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`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
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`MYLAN PHARMACEUTICALS INC.,
`
`Petitioner,
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`v.
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`BAUSCH HEALTH IRELAND LIMITED,
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`Patent Owner.
`
`__________________
`
`Case IPR2022-00722
`U.S. Patent No. 7,041,786
`__________________
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`DECLARATION OF SCOTT A. WALDMAN, M.D., PHD, FDP, FAHA,
`FNAI, FASPET
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`Table of Contents
`Introduction ...................................................................................................... 1
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`Qualifications and Experience ......................................................................... 2
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`I.
`
`II.
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`III. Legal Standards ............................................................................................... 5
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`IV. Background ...................................................................................................... 8
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`A.
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`B.
`
`C.
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`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. Guanylate Cyclase C Receptor Agonists ............................................20
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`1.
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`2.
`
`3.
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`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
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`E.
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`Trulance® .............................................................................................44
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`V. Objective Evidence Supports the Nonobviousness of the ’786 Patent .........47
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`A.
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`B.
`
`C.
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`Plecanatide’s Superior Binding Affinity Would Not Have Been
`Expected ..............................................................................................47
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`Plecanatide’s Superior cGMP Potency Would Not Have Been
`Expected ..............................................................................................49
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`Plecanatide’s Increased pH Sensitivity Would Not Have Been
`Expected ..............................................................................................56
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`VI. Materials Considered in Forming Opinions ..................................................60
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`VII. Compensation ................................................................................................60
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` 0
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`I.
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`Introduction
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`
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`1.
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`I have been retained by counsel for Patent Owner Bausch Health Ireland
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`Limited (“Bausch”)1 as an expert in connection with the above-captioned inter
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`partes review proceeding.
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`2.
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`I understand that Petitioner Mylan Pharmaceuticals Inc.’s (“Mylan”)
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`has asserted that claims 1-6 of U.S. Patent No. 7,041,786 (Ex. 1001 (“the ’786
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`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.
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`3.
`
`I have been asked to provide information regarding the state of the art
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`as of January 17, 2002. In particular, I have been asked to provide information about
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`the gastrointestinal (“GI”) tract; constipation, including chronic idiopathic
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`constipation (“CIC”) and irritable bowel syndrome with constipation (“IBS-C”); and
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`guanylate cyclase C (“GCC”) receptors and ligands.
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`1 I understand that Bausch acquired the ’786 patent from Synergy Pharmaceuticals,
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`Inc. In my declaration, I use Bausch to also refer to Synergy Pharmaceuticals, Inc.
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`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
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`
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` 1
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`
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`patent”)).
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`4.
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`I have also been asked to provide my opinions regarding the activity of
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`plecanatide versus the activity of human uroguanylin.
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`II. Qualifications and Experience
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`5. My qualifications and experience are reflected in my curriculum vitae,
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`attached as Exhibit 20303 and incorporated herein by reference. Also included in my
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`curriculum vitae is a list of publications that I have authored to date.
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`6.
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`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
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`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
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`al., Mechanisms of action of current treatment options for chronic idiopathic
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`constipation and irritable bowel syndrome with constipation. Am. J. Gastro. 117:S6-
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`S13 (2022); Brenner, D.M., et al. Real-world treatment strategies to improve
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`
`3 Scott Arthur Waldman, MD, PhD, FCP, FAHA, FNAI, FASPET Curriculum Vitae
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`
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` 2
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`
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`(Ex. 2030).
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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).
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`7.
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`I am currently Chair of the Department of Pharmacology, Physiology
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`and Cancer Biology at Thomas Jefferson University. I am also the MD/PhD Program
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`Director and the Samuel M.V. Hamilton Professor of Medicine at Thomas Jefferson
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`University.
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`8. My research focuses on GCC, GCC agonists, cyclic guanosine
`
`monophosphate (“cGMP”), and their therapeutic implications. In 2021, I ranked
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`among the top 30 most cited authors in cell signaling per Google Scholar and among
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`the top 0.01% (top 50) of authors in Translational Medicine per Expertscape.
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`9.
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`I received a B.S. in Biology from State University of New York at
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`Albany in 1975, followed by a Ph.D. in Human Anatomy from Thomas Jefferson
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`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
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`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
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`practice medicine in Pennsylvania.
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`11. My areas of teaching include medical and molecular pharmacology and
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`advanced cellular and molecular immunology. My areas of research include GCC,
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`cGMP signaling, and diagnosis and therapies of gastrointestinal disorders such as
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`CIC and IBS-C. I have co-authored a pharmacology textbook, Pharmacology and
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`Therapeutics: Principles to Practice (Saunders-Elsevier). I have also authored or
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`coauthored more than 300 research articles in peer-reviewed journals. My most cited
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`references include: i) Lucas KA, et al., Guanylyl cyclases and signaling by cyclic
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`GMP. Pharmacol Rev. 2000 Sep;52(3):375-414, cited more than 1,500 times
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`according to Google Scholar; ii) Waldman SA, et al., Cyclic GMP synthesis and
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`function. Pharmacol Rev. 1987 Sep;39(3):163-96, cited more than 1,000 times
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`according to Google Scholar; and iii) Waldman SA et al, Atrial natriuretic factor
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`selectively activates particulate guanylate cyclase and elevates cyclic GMP in rat
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`tissues. J Biol Chem. 1984 Dec 10;259(23):14332-4, cited more than 800 times
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`according to Google Scholar.
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`12.
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`I have been a peer reviewer for multiple National Cancer Institute Study
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`Sections and have served on the editorial boards of multiple peer-reviewed
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` 4
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`publications, including Expert Reviews in Clinical Pharmacology and World Journal
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`of Gastroenterology. For example, I am an editorial board member of Personalized
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`Medicine; Expert Reviews in Clinical Pharmacology; Drug Design, Development
`
`and Therapy; and Regenerative Medicine. I have served as inaugural deputy editor
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`of Clinical and Translational Science and Biomarkers in Medicine, and I have
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`served an editorial board member of World Journal of Gastroenterology;
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`Therapeutics and Clinical Risk Management; Physicians OnLine; Biotechnology
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`Healthcare; and Cancer Therapeutics. I have received research grants and contracts
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`from the National Institutes of Health, the National Cancer Institute, and private
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`industry.
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`III. Legal Standards
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`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
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`these standards in rendering my opinions. I reserve the right to supplement my
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`declaration to take into account any modifications to these standards, if I am
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`informed of such.
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`14.
`
`I understand that to find a patent claim unpatentable for obviousness,
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`the claimed invention, as a whole, when considered against the prior art, as a whole,
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`would have been obvious to a person having ordinary skill in the art at the time the
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` 5
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`invention was made. I understand that in considering this issue, I must consider 1)
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`the level of skill in the art, 2) scope and content of the prior art, 3) differences
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`between the claimed invention and prior art, and 4) objective evidence of non-
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`obviousness. I understand that some examples of such objective indicia of non-
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`obviousness include: 1) a long-felt but unsolved need for the claimed invention, 2)
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`the failure of others in the prior art to fill this need, 3) unexpected or surprising
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`results of the claimed invention, 4) skepticism as to the inventor’s chances for
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`success, 5) industry praise for the invention, and 6) commercial success of the
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`claimed invention.
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`15.
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`I understand that “the time the invention was made” is no later than
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`January 17, 2002.
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`16.
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`I understand that “a person having ordinary skill in the art” is a
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`hypothetical person presumed to be aware of all the pertinent prior art. I have been
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`informed that the parties have set forth definitions for the person having ordinary
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`skill in the art.
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`17.
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`I understand that Mylan has asserted a person of ordinary skill in the art
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`as of January 17, 2002, “would typically have a Ph.D. in chemistry or protein
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`engineering or a related field” and “could also include individuals with a master’s
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`degree in one of these fields plus two-to-five years of experience in drug
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` 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
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`peptides for administration.” Id.
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`18.
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`I understand that Bausch has asserted a person of ordinary skill in the
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`art would have a B.S. degree in chemistry or a related field and 2-5 years of
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`experience in drug development that could include experience with peptide
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`chemistry and/or peptide engineering. I understand that the person of ordinary skill
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`in the art could also include individuals with a master’s degree or Ph.D. in chemistry
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`or a related field with comparatively less experience in drug development involving
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`peptide chemistry and/or peptide engineering. I understand that the person of
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`ordinary skill in the art could have worked in consultation with individuals with
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`knowledge and experience with the target drug receptor and of the disease condition
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`to be treated. In particular, I understand that this team could include a clinical
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`pharmacologist with experience with the target drug receptor (here, guanylate
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`cyclase-C (“GCC”) receptors) or a medical doctor with experience in treating GI
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`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
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`pharmacologist specializing in GCC receptors and GCC receptor agonists.
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`IV. Background
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`A. The Gastrointestinal Tract
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`20. The GI tract, also called digestive tract, is a pathway by which food
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`enters the body and solid wastes are expelled. Distinct and tightly regulated pH
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`environments have well-established roles in physiological processes in different
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`regions of the GI tract. Intraluminal pH values are tightly regulated by a number of
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`ion channels, including the cystic fibrosis transmembrane conductance regulator
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`(“CFTR”) and the Na+/H+ exchanger, which in turn are regulated by GCC
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`activation.
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`21. Acidic gastric contents empty into the duodenum where they mix with
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`alkaline secretions from the pancreas and biliary tract, producing a moderate rise in
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`pH that protects the intestinal columnar epithelium from the deleterious effects of
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`acid, while creating the pH optimum for pancreatic enzymes to enhance nutrient
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`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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` 8
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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
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`for commensal bacteria. Prior to 2002, pH values in different areas of the GI tract
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`were known. Ex. 20326 at 759; Ex. 2033 at 572.
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`B.
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`IBS-C and CIC
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`22. CIC and IBS-C are serious conditions that can significantly reduce
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`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
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`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
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`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
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`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
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`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
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`26. Prior to 2002, no FDA approved therapies were available to treat global
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`CIC and IBS-C symptoms.
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`27.
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`In 2002, treatment of constipation included dietary and behavioral
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`approaches, pharmacologic therapy, and in rare instances, surgery, which to date
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`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).
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`14 Sandler et al., “Demographic and dietary determinants of constipation in the US
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`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
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`interventions for most adults with constipation. Ex. 2050 at 919. Fiber may serve as
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`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.
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`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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`13
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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. 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. 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
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`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.
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`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
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`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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`cisapride was withdrawn from the market in the US for safety concerns, specifically
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`the risk of serious and potentially fatal cardiac arrhythmias. See Ex 2057 16 at 1.
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`37. Table 1 shows the pharmacologic therapies available as of January 17,
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`2002.
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`Table 1: Available Treatment Options for CIC or IBS-C17
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`Class
`
`Compounds
`
`Side Effects
`
`Bulk forming laxatives (increase water retention, stool weight and volume)
`
`Site of action: small intestine /colon
`
`Dietary
`
`Fiber Psyllium
`
`Bloating,
`
`nausea,
`
`Supplements
`
`Calcium polycarbophil
`
`vomiting, diarrhea
`
`Methycellulose
`
`Bran
`
`16 Zelawski, "Cisapride Withdrawal Requires Alternative Therapy," Cleveland
`
`Clinic (2000) (Ex. 2057).
`
`17 Ex. 2050 at 919-22~ Ex. 2058 at 1232-1 249 (Bharucha et al., "Mechanisms,
`
`Evaluation, and Management of Chronic Constipation", Gastroenterology, Vol. 158,
`
`No. 5, 1232-1 249 (2020) (Ex. 2058)).
`
`16
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`Class
`
`Compounds
`
`Side Effects
`
`Stimulants Laxatives (increase colonic motility)
`
`Site of action: colon
`
`Triglyceride
`
`Castor oil
`
`Abdominal pain, neuronal
`
`derivatives
`
`or muscular injury
`
`Diphenylmethane
`
`Bisacodyl (Dulcolax)
`
`Nausea,
`
`vomiting,
`
`derivatives
`
`diarrhea,
`
`abdominal
`
`Anthraquinones
`
`Aloe
`
`Diarrhea,
`
`abdominal
`
`cramps
`
`Cascara Sagrada
`
`cramps
`
`Senna/sennosides
`
`(Senokot)
`
`Stool Softeners (increase fluid retention in stool)
`
`Site of action: small intestine/colon
`
`Sulfonic Acids
`
`Docusate
`
`sodium Abdominal
`
`cramps,
`
`(Colace)
`
`diarrhea,
`
`intestinal
`
`Docusate calcium
`
`obstruction,
`
`rectal
`
`bleeding, throat irritation,
`
`rash
`
`17
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`Class
`
`Compounds
`
`Side Effects
`
`Emollient Laxatives (lubricate the stool surface and intestinal wall)
`
`Site of action: colon
`
`Hydrocarbons
`
`Mineral Oil
`
`Abdominal
`
`cramps,
`
`flatulence,
`
`intestinal
`
`malabsorption,
`
`nausea,
`
`vomiting, rectal discharge
`
`Hyperosmolar Laxatives (increase water secretion into the intestinal lumen)
`
`Site of action: small intestine/colon
`
`Sugar/Sugar Alcohols
`
`Lactulose (Kristalose)
`
`Transient flatulence, colic,
`
`Lactitol (Pizensy)
`
`abdominal
`
`cramps,
`
`Mannitol
`
`Sorbitol
`
`diarrhea,
`
`electrolyte
`
`imbalance,
`
`volume
`
`overload
`
`18
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`Class
`Inert Polymer
`
`Side Effects
`Compounds
`Polyethylene
`glycol Abdominal
`cramps,
`
`(PEG-3350/Miralax)
`
`nausea,
`
`vomiting,
`
`flatulence
`
`Saline Laxatives (increase water secretion into the intestinal lumen)
`
`Site of action: colon
`
`Saline Agents
`
`Magnesium Hydroxide Diarrhea, nausea, vomiting
`
`(Milk of magnesia)
`
`Magnesium citrate
`
`Prokinetics (increase colonic peristalsis or motility)
`
`Site of action: small intestines/colon
`
`Serotonin
`
`(5-HT 4) Cisapride
`
`Cardiovascular
`
`adverse
`
`receptor agonists
`
`effects
`
`( withdrawn from the US
`
`market in 2000 because of
`
`its cardiac side effects.)
`
`38. As of 2002, all available treatment options targeted the colon or both
`
`the colon and small intestine as the site of action. This is in stark contrast to
`
`plecanatide, which even today, is the only CIC and IBS-C treatment to preferentially
`
`19
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`target the small intestine. Indeed, as of 2002, the colon was universally accepted as
`
`a necessary site of action for treating constipation. Thus, persons of ordinary skill in
`
`the art would have focused on developing a drug acting in the colon rather than in
`
`the small intestine. See generally Ex. 205918.
`
`D. Guanylate Cyclase C Receptor Agonists
`
`39. GCC is the receptor for the endogenous peptides guanylin and
`
`uroguanylin as well as their molecular mimics, the heat-stable enterotoxins or STs.
`
`Ex. 206119 at 377. Uroguanylin and guanylin are found in the intestines and bind to
`
`a GCC receptor to stimulate intracellular production of cGMP. Ex. 1001 at 1:26-29.
`
`Heat-stable enterotoxins are peptides secreted by enteric bacteria such as
`
`enterotoxigenic E. coli. Ex. 101620 at E957.
`
`
`18 Chey et al., “Randomized Trial of 2 Delayed-Release Formulations of Linaclotide
`
`in Patients With Irritable Bowel Syndrome With Constipation”, The American
`
`Journal of Gastroenterology, Vol. 116, Iss. 2, 354-361 (2021) (Ex. 2059).
`
`19 Lucas et al., “Guanylyl cyclases and signaling by cyclic GMP”, Pharmacological
`
`Reviews, Vol. 52, No. 3, 375-413 (2000) (Ex. 2061).
`
`20 Fan et al., “Structure and activity of uroguanylin and guanylin from the intestine
`
`and urine of rats”, Am. J. Physiol., Vol. 273, No. 5, E957-E964 (1997) (Ex. 1016).
`
`
`
`
`
`20
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`40. GCC is expressed along the length of the GI tract, but it is differentially
`
`activated in a pH-dependent manner by uroguanylin in the small intestine and by
`
`guanylin in the colorectum.
`
`
`
`Ex. 2061 at 404, Fig. 5.
`
`41.
`
`cGMP activation results in the activation of CFTR, an apical membrane
`
`channel for efflux of chloride from enterocytes lining the intestinal tract as shown in
`
`the above figure. Ex. 1001 at 1:29-32. Activation of CFTR and the subsequent
`
`enhancement of transepithelial secretion of chloride leads to stimulation of sodium
`
`
`
`
`
`21
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`and water secretion into the intestinal lumen. Ex. 1001 at 1:33-35. Therefore, these
`
`GCC receptor agonists stimulate cGMP production and promote chloride efflux,
`
`which drives water transport into the intestinal lumen. Ex. 1001 at 1:35-39.
`
`42. Before January 17, 2002, T84 cell assays were industry standard for
`
`assessing a peptide’s ability to bind to GCC receptors and to stimulate cGMP
`
`production, thus drawing in water and electrolytes to the intestines. Ex. 1001 at
`
`15:25-17:5.
`
`43. The sequences of human and certain animal uroguanylins and
`
`guanylins and of various heat-stable enterotoxins were known in the art. Prior to
`
`2002, it was known that uroguanylin, guanylin, and heat-stable enterotoxins could
`
`bind to GCC receptors and stimulate cGMP production. It was known in the art that
`
`the heat-stable enterotoxin’s activity far surpassed that of uroguanylin and guanylin
`
`
`
`
`
`22
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`and was pH-independent, unlike uroguanylin and guanylin. Ex. 1005 at Fig. 3A, 3B;
`
`Ex. 102121 at 2706-08, Figs. 1-4; Ex. 101922 at G710, Fig. 1.
`
`44.
`
`It was known by January 2002 that uroguanylin was more active and
`
`prevalent in acidic environments (e.g., the duodenum) whereas guanylin was more
`
`active and prevalent in alkaline environments (e.g., the ileum and colon). E.g., Ex.
`
`1021. Thus, while GC-C is expressed along the length of the GI tract, it is
`
`differentially activated by uroguanylin in small intestine and by guanylin in
`
`colorectum in a pH-dependent manner. As such, uroguanylin and guanylin
`
`cooperatively regulate the GCC activity in the GI tract. Ex. 206223 at 361; Ex. 1021
`
`at 2705. In a healthy individual, fluid volumes are balanced by secretory and
`
`
`21 Hamra et al., “Regulation of intestinal uroguanylin/guanylin receptor-mediated
`
`responses by mucosal acidity”, Proc. Natl. Acad. Sci. USA, Vol. 94, 2705-2710
`
`(1997) (Ex. 1021 (“Hamra 1997”)).
`
`22 Hamra et al., “Opossum Colonic Muscosa Contains Uroguanylin and Guanylin
`
`Peptides”, Am. J. Physiol. Gastrointest. Liver Physiol. Vol. 270, G708-G716 (1996)
`
`(Ex. 1019).
`
`23 Bełtowski, “Guanylin and related peptides”, Journal of Physiology and
`
`Pharmacology, Vol. 52, No. 3, 351-75 (2001) (Ex. 2062).
`
`
`
`
`
`23
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`absorption mechanisms, with highest net secretion in the proximal small intestine
`
`
`
`and highest net absorption in the colon.
`
`1.
`
`Uroguanylin
`
`45. Uroguanylin was discovered as an endogenous peptide hormone in
`
`mammals because of its similarity to heat-stable enterotoxins. Ex. 201124 at 27.
`
`Human uroguanylin, which is predominantly found in the small intestine, is a 16
`
`amino acid chain shown in Figure 3 below.
`
`Ex. 100625 at 52.
`
`Figure 3
`
`
`
`
`24 Chino et al., “Topological isomers of human uroguanylin: interconversion
`
`between biologically active and inactive isomers,” FEBS Letters, 421, 27-31 (1998)
`
`(Ex. 2011 (“Chino”)).
`
`25 Li et al., “Purification, cDNA Sequence, and Tissue Distribution of Rat
`
`Uroguanylin”, Regul. Pept., Vol. 68, 45-56 (1997) (Ex. 1006).
`
`
`
`
`
`24
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`46. Unlike heat-stable enterotoxins having three disulfide bonds, human
`
`uroguanylin is “characterized