of the disease comprises measuring JAK inhibitor levels in serum over a period of about 1-14 weeks, such as about 6-8 weeks following administration of the JAK inhibitor, including at the 6-8 week time point. In some embodiments, monitoring the progress of the disease comprises measuring JAK inhibitor levels in serum over a period of about 52 weeks following administration of the JAK inhibitor, including at the 52 week time point.

Patients condition, diagnosis and treatment

In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises one or more of the following:

a) identifying a subject having a disease of the gastrointestinal tract, for example by endoscopy or colonoscopy;

b) determination of the severity of the disease, for example with reference to the Mayo Clinic Score, the Crohn's Disease Activity Index (CDAI), the Harvey-Bradshaw Index (HBI), or a combination of the above;

c) determination of the location of the disease, for example as determined by the

presence of lesions indicative of the disease;

d) evaluating the subject for suitability to treatment, for example by determining the patency of the subject's GI tract, for example if the indication is small intestinal diseases, pancolitis, Crohn's disease, or if the patients has strictures or fistulae; e) administration of an induction dose or of a maintenance dose of a drug, such as the JAK inhibitor or such as another drug that is effective in the treatment of IBD conditions;

f) monitoring the progress of the disease, for example with reference to the Mayo Clinic Score, the Crohn's Disease Activity Index (CDAI), the Harvey-Bradshaw Index (HBI), the PRO, PR02 or PR03 tools, or a combination of the above; and/or g) optionally repeating steps e) and f) one or more times, for example over a period of about 1-14 weeks, such as about 6-8 weeks following administration of the JAK inhibitor, including at the 6-8 week time point, or over a period of about 52 weeks following administration of the JAK inhibitor, including at the 52 week time point. As used herein, an induction dose is a dose of drug that may be administered, for example, at the beginning of a course of treatment, and that is higher than the maintenance dose administered during treatment. An induction dose may also be administered during treatment, for example if the condition of the patients becomes worse. As used herein, a maintenance dose is a dose of drug that is provided on a repetitive basis, for example at regular dosing intervals.

In some embodiments the JAK inhibitor is released from an ingestible device.

In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises a) hereinabove.

In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises b) hereinabove.

In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises c) hereinabove.

In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises d) hereinabove.

In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises e) hereinabove.

In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises f) hereinabove.

In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises g) hereinabove.

In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises a) and b) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises a) and c) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises a) and d) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises a) and e) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises a) and f) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises a) and g) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises b) and c) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises b) and d) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises b) and e) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises b) and f) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises b) and g) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises c) and d) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises c) and e) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the gastrointestinal tract that is proximate to one or more sites of disease comprises c) and f) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the

gastrointestinal tract that is proximate to one or more sites of disease comprises c) and g) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the

gastrointestinal tract that is proximate to one or more sites of disease comprises d) and e) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the

gastrointestinal tract that is proximate to one or more sites of disease comprises d) and f) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the

gastrointestinal tract that is proximate to one or more sites of disease comprises d) and g) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the

gastrointestinal tract that is proximate to one or more sites of disease comprises e) and f) hereinabove. In some embodiments herein, the method of treating a disease of the gastrointestinal tract that comprises releasing a JAK inhibitor at a location in the

gastrointestinal tract that is proximate to one or more sites of disease comprises g) hereinabove.

In some embodiments, one or more steps a) to e) herein comprise endoscopy of the gastrointestinal tract. In some embodiments, one or more steps a) to e) herein comprise colonoscopy of the gastrointestinal tract. In some embodiments, one or more steps a) to e) herein is performed one or more times. In some embodiments, such one or more of such one or more steps a) to e) is performed after releasing the JAK inhibitor at the location in the gastrointestinal tract that is proximate to one or more sites of disease.

In some embodiments, the method comprises administering one or more maintenance doses following administration of the induction dose in step e). In some embodiments an induction dose of JAK inhibitor and a maintenance dose of JAK inhibitor are each administered to the subject by administering a pharmaceutical composition comprising a therapeutically effective amount of the JAK inhibitor. In some embodiments an induction dose of JAK inhibitor is administered to the subject in a different manner from the maintenance dose. As an example, the maintenance dose may be administered systemically, while the maintenance dose is administered locally using a device. In one embodiment, a maintenance dose is administered systemically, and an induction dose is administered using a device every 1 , 2, 3, 4, 5, 6, 7, 10, 15, 20, 25, 30, 35, 40, or 45 days. In another embodiment, a maintenance dose is administered systemically, and an induction dose is administered when a disease flare up is detected or suspected.

In some embodiments, the induction dose is a dose of the JAK inhibitor administered in an ingestible device as disclosed herein. In some embodiments, the maintenance dose is a dose of the JAK inhibitor administered in an ingestible device as disclosed herein.

In some embodiments, the induction dose is a dose of the JAK inhibitor administered in an ingestible device as disclosed herein. In some embodiments, the maintenance dose is a dose of the JAK inhibitor delivered systemically, such as orally with a tablet or capsule, or subcutaneously, or intravenously.

In some embodiments, the induction dose is a dose of the JAK inhibitor delivered systemically, such as orally with a tablet or capsule, or subcutaneously, or intravenously. In some embodiments, the maintenance dose is a dose of the JAK inhibitor administered in an ingestible device as disclosed herein.

In some embodiments, the induction dose is a dose of the JAK inhibitor administered in an ingestible device as disclosed herein. In some embodiments, the maintenance dose is a dose of a second agent as disclosed herein delivered systemically, such as orally with a tablet or capsule, or subcutaneously, or intravenously.

In some embodiments, the induction dose is a dose of a second agent as disclosed herein delivered systemically, such as orally with a tablet or capsule, or subcutaneously, or intravenously. In some embodiments, the maintenance dose is a dose of the JAK inhibitor administered in an ingestible device as disclosed herein.

In one embodiment of the methods provided herein, the patient is not previously treated with a JAK inhibitor. In one embodiment, the gastrointestinal inflammatory disorder is an inflammatory bowel disease. In one embodiment, the inflammatory bowel disease is ulcerative colitis or Crohn's disease. In one embodiment, the inflammatory bowel disease is ulcerative colitis and the response is selected from clinical response, mucosal healing and remission. In certain embodiments, remission in the patient is determined to be induced when the Mayo Clinic Score < 2 and no individual subscore >1, which is also referred to as clinical remission. In certain embodiments, mucosal healing is determined to have occurred when the patient is determined to have an endoscopy subscore of 0 or 1 as assessed by flexible sigmoidoscopy. In certain such embodiments, patients who experience mucosal healing are determined to have an endoscopy subscore of 0. In certain embodiments, clinical response is determined to have occurred when the patient experiences a 3 -point decrease and 30% reduction from baseline in MCS and > 1 -point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1.

In some embodiments, the method comprises identifying the disease site substantially at the same time as releasing the JAK inhibitor.

In some embodiments, the method comprises monitoring the progress of the disease. In some embodiments, monitoring the progress of the disease comprises measuring the weight of the subject over a period of about 1-14 weeks, such as about 6-8 weeks following administration of the JAK inhibitor, including at the 6-8 week time point, or over a period of about 52 weeks following administration of the JAK inhibitor, including at the 52 week time point. In some embodiments, monitoring the progress of the disease comprises measuring the food intake of the subject; measuring the level of blood in the feces of the subject; measuring the level of abdominal pain of the subject; and/or a combination of the above, for example over a period of about 1-14 weeks, such as about 6-8 weeks following administration of the JAK inhibitor, including at the 6-8 week time point, or over a period of about 52 weeks following administration of the JAK inhibitor, including at the 52 week time point.

In some embodiments, the method comprises administering a JAK inhibitor with a spray catheter. For example, administering a JAK inhibitor with a spray catheter may be performed in step (e) hereinabove.

In some embodiments, the method does not comprise administering a JAK inhibitor with a spray catheter.

Pharmaceutical Formulations

As used herein, a "formulation" of a JAK inhibitor may refer to either the JAK inhibitor in pure form - such as, for example, the lyophilized JAK inhibitor - or a mixture of the JAK inhibitor with one or more physiologically acceptable carriers, excipients or stabilizers. Thus, therapeutic formulations or medicaments can be prepared by mixing the JAK inhibitor having the desired degree of purity with optional physiologically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids;

antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) antibody; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt- forming counter-ions such as sodium; metal complexes (e.g. , Zn- protein complexes); and/or non- ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).

Exemplary pharmaceutically acceptable carriers herein further include insterstitial drug dispersion agents such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP), for example, human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20

(HYLENEX<®>, Baxter International, Inc.). Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in US Patent Publication Nos. 2005/0260186 and 2006/0104968. In one aspect, a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases. Exemplary lyophilized formulations are described in US Patent No. 6,267,958. Aqueous formulations include those described in US Patent No. 6, 171,586 and WO2006/044908, the latter formulations including a histidine- acetate buffer.

A formulation of a JAK inhibitor as disclosed herein, e.g., sustained-release formulations, can further include a mucoadhesive agent, e.g., one or more of polyvinyl pyrolidine, methyl cellulose, sodium carboxyl methyl cellulose, hydroxyl propyl cellulose, carbopol, a polyacrylate, chitosan, a eudragit analogue, a polymer, and a thiomer. Additional examples of mucoadhesive agents that can be included in a formulation with a JAK inhibitor are described in, e.g., Peppas et al, Biomaterials 17(16): 1553-1561, 1996; Kharenko et al, Pharmaceutical Chemistry J. 43(4):200-208, 2009; Salamat-Miller et A., Adv. Drug Deliv. Reviews 57(11): 1666-1691, 2005; Bemkop-Schnurch, 4<iv. Drug Deliv. Rev. 57(1 1): 1569- 1582, 2005; and Harding et al, Biotechnol. Genet. Eng. News 16(l):41-86, 1999.

In some embodiments, components of a formulation may include any one of the following components, or any combination thereof:

Acacia, Alginate, Alginic Acid, Aluminum Acetate, an antiseptic, Benzyl Alcohol, Butyl Paraben, Butylated Hydroxy Toluene, an antioxidant. Citric acid, Calcium carbonate, Candelilla wax, a binder, Croscarmellose sodium, Confectioner sugar, Colloidal silicone dioxide, Cellulose, Carnuba wax, Corn starch, Carboxymethylcellulose calcium, Calcium stearate, Calcium disodium EDTA, Chelation agents, Copolyvidone, Castor oil hydrogenated, Calcium hydrogen phosphate dehydrate, Cetylpyridine chloride, Cysteine HC1,

Crosspovidone, Dibasic Calcium Phosphate, Disodium hydrogen phosphate, Dimethicone, Erythrosine Sodium, Ethyl Cellulose, Gelatin, Glyceryl monooleate, Glycerin, Glycine, Glyceryl monostearate, Glyceryl behenate, Hydroxy propyl cellulose, Hydroxyl propyl methyl cellulose, Hypromellose, HPMC Pthalate, Iron oxides or ferric oxide, Iron oxide yellow, Iron oxide red or ferric oxide, Lactose (hydrous or anhydrous or monohydrate or spray dried), Magnesium stearate, Microcrystalline cellulose, Mannitol, Methyl cellulose,, Magnesium carbonate, Mineral oil, Methacrylic acid copolymer, Magnesium oxide, Methyl paraben, PEG, Polysorbate 80, Propylene glycol, Polyethylene oxide, Propylene paraben, Polaxamer 407 or 188 or plain, Potassium bicarbonate, Potassium sorbate, Potato starch, Phosphoric acid, Polyoxyl40 stearate, Sodium starch glycolate, Starch pregelatinized, Sodium crossmellose, Sodium lauryl sulfate, Starch, Silicon dioxide, Sodium benzoate,, Stearic acid, Sucrose base for medicated confectionery, a granulating agent, Sorbic acid, Sodium carbonate, Saccharin sodium, Sodium alginate, Silica gel, Sorbiton monooleate, Sodium stearyl fumarate, Sodium chloride, Sodium metabisulfite, Sodium citrate dehydrate, Sodium starch, Sodium carboxy methyl cellulose, Succinic acid, Sodium propionate, Titanium dioxide, Talc, Triacetin, Triethyl citrate.

Accordingly, in some embodiments of the method of treating a disease as disclosed herein, the method comprises administering to the subject a pharmaceutical composition that is a formulation as disclosed herein. In some embodiments the formulation is a dosage form, which may be, as an example, a solid form such as, for example, a capsule, a tablet, a sachet, or a lozenge; or which may be, as an example, a liquid form such as, for example, a solution, a suspension, an emulsion, or a syrup.

In some embodiments the formulation is not comprised in an ingestible device. In some embodiments wherein the formulation is not comprised in an ingestible device, the formulation may be suitable for oral administration. The formulation may be, for example, a solid dosage form or a liquid dosage form as disclosed herein. In some embodiments wherein the formulation is not comprised in an ingestible device, the formulation may be suitable for rectal administration. The formulation may be, for example, a dosage form such as a suppository or an enema. In embodiments where the formulation is not comprised in an ingestible device, the formulation releases the JAK inhibitor at a location in the

gastrointestinal tract of the subject that is proximate to one or more sites of disease. Such localized release may be achieved, for example, with a formulation comprising an enteric coating. Such localized release may be achieved, an another example, with a formulation comprising a core comprising one or more polymers suitable for controlled release of an active substance. A non-limiting list of such polymers includes: poly(2-(diethylamino)ethyl methacrylate, 2-(dimethylamino)ethyl methacrylate, poly(ethylene glycol), poly(2- aminoethyl methacrylate), (2-hydroxypropyl)methacrylamide, poly( -benzyl-l-aspartate), poly(N-isopropylacrylamide), and cellulose derivatives.

In some embodiments the formulation is comprised in an ingestible device as disclosed herein. In some embodiments wherein the formulation is comprised in an ingestible device, the formulation may be suitable for oral administration. The formulation may be, for example, a solid dosage form or a liquid dosage form as disclosed herein. In some embodiments the formulation is suitable for introduction and optionally for storage in the device. In some embodiments the formulation is suitable for introduction and optionally for storage in the reservoir comprised in the device. In some embodiments the formulation is suitable for introduction and optionally for storage in the reservoir comprised in the device. Thus, in some embodiments, provided herein is a reservoir comprising a therapeutically effective amount of a JAK inhibitor, wherein the reservoir is configured to fit into an ingestible device. In some embodiments, the reservoir comprising a therapeutically effective amount of a JAK inhibitor is attachable to an ingestible device. In some embodiments, the reservoir comprising a therapeutically effective amount of a JAK inhibitor is capable of anchoring itself to the subject's tissue. As an example, the reservoir capable of anchoring itself to the subject's tissue comprises silicone. As an example, the reservoir capable of anchoring itself to the subject's tissue comprises polyvinyl chloride.

In some embodiments the formulation is suitable for introduction in the spray catheters disclosed herein.

The formulation/medicament herein may also contain more than one active compound as necessary for the particular indication being treated, for example, those with

complementary activities that do not adversely affect each other. For instance, the formulation may further comprise another JAK inhibitor or a chemotherapeutic agent. Such molecules are suitably present in combination in amounts that are effective for the purpose intended.

I l l The active ingredients may also be entrapped in microcapsule prepared, for example, by coacervation techniques or by interfacial polymerization, for

example, hydroxymethylcellulose or gelatin-microcapsule and poly-(methylmethacylate) microcapsule, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in

macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes.

Sustained-release preparations may be prepared. Suitable examples of sustained- release preparations include semipermeable matrices of solid hydrophobic polymers containing the JAK inhibitor, which matrices are in the form of shaped articles, e.g., films, or microcapsule. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2- hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and γ ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-gly colic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-gly colic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. While polymers such as ethylene- vinyl acetate and lactic acid-gly colic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods. When encapsulated JAK inhibitors remain in the body for a long time, they may denature or aggregate as a result of exposure to moisture at 37°C, resulting in a loss of biological activity and possible changes in

immunogenicity. Rational strategies can be devised for stabilization depending on the mechanism involved. For example, if the aggregation mechanism is discovered to be intermolecular S-S bond formation through thio-disulfide interchange, stabilization may be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions.

Pharmaceutical formulations may contain one or more JAK inhibitors. The pharmaceutical formulations may be formulated in any manner known in the art. In some embodiments the formulations include one or more of the following components: a sterile diluent (e.g., sterile water or saline), a fixed oil, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents, antibacterial or antifungal agents, such as benzyl alcohol or methyl parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like, antioxidants, such as ascorbic acid or sodium bisulfite, chelating agents, such as

ethylenediaminetetraacetic acid, buffers, such as acetates, citrates, or phosphates, and isotonic agents, such as sugars (e.g., dextrose), polyalcohols (e.g., mannitol or sorbitol), or salts (e.g., sodium chloride), or any combination thereof. Liposomal suspensions can also be used as pharmaceutically acceptable carriers (see, e.g., U. S. Patent No. 4,522,811 , incorporated by reference herein in its entirety). The formulations can be formulated and enclosed in ampules, disposable syringes, or multiple dose vials. Where required, proper fluidity can be maintained by, for example, the use of a coating, such as lecithin, or a surfactant. Controlled release of the JAK inhibitor can be achieved by implants and microencapsulated delivery systems, which can include biodegradable, biocompatible polymers (e.g., ethylene vinyl acetate, polyanhydrides, polygly colic acid, collagen, polyorthoesters, and polylactic acid; Alza Corporation and Nova Pharmaceutical, Inc.).

In some embodiments, the JAK inhibitor is present in a pharmaceutical formulation within the device.

In some embodiments, the JAK inhibitor is present in solution within the device.

In some embodiments, the JAK inhibitor is present in a suspension in a liquid medium within the device.

In some embodiments, data obtained from cell culture assays and animal studies can be used in formulating an appropriate dosage of any given JAK inhibitor. The effectiveness and dosing of any JAK inhibitor can be determined by a health care professional or veterinary professional using methods known in the art, as well as by the observation of one or more disease symptoms in a subject (e.g., a human). Certain factors may influence the dosage and timing required to effectively treat a subject (e.g., the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and the presence of other diseases).

In some embodiments, the subj ect is further administered an additional therapeutic agent (e.g., any of the additional therapeutic agents described herein). The additional therapeutic agent can be administered to the subject at substantially the same time as the JAK inhibitor or pharmaceutical composition comprising it is administered and/or at one or more other time points. In some embodiments, the additional therapeutic agent is formulated together with the JAK inhibitor (e.g., using any of the examples of formulations described herein). In some embodiments, the subject is administered a dose of the JAK inhibitor at least once a month (e.g., at least twice a month, at least three times a month, at least four times a month, at least once a week, at least twice a week, three times a week, once a day, or twice a day). The JAK inhibitor may be administered to a subject chronically. Chronic treatments include any form of repeated administration for an extended period of time, such as repeated administrations for one or more months, between a month and a year, one or more years, more than five years, more than 10 years, more than 15 years, more than 20 years, more than 25 years, more than 30 years, more than 35 years, more than 40 years, more than 45 years, or longer. Alternatively, or in addition, chronic treatments may be administered. Chronic treatments can involve regular administrations, for example one or more times a day, one or more times a week, or one or more times a month. For example, chronic treatment can include administration (e.g., intravenous administration) about every two weeks (e.g., between about every 10 to 18 days).

A suitable dose may be the amount that is the lowest dose effective to produce a desired therapeutic effect. Such an effective dose will generally depend upon the factors described herein. If desired, an effective daily dose of JAK inhibitor can be administered as two, three, four, five, or six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Combination therapy:

The JAK inhibitors disclosed herein may be optionally be used with additional agents in the treatment of the diseases disclosed herein. Nonlimiting examples of such agents for treating or preventing inflammatory bowel disease in such adjunct therapy (e.g., Crohn's disease, ulcerative colitis) include substances that suppress cytokine production, down- regulate or suppress self-antigen expression, or mask the MHC antigens. Examples of such agents include 2- amino-6-aryl-5 -substituted pyrimidines (see U.S. Patent No. 4,665,077); non-steroidal antiinflammatory drugs (NSAIDs); ganciclovir; tacrolimus; lucocorticoids such as Cortisol or aldosterone; anti-inflammatory agents such as a cyclooxygenase inhibitor; a 5 - lipoxygenase inhibitor; or a leukotriene receptor antagonist; purine antagonists such as azathioprine or mycophenolate mofetil (MMF); alkylating agents such as cyclophosphamide; bromocryptine; danazol; dapsone; glutaraldehyde (which masks the MHC antigens, as described in U.S. Patent No. 4,120,649); anti-idiotypic antibodies for MHC antigens and MHC fragments; cyclosporine; 6-mercaptopurine; steroids such as corticosteroids or glucocorticosteroids or glucocorticoid analogs, e.g., prednisone, methylprednisolone, including SOLU-MEDROL®, methylprednisolone sodium succinate, and dexamethasone; dihydrofolate reductase inhibitors such as methotrexate (oral or subcutaneous); anti-malarial agents such as chloroquine and hydroxychloroquine; sulfasalazine; leflunomide; cytokine or cytokine receptor antibodies or antagonists including anti-interferon-alpha, -beta, or -gamma antibodies, anti-tumor necrosis factor(TNF)-alpha antibodies (infliximab (REMICADE®) or adalimumab), anti-TNF- alpha immunoadhesin (etanercept), anti-TNF-beta antibodies, anti- interleukin-2 (IL-2) antibodies and anti-IL-2 receptor antibodies, and anti-interleukin-6 (IL-6) receptor antibodies and antagonists; anti-LFA-1 antibodies, including anti-CD 1 la and anti- CD 18 antibodies; anti- L3T4 antibodies; heterologous anti-lymphocyte globulin; pan-T antibodies, anti-CD3 or anti- CD4/CD4a antibodies; soluble peptide containing a LFA-3 binding domain (WO 90/08187 published Jul. 26, 1990); streptokinase; transforming growth factor-beta (TGF-beta); streptodomase; RNA or DNA from the host; FK506; RS-61443; chlorambucil; deoxyspergualin; rapamycin; T-cell receptor (Cohen et al, U.S. Patent No. 5,114,721); T-cell receptor fragments (Offner et al, Science, 251 : 430-432 (1991); WO

90/11294; Ianeway, Nature, 341 : 482 (1989); and WO 91/01133); BAFF antagonists such as BAFF or BR3 antibodies or immunoadhesins and zTNF4 antagonists (for review, see Mackay and Mackay, Trends Immunol, 23: 113-5 (2002) and see also definition below); biologic agents that interfere with T cell helper signals, such as anti-CD40 receptor or anti- CD40 ligand (CD 154), including blocking antibodies to CD40-CD40 ligand.(e.g., Durie et al, Science, 261 : 1328-30 (1993); Mohan et al, J. Immunol, 154: 1470-80 (1995)) and CTLA4-Ig (Finck et al, Science, 265: 1225-7 (1994)); and T-cell receptor antibodies (EP 340,109) such as T10B9. Non-limiting examples of adjunct agents also include the following: budenoside; epidermal growth factor; aminosalicylates; metronidazole;

mesalamine; olsalazine; balsalazide; antioxidants; thromboxane inhibitors; IL-1 receptor antagonists; anti-IL-1 monoclonal antibodies; growth factors; elastase inhibitors; pyridinyl- imidazole compounds; TNF antagonists; IL-4, IL-10, IL-13 and/or TGFfi cytokines or agonists thereof (e.g., agonist antibodies); IL-11 ; glucuronide- or dextran-conjugated prodrugs of prednisolone, dexamethasone or budesonide; ICAM-I antisense phosphorothioate oligodeoxynucleotides (ISIS 2302; Isis Pharmaceuticals, Inc.); soluble complement receptor 1 (TPIO; T Cell Sciences, Inc.); slow-release mesalazine; antagonists of platelet activating factor (PAF); ciprofloxacin; and lignocaine. Examples of agents for UC are sulfasalazine and related salicylate-containing drugs for mild cases and corticosteroid drugs in severe cases. Topical administration of either salicylates or corticosteroids is sometimes effective, particularly when the disease is limited to the distal bowel, and is associated with decreased side effects compared with systemic use. Supportive measures such as administration of iron and antidiarrheal agents are sometimes indicated. Azathioprine, 6-mercaptopurine and methotrexate are sometimes also prescribed for use in refractory corticosteroid-dependent cases.

In other embodiments, a JAK inhibitor as described herein can be administered with one or more of: a CHST15 inhibitor, a IL-6 receptor inhibitor, an IL-12/IL-23 inhibitor, an integrin inhibitor, a JAK inhibitor, a SMAD7 inhibitor, a IL-13 inhibitor, an IL-1 receptor inhibitor, a TLR agonist, a TNF inhibitor, or a stem cell. In other embodiments, a JAK inhibitor as described herein can be administered with a vitamin C infusion, one or more corticosteroids, and optionally thiamine.

In some embodiments, the methods disclosed herein comprise administering (i) the JAK inhibitor as disclosed herein, and (ii) a second agent orally, intravenously or subcutaneously, wherein the second agent in (ii) is the same JAK inhibitor in (i); a different JAK inhibitor; or an agent having a different biological target from the JAK inhibitor.

In some embodiments, the methods disclosed herein comprise administering (i) the JAK inhibitor in the manner disclosed herein, and (ii) a second agent orally, intravenously or subcutaneously, wherein the second agent in (ii) is an agent suitable for treating an inflammatory bowel disease.

In some embodiments, the JAK inhibitor is administered prior to the second agent. In some embodiments, the JAK inhibitor is administered after the second agent. In some embodiments, the JAK inhibitor and the second agent are administered substantially at the same time. In some embodiments, the JAK inhibitor is delivered prior to the second agent. In some embodiments, the JAK inhibitor is delivered after the second agent. In some embodiments, the JAK inhibitor and the second agent are delivered substantially at the same time.

In some embodiments, the second agent is an agent suitable for the treatment of a disease of the gastrointestinal tract. In some embodiments, the second agent is an agent suitable for the treatment of an inflammatory bowel disease. In some embodiments, the second agent is administered intravenously. In some embodiments, the second agent is administered subcutaneously. In some embodiments, the second agent is methotrexate. In some embodiments, delivery of the JAK inhibitor to the location, such as delivery to the location by mucosal contact, results in systemic immunogenicity levels at or below systemic immunogenicity levels resulting from administration of the JAK inhibitor systemically. In some embodiments comprising administering the JAK inhibitor in the manner disclosed herein and a second agent systemically, delivery of the JAK inhibitor to the location, such as delivery to the location by mucosal contact, results in systemic

immunogenicity levels at or below systemic immunogenicity levels resulting from administration of the JAK inhibitor systemically and the second agent systemically. In some embodiments, the method comprises administering the JAK inhibitor in the manner disclosed herein and a second agent, wherein the amount of the second agent is less than the amount of the second agent when the JAK inhibitor and the second agent are both administered systemically. In some aspects of these embodiments, the second agent is a JAK inhibitor.

In some embodiments, the method comprises administering the JAK inhibitor in the manner disclosed herein and does not comprise administering a second agent.

Examples:

Example 1 - Preclinical Murine Colitis Model

Experimental Induction of Colitis

Colitis is experimentally induced to in mice via the dextran sulfate sodium (DSS)- induced colitis model. This model is widely used because of its simplicity and many similarities with human ulcerative colitis. Briefly, mice are subjected to DSS via cecal catheterization, which is thought to be directly toxic to colonic epithelial cells of the basal crypts, for several days until colitis is induced.

Groups

Mice are allocated to one of seven cohorts, depending on the agent that is administered:

1. Control (no agent)

2. Tofacitinib (2.5 mg/kg)

3. Tofacitinib (5 mg/kg)

4. Tofacitinib (10 mg/kg) The control or agent is applied to a damaged mucosal surface of the bowel via administration through a cecal catheter at the dose levels described above.

Additionally, for each cohort, the animals are separated into two groups. One group receives a single dose of the control or agent on day 10 or 12. The other group receives daily (or similar) dosing of the control or agent.

Analysis

For each animal, efficacy is determined (e.g., by endoscopy, histology, etc.), and JAK levels are determined in blood, feces, and tissue (tissue levels are determined after animal sacrifice). For tissue samples, levels HER2 are additionally determined, and the level of JAK is normalized to the level of HER2. Additionally, other cytokine levels are determined in tissue (e.g., phospho STAT 1, STAT 3 and STAT 5), in plasma (e.g., VEGF, VCAM, ICAM, IL-6), or both.

Pharmacokinetics are determined both systemically (e.g., in the plasma) and locally (e.g., in colon tissue). For systemic pharmacokinetic analysis, blood and/or feces is collected from the animals at one or more timepoints after administration (e.g., plasma samples are collected at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, and/or 8 hours after administration). Local/colon tissue samples are collected once after animal sacrifice.

Example 2a - Development of Preclinical Porcine Colitis Model

Experimental Induction of Colitis

Female swine weighing approximately 35 to 45 kg at study start are fasted at least 24 hours prior to intra-rectal administration of trinitrobenzene sulfonic acid (TNBS). Animals are lightly anesthetized during the dosing and endoscopy procedure. An enema to clean the colon is used, if necessary. One animal is administered 40 ml of 100% EtOH mixed with 5 grams of TNBS diluted in 10 ml of water via an enema using a ball-tipped catheter. The enema is deposited in the proximal portion of the descending colon just past the bend of the transverse colon. The TNBS is retained at the dose site for 12 minutes by use of two Foley catheters with 60-ml balloons placed in the mid-section of the descending colon below the dose site. A second animal is similarly treated, but with a solution containing 10 grams of TNBS. An Endoscope is employed to positively identify the dose site in both animals prior to TNBS administration. Dosing and endoscopy are performed by a veterinary surgeon Seven (7) days after TNBS administration, after light anesthesia, the dose site and mucosal tissues above and below the dose site are evaluated by the veterinary surgeon using an endoscope. Pinch Biopsies are obtained necessary, as determined by the surgeon. Based on the endoscopy findings, the animals may be euthanized for tissue collection on that day, or may proceed on study pending the results of subsequent endoscopy exams for 1 to 4 more days. Macroscopic and microscopic alterations of colonic architecture, possible necrosis, thickening of the colon, and substantial histologic changes are observed at the proper TNBS dose.

Clinical signs (e.g., ill health, behavioral changes, etc.) are recorded at least daily during acclimation and throughout the study. Additional pen-side observations are conducted twice daily (once-daily on weekends). Body weight is measured for both animals Days 1 and 7 (and on the day of euthanasia if after Day 7).

On the day of necropsy, the animals are euthanized via injection of a veterinarian- approved euthanasia solution. Immediately after euthanasia in order to avoid autolytic changes, colon tissues are collected, opened, rinsed with saline, and a detailed macroscopic examination of the colon is performed to identify macroscopic finings related to TNBS- damage. Photos are taken. Tissue samples are taken from the proximal, mid, and distal transverse colon; the dose site; the distal colon; the rectum; and the anal canal. Samples are placed into NBF and evaluated by a board certified veterinary pathologist.

Example 2b - Pharmacokinetic/Pharmacodynamic and Bioavailability of Tofacitinib After Topical Application

Animal Model

Animals are subjected to intra-rectal administration of trinitrobenzene Sulfonic acid

(TNBS) to induce chronic colitis on Day -6. All animals are fasted prior to colitis induction on Day -7. The TNBS is dissolved in 25% ethanol then instilled into the colon intra-rectally using a flexible plastic ball-tip gavage needle. Approximately seven (7) days after induction, macroscopic and microscopic alterations of colonic architecture are apparent: some necrosis, thickening of the colon, substantial histologic changes that only partially resolve by Day 60.

Groups Sixteen (16) swine (approximately 35 to 45 kg at study start) are allocated to one of five groups:

1. Vehicle Control: (3.2 mL saline); intra-rectal; (n=2)

2. Treated Control: Tofacitinib (40mg in 3.2mL saline); subcutaneous; (n=2)

3. Tofacitinib (low): 4. Tofacitinib (40mg in 3.2mL saline); intra-rectal; (n=4)

4. Tofacitinib (med): Tofacitinib (80mg in 3.2 mL saline); intra-rectal; (n=4)

5. Tofacitinib (high): Tofacitinib (160mg in 3.2 mL saline); intra-rectal; (n=4) On Day 0, the test article is applied to a damaged mucosal surface of the bowel via intra-rectal administration or subcutaneous injection by a veterinary surgeon at the dose levels and volume described above.

Clinical Observations and Body Weight

Clinical observations are conducted at least once daily. Clinical signs (e.g., ill health, behavioral changes, etc.) are recorded on all appropriate animals at least daily prior to the initiation of experiment and throughout the study until termination. Additional clinical observations may be performed if deemed necessary. Animals whose health condition warrants further evaluation are examined by a Clinical Veterinarian. Body weight is measured for all animals Days -6, 0, and after the last blood collections.

Samples

Blood:

Blood is collected (cephalic, jugular, and/or catheter) into EDTA tubes during acclimation on Day-7, just prior to dose on Day 0, and 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours post-dose. The EDTA samples are split into two aliquots and one is centrifuged for pharmacokinetic plasma and either analyzed immediately, or stored frozen (-80°C) for later pharmacokinetic analyses. The remaining sample of whole blood is used for

pharmacodynamic analyses.

Feces:

Feces is collected Day -7, 0 and 0.5, 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose, and either analyzed immediately, or flash-frozen on liquid nitrogen and stored frozen at -70°C pending later analysis of drug levels and inflammatory cytokines. Tissue:

Immediately after euthanasia in order to avoid autolytic changes, colon tissues are collected, opened, rinsed with saline, and a detailed macroscopic examination of the colon is performed to identify macroscopic finings related to TNBS-damage. Triplicate samples of normal and damaged tissues are either analyzed immediately, or are flash-frozen on liquid nitrogen and stored frozen at -70°C pending later analysis of drug concentration, inflammatory cytokines and histology.

Samples are analyzed for tofacitinib levels (local mucosal tissue levels and systemic circulation levels), and for levels of JAK.

Terminal Procedures

Animals are euthanized as per the schedule in Table AA, where one animal each of Vehicle and Treated Control groups is euthanized at 6 and 48 hours post-dose, and one animal of each the tofacitinib groups are euthanized at 6, 12, 24 and 48 hours post-dose.

Animals are discarded after the last blood collection unless retained for a subsequent study.

Table AA

Claims

Claims:

1. A method of treating a disease of the gastrointestinal tract in a subj ect, comprising: releasing a JAK inhibitor at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease, wherein the method comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of the JAK inhibitor, wherein the pharmaceutical composition is an ingestible device and the method comprises administering orally to the subject the pharmaceutical composition.

2. The method of claim 1 , wherein the pharmaceutical composition is an ingestible device and the method comprises administering orally to the subject the pharmaceutical composition.

3. The method of claim 1 or 2, wherein the method does not comprise releasing more than 10% of the JAK inhibitor at a location that is not proximate to a site of disease.

4. The method of claim 1 or 2, wherein the method provides a concentration of the JAK inhibitor at a location that is a site of disease or proximate to a site of disease that is 2-100 times greater than at a location that is not proximate to a site of disease.

5. The method of any one of the preceding claims, wherein the method provides a concentration of the JAK inhibitor in the plasma of the subject that is less than 3 μg/ml.

6. The method of claim 5, wherein the method provides a concentration of the JAK inhibitor in the plasma of the subject that is less than 0.3 μg/ml.

7. The method of claim 6, wherein the method provides a concentration of the JAK inhibitor in the plasma of the subject that is less than 0.01 μg/ml.

8. The method of any one of claims 1 to 4, wherein the method provides a C24 value of the JAK inhibitor in the plasma of the subject that is less than 3 μg/ml.

9. The method of claim 8, wherein the method provides a C24 value of the JAK inhibitor in the plasma of the subject that is less than 0.3 μg/ml.

10. The method of claim 9, wherein the method provides a C24 value of the JAK inhibitor in the plasma of the subject that is less than 0.01 μg/ml.

11. The method of any one of claims 1 to 10, wherein the JAK inhibitor decreases the expression of JAK1.

12. The method of any one of claims 1 to 10, wherein the JAK inhibitor decreases the expression of JAK2.

13. The method of any one of claims 1 to 10, wherein the JAK inhibitor decreases the expression of JAK3.

14. The method of any one of claims 1 to 10, wherein the JAK inhibitor decreases the expression of TYK-2.

15. The method of any one of claims 1 to 10, wherein the JAK inhibitor decreases the the kinase activity of TYK-2.

16. The method of any one of claims 2 to 15, wherein the JAK inhibitor is present in a pharmaceutical formulation within the device.

17. The method of claim 16, wherein the formulation is a solution of the JAK inhibitor in a liquid medium.

18. The method of claim 17, wherein the formulation is a suspension of the JAK inhibitor in a liquid medium.

19. The method of any one of claims 1 to 18, wherein the disease of the GI tract is an inflammatory bowel disease.

20. The method of any one of claims 1 to 18, wherein the disease of the GI tract is ulcerative colitis.

21. The method of any one of claims 1 to 18, wherein the disease of the GI tract is Crohn's disease.

22. The method of any one of claims 1 to 21, wherein the JAK inhibitor is released at a location in the large intestine of the subject.

23. The method of claim 22, wherein the location is in the proximal portion of the large intestine.

24. The method of claim 22, wherein the location is in the distal portion of the large intestine.

25. The method of any one of claims 1 to 21, wherein the JAK inhibitor is released at a location in the ascending colon of the subject.

26. The method of claim 25, wherein the location is in the proximal portion of the ascending colon.

27. The method of claim 25, wherein the location is in the distal portion of the ascending colon.

28. The method of any one of claims 1 to 21, wherein the JAK inhibitor is released at a location in the cecum of the subject.

29. The method of claim 28, wherein the location is in the proximal portion of the cecum.

30. The method of claim 28, wherein the location is in the distal portion of the cecum.

31. The method of any one of claims 1 to 21, wherein the JAK inhibitor is released at a location in the sigmoid colon of the subject.

32. The method of claim 31, wherein the location is in the proximal portion of the sigmoid colon.

33. The method of claim 31, wherein the location is in the distal portion of the sigmoid colon.

34. The method of any one of claims 1 to 21, wherein the JAK inhibitor is released at a location in the transverse colon of the subject.

35. The method of claim 34, wherein the location is in the proximal portion of the transverse colon.

36. The method of claim 34, wherein the location is in the distal portion of the transverse colon.

37. The method of any one of claims 1 to 21, wherein the JAK inhibitor is released at a location in the descending colon of the subject.

38. The method of claim 37, wherein the location is in the proximal portion of the descending colon.

39. The method of claim 37, wherein the location is in the distal portion of the descending colon.

40. The method of any one of claims 1 to 21, wherein the JAK inhibitor is released at a location in the small intestine of the subject.

41. The method of claim 40, wherein the location is in the proximal portion of the small intestine.

42. The method of claim 40, wherein the location is in the distal portion of the small intestine.

43. The method of any one of claims 1 to 21, wherein the JAK inhibitor is released at a location in the duodenum of the subject.

44. The method of claim 43, wherein the location is in the proximal portion of the duodenum.

45. The method of claim 43, wherein the location is in the distal portion of the duodenum.

46. The method of any one of claims 1 to 21, wherein the JAK inhibitor is released at a location in the jejunum of the subject.

47. The method of claim 46, wherein the location is in the proximal portion of the jejunum.

48. The method of claim 46, wherein the location is in the distal portion of the jejunum.

49. The method of any one of claims 1 to 21, wherein the JAK inhibitor is released at a location in the ileum of the subject.

50. The method of claim 49, wherein the location is in the proximal portion of the ileum.

51. The method of claim 49, wherein the location is in the distal portion of the ileum.

52. The method of any one of the preceding claims, wherein the location at which the JAK inhibitor is released is 10 cm or less from one or more sites of disease.

53. The method of any one of the preceding claims, wherein the location at which the JAK inhibitor is released is 5 cm or less from one or more sites of disease.

54. The method of any one of the preceding claims, wherein the location at which the JAK inhibitor is released is 2 cm or less from one or more sites of disease.

55. The method of any one of the preceding claims, wherein the JAK inhibitor is released by mucosal contact.

56. The method of any one of the preceding claims, wherein the JAK inhibitor is delivered to the location by a process that does not comprise systemic transport of the JAK inhibitor.

57. The method of any one of the preceding claims, further comprising identifying the one or more sites of disease by a method comprising imaging of the gastrointestinal tract.

58. The method of claim any one of the preceding claims, wherein the method comprises identifying the disease site prior to administering the pharmaceutical composition.

59. The method of claim 58, wherein the method comprises releasing the JAK inhibitor substantially at the same time as identifying the disease site.

60. The method of any one of the preceding claims, comprising (a) identifying a subject having a disease of the gastrointestinal tract and (b) evaluating the subject for suitability to treatment.

61. The method of any one of claims 1 or 3 to 15 or 17 to 60, wherein releasing the JAK inhibitor is triggered by one or more of: a pH in the jejunum from 6.1 to 7.2, a pH in the mid small bowel from 7.0 to 7.8, a pH in the ileum from 7.0 to 8.0, a pH in the right colon from 5.7 to 7.0, a pH in the mid colon from 5.7 to 7.4, a pH in the left colon from 6.3 to 7.7, such as 7.0.

62. The method of any one of claims 1 to 60, wherein releasing the JAK inhibitor is not dependent on the pH at or in the vicinity of the location.

63. The method of any one of claims 1 or 3 to 15 or 17 to 60, wherein releasing the JAK inhibitor is triggered by degradation of a release component located in the device.

64. The method of any one of claims 1 to 60, wherein releasing the JAK inhibitor is not triggered by degradation of a release component located in the device.

65. The method of any one of claims 1 to 60, wherein releasing the JAK inhibitor is not dependent on enzymatic activity at or in the vicinity of the location.

66. The method of any one of claims 1 to 60, wherein releasing the JAK inhibitor is not dependent on bacterial activity at or in the vicinity of the location.

67. The method of any one of claims 1 to 60, wherein the composition comprises a plurality of electrodes comprising a coating, and releasing the JAK inhibitor is triggered by an electric signal by the electrodes resulting from the interaction of the coating with the one or more sites of disease.

68. The method of any one of claims 1 to 60, wherein releasing the JAK inhibitor is triggered by a remote electromagnetic signal.

69. The method of any one of claims 1 to 60, wherein releasing the JAK inhibitor is triggered by generation in the composition of a gas in an amount sufficient to expel the JAK inhibitor.

70. The method of any one of claims 1 to 60, wherein releasing the JAK inhibitor is triggered by an electromagnetic signal generated within the device according to a predetermined drug release profile.

71. The method of any one of claims 2 to 60, wherein the ingestible device comprises an ingestible housing, wherein a reservoir storing the JAK inhibitor is attached to the housing.

72. The method of claim 71, further comprising:

detecting when the ingestible housing is proximate to a respective disease site of the one of the one or more sites of disease,

wherein releasing the JAK inhibitor comprises releasing the therapeutically effective amount of the JAK inhibitor from the reservoir proximate the respective disease site in response to the detection.

73. The method of claim72, wherein detecting comprises detecting via one or more sensors coupled to the ingestible housing.

74. The method of claim 73, wherein the one or more sensors comprise a plurality of coated electrodes and wherein detecting comprises receiving an electric signal by one or more of the coated electrodes responsive to the one or more electrode contacting the respective disease site.

75. The method of claim 72, wherein releasing comprises opening one or more valves in fluid communication with the reservoir.

76. The method of claim 75, wherein the one or more valves is communicably coupled to a processor positioned in the housing, the processor communicably coupled to one or more sensors configured to detect the one or more sites of disease.

77. The method of claim 72, wherein releasing comprises pumping the therapeutically effective amount of the JAK inhibitor from the reservoir via pump positioned in the ingestible housing.

78. The method of claim 77, wherein the pump is communicably coupled to a processor positioned in the housing, the processor communicably coupled to one or more sensors configured to detect the one or more sites of disease.

79. The method of claim 71, wherein the therapeutically effective amount of the JAK inhibitor is stored in the reservoir at a reservoir pressure higher than a pressure in the gastrointestinal tract of the subject.

80. The method of claim 71 , further comprising anchoring the ingestible housing at a location proximate to the respective disease site in response to the detection.

81. The method of claim 80, wherein anchoring the ingestible housing comprises one or more legs to extend from the ingestible housing.

82. The method of any one of the preceding claims, wherein the amount of the JAK inhibitor that is administered is from about 1 mg to about 500 mg.

83. The method of any one of the preceding claims, wherein the JAK inhibitor is selected from tofacitinib (Xeljanz®), filgotinib (GLPG0634, Galapagos NV); TD-1473 (Theravance Biopharma, Inc.); ruxolitinib; and generic equivalents thereof.

84. The method of any one of the preceding claims, wherein the JAK inhibitor is ruxolitinib.

85. The method of any one of claims 1 to 84, wherein the amount of the JAK inhibitor is less than an amount that is effective when JAK inhibitor is administered systemically.

86. The method of any one of the preceding claims, comprising administering (i) an amount of the JAK inhibitor that is an induction dose.

87. The method of claim 86, further comprising (ii) administering an amount of the JAK inhibitor that is a maintenance dose following the administration of the induction dose.

88. The method of claim 86 or 87, wherein the induction dose is administered once a day.

89. The method of claim 86 or 87, wherein the induction dose is administered once every three days.

90. The method of claim 86 or 87, wherein the induction dose is administered once a week.

91. The method of claim 87, wherein step (ii) is repeated one or more times.

92. The method of claim 87, wherein step (ii) is repeated once a day over a period of about 6-8 weeks.

93. The method of claim 87, wherein step (ii) is repeated once every three days over a period of about 6-8 weeks.

94. The method of claim 87, wherein step (ii) is repeated once a week over a period of about 6-8 weeks.

95. The method of claim 87, wherein the induction dose is equal to the maintenance dose.

96. The method of claim 87, wherein the induction dose is greater than the maintenance dose.

97. The method of claim 87, wherein the induction dose is 5 times greater than the maintenance dose.

98. The method of claim 87, wherein the induction dose is 2 times greater than the maintenance dose.

99. The method of any one of the preceding claims, wherein the method comprises releasing the JAK inhibitor at the location in the gastrointestinal tract as a single bolus.

100. The method of any one of claims 1 to 98, wherein the method comprises releasing the JAK inhibitor at the location in the gastrointestinal tract as more than one bolus.

101. The method of any one of claims 1 to 98, wherein the method comprises delivering the JAK inhibitor at the location in the gastrointestinal tract in a continuous manner.

102. The method of claim 101, wherein the method comprises delivering the JAK inhibitor at the location in the gastrointestinal tract over a time period of 20 or more minutes.

103. The method of any one of claims 1 to 102, wherein the method does not comprise delivering a JAK inhibitor rectally to the subject.

104. The method of any one of claims 1 to 102, wherein the method does not comprise delivering a JAK inhibitor via an enema to the subject.

105. The method of any one of claims 1 to 102, wherein the method does not comprise delivering a JAK inhibitor via suppository to the subject.

106. The method of any one of claims 1 to 102, wherein the method does not comprise delivering a JAK inhibitor via instillation to the rectum of the subject.

107. The method of any one of claims 1 to 102, wherein the method does not comprise surgical implantation.

108. The method of any one of claims 1 to 107, wherein the JAK inhibitor decreases the kinase activity of JAK1.

109. The method of any one of claims 1 to 107, wherein the JAK inhibitor decreases the kinase activity of JAK2.

110. The method of any one of claims 1 to 107, wherein the JAK inhibitor decreases the kinase activity of JAK3.

111. The method of any one of claims 1 to 107, wherein the JAK inhibitor decreases the kinase activity of a single JAK isoform.

112. The method of any one of claims 1 to 107, wherein the JAK inhibitor decreases the kinase activity of two or more (e.g., 3 or 4) of: JAK1, JAK2, JAK3 and TYK2.

113. The method of any one of claims 1 to 67 or 69 to 112, wherein the composition is an autonomous device.

114. The method of any one of claims 1 to 113, wherein the composition comprises a mechanism capable of releasing the JAK inhibitor.

115. The method of any one of claims 1 to 114, wherein the composition comprises a tissue anchoring mechanism for anchoring the composition to the location.

116. The method of claim 115, wherein the tissue anchoring mechanism is capable of activation for anchoring to the location.

117. The method of claim 115 to 116, wherein the tissue anchoring mechanism comprises an osmotically-driven sucker.

118. The method of claim 115, 116, or 117, wherein the tissue anchoring mechanism comprises a connector operable to anchor the composition to the location.

119. The method of claim 118, wherein the connector is operable to anchor the composition to the location using an adhesive, negative pressure and/or fastener.

120. The method of claim 71, wherein the reservoir is an anchorable reservoir.

121. The method of any one of claims 1 to 60, wherein the pharmaceutical composition is an ingestible device, comprising:

a housing;

a reservoir located within the housing and containing the JAK inhibitor;

a mechanism for releasing the JAK inhibitor from the reservoir, and;

an exit valve configured to allow the JAK inhibitor to be released out of the housing from the reservoir.

122. The method of claim 121 , wherein the ingestible device further comprises:

an electronic component located within the housing; and

a gas generating cell located within the housing and adjacent to the electronic component,

wherein the electronic component is configured to activate the gas generating cell to generate gas.

123. The method of claim 121 or 122, wherein the ingestible device further comprises: a safety device placed within or attached to the housing,

wherein the safety device is configured to relieve an internal pressure within the housing when the internal pressure exceeds a threshold level.

124. The method of claim 1 to 60, wherein the pharmaceutical composition is an ingestible device, comprising:

a housing defined by a first end, a second end substantially opposite from the first end, and a wall extending longitudinally from the first end to the second end;

an electronic component located within the housing;

a gas generating cell located within the housing and adjacent to the electronic component,

wherein the electronic component is configured to activate the gas generating cell to generate gas;

a reservoir located within the housing,

wherein the reservoir stores a dispensable substance and a first end of the reservoir is attached to the first end of the housing;

an exit valve located at the first end of the housing, wherein the exit valve is configured to allow the dispensable substance to be released out of the first end of the housing from the reservoir; and

a safety device placed within or attached to the housing,

wherein the safety device is configured to relieve an internal pressure within the housing when the internal pressure exceeds a threshold level.

125. The method of claim 1 to 60, wherein the pharmaceutical composition is an ingestible device, comprising:

a housing defined by a first end, a second end substantially opposite from the first end, and a wall extending longitudinally from the first end to the second end;

an electronic component located within the housing,

a gas generating cell located within the housing and adjacent to the electronic component,

wherein the electronic component is configured to activate the gas generating cell to generate gas;

a reservoir located within the housing,

wherein the reservoir stores a dispensable substance and a first end of the reservoir is attached to the first end of the housing;

an injection device located at the first end of the housing,

wherein the jet injection device is configured to inject the dispensable substance out of the housing from the reservoir; and

a safety device placed within or attached to the housing,

wherein the safety device is configured to relieve an internal pressure within the housing.

126. The method of claim 1 to 60, wherein the pharmaceutical composition is an ingestible device, comprising:

a housing defined by a first end, a second end substantially opposite from the first end, and a wall extending longitudinally from the first end to the second end;

an optical sensing unit located on a side of the housing,

wherein the optical sensing unit is configured to detect a reflectance from an environment external to the housing;

an electronic component located within the housing; a gas generating cell located within the housing and adjacent to the electronic component,

wherein the electronic component is configured to activate the gas generating cell to generate gas in response to identifying a location of the ingestible device based on the reflectance;

a reservoir located within the housing,

wherein the reservoir stores a dispensable substance and a first end of the reservoir is attached to the first end of the housing;

a membrane in contact with the gas generating cell and configured to move or deform into the reservoir by a pressure generated by the gas generating cell; and

a dispensing outlet placed at the first end of the housing,

wherein the dispensing outlet is configured to deliver the dispensable substance out of the housing from the reservoir.

127. The method of any one of claims 1 to 60, wherein the pharmaceutical composition is an ingestible device as disclosed in US Patent Application Ser. No. 62/385,553, incorporated by reference herein in its entirety.

128. The method of any one of claims 1 to 60, wherein the pharmaceutical composition is an ingestible device comprising a localization mechanism as disclosed in international patent application PCT/US2015/052500, incorporated by reference herein in its entirety.

129. The method of any one of claims 1 to 60, wherein the pharmaceutical composition is not a dart-like dosage form.

130. A method of treating a disease of the large intestine of a subject, comprising:

releasing a JAK inhibitor at a location in the proximal portion of the large intestine of the subject that is proximate to one or more sites of disease,

wherein the method comprises administering endoscopically to the subject a therapeutically effective amount of the JAK inhibitor, wherein the method does not comprise releasing more than 20% of the JAK inhibitor at a location that is not proximate to a site of disease.

131. A method of treating a disease of the gastrointestinal tract in a subj ect, comprising: releasing a JAK inhibitor at a location in the proximal portion of the large intestine of the subject that is proximate to one or more sites of disease, wherein the method comprises administering endoscopically to the subject a pharmaceutical composition comprising a therapeutically effective amount of the JAK inhibitor, wherein the pharmaceutical composition is an ingestible device.

132. The method of claim 130 or 131, wherein the method does not comprise releasing more than 20% of the JAK inhibitor at a location that is not proximate to a site of disease

133. The method of claim 130, 131 or 132 wherein the method does not comprise releasing more than 10% of the JAK inhibitor at a location that is not proximate to a site of disease.

134. The method of any one of claims 130, 131 or 132, wherein the method provides a concentration of the JAK inhibitor at a location that is a site of disease or proximate to a site of disease that is 2-100 times greater than at a location that is not proximate to a site of disease.

135. The method of any one of claims 130 to 134, wherein the method provides a concentration of the JAK inhibitor in the plasma of the subject that is less than 3 μg/ml.

136. The method of claim 135, wherein the method provides a concentration of the JAK inhibitor in the plasma of the subject that is less than 0.3 μg/ml.

137. The method of claim 136, wherein the method provides a concentration of the JAK inhibitor in the plasma of the subject that is less than 0.01 μg/ml.

138. The method of any one of claims 130 to 134, wherein the method provides a C24 value of the JAK inhibitor in the plasma of the subject that is less than 3 μg/ml.

139. The method of any one of claims 130 to 134, wherein the method provides a C24 value of the JAK inhibitor in the plasma of the subject that is less than 0.3 μg/ml.

140. The method of any one of claims 130 to 134, wherein the method provides a C24 value of the JAK inhibitor in the plasma of the subject that is less than 0.01 μg/ml.

141. The method of any one of claims 130 to 134, wherein the composition does not comprise an enteric coating.

142. The method of any one of claims 130 to 141, wherein the JAK inhibitor is not a cyclic peptide.

143. The method of any one of claims 130 to 141, wherein the JAK inhibitor is present in a pharmaceutical formulation within the device.

144. The method of claim 143, wherein the formulation is a solution of the JAK inhibitor in a liquid medium.

145. The method of claim 143, wherein the formulation is a suspension of the JAK inhibitor in a liquid medium.

146. The method of any one of claims 130 to 145, wherein the disease of the large intestine is an inflammatory bowel disease.

147. The method of any one of claims 130 to 145, wherein the disease of the large intestine is ulcerative colitis.

148. The method of any one of claims 130 to 145, wherein the disease the large intestine is Crohn's disease.

149. The method of any one of claims 130 to 148, wherein the JAK inhibitor is released at a location in the proximal portion of the ascending colon.

150. The method of any one of claims 130 to 148, wherein the JAK inhibitor is released at a location in the proximal portion of the cecum.

151. The method of any one of claims 130 to 148, wherein the JAK inhibitor is released at a location in the proximal portion of the sigmoid colon.

152. The method of any one of claims 130 to 148, wherein the JAK inhibitor is released at a location in the proximal portion of the transverse colon.

153. The method of any one of claims 130 to 148, wherein the JAK inhibitor is released at a location in the proximal portion of the descending colon.

154. The method of any one of claims 130 to 148, wherein the method comprises administering to the subject a reservoir comprising the therapeutically effective amount of the JAK inhibitor, wherein the reservoir is connected to the endoscope.

155. The method of any one of the preceding claims, further comprising administering a second agent orally, intravenously or subcutaneously, wherein the second agent is the same JAK inhibitor; a different JAK inhibitor; or an agent having a different biological target from the JAK inhibitor, wherein the second agent is an agent suitable for treating an inflammatory bowel disease.

156. The method of claim 155, wherein the JAK inhibitor is administered prior to the second agent.

157. The method of claim 155, wherein the JAK inhibitor is administered after the second agent.

158. The method of claim 155, wherein the JAK inhibitor and the second agent are administered substantially at the same time.

159. The method of any one of claims 155, wherein the second agent is administered intravenously.

160. The method of any one of claims 155, wherein the second agent is administered subcutaneously.

161. The method of any one of claims 155 to 160, wherein the amount of the second agent is less than the amount of the second agent when the JAK inhibitor and the second agent are both administered systemically.

162. The method of claim 161, wherein the second agent is a JAK inhibitor.

163. The method of claim 161, wherein second agent is methotrexate.

164. The method of any one of claims 1 to 154, wherein the method does not comprise administering a second agent.

165. The method of any one of claims 119 to 164, wherein the method comprises identifying the disease site prior to endoscopic administration.

166. The method of any one of claims 119 to 164, wherein the method comprises identifying the disease site substantially at the same time as releasing the JAK inhibitor.

167. The method of any one of the preceding claims, wherein the method comprising monitoring the progress of the disease.

168. The method of claim 167, wherein monitoring the progress of the disease comprises measuring the weight of the subject over a period of about 1-14 weeks, such as about 6-8 weeks following administration of the JAK inhibitor.

169. The method of claim 167 or 168, wherein monitoring the progress of the disease comprises measuring the food intake of the subject over a period of about 1-14 weeks, such as about 6-8 weeks following administration of the JAK inhibitor.

170. The method of claim 167, 168 or 169, wherein monitoring the progress of the disease comprises measuring the level of blood in the feces of the subject over a period of about 1-14 weeks, such as about 6-8 weeks following administration of the JAK inhibitor.

171. The method of claim 167, 168 or 169, wherein monitoring the progress of the disease comprises measuring the level of abdominal pain of the subject over a period of about 1-14 weeks, such as about 6-8 weeks following administration of the JAK inhibitor.

172. The method of any one of claims 1 to 171, wherein the method does not comprise administering a JAK inhibitor with a spray catheter.

173. The method of any one of claims 1 to 172, wherein the method comprises administering a JAK inhibitor with a spray catheter.

174. A method of treating a disease of the gastrointestinal tract in a subject, comprising: releasing a JAK inhibitor at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease, wherein the method comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of the JAK inhibitor the method comprising one or more of the following steps:

a) identifying a subject having a disease of the gastrointestinal tract;

b) determination of the severity of the disease;

c) determination of the location of the disease;

d) evaluating the subject for suitability to treatment;

e) administration of an induction dose of the JAK inhibitor;

f) monitoring the progress of the disease; and/or

g) optionally repeating steps e) and f) one or more times.

175. The method of claim 174, wherein the pharmaceutical composition is an ingestible device and the method comprises administering orally to the subject the pharmaceutical composition.

176. The method of claim 174 or 175, wherein the method comprises administering one or more maintenance doses following administration of the induction dose in step e).

177. The method of claim 176, wherein the induction dose is a dose of the JAK inhibitor administered in an ingestible device.

178. The method of claim 176 or 177, wherein the maintenance dose is a dose of the JAK inhibitor administered in an ingestible device as disclosed herein.

179. The method of claim 176 or 177, wherein the maintenance dose is a dose of the JAK inhibitor delivered systemically.

180. The method of claim 176, wherein the induction dose is a dose of the JAK inhibitor delivered systemically.

181. The method of claim 176 or 180, wherein the maintenance dose is a dose of the JAK inhibitor administered in an ingestible device.

182. The method of claim 176, wherein the induction dose is a dose of a second agent as delivered systemically.

183. The method of claim 176 or 180, wherein the maintenance dose is a dose of the JAK inhibitor administered in an ingestible device.

184. An JAK inhibitor delivery apparatus comprising:

an ingestible housing comprising a reservoir having a pharmaceutical composition comprising a therapeutically effective amount of the JAK inhibitor stored therein;

a detector coupled to the ingestible housing, the detector configured to detect when the ingestible housing is proximate to a respective disease site of the one of the one or more sites of disease;

a valve system in fluid communication with the reservoir system; and

a controller communicably coupled to the valve system and the detector, the controller configured to cause the valve system to open in response to the detector detecting that the ingestible housing is proximate to the respective disease site so as to release the therapeutically effective amount of the JAK inhibitor at the respective disease site.

185. The JAK inhibitor delivery apparatus according to claim 184, further comprising a pump positioned in the ingestible housing, the pump configured to pump the therapeutically effective amount of the JAK inhibitor from the reservoir in response to activation of the pump by the controller responsive to detection by the detector of the ingestible housing being proximate to the respective disease site.

186. The JAK inhibitor delivery apparatus according to claim 185, wherein the controller is configured to cause the pump to pump the therapeutically effective amount of the JAK inhibitor from the reservoir according to the following protocol.

187. The JAK inhibitor delivery apparatus according to claim 184, wherein the valve system comprises a dissolvable coating.

188. The JAK inhibitor delivery apparatus according to claim 184, wherein the valve system comprises one or more doors configured for actuation by at least one of sliding, pivoting, and rotating.

189. The JAK inhibitor delivery apparatus according to claim 184, wherein the valve system comprises an electrostatic shield.

190. The JAK inhibitor delivery apparatus according to claim 184, wherein the reservoir comprises a pressurized cell.

191. The JAK inhibitor delivery apparatus according to claim 184, further comprising at least one actuatable anchor configured to retain the ingestible housing at the respective disease site upon actuation.

192. The JAK inhibitor delivery apparatus according to claim 184, herein the actuatable anchor is retractable.

193. A composition comprising a therapeutically effective amount of the JAK inhibitor of any one of the preceding claims, wherein the composition is capable of releasing the JAK inhibitor at a location in the gastrointestinal tract of the subject.

194. The composition of claim 193, wherein the composition comprises a tissue anchoring mechanism for anchoring the composition to the location.

195. The composition of claim 194, wherein the tissue anchoring mechanism is capable of anchoring for anchoring to the location.

196. The composition of claim 194 or 195, wherein the tissue anchoring mechanism comprises an osmotically-driven sucker.

197. The composition of claim 194, 195 or 196, wherein the tissue anchoring mechanism comprises a connector operable to anchor the composition to the location.

198. The composition of claim 197, wherein the connector is operable to anchor the composition to the location using an adhesive, negative pressure and/or fastener.

199. An JAK inhibitor for use in a method of treating a disease of the gastrointestinal tract in a subject, wherein the method comprises orally administering to the subject an ingestible device loaded with the JAK inhibitor, wherein the JAK inhibitor is released by the device at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease.

200. The JAK inhibitor for use of claim 199, wherein the JAK inhibitor is contained in a reservoir suitable for attachment to a device housing, and wherein the method comprises attaching the reservoir to the device housing to form the ingestible device, prior to orally administering the ingestible device to the subject.

201. An attachable reservoir containing a JAK inhibitor for use in a method of treating a disease of the gastrointestinal tract, wherein the method comprises attaching the reservoir to a device housing to form an ingestible device and orally administering the ingestible device to a subject, wherein the JAK inhibitor is released by device at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease.

202. A composition comprising or consisting of an ingestible device loaded with a therapeutically effective amount of a JAK inhibitor, for use in a method of treatment, wherein the method comprises orally administering the composition to the subject, wherein the JAK inhibitor is released by the device at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease.

203. The JAK inhibitor for use according to claim 199 or 200, the attachable reservoir compartment for use according to claim 201 , or the composition for use according to claim 202, wherein the sites of disease have been pre-determined.

204. The JAK inhibitor for use according to claim 199 or 200, the attachable reservoir compartment for use according to claim 201 , or the composition for use according to claim 202, wherein the ingestible device further comprises an environmental sensor and the method further comprises using the environmental sensor to identify the location of one or more sites of disease.

205. The JAK inhibitor for use, the attachable reservoir compartment for use the composition for use, according to claim 204, wherein the environmental sensor is an imaging sensor and the method further comprising imaging the gastrointestinal tract to identify the location of one or more sites of disease.

206. The JAK inhibitor for use, the attachable reservoir compartment for use, or the composition for use, according to claim 205, wherein the imaging detects inflamed tissue and/or lesions associated with a disease of the gastrointestinal tract.

207. The JAK inhibitor for use, the attachable reservoir compartment for use or the composition for use, according to any one of claims 199 to 205, wherein the disease of the GI tract is one or more of an inflammatory bowel disease, ulcerative colitis and Crohn's disease.

208. An ingestible device loaded with a therapeutically effective amount of a JAK inhibitor, wherein the device is controllable to release the JAK inhibitor at a location in the gastrointestinal tract of the subject that is proximate to one or more sites of disease.

209. The device of claim 208 for use in a method of treatment of the human or animal body.

210. The JAK inhibitor for use, the attachable reservoir compartment for use or the composition for use according to any one of claims 199 to 207, or the device according to claim 208 or claim 209, wherein the ingestible device comprises:

a housing defined by a first end, a second end substantially opposite from the first end, and a wall extending longitudinally from the first end to the second end;

a reservoir located within the housing and containing the JAK inhibitor wherein a first end of the reservoir is connected to the first end of the housing;

a mechanism for releasing the JAK inhibitor from the reservoir, and;

an exit value configured to allow the JAK inhibitor to be released out of the housing from the reservoir.

211. The JAK inhibitor for use, the attachable reservoir compartment for use or the composition for use according to any one of claims 199 to 207, or the device according to claim 208 or claim 209, wherein the ingestible device comprises:

an ingestible housing comprising a reservoir compartment having a therapeutically effective amount of the JAK inhibitor stored therein;

a release mechanism having a closed state which retains the JAK inhibitor in the reservoir and an open state which releases the JAK inhibitor from the reservoir to the exterior of the device; and

an actuator which changes the state of the release mechanism from the closed to the open state.

212. The JAK inhibitor for use, the attachable reservoir compartment for use, the composition for use, or the device according to claims 210 or 211 , wherein the ingestible device further comprises an environmental sensor for detecting the location of the device in the gut and/or for detecting the presence of disease in the GI tract.

213. The JAK inhibitor for use, the attachable reservoir compartment for use, the composition for use, or the device according to claim 212, wherein the ingestible device further comprises a communication system for transmitting data from the environmental sensor to an external receiver.

214. The JAK inhibitor for use, the attachable reservoir compartment for use, the composition for use, or the device according to claim 212 or 213, wherein the ingestible device further comprises a processor or controller which is coupled to the environmental sensor and to the actuator and which triggers the actuator to cause the release mechanism to transition from its closed state to its open state when it is determined that the device is in the presence of diseased tissue and/or is in a location in the gut that has been predetermined to be proximal to diseased tissue.

215. The JAK inhibitor for use, the attachable reservoir compartment for use, the composition for use, or the device according to claim 213, wherein the communication system further comprises means for receiving a signal from an external transmitter, and wherein the actuator is adapted to be triggered in response to the signal.

216. The JAK inhibitor for use, the attachable reservoir compartment for use, the composition for use, or the device according to any one of claims 210 to 215, wherein the ingestible device further comprises a communication system for transmitting localization data to an extemal receiver.

217. The JAK inhibitor for use, the attachable reservoir compartment for use, the composition for use, or the device according to any one of claims 210 to 213, wherein the ingestible device further comprises a communication system for transmitting localization data to an external receiver and for receiving a signal from an extemal transmitter; wherein the actuator is adapted to be triggered in response to the signal.

218. The JAK inhibitor for use, the attachable reservoir compartment for use, the composition for use, or the device according to any one of claims 1 19 to 217, wherein the ingestible device further comprises a deployable anchoring system and an actuator for deploying the anchoring system, wherein the anchoring system is capable of anchoring or attaching the ingestible device to the subject's tissue.