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`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`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
`__________________
`
`PATENT OWNER’S RESPONSE
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`
`
`
`Case IPR2022-00722
`U.S. Patent No. 7,041,786
`
`
`I.
`II.
`
`Table of Contents
`Introduction ...................................................................................................... 1
`Scope and Content of the Art .......................................................................... 4
`A.
`The Gastrointestinal Tract and Chronic Constipation ........................... 4
`B. Naturally Occurring Guanylate Cyclase-C Agonist Peptides ............... 7
`1.
`Uroguanylin and its topoisomerism problem.............................. 9
`2.
`Guanylin ....................................................................................12
`3.
`Heat-stable enterotoxins ............................................................13
`4.
`Relative activity of naturally occurring guanylate cyclase-
`C agonist peptides .....................................................................15
`C. Development of Therapeutic Peptides Was Unpredictable ................20
`D. Development of GCC Agonists...........................................................22
`III. The Invention of Plecanatide .........................................................................24
`A. U.S. Patent No. 7,041,786 ...................................................................24
`B.
`The Person of Ordinary Skill in the Art ..............................................25
`IV. Ground 1: Claim 1 Would Not Have Been Obvious Over Currie and
`Li ....................................................................................................................26
`A. Absent Hindsight, a POSA Would Not Have Selected Human
`Uroguanylin as a Lead Compound ......................................................28
`1.
`Human uroguanylin’s interconverting topoisomers made
`it an unattractive option for further development .....................29
`Heat-stable enterotoxins were a far more attractive option ......33
`2.
`Even Accepting Human Uroguanylin as a Lead Compound, a
`POSA Would Not Have Been Motivated to Substitute Asp3 with
`
`B.
`
`i
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`2.
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`b.
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`Case IPR2022-00722
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`Glu3 with Any Expectation of Yielding a Peptide with Improved
`Properties .............................................................................................38
`1.
`Nothing in the art suggested substituting Asp3 for Glu3
`would
`have
`addressed
`human
`uroguanylin’s
`interconversion ..........................................................................39
`Nothing in the art suggested that substituting Asp3 for Glu3
`would have reasonably been expected to improve the
`resulting peptide’s activity ........................................................40
`a.
`A POSA seeking to improve human uroguanylin’s
`activity would not have made a “conservative
`substitution” ....................................................................41
`The art taught that Asp2 and Asp3 were required,
`and a POSA would not have replaced either amino
`acid with an expectation of maintaining activity ............45
`i.
`Li did not suggest Glu as an obvious
`substitution at position 3 of human
`uroguanylin ...........................................................45
`Contemporaneously with Li, the art taught
`the
`importance of Asp3
`to human
`uroguanylin’s activity ...........................................49
`iii. By January 2002, the art had confirmed the
`perceived importance of retaining Asp2 and
`Asp3 ......................................................................50
`A POSA would not have expected that substituting
`Asp3 for Glu3 would result in a peptide that was
`protonated longer than human uroguanylin or had
`improved activity ............................................................52
`Aspartimide formation would not have motivated
`substituting Asp3 for Glu3 ...............................................56
`
`ii.
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`c.
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`d.
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`ii
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`
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`3.
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`Case IPR2022-00722
`U.S. Patent No. 7,041,786
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`Unexpected Superior Results Underscore the Lack of any
`Reasonable Expectation of Success and Reinforce the
`Nonobviousness of Plecanatide ................................................57
`a.
`Unexpected stabilization against interconversion ..........58
`b.
`Unexpectedly superior potency ......................................60
`c.
`Unexpectedly superior heat stability ..............................64
`d.
`Unexpectedly superior binding affinity ..........................66
`V. Grounds 2-4: Claims 2-6 Would Not Have Been Obvious Over
`Combinations Based on Currie and Li ..........................................................67
`VI. Conclusion .....................................................................................................67
`
`
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`iii
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`Case IPR2022-00722
`U.S. Patent No. 7,041,786
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`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Federal Cases
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Pat.
`Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) .............................................................. 27, 57-58
`Daiichi Sankyo Co. v. Matrix Lab’ys, Ltd.,
`619 F.3d 1346 (Fed. Cir. 2010) ........................................................ 28, 29, 33, 35
`Eli Lilly & Co. v. Zenith Goldline Pharms., Inc.,
`471 F.3d 1369 (Fed. Cir. 2006) .................................................................... 28-29
`Hybritech Inc. v. Monoclonal Antibodies, Inc.,
`802 F.2d 1367 (Fed. Cir. 1986) .............................................................. 27, 57-58
`InfoBionic, Inc. v. Braemer Mfg., LLC,
`IPR2015-01704, Paper 11 (PTAB Feb. 16, 2016) .............................................. 42
`Kinetic Techs., Inc. v. Skywork Sols., Inc.,
`IPR2014-00529, Paper 8 (PTAB Sept. 23, 2014) ............................................... 42
`In re Kubin,
`561 F.3d 1351 (Fed. Cir. 2009) .......................................................................... 44
`Mintz v. Dietz & Watson, Inc.,
`679 F.3d 1372 (Fed. Cir. 2012) .......................................................................... 57
`Otsuka Pharm. Co. v. Sandoz, Inc.,
`678 F.3d 1280 (Fed. Cir. 2012) .......................................................... 3, 26, 29, 41
`Rohm & Haas Co. v. Brotech Corp.,
`127 F.3d 1089 (Fed. Cir. 1997) .......................................................................... 42
`Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd.,
`492 F.3d 1350 (Fed. Cir. 2007) .................................................................... 38, 41
`
`iv
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`
`TQ Delta, LLC v. CISCO Sys., Inc.,
`942 F.3d 1352 (Fed. Cir. 2019) .......................................................................... 42
`Yeda Rsch. v. Mylan Pharms. Inc.,
`906 F.3d 1031 (Fed. Cir. 2018) .......................................................................... 37
`Federal Statutes
`35 U.S.C. § 316 ........................................................................................................ 26
`
`
`
`
`
`v
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`I.
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`Case No. IPR2022-00722
`U.S. Patent No. 7,041,786
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`Introduction
`U.S. Patent No. 7,041,786 (“the ’786 patent”) claims a peptide consisting of
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`the amino acid sequence of SEQ ID NO:20 (hereinafter, “plecanatide”). Plecanatide
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`is a guanylate cyclase-C (“GCC”) receptor agonist and is the active pharmaceutical
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`ingredient in Trulance®, which is FDA-approved for the treatment of chronic
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`idiopathic constipation (“CIC”) and irritable bowel syndrome with constipation
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`(“IBS-C”). Despite the fact that the colon was universally accepted as a necessary
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`site of action for treating constipation, plecanatide remains the only treatment that
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`preferentially targets the small intestine to treat CIC and IBS-C.
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`Plecanatide would not have been obvious as of the earliest effective filing date
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`of the claimed invention (January 17, 2002). Petitioner asserts that a person of
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`ordinary skill in the art (“POSA”) would have selected human uroguanylin as a lead
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`compound based on the teachings of Currie and modified it at the 3-position by
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`replacing aspartic acid (“Asp) with glutamic acid (“Glu”) based on the teachings of
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`Li. Petitioner’s obviousness assertions ignore the prior-art teachings and use
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`impermissible hindsight knowledge of plecanatide to pick and choose among
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`isolated disclosures in the prior art while ignoring other disclosures necessary to
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`fully appreciate what the art would have fairly suggested.
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`Nowhere is this hindsight more apparent than in Petitioner’s selection of
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`human uroguanylin as a “lead compound.” Human uroguanylin was known to freely
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`
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`1
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`
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`interconvert to an inactive topoisomer, including in conditions present in the
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`gastrointestinal (“GI”) tract and during manufacture and formulation. This
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`interconversion would have injected a level of uncertainty and unpredictability at
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`every stage of the drug development process sufficient by itself to have
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`disincentivized a POSA from selecting human uroguanylin for further development.
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`Yet other more highly active compounds existed—heat-stable enterotoxins—that
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`did not suffer from the topoisomerism and would have been the most promising lead
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`compounds for further development. Referred to as “GCC superagonists,” the heat-
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`stable enterotoxins have a third disulfide bridge known to enhance their
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`conformational rigidity and to prevent topoisomerism while also contributing to their
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`uniformly better activity. In fact, the person who discovered human uroguanylin,
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`Mark Currie, did as a POSA would have done and selected a heat-stable enterotoxin
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`as a lead compound in developing the commercial product Linzess®.
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`But even accepting human uroguanylin as a lead compound, a POSA would
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`not have substituted Asp3 with Glu3 with a reasonable expectation of successfully
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`achieving the claimed invention. Nothing in the art suggested substituting Asp3 for
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`Glu3 would have prevented human uroguanylin’s interconversion. To the contrary,
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`the art expressly suggested adding a third disulfide bridge to human uroguanylin to
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`address its topoisomerism and improve its activity.
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`
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`2
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`Similarly, nothing in the art suggested that the substitution would have
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`
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`improved the resulting peptide’s activity. Petitioner seems to concede as much in
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`asserting that a POSA would have been motivated to make a “conservative
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`substitution”
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`to retain—not
`
`improve—activity.
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` Petitioner’s “conservative
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`substitution” motivation completely disregards the legal framework, which requires
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`selection of a lead compound that is most promising to modify in order to improve
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`upon its activity and obtain a compound with better activity. Otsuka Pharm. Co. v.
`
`Sandoz, Inc., 678 F.3d 1280, 1291-93 (Fed. Cir. 2012). Further, Petitioner reads Li
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`in isolation, ignoring contemporaneous publications describing the importance of
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`the N-terminal residues generally and Asp3 specifically. By January 2002, the art
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`had confirmed that Asp2 and Asp3 were required for maintaining human
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`uroguanylin’s activity.
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`Moreover, Petitioner’s theory that the resulting peptide would be comparably
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`more protonated, thereby having improved activity in the large intestine, is
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`fundamentally flawed. Petitioner relies on the pKa values for the side-chain groups
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`of Asp and Glu as free amino acids, but as even Dr. Peterson admits, the free amino
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`acid pKa cannot be accurately applied when the amino acids are incorporated into a
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`peptide chain. Nor would a POSA have avoided use of Asp to eliminate known
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`sources of aspartimide formation during synthesis because the art described various
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`easily implemented, alternative methods of avoiding aspartimide formation.
`3
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`Petitioner recognizes as much, asserting the elimination of sources of aspartimide
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`formation as a mere “additional benefit” rather than an alleged motivation.
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`Objective evidence of unexpected superior results underscores the lack of any
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`reasonable expectation of success and reinforces the nonobviousness of plecanatide.
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`In particular, as compared to human uroguanylin, plecanatide has significantly and
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`unexpectedly superior stability against interconversion and surprisingly superior
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`binding affinity, potency for cGMP production, and heat stability. Nothing in the
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`prior art—neither human uroguanylin nor rat uroguanylin—suggested the particular
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`features of plecanatide would result in these unexpected superior properties.
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`For these and other reasons detailed below, the Board should confirm the
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`patentability of the ’786 patent claims.
`
`II.
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`Scope and Content of the Art
`A. The Gastrointestinal Tract and Chronic Constipation
`The GI tract includes the organs through which foods and liquids travel when
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`swallowed, digested, absorbed, and excreted. These organs include the mouth,
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`pharynx (or throat), esophagus, stomach, small intestine, colon, rectum, and anus.
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`The GI tract is a complex pathway with a myriad of changing conditions (such as
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`pH) and endogenous enzymes that can unpredictably impact and undermine how a
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`particular therapeutic might be expected to behave. Ex. 2024 ¶ 42; see also id. ¶¶ 1-
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`29; Ex. 2025 ¶ 20; see also id. ¶¶ 1-19.
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`4
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`
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`The pH of the GI tract varies significantly. Ex. 2024 ¶ 43; Ex. 2025 ¶ 21. The
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`stomach is a highly acidic environment, with pH varying from of 1.4-5.4. Ex. 2032
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`at 759. The pH in the proximal small intestine ranges from 5.5 to 7.0 and gradually
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`rises to 6.5-7.5 in the distal ileum. Ex. 2033 at 572. The pH falls from the terminal
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`ileum to the caecum (pH range 5.5-7.5) and rises in the left colon and rectum to 6.1-
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`7.5. Ex. 2033 at 572. As of 2002, POSAs understood that the relevant pH for testing
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`compounds in the small intestine and large intestine was from 5.0 to 8.0. See
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`Ex. 1021 at 2706 (noting uroguanylin and guanylin were assessed at pH values of
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`5.0 and 8.0 because these “represent the extremes of microclimate pH found at the
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`mucosal surface of the intestine”).
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`CIC and IBS-C are disorders of the GI tract. The causes of CIC and IBS-C
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`are largely unknown. CIC is categorized as functional constipation and, as of 2002,
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`was diagnosed based on the following criteria:
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`5
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`Ex. 2051 at II43, II45. IBS-C is differentiated clinically from CIC by its
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`predominant symptom of abdominal pain, especially in the lower abdomen, and this
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`pain is associated with alternations in stool frequency and/or texture. Ex. 2050 at
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`914; Ex. 2051 at II44. As of 2002, IBS-C was diagnosed based on the following
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`criteria:
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`Ex. 2051 at II44; Ex. 2025 ¶¶ 22-24.
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`6
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`While statistics vary, it is estimated that at least 20% of adults have CIC and
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`that 6.6–21.6% of adults have IBS-C. Ex. 2048 at 448; Ex. 2051 at II45. Despite
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`the prevalence of CIC and IBS-C, treatment options were limited prior to 2002 and
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`included dietary and behavioral approaches, pharmacologic treatments, and in some
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`instances, surgery. Ex. 2050 at 919. Among the pharmacologic treatments were
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`bulk-forming laxatives, emollient laxatives (stool softeners), hyperosmolar agents,
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`saline laxatives, stimulant laxatives, and prokinetics. All of these treatments
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`commonly targeted at least the colon because, prior to 2002, the colon was
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`universally accepted as a necessary site of action for treating constipation. Even to
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`date, plecanatide is the only treatment that preferentially targets the small intestine
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`to treat CIC and IBS-C. Ex. 2024 ¶¶ 44-46; Ex. 2025 ¶¶ 25-38.
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`B. Naturally Occurring Guanylate Cyclase-C Agonist Peptides
`Naturally occurring GCC agonist peptides include uroguanylin, guanylin, and
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`heat stable enterotoxins. These peptides bind to GCC receptors and stimulate
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`intracellular production of cyclic guanosine monophosphate (“cGMP”.) Ex. 1001 at
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`1:26-29. This results in the activation of the cystic fibrosis transmembrane
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`conductance regulatory (“CFTR”), an apical membrane channel for efflux of
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`chloride from enterocytes lining the intestinal tract. Id. at 1:29-32. Activation of
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`CFTR and the subsequent enhancement of transepithelial secretion of chloride leads
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`to stimulation of sodium and water secretion into the intestinal lumen, thereby
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`7
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`regulating fluid and electrolyte transport in the GI tract. Id. at 1:33-39; Ex. 2024
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`¶ 47; Ex. 2025 ¶¶ 39-41, 43.
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`By January 2002, it was known that uroguanylin was more abundant in the
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`small intestine (acidic pH) and that guanylin was more abundant in the large intestine
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`or colon (neutral to alkaline pH). Ex. 1016 at E957; Ex. 2025 ¶ 44. In particular, it
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`was known that uroguanylin mRNA was highly expressed in the duodenum (small
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`intestine) whereas guanylin mRNA was highly expressed in the ileum and colon.
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`Uroguanylin was thus known to be more active in acidic environments (e.g., the
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`duodenum) whereas guanylin was more active in alkaline environments (e.g., the
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`ileum and colon). E.g., Ex. 1021. As such, uroguanylin and guanylin were
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`considered cooperative peptides with each other. Ex. 2062 at 361; Ex. 1021 at 2705
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`(“Uroguanylin and guanylin cooperatively regulate the guanylate cyclase activity of
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`a common set of mucosal receptors in a pH-dependent fashion, thus providing an
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`enteric signaling pathway for the intrinsic, paracrine regulation of intestinal salt and
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`water transport.”). Advantageously, the more highly active heat-stable enterotoxins,
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`which are peptides secreted by enteric bacteria such as enterotoxigenic E. coli that
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`act as molecular mimics of uroguanylin and guanylin (Ex. 1016 at E957; Ex. 2024
`
`¶ 87; Ex. 2025 ¶ 64), were also known to be pH-independent. E.g., Ex. 1005 at Fig.
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`3A, 3B; Ex. 1021 at 2706-08. Unlike uroguanylin and guanylin, this allowed the
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`8
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`heat-stable enterotoxins to work in a more versatile fashion in both the small and
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`large intestines. See Ex. 1021 at 2710.
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`Uroguanylin and its topoisomerism problem
`1.
`Human uroguanylin is the 16 amino acid peptide shown below.
`
`
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`Ex. 1006 at 52. It was known in the art that human uroguanylin has two disulfide
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`bridges that are “crucial for biological activity.” Ex. 2010 at 230; see also
`
`Ex. 2020 at 222. The presence of these disulfide bridges results in two
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`topoisomers. Ex. 2010 at 230. It was known that only one of these topological
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`isomers is biologically active, i.e., binds with the GCC receptor. Id. at 229-230.
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`And while it was known that the other topological isomer does not bind with the
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`GCC receptor, its biological properties were otherwise “completely unknown.”
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`Id.; see also Ex. 2020 at 223, 229. These isomers are depicted below as Isomer A
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`(active conformation) and Isomer B (inactive conformation).
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`Ex. 2010 at 235; Ex. 2024 ¶¶ 61-66; Ex. 2025 ¶¶ 45-48.
`It was known in the art that human uroguanylin’s isomers are interconvertible
`
`in aqueous media at rates that vary with pH and temperature, eventually reaching an
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`equilibrium isomer ratio of approximately 1:1. Ex. 2011 at 27; see also Ex. 2010 at
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`229; Ex. 2024 ¶¶ 67-68, 70-72; Ex. 2025 ¶¶ 49-52. At acidic pH, human
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`uroguanylin’s isomers are “freely convertible (same conversion rates) and
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`eventually come to a 1:1 equilibrium ratio.” Ex. 2011 at 30. But at pH 7.7, the
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`isomers “seem to be hampered and thereby their rates are significantly decreased.”
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`Id.; see also Ex. 2010 at 236. With respect to temperature, human uroguanylin’s
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`isomers “are completely stable at 0°C, whereas a temperature of 60°C caused an
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`accelerated formation of the complementary isomer within about 4 h.” Ex. 2010 at
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`236. “At 37°C, 25% of both uroguanylin-16 isomers are interconverted within
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`24 h.” Id.; see also Ex. 2011 at 30.
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`In developing any therapeutic drug product, a POSA would consider it of
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`paramount importance to have a high level of certainty regarding the therapeutically
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`10
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`effective amount of the active ingredient in the product—initially, during storage,
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`and within the human body. Ex. 2024 ¶¶ 69, 73; Ex. 2025 ¶ 53. Human
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`uroguanylin’s interconversion would have presented problems for reliable
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`manufacture and formulation of a drug product containing a fixed amount of the
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`biologically active isomer. Ex. 2024 ¶¶ 69, 73; Ex. 2025 ¶ 53; Ex. 2040. Its rate of
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`interconversion was also known to be pH-dependent. Ex. 2011 at 30; see also
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`Ex. 2010 at 236. Given the significant variability in pH in the GI tract, a POSA
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`would have expected human uroguanylin to undergo varying rates of interconversion
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`as it travels through the GI tract, making it nearly impossible to reasonably predict
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`the therapeutic dose of active Isomer A in the body. Ex. 2032 at 759; Ex. 2033 at
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`572; Ex. 2024 ¶¶ 69, 73; Ex. 2025 ¶ 53.
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`Rat uroguanylin is the 18 amino acid peptide shown below.
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`
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`Ex. 1006 at 52; but see Ex. 2011 (excluding the N-terminal amino acids, T/E, I,
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`and A); Ex. 2024 ¶ 74; Ex. 2025 ¶ 54. It was known in the art that rat uroguanylin,
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`like human uroguanylin, suffered from topoisomerism. Ex. 2011 at 30. The rat
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`uroguanylin isomers, however, were known to be markedly less stable and could
`11
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`only be separated at lower temperatures such as 8°C. Id.; Ex. 2024 ¶ 76; Ex. 2025
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`¶ 55. Additionally, rat uroguanylin was known to be less potent than opossum
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`uroguanylin. Ex. 1006 at Fig. 3 and 54; Ex. 2024 ¶ 75, 77-79.
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`Opossum uroguanylin is the 15 amino acid peptide shown in the figure below.
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`Ex. 1006 at 52; Ex. 2024 ¶ 80; Ex. 2025 ¶ 56. Opossum uroguanylin was known to
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`be more potent than rat uroguanylin and as or more potent than human uroguanylin.
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`Ex. 1006 at 49, Fig. 3, 54; Ex. 1019 at G710, Fig. 2; Ex. 2025 ¶ 57.
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`As discussed in more detail below, uroguanylin’s potency and binding affinity
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`were known to be pH-dependent, with uroguanylin being more potent and having
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`higher binding affinities in acidic pH prevalent in the small intestine. Ex. 2024
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`¶¶ 81-82; Ex. 2025 ¶ 58.
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`2. Guanylin
`Human guanylin is the 15 amino acid peptide shown in the figure below.
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`12
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`Ex. 1006 at 52. Like uroguanylin, guanylin is present in many species, including
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`human, rat, and opossum. Ex. 2024 ¶¶ 83-85; Ex. 2025 ¶¶ 59-62.
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`As discussed in more detail below, guanylin’s potency and binding affinity
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`were known to be pH-dependent, with guanylin being more potent and having higher
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`binding affinities in alkaline pH prevalent in the large intestine (colon) where
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`constipation was primarily treated. E.g., Ex. 1021 at 2706-08; see also Ex. 1002
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`¶ 162; Ex. 2024 ¶ 86; Ex. 2025 ¶ 63.
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`3. Heat-stable enterotoxins
`Heat stable enterotoxins (STs) are secretory peptides produced by some
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`bacterial strains, such as enterotoxigenic E. coli. Heat-stable enterotoxin STa is the
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`18 amino acid peptide shown in the figure below.
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`13
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`Ex. 1006 at 52. Heat-stable enterotoxins were known to be more stable than the
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`other GCC agonist peptides. Ex. 2010 at 230; Ex. 2060 at 4710 (referring to heat-
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`stable enterotoxins as “long-lived superagonist[s]”). This stability was attributed to
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`a third disulfide bridge that enhanced conformational rigidity, prevented an
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`interconversion/topoisomerism problem, and promoted “a possibly more efficient
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`interaction with the receptor.” Id. In fact, the benefits of this third disulfide bridge
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`to stability and activity led POSAs to suggest that it be added to human uroguanylin:
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`Structure calculations of uroguanylin-16 with an additional
`distance restraint between protons that occupy the positions of
`fictitious sulfur atoms of a third disulfide bridge between
`residues 3 and 8 show that a third disulfide bridge is possible for
`the A form structure without distortion of the peptide
`backbone. . . . A third disulfide bond apparently would lead to a
`preference of a structure similar to the A form isomer that was
`found for ST (22).
`
`Id. at 235; see also id. at 229 (“[T]he structure of the GC-C-activating uroguanylin
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`isomer A closely resembles the structure of the agonistic Escherichia coli heat-
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`stable enterotoxin.”); Ex. 2024 ¶¶ 88-91; Ex. 2025 ¶¶ 64-66.
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`Additionally, as discussed further below, these more stabilized heat stable
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`enterotoxins were advantageously known to be pH-independent and exhibited a
`
`potency and binding affinity that surpassed uroguanylin and guanylin in the acidic
`
`and alkaline pHs of both the small and large intestines.
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`U.S. Patent No. 7,041,786
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`4.
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`Relative activity of naturally occurring guanylate cyclase-C
`agonist peptides
`The art is replete with comparisons of the activities of uroguanylin, guanylin,
`
`and heat-stable enterotoxins. Currie, for example, compared the potencies of the
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`three peptides by evaluating their ability to stimulate cGMP production in T84 cells.
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`Ex. 1005 at 3:55-61. As shown in Figure 3A, Currie reported that “[h]uman
`
`uroguanylin appeared to be more potent than human guanylin, but less potent than
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`ST for activation of GC-C in T84 cells.” Id. at 6:13-15.
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`
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`Id. at Fig. 3A; Ex. 2024 ¶ 93; Ex. 2025 ¶ 74.
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`Currie likewise compared the binding affinities of the three peptides by
`
`evaluating their performance using a competitive binding assay with 125I-ST5-18 as
`
`the radioligand. Id. at 4:62-5:15. Heat-stable enterotoxins had the highest affinity
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`15
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`for the GCC receptor, followed by uroguanylin and then guanylin. Id. at 6:15-19,
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`U.S. Patent No. 7,041,786
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`Fig. 3B; Ex. 2024 ¶¶ 94-95; Ex. 2025 ¶ 75.
`
`The art also reported the pH-dependency (or lack thereof) of the activities of
`
`uroguanylin, guanylin, and heat-stable enterotoxins. Hamra 1997, for example,
`
`compared the potencies of the three peptides at acidic (pH 5.5) and alkaline (pH 7.8)
`
`pH, reporting that “[t]he rank order of potencies for agonist-mediated stimulation of
`
`chloride secretion was ST > uroguanylin > guanylin at acidic pH and ST >
`
`guanylin > uroguanylin at an alkaline pH.” Ex. 1021 at 2706-07 (emphasis
`
`added); see also id. at 2708, Fig. 3; Ex. 1019 at G711, Fig. 3; Ex. 2024 ¶ 96;
`
`Ex. 2025 ¶ 76.
`
`Hamra 1997 likewise compared the binding affinities of the three peptides at
`
`acidic (pH 5.0) and alkaline (pH 8.0) pH, confirming that uroguanylin worked best
`
`in the acidic conditions of the small intestine, guanylin worked best in the alkaline
`
`conditions of the colon (where constipation was commonly treated), and STs worked
`
`best overall in both the small intestine and the colon. Ex. 1021 at 2707; see also id.
`
`at 2708, Fig. 4; Ex. 2024 ¶ 97; Ex. 2025 ¶ 77.
`
`Hamra 1997 concludes that “E. coli ST-(5–17) binds with extraordinarily
`
`high affinities to the uroguanylin / guanylin receptors on the apical surface of T84
`
`cells and potently stimulates cGMP production and chloride secretion at both
`
`alkaline and acidic pH.” Ex. 1021 at 2710 (emphasis added). Hamra 1997 also
`16
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`states that “[t]he remarkable potencies of ST peptides compared with the potencies
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`Case No. IPR2022-00722
`U.S. Patent No. 7,041,786
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`of the enteric hormones is caused by higher affinities for ST binding to the intestinal
`
`receptors for uroguanylin and guanylin.” Id.; see also Ex. 1006 at 46 (reporting that
`
`uroguanylin’s “EC50 for activating cyclic GMP synthesis in GCC-expressing cells is
`
`intermediate between that of guanylin and Sta”) (emphasis added); Ex. 2024 ¶ 98;
`
`Ex. 2025 ¶¶ 67, 78.
`
`The art also compared the pH-dependency of the activities of uroguanylin
`
`versus guanylin. Ex. 2025 ¶¶ 79-81. As shown in Figure 1, Hamra 1996 reported
`
`that “[u]roguanylin caused a greater increase in cellular cGMP levels when assayed
`
`at pH 5 compared with pH 8” and that “[i]n contrast, guanylin caused only a doubling
`
`in cGMP accumulation above basal levels at pH 5, with the cGMP response
`
`increasing to 13-fold at pH 8.” Ex. 1019 at G710, Fig. 1.
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`Id. Hamra 1997 similarly reported the pH dependent nature of the potencies and
`
`binding affinities of uroguanylin and guanylin. Ex. 1021 at 2707, Figs. 1-2. Hamra
`
`1997 concludes that “[u]roguanylin is a highly potent agonist under high mucosal
`
`acidity, a condition that renders guanylin ineffective,” and that “[c]onversely,
`
`guanylin is highly potent under low mucosal acidity, conditions that reduce the
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`potency of uroguanylin.” Id. at 2710.
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`The art also compared the activities of the various uroguanylin peptides.
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`Ex. 2025 ¶ 82. Li, for example, reports that rat uroguanylin (fraction 16) is less
`
`potent than opossum uroguanylin:
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`U.S. Patent No. 7,041,786
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`Ex. 1006 at 49, Fig. 3; see also id. at 48, 51 (showing that fraction 16 is rat
`
`uroguanylin and uroguanylin is synthetic opossum uroguanylin). Further, Hamra
`
`1996 reports that opossum uroguanylin was known to be as or more potent than
`
`human uroguanylin. Ex. 1019 at G710, Fig. 2.
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`Accordingly, opossum uroguanylin was known to be more potent than rat
`
`uroguanylin and as or more potent than human uroguanylin, with rat uroguanylin
`
`being the least potent of the three.
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`C. Development of Therapeutic Peptides Was Unpredictable
`Development of therapeutic peptides was, and continues to be, unpredictable.
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`Absent empirical testing, a POSA would not have any expectation as to the effects
`
`of a specific amino acid modification on a particular peptide, much less an
`
`expectation of improving the properties of the peptide. Ex. 2024 ¶¶ 40-41, 100.
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`Indeed, it was known in the art that any amino acid substitution—including a
`
`purported conservative amino acid substitution—could result in unpredictable
`
`changes in a peptide’s properties and function. Ex. 2035 at Abstract; Ex. 2036 at
`
`225; see also Ex. 1004 at 167; Ex. 2024 ¶ 101.
`
`As of 2001, for example, Jonson noted that “the concept of conservative
`
`mutation needs substantial revision.” Ex. 2035 at Abstract. Jonson found that “the
`
`spatial preferences for similar residues can be dramatically different in protein
`
`structures under similar circumstances” and specifically reported “very different
`
`spatial preferences . . . for glutamic acid and aspartic acid.” Id. Jonson found that
`
`“[t]he common belief that a glutamic acid to aspartic acid mutation is conservative
`
`is contrary to the observations shown.” Id. at 400. Instead, substitution of glutamic
`
`acid for aspartic acid would have unpredictable effects on peptide activity and
`
`function, due in part to the difference between length of the side chain between
`
`aspartic acid and glutamic acid. Id. at 401; Ex. 2024 ¶ 102.
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`20
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`Other researchers were reaching similar conclusions. Fiser, for example,
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`Case No. IPR2022-00722
`U.S. Patent No. 7,041,786
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`
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`studied amino acid conservation in homologous proteins and reported an
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`“unexpected difference” between the conservation of Asp and Glu with Asp being
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`more highly conserved than Glu. Ex. 2036 at 225. Fiser postulated that the
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`“preferred conservation of Asp is likely to be due to differing side-chain
`
`interactions” and that “[t]he most obvious hypothesis is that since Glu has a higher
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`proportion of non-polar atoms than Asp[,] it can make more non-specific interactions
`
`and so there are fewer constraints on its environment.” Id. at 227. Fiser further
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`postulated that “[t]he short Asp side chain is restricte
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