`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`MYLAN PHARMACEUTICALS INC.,
`
`Petitioner,
`
`v.
`
`BAUSCH HEALTH IRELAND LIMITED,
`
`Patent Owner.
`
`__________________
`
`Case IPR2022-00722
`U.S. Patent No. 7,041,786
`__________________
`
`DECLARATION OF SCOTT A. WALDMAN, M.D., PHD, FDP, FAHA,
`FNAI, FASPET
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`Bausch Health Ireland Exhibit 2025, Page 1 of 64
`Mylan v. Bausch Health Ireland - IPR2022-00722
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`Table of Contents
`Introduction ...................................................................................................... 1
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`Qualifications and Experience ......................................................................... 2
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`I.
`
`II.
`
`III.
`
`Legal Standards ............................................................................................... 5
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`IV. Background ...................................................................................................... 8
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`A.
`
`B.
`
`C.
`
`The Gastrointestinal Tract ..................................................................... 8
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`IBS-C and CIC ...................................................................................... 9
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`Available Treatment Options Were Inadequate ..................................12
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`1.
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`2.
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`Dietary Approaches...................................................................13
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`Pharmacologic Therapy ............................................................13
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`D.
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`Guanylate Cyclase C Receptor Agonists ............................................20
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`1.
`
`2.
`
`3.
`
`4.
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`Uroguanylin ..............................................................................24
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`Guanylin ....................................................................................29
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`Heat-Stable Enterotoxins ..........................................................30
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`Relative Activity of Guanylate Cyclase C Receptor Agonists .35
`
`E.
`
`Trulance® .............................................................................................44
`
`V.
`
`Objective Evidence Supports the Nonobviousness of the ’786 Patent .........47
`
`A.
`
`B.
`
`C.
`
`Plecanatide’s Superior Binding Affinity Would Not Have Been
`Expected ..............................................................................................47
`
`Plecanatide’s Superior cGMP Potency Would Not Have Been
`Expected ..............................................................................................49
`
`Plecanatide’s Increased pH Sensitivity Would Not Have Been
`Expected ..............................................................................................56
`
`VI. Materials Considered in Forming Opinions ..................................................60
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`VII. Compensation ................................................................................................60
`
`0
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`Bausch Health Ireland Exhibit 2025, Page 2 of 64
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`I.
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`Introduction
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`1.
`
`I have been retained by counsel for Patent Owner Bausch Health Ireland
`
`Limited (“Bausch”)1 as an expert in connection with the above-captioned inter
`
`partes review proceeding.
`
`2.
`
`I understand that Petitioner Mylan Pharmaceuticals Inc.’s (“Mylan”)
`
`has asserted that claims 1-6 of U.S. Patent No. 7,041,786 (Ex. 1001 (“the ’786
`
`patent”))2 would have been obvious and that the Patent Trial and Appeal Board
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`(“Board”) has instituted inter partes review of claims 1-6 of the ’786 patent based
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`on four grounds of unpatentability.
`
`3.
`
`I have been asked to provide information regarding the state of the art
`
`as of January 17, 2002. In particular, I have been asked to provide information about
`
`the gastrointestinal (“GI”) tract; constipation, including chronic idiopathic
`
`constipation (“CIC”) and irritable bowel syndrome with constipation (“IBS-C”); and
`
`guanylate cyclase C (“GCC”) receptors and ligands.
`
`1 I understand that Bausch acquired the ’786 patent from Synergy Pharmaceuticals,
`
`Inc. In my declaration, I use Bausch to also refer to Synergy Pharmaceuticals, Inc.
`
`2 U.S. Patent No. 7,041,786, titled “Guanylate Cyclase Receptor Agonist for the
`
`Treatment of Tissue inflammation and Carcinogenesis” (Ex. 1001 (“the ’786
`
`patent”)).
`
`1
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`4.
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`I have also been asked to provide my opinions regarding the activity of
`
`plecanatide versus the activity of human uroguanylin.
`
`II. Qualifications and Experience
`
`5. My qualifications and experience are reflected in my curriculum vitae,
`
`attached as Exhibit 20303 and incorporated herein by reference. Also included in my
`
`curriculum vitae is a list of publications that I have authored to date.
`
`6.
`
`I am a clinical pharmacologist, physician, and biomedical scientist with
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`over 30 years of experience with GCC and gastrointestinal disorders, including CIC
`
`and IBS-C. For example, I have presented on CIC and IBS-C. I have also published
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`peer-reviewed journal articles that discuss chronic constipation, including:
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`Bharucha, A.E. et al., Taking a lesson from microbial diarrheagenesis in the
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`management of chronic constipation. Gastroenterology 138(3):813-7 (2010);
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`Waldman, S.A., et al., Blunted evoked prouroguanylin endocrine secretion in
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`chronic constipation. Clin Trans Gastroenterol. 00:e-00016 (2019); Sayuk, G.S., et
`
`al., Mechanisms of action of current treatment options for chronic idiopathic
`
`constipation and irritable bowel syndrome with constipation. Am. J. Gastro. 117:S6-
`
`S13 (2022); Brenner, D.M., et al. Real-world treatment strategies to improve
`
`
`3 Scott Arthur Waldman, MD, PhD, FCP, FAHA, FNAI, FASPET Curriculum Vitae
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`
`
` 2
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`
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`(Ex. 2030).
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`
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`outcomes in patients with chronic idiopathic constipation and irritable bowel
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`syndrome with constipation. Am. J. Gastro. 117:S21-S26 (2022).
`
`7.
`
`I am currently Chair of the Department of Pharmacology, Physiology
`
`and Cancer Biology at Thomas Jefferson University. I am also the MD/PhD Program
`
`Director and the Samuel M.V. Hamilton Professor of Medicine at Thomas Jefferson
`
`University.
`
`8.
`
`My research focuses on GCC, GCC agonists, cyclic guanosine
`
`monophosphate (“cGMP”), and their therapeutic implications. In 2021, I ranked
`
`among the top 30 most cited authors in cell signaling per Google Scholar and among
`
`the top 0.01% (top 50) of authors in Translational Medicine per Expertscape.
`
`9.
`
`I received a B.S. in Biology from State University of New York at
`
`Albany in 1975, followed by a Ph.D. in Human Anatomy from Thomas Jefferson
`
`University in 1980, where I worked at the Daniel Baugh Institute of Anatomy. I
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`completed postdoctoral fellowships in pharmacology at the University of Virginia
`
`in 1981 and at Stanford University in 1983. I then attended medical school and
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`graduated with an M.D. from Stanford University in 1987. I completed my
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`internship (1987–1988) and clinical residency (1988–1990) in the department of
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`medicine at the Stanford University Hospital.
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`3
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`10.
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`I am a diplomate of the American Board of Clinical Pharmacology and
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`a former diplomate of the American Board of Internal Medicine. I am licensed to
`
`practice medicine in Pennsylvania.
`
`11. My areas of teaching include medical and molecular pharmacology and
`
`advanced cellular and molecular immunology. My areas of research include GCC,
`
`cGMP signaling, and diagnosis and therapies of gastrointestinal disorders such as
`
`CIC and IBS-C. I have co-authored a pharmacology textbook, Pharmacology and
`
`Therapeutics: Principles to Practice (Saunders-Elsevier). I have also authored or
`
`coauthored more than 300 research articles in peer-reviewed journals. My most cited
`
`references include: i) Lucas KA, et al., Guanylyl cyclases and signaling by cyclic
`
`GMP. Pharmacol Rev. 2000 Sep;52(3):375-414, cited more than 1,500 times
`
`according to Google Scholar; ii) Waldman SA, et al., Cyclic GMP synthesis and
`
`function. Pharmacol Rev. 1987 Sep;39(3):163-96, cited more than 1,000 times
`
`according to Google Scholar; and iii) Waldman SA et al, Atrial natriuretic factor
`
`selectively activates particulate guanylate cyclase and elevates cyclic GMP in rat
`
`tissues. J Biol Chem. 1984 Dec 10;259(23):14332-4, cited more than 800 times
`
`according to Google Scholar.
`
`12.
`
`I have been a peer reviewer for multiple National Cancer Institute Study
`
`Sections and have served on the editorial boards of multiple peer-reviewed
`
`
`
` 4
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`publications, including Expert Reviews in Clinical Pharmacology and World Journal
`
`of Gastroenterology. For example, I am an editorial board member of Personalized
`
`Medicine; Expert Reviews in Clinical Pharmacology; Drug Design, Development
`
`and Therapy; and Regenerative Medicine. I have served as inaugural deputy editor
`
`of Clinical and Translational Science and Biomarkers in Medicine, and I have
`
`served an editorial board member of World Journal of Gastroenterology;
`
`Therapeutics and Clinical Risk Management; Physicians OnLine; Biotechnology
`
`Healthcare; and Cancer Therapeutics. I have received research grants and contracts
`
`from the National Institutes of Health, the National Cancer Institute, and private
`
`industry.
`
`III. Legal Standards
`
`13.
`
`I have no formal legal training, but I have been informed by Bausch’s
`
`counsel about the appropriate legal standards as set forth below and have applied
`
`these standards in rendering my opinions. I reserve the right to supplement my
`
`declaration to take into account any modifications to these standards, if I am
`
`informed of such.
`
`14.
`
`I understand that to find a patent claim unpatentable for obviousness,
`
`the claimed invention, as a whole, when considered against the prior art, as a whole,
`
`would have been obvious to a person having ordinary skill in the art at the time the
`
`
`
` 5
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`invention was made. I understand that in considering this issue, I must consider 1)
`
`the level of skill in the art, 2) scope and content of the prior art, 3) differences
`
`between the claimed invention and prior art, and 4) objective evidence of non-
`
`obviousness. I understand that some examples of such objective indicia of non-
`
`obviousness include: 1) a long-felt but unsolved need for the claimed invention, 2)
`
`the failure of others in the prior art to fill this need, 3) unexpected or surprising
`
`results of the claimed invention, 4) skepticism as to the inventor’s chances for
`
`success, 5) industry praise for the invention, and 6) commercial success of the
`
`claimed invention.
`
`15.
`
`I understand that “the time the invention was made” is no later than
`
`January 17, 2002.
`
`16.
`
`I understand that “a person having ordinary skill in the art” is a
`
`hypothetical person presumed to be aware of all the pertinent prior art. I have been
`
`informed that the parties have set forth definitions for the person having ordinary
`
`skill in the art.
`
`17.
`
`I understand that Mylan has asserted a person of ordinary skill in the art
`
`as of January 17, 2002, “would typically have a Ph.D. in chemistry or protein
`
`engineering or a related field” and “could also include individuals with a master’s
`
`degree in one of these fields plus two-to-five years of experience in drug
`
`6
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`development.” Ex. 10024 ¶ 42. I understand that Mylan’s expert, Dr. Peterson,
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`further asserts that “[t]his individual would have worked in consultation with a team
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`including, e.g., a pharmaceutical chemist or a pharmacist familiar with formulating
`
`peptides for administration.” Id.
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`18.
`
`I understand that Bausch has asserted a person of ordinary skill in the
`
`art would have a B.S. degree in chemistry or a related field and 2-5 years of
`
`experience in drug development that could include experience with peptide
`
`chemistry and/or peptide engineering. I understand that the person of ordinary skill
`
`in the art could also include individuals with a master’s degree or Ph.D. in chemistry
`
`or a related field with comparatively less experience in drug development involving
`
`peptide chemistry and/or peptide engineering. I understand that the person of
`
`ordinary skill in the art could have worked in consultation with individuals with
`
`knowledge and experience with the target drug receptor and of the disease condition
`
`to be treated. In particular, I understand that this team could include a clinical
`
`pharmacologist with experience with the target drug receptor (here, guanylate
`
`cyclase-C (“GCC”) receptors) or a medical doctor with experience in treating GI
`
`
`4 Expert Declaration of Blake R. Peterson, Ph.D. (Ex. 1002).
`
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` 7
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`disorders, who may also have experience designing and running clinical trials, or a
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`pharmaceutical formulator.
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`19. As of January 17, 2022, I was a medical doctor and clinical
`
`pharmacologist specializing in GCC receptors and GCC receptor agonists.
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`IV. Background
`
`A. The Gastrointestinal Tract
`
`20. The GI tract, also called digestive tract, is a pathway by which food
`
`enters the body and solid wastes are expelled. Distinct and tightly regulated pH
`
`environments have well-established roles in physiological processes in different
`
`regions of the GI tract. Intraluminal pH values are tightly regulated by a number of
`
`ion channels, including the cystic fibrosis transmembrane conductance regulator
`
`(“CFTR”) and the Na+/H+ exchanger, which in turn are regulated by GCC
`
`activation.
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`21. Acidic gastric contents empty into the duodenum where they mix with
`
`alkaline secretions from the pancreas and biliary tract, producing a moderate rise in
`
`pH that protects the intestinal columnar epithelium from the deleterious effects of
`
`acid, while creating the pH optimum for pancreatic enzymes to enhance nutrient
`
`absorption. There is a steady rise in pH across the rostral-caudal axis of the GI tract,
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`from approximately pH 5.5 in the proximal jejunum to pH of 7.5 in the distal ileum.
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`
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` 8
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`Bausch Health Ireland Exhibit 2025, Page 10 of 64
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`Ex. 20335 at 572. With the exception of a slight drop in the caecum, pH values
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`remain close to neutral throughout the colon, providing a supporting environment
`
`for commensal bacteria. Prior to 2002, pH values in different areas of the GI tract
`
`were known. Ex. 20326 at 759; Ex. 2033 at 572.
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`B.
`
`IBS-C and CIC
`
`22. CIC and IBS-C are serious conditions that can significantly reduce
`
`patients’ physical, social, emotional and/or material quality of life. Ex. 20487 at 448,
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`450; Ex. 20498 at 1, 6.
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`5 Nugent, et al., “Intestinal luminal pH in inflammatory bowel disease: possible
`
`determinants and implications for therapy with aminosalicylates and other drugs”,
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`Gut, Vol. 48, No. 4, 571-77 (2001) (Ex. 2033).
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`6 Dressman, et al., “Upper Gastrointestinal (GI) pH in Young, Healthy Men and
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`Women”, Pharmaceutical Research, Vol. 7, No. 7, 756-61 (1990) (Ex. 2032).
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`7 Borgaonkar et al., “Quality of life measurement in gastrointestinal and liver
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`disorders”, Gut, Vol. 47, Iss. 3, 444-54 (2000) (Ex. 2048).
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`8 Francis et al., “The irritable bowel syndrome”, Postgraduate Medical Journal.
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`Vol. 73, 1-7 (1997) (Ex. 2049).
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`9
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`23. The underlying cause is unknown in most CIC patients. Ex. 20509 at
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`913. Although the precise categorization of CIC is somewhat difficult because of
`
`inconsistent definitions and methodologies, CIC is categorized as functional
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`constipation. Id. According to Rome II criteria, which was widely used in 2002,
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`functional constipation was diagnosed based on the following criteria. Ex. 205110 at
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`II43, II45.
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`
`
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`9 Yamada et al., “Textbook of Gastroenterology”, Third Edition, Vol. 1, Lippincott
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`Williams & Wilkins (1999) (Ex. 2050).
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`10 Thompson et al., “Functional bowel disorders and functional abdominal pain”,
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`Gut, Vol. 45, Suppl. II, II43-7 (1999) (Ex. 2051).
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`10
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`24.
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`IBS-C is a chronic and incurable GI disorder characterized by changes
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`in bowel function, and alterations in mucosal and immune functions, microbiota and
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`visceral sensitivity. Ex. 205211 at 743-5; Ex, 205312 at 125. In 2002, it was known
`
`that the symptoms of IBS-C and CIC overlap, but IBS-C involves a pain element.
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`Ex. 2051 at II44-II45. It is now known that CIC also involves some pain and
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`discomfort, but the degree of pain in IBS-C patients is higher as a predominant
`
`symptom of IBS-C is pain. According to Rome II criteria, in 2002, IBS-C was
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`diagnosed based on the following criteria. Id. at II44.
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`
`
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`11 Collins et al., “The putative role of inflammation in the irritable bowel syndrome”,
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`Gut, Vol. 49, Iss. 6, 743-5 (2001) (Ex. 2052).
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`12 Camilleri et al., “Visceral hypersensitivity: facts, speculations, and challenges”,
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`Gut, Vol. 48, Iss. 1, 125-31 (2001) (Ex. 2053).
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`11
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`25. While statistics vary based on the study scope, it is estimated that at
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`least 20% of adults have functional constipation or CIC, that 6%–21.6% of adults
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`have IBS-C, and that there is overlap of these disorders. Ex. 2048 at 448; Ex. 2051
`
`at II45; Ex. 205413 at 1582; Ex. 205514 at 185; Ex. 205615 at 11.
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`C.
`
`Available Treatment Options Were Inadequate
`
`26.
`
`Prior to 2002, no FDA approved therapies were available to treat global
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`CIC and IBS-C symptoms.
`
`27.
`
`In 2002, treatment of constipation included dietary and behavioral
`
`approaches, pharmacologic therapy, and in rare instances, surgery, which to date
`
`remains controversial. Ex. 2050 at 919.
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`13 Suares et al., “Prevalence of, and risk factors for, chronic idiopathic constipation
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`in the community: systematic review and meta-analysis”, The American Journal of
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`Gastroenterology, Vol. 106, No. 9, 1582-91 (2011) (Ex. 2054).
`
`14 Sandler et al., “Demographic and dietary determinants of constipation in the US
`
`population”, The American Journal of Public Health, Vol. 80, No.2, 185-9 (1990)
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`(Ex. 2055).
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`15 Faigel, “A clinical approach to constipation”, Clinical Cornerstone, Vol. 4, No. 4,
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`11-18 (2002) (Ex. 2056).
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`12
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`1.
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`Dietary Approaches
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`28. Dietary approaches, such as intake of dietary fiber, are first line
`
`interventions for most adults with constipation. Ex. 2050 at 919. Fiber may serve as
`
`a substrate for colonic bacteria and thus increase stool bulk by proliferation of
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`bacteria and production of gases that are trapped in the stool. Id. Many practitioners
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`also recommend timed voiding, instructing patients to use the bathroom after
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`breakfast or dinner to take advantage of meal-stimulated increases in colonic
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`motility. Id. at 920.
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`2.
`
`Pharmacologic Therapy
`
`a.
`
`Laxatives
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`29. Laxatives are commonly employed by patients as first line treatments
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`for CIC and IBS-C. The use of laxatives is deeply rooted in medical and social
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`traditions and vast amounts are consumed especially by elderly persons. Ex. 2050 at
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`920. Chronic use of laxatives may lead to complications, including dependency,
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`tolerance, and GI symptoms, including abdominal pain and diarrhea. Id. Further,
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`over the counter laxatives may prove ineffective for the treatment of CIC and IBS-
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`C.
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`30. Laxatives are classified based on their presumed mode of action.
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`Ex. 2050 at 920. I discuss each mode of action below.
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`(1) Bulk-forming laxatives
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`31. Bulk-forming laxatives comprise natural (psyllium) or synthetic
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`polysaccharides or cellulose derivatives that act in a manner similar to that of fiber
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`naturally contained in the diet. Ex. 2050 at 920. Bulk-forming laxatives increase the
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`weight and water-absorbent properties of stool. Id. By retaining fluid in the stool,
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`these agents increase stool bulk and soften stool consistency. Id.
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`(2)
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` Emollient laxatives (Stool Softener)
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`32. Emollient laxatives include mineral oil and docusate salts. Ex. 2050 at
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`920. Mineral oil can be given orally or by enema. Id. at 921. Mineral oil may
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`decrease the absorption of fat-soluble vitamins A, D, and K. Id. As stool softeners,
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`docusate salts are anionic surfactants that lower the surface tension of stool to allow
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`mixing of aqueous and fatty substances. Id. This enables water and lipids to
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`penetrate, thereby hydrating and softening stool. Id.
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`(3) Hyperosmolar agents
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`33. Hyperosmolar agents include mixed electrolyte solutions containing
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`polyethylene glycol and nonabsorbable sugars such as lactulose and sorbitol. Ex.
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`2050 at 921. Sorbitol and lactulose are degraded by colonic bacteria to low molecular
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`weight acids that increase stool acidity and osmolarity. Id. These agents create an
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`osmotic gradient that promotes water and electrolyte secretion into the intestinal
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`lumen, thereby increasing stool volume and peristalsis. Id.
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`(4)
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`Saline Laxatives
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`34.
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`Saline laxatives contain relatively nonabsorbable cations and anions,
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`such as magnesium hydroxide, that exert on osmotic effect to increase intralumenal
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`water content. Ex. 2050 at 921. Because an appreciable amount of magnesium may
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`be absorbed, there is a risk from magnesium toxicity. Id.
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`(5)
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`Stimulant Laxatives
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`35.
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`Stimulant laxatives include castor oil, anthraquinones (cascara sagrada,
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`senna, casanthranol, and danthron), and diphenyl-methanes (phenolphthalein and
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`bisacodyl). Ex. 2050 at 921. Castor oil stimulates intestinal secretion, decreases
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`glucose absorption, and increases intestinal motility. Id. The anthraquinone laxatives
`
`increase fluid and electrolyte accumulation in the distal ileum and colon. Id. at 921-
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`22. The diphenyl-methane laxatives act on intestine fluid accumulation and colonic
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`motor activity. Id.
`
`b.
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`Prokinetics
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`36. Around 2002, prokinetic agents were a new class of drugs that stimulate
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`gastrointestinal motor activity to enhance transit of intralumenal contents. Ex. 2050
`
`at 922. Prokinetic agents work as agonists of serotonin (5-hydroxytryptamine)
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`receptor sub-types in the gastrointestinal tract. Id. These agents increase colonic
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`peristalsis and motility via serotonin release, which controls gut smooth-muscle
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`contractions and relaxations. Id. Notably, in 2000, a widely used prokinetic agent
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`15
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`Bausch Health Ireland Exhibit 2025, Page 18 of 64
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`Bausch Health Ireland Exhibit 2025, Page 19 of 64
`Mylan v. Bausch Health Ireland - IPR2022-00722
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`Bausch Health Ireland Exhibit 2025, Page 20 of 64
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`Bausch Health Ireland Exhibit 2025, Page 21 of 64
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`target the small intestine. Indeed, as of 2002, the colon was universally accepted as
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`a necessary site of action for treating constipation. Thus, persons of ordinary skill in
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`the art would have focused on developing a drug acting in the colon rather than in
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`the small intestine. See generally Ex. 205918.
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`D. Guanylate Cyclase C Receptor Agonists
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`39. GCC is the receptor for the endogenous peptides guanylin and
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`uroguanylin as well as their molecular mimics, the heat-stable enterotoxins or STs.
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`Ex. 206119 at 377. Uroguanylin and guanylin are found in the intestines and bind to
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`a GCC receptor to stimulate intracellular production of cGMP. Ex. 1001 at 1:26-29.
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`Heat-stable enterotoxins are peptides secreted by enteric bacteria such as
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`enterotoxigenic E. coli. Ex. 101620 at E957.
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`
`18 Chey et al., “Randomized Trial of 2 Delayed-Release Formulations of Linaclotide
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`in Patients With Irritable Bowel Syndrome With Constipation”, The American
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`Journal of Gastroenterology, Vol. 116, Iss. 2, 354-361 (2021) (Ex. 2059).
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`19 Lucas et al., “Guanylyl cyclases and signaling by cyclic GMP”, Pharmacological
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`Reviews, Vol. 52, No. 3, 375-413 (2000) (Ex. 2061).
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`20 Fan et al., “Structure and activity of uroguanylin and guanylin from the intestine
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`and urine of rats”, Am. J. Physiol., Vol. 273, No. 5, E957-E964 (1997) (Ex. 1016).
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`20
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`Bausch Health Ireland Exhibit 2025, Page 22 of 64
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`40. GCC is expressed along the length of the GI tract, but it is differentially
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`activated in a pH-dependent manner by uroguanylin in the small intestine and by
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`guanylin in the colorectum.
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`Ex. 2061 at 404, Fig. 5.
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`41.
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`cGMP activation results in the activation of CFTR, an apical membrane
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`channel for efflux of chloride from enterocytes lining the intestinal tract as shown in
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`the above figure. Ex. 1001 at 1:29-32. Activation of CFTR and the subsequent
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`enhancement of transepithelial secretion of chloride leads to stimulation of sodium
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`21
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`Bausch Health Ireland Exhibit 2025, Page 23 of 64
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`and water secretion into the intestinal lumen. Ex. 1001 at 1:33-35. Therefore, these
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`GCC receptor agonists stimulate cGMP production and promote chloride efflux,
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`which drives water transport into the intestinal lumen. Ex. 1001 at 1:35-39.
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`42. Before January 17, 2002, T84 cell assays were industry standard for
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`assessing a peptide’s ability to bind to GCC receptors and to stimulate cGMP
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`production, thus drawing in water and electrolytes to the intestines. Ex. 1001 at
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`15:25-17:5.
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`43. The sequences of human and certain animal uroguanylins and
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`guanylins and of various heat-stable enterotoxins were known in the art. Prior to
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`2002, it was known that uroguanylin, guanylin, and heat-stable enterotoxins could
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`bind to GCC receptors and stimulate cGMP production. It was known in the art that
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`the heat-stable enterotoxin’s activity far surpassed that of uroguanylin and guanylin
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`22
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`Bausch Health Ireland Exhibit 2025, Page 24 of 64
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`and was pH-independent, unlike uroguanylin and guanylin. Ex. 1005 at Fig. 3A, 3B;
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`Ex. 102121 at 2706-08, Figs. 1-4; Ex. 101922 at G710, Fig. 1.
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`44.
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`It was known by January 2002 that uroguanylin was more active and
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`prevalent in acidic environments (e.g., the duodenum) whereas guanylin was more
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`active and prevalent in alkaline environments (e.g., the ileum and colon). E.g., Ex.
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`1021. Thus, while GC-C is expressed along the length of the GI tract, it is
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`differentially activated by uroguanylin in small intestine and by guanylin in
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`colorectum in a pH-dependent manner. As such, uroguanylin and guanylin
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`cooperatively regulate the GCC activity in the GI tract. Ex. 206223 at 361; Ex. 1021
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`at 2705. In a healthy individual, fluid volumes are balanced by secretory and
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`21 Hamra et al., “Regulation of intestinal uroguanylin/guanylin receptor-mediated
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`responses by mucosal acidity”, Proc. Natl. Acad. Sci. USA, Vol. 94, 2705-2710
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`(1997) (Ex. 1021 (“Hamra 1997”)).
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`22 Hamra et al., “Opossum Colonic Muscosa Contains Uroguanylin and Guanylin
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`Peptides”, Am. J. Physiol. Gastrointest. Liver Physiol. Vol. 270, G708-G716 (1996)
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`(Ex. 1019).
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`23 Bełtowski, “Guanylin and related peptides”, Journal of Physiology and
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`Pharmacology, Vol. 52, No. 3, 351-75 (2001) (Ex. 2062).
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`23
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`Bausch Health Ireland Exhibit 2025, Page 25 of 64
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`absorption mechanisms, with highest net secretion in the proximal small intestine
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`and highest net absorption in the colon.
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`1.
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`Uroguanylin
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`45. Uroguanylin was discovered as an endogenous peptide hormone in
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`mammals because of its similarity to heat-stable enterotoxins. Ex. 201124 at 27.
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`Human uroguanylin, which is predominantly found in the small intestine, is a 16
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`amino acid chain shown in Figure 3 below.
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`Ex. 100625 at 52.
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`Figure 3
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`24 Chino et al., “Topological isomers of human uroguanylin: interconversion
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`between biologically active and inactive isomers,” FEBS Letters, 421, 27-31 (1998)
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`(Ex. 2011 (“Chino”)).
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`25 Li et al., “Purification, cDNA Sequence, and Tissue Distribution of Rat
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`Uroguanylin”, Regul. Pept., Vol. 68, 45-56 (1997) (Ex. 1006).
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`24
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`Bausch Health Ireland Exhibit 2025, Page 26 of 64
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`46. Unlike heat-stable enterotoxins having three disulfide bonds, human
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`uroguanylin is “characterized by two disulfide bonds [that] are crucial for biological
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`activity.” Ex. 201026 at 230. These disulfide bonds result in two topoisomers. Id. at
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`230.
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`47.
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`It was known in the art that only one of these topological isoforms is
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`biologically active, i.e., binds with the GCC receptor. Id. at 229; see also Ex. 202027
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`at 223 (“It is generally accepted that the other two disulfide isomers of uroguanylin
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`are biologically inactive.”). It was known in the art that the other topological isoform
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`did not bind with the GCC receptor, but its biological properties were otherwise
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`“completely unknown.” Ex. 2020 at 229.
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`48. These topoisomers are depicted below as Isomer A (biologically active
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`conformation) and Isomer B (biologically inactive conformation).
`
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`26 Marx et al., “One peptide, two topologies: structure and interconversion dynamics
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`of human uroguanylin isomers,” J. Peptide Res. 52, 229-240 (1998) (Ex. 2010
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`(“Marx”)).
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`27 Klodt et al., “Synthesis, biological activity and isomerism of guanylate cyclase C-
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`activating peptides guanylin and uroguanylin,” J. Peptide Res. 50, 222-230 (1997)
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`(Ex. 2020).
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`25
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`Bausch Health Ireland Exhibit 2025, Page 27 of 64
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`Ex. 2010 at 235.
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`49.
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`It was known in the art that human uroguanylin’s “isomers are
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`interconvertible” and exist in an equilibrium ratio of 1:1. Ex. 2011 at 27; see also
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`Ex. 2010 at 229 (Both human uroguanylin isoforms “are subject to a slow pH-
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`dependent mutual isomerization at 37°C with an equilibrium isomer ratio of
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`approximately 1:1.”).
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`50. Human uroguanylin’s interconversion rates vary with pH and
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`temperature. Ex. 2011 at 27; see also Ex. 2010 at 229.
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`51. At acidic pH, Chino reports that human uroguanylin’s isomers are
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`“freely convertible (same conversion rates) and eventually come to a 1:1 equilibrium
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`ratio.” Ex. 2011 at 30. But at pH 7.7, Chino reports that the isomers “seem to be
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`hampered and thereby their rates are significantly decreased.” Ex. 2011 at 30. Marx
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`similarly reports that “a decrease of pH below 4.5 did not change the kinetics of
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`interconversion,” bu