UNITED STATES PATENT AND TRADEMARK OFFICE
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`————————————————
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`————————————————
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`MYLAN PHARMACEUTICALS INC.,
`MSN LABORATORIES PRIVATE LTD.,
`and MSN PHARMACEUTICALS INC.,
`Petitioners,
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`v.
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`BAUSCH HEALTH IRELAND LIMITED,
`Patent Owner.
`
`————————————————
`Case IPR2022-007221
`Patent 7,041,786
`————————————————
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`PETITIONERS’ REPLY TO PATENT OWNER RESPONSE
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`1 IPR2023-00016 has been joined with this proceeding.
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`

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`I.
`II.
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`TABLE OF CONTENTS
`Introduction ...................................................................................................... 1
`Argument ......................................................................................................... 1
`A.
`Bausch’s Arguments Are Legally Erroneous. ....................................... 2
`B.
`Bausch’s Lead-Compound Arguments Are Wrong. .............................. 4
`1.
`Bausch Fails to Show Maximizing Potency Would Lead
`Away from Modifying Uroguanylin. .......................................... 6
`Bausch Fails to Show Topoisomerism Led Away from
`Modifying Uroguanylin. ............................................................. 7
`Bausch’s Arguments Against [Glu3]-Substitution are Wrong. ............ 11
`1.
`Potential Interconversion Provides Additional
`Motivation. ................................................................................ 12
`Bausch’s Exhibits Support Making the Conservative,
`Homologous [Glu3]-Substitution. ............................................. 14
`Asp3 Was Not Required to Maintain Activity. .......................... 16
`3.
`Bausch’s Buried Asp and Glu pKa Values are Inapposite. ....... 20
`4.
`Aspartimide Formation Provides Additional Motivation. ........ 21
`5.
`Bausch’s Unexpected Results Arguments Are Unsupported. ............. 22
`1.
`Bausch’s Potency and Affinity Results Show Neither
`Unexpected Improvement Nor Difference in Kind. ................. 24
`Bausch’s Heat Stability Results Show Neither
`Unexpected Improvement Nor Difference in Kind. ................. 26
`Bausch’s Topoisomerism Experiment Shows Neither
`Unexpected Improvement Nor Difference in Kind. ................. 27
`III. Conclusion ..................................................................................................... 28
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`C.
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`D.
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`2.
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`2.
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`2.
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`3.
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`TABLE OF AUTHORITIES
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`Cases
`Altana Pharma AG. v. Teva Pharms., 566 F.3d 999 (Fed. Cir. 2009) ...................... 3
`Bristol-Myers Squibb v. Teva Pharms., 752 F.3d 967 (Fed. Cir. 2014) .................... 3
`DuPont v. Synvina, 904 F.3d 996 (Fed. Cir. 2018) .................................................23
`In re Fulton, 391 F.3d 1195 (Fed. Cir. 2004) ............................................................ 3
`Intel Corp. v. PACT XXP Schweiz AG, 2023 WL 2469631 (Fed. Cir. 2023) ........... 3
`Intelligent Bio-Systems v. Illumina Cambridge, 821 F.3d 135 (Fed. Cir.
`2016) ..................................................................................................................... 2
`KSR Int’l v. Teleflex Inc., 550 U.S. 398 (2007) ......................................................... 3
`McCarty v. Lehigh Valley R. Co., 160 U.S. 110 (1895) ..........................................22
`Pfizer v. Apotex, 480 F.3d 1348 (Fed. Cir. 2007) ....................................................14
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`Statutes
`35 U.S.C. §112 .........................................................................................................16
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`I.
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`INTRODUCTION
`Making and using [Glu3]-uroguanylin2 would have been obvious before the
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`critical date. Bausch’s Patent Owner Response (POR) counters with legally- and
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`factually-erroneous arguments. The legally-proper standard does not require
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`proving uroguanylin was the only promising lead compound or Glu3 was the only
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`obvious substitution. Bausch also fails to show a POSA would have been “led
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`away” from modifying uroguanylin; instead pursuing the toxic potency and pH
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`insensitivity of the pathogenic, heat-stable E. coli enterotoxins (STs). Bausch’s
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`arguments ignore the literature and skill in the art, misconceive obviousness law,
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`and thus should be rejected.
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`II.
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`ARGUMENT
`The POR presents no independent arguments against Grounds 2-4 (claims 2-
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`6), instead they stand or fall with claim 1. POR, 67. Claim 1 recites a peptide
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`consisting of amino-acid sequence SEQ ID NO: 20, which is [Glu3]-uroguanylin.
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`For claim 1, Bausch first argues a POSA would not have selected uroguanylin as
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`lead compound because enterotoxins were more potent and interconverting
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`topoisomers allegedly made uroguanylin unattractive. POR, i. Bausch next argues
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`a POSA had no reason to substitute Asp3 with Glu3. POR, ii. Bausch last alleges
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`2 Human unless otherwise indicated.
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`unexpected, superior results counter reasonable expectation of success. POR, iii.
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`Each Bausch argument is wrong.
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`Bausch’s Arguments Are Legally Erroneous.
`A.
`Bausch implies claim 1 recites limitations (e.g., pathogenic potency or no
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`topoisomerism) that are clearly absent. E.g., POR, i-ii, 2, 26, 38 (arguing
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`reasonable expectation of success required re same). Claim 1 merely recites [Glu3]-
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`uroguanylin peptide sequence, not any level of potency or topoisomerism.
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`EX1063, ¶¶114-117; EX1060, 20:3-14 (“Claim 1 is for a peptide of the given
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`sequence, and that’s all”), 111:17-112:13, 108:22-110:15 (SEQ ID NO. 20 “just
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`gives you the linear sequence”). Bausch’s arguments are not commensurate with
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`its claims.
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`Reasonable expectation of success is only required for what is claimed.
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`Intelligent Bio-Systems v. Illumina Cambridge, 821 F.3d 1359, 1367 (Fed. Cir.
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`2016). Yet a POSA could make [Glu3]-uroguanylin easily using known methods.
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`See, e.g., Pet., 21-22, EX1002, ¶¶66-67; Pet., 24, EX1002, ¶¶130-31; Pet., 35-36;
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`EX1005, 3:8-45; EX1002, ¶¶130-31. This evidence is unrebutted. EX1060, 130:9-
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`20, 126:10-128:4; EX1063, ¶¶8, 115. Bausch’s reasonable-expectation arguments
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`are wrong.
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`Bausch improperly requires a POSA to choose a synthetic enterotoxin over a
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`synthetic uroguanylin, arguing a POSA would only maximize potency and
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`minimize topoisomerism. E.g., POR, i-ii, 2-3, 26, 41. But obviousness is not that
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`rigid. KSR Int’l v. Teleflex Inc., 550 U.S. 398, 419 (2007) (“neither the particular
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`motivation nor the avowed purpose of the patentee controls”).
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`Despite Board cautions (Paper 16 at 20-23), Bausch continues erroneously
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`arguing another compound’s obviousness precludes [Glu3]-uroguanylin from being
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`obvious. See, e.g., POR 1-2, 8, 24, 28, 34-35, 37 (linaclotide), 40 (third disulfide
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`bridge), 45 ([Glu2]). However, a petitioner need only identify “some reason” that
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`would have sufficed for a chemist to modify a known compound, including that the
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`“new compound will have similar properties to the old.” Bristol-Myers Squibb v.
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`Teva Pharms., 752 F.3d 967, 973 (Fed. Cir. 2014). Other obvious compounds and
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`modifications, even superior compounds, do not render the proposed compound
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`nonobvious. Altana Pharma AG. v. Teva Pharms., 566 F.3d 999, 1007-08 (Fed.
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`Cir. 2009) (legally impermissible to require the prior art to “point to only a single
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`lead compound”); In re Fulton, 391 F.3d 1195, 1200 (Fed. Cir. 2004) (no
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`requirement “that the combination is the most desirable combination available”);
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`Intel Corp. v. PACT XXP Schweiz AG, 2023 WL 2469631, *5 (Fed. Cir. 2023)
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`(reversing requirement to show modification “was an ‘improvement’ in a
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`categorical sense”; “suitable option” sufficient). Bausch invites error by insisting
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`only one lead compound and only one modification exist.
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`Another obvious compound cannot negate the claimed compound’s
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`obviousness. Pet. 38-39; EX1002, ¶¶29, 121-123, 144-46, 154-56 ([Glu3]-
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`uroguanylin obvious); EX2026, 67:23-68:6 (both Glu2- and Glu3-uroguanylin
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`obvious). Good reason existed for making [Glu3]-uroguanylin as a rational design.
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`EX1063, ¶¶21, 50, 54, 69, 108. Bausch’s contrary argument is legal error.
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`Bausch’s Lead-Compound Arguments Are Wrong.
`B.
`Uroguanylin’s known properties were very promising for synthesizing an
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`analogue. Uroguanylin is a natural ligand the body produces to draw water into the
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`intestinal lumen, increasing cyclic guanosine monophosphate (cGMP) levels by
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`activating the GC-C receptor, which is expressed “throughout the entire length of
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`the small and large intestines” but with higher density in the proximal small
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`intestine. Pet., 17; EX1002, ¶¶58-59; EX1016, E957, E962; EX1020, 222 & Fig. 2;
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`EX1018, G635-36, G639-41; EX1019, G708; EX1017, 807; see also EX2021, 3:1-
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`2; EX1063, ¶9; EX1062, 62:7-67:6; EX1064, ¶¶23-24. At relevant intestinal pH
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`uroguanylin had enhanced potency attributed to acidic residues (aspartate or
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`glutamate) at positions 2 and 3. Pet., 18-19; EX1002, ¶¶61-65, 91; EX1021, 2705,
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`2709; EX1063, ¶13. Its oral administration markedly stimulated intestinal-fluid
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`secretion, identifying uroguanylin as a good candidate for oral administration to
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`treat constipation. Pet., 19-20; EX1018, G641-G642; EX1002, ¶¶99, 59-60, 85-86,
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`107; EX1005, 1:34-44, 1:50-55, 2:6-24, 2:53-65, 6:11-22; EX1063, ¶10; EX2025,
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`¶¶32-35, 41, 44 (adding fluid was a known method of treating constipation).
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`Uroguanylin’s known properties thus made it very promising.
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`For example, Currie acknowledged enterotoxins’ higher potency yet
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`identified uroguanylin as a very promising lead compound for further modification.
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`EX1063, ¶¶10-12. Currie recognized the placement and import of uroguanylin’s
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`disulfide bridges, and observed this natural ligand’s “physiological characteristics”
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`suggested it “is important to medical science in the study of regulators of guanylate
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`cyclase.” EX1005, 1:47-63, 2:3-7. Currie explained uroguanylin stimulates
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`“increases in cyclic GMP levels in a manner similar to guanylin and the STs” (heat
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`stable enterotoxins) and is “an endogenous stimulator of intestinal guanylate
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`cyclase,” that is “useful for the control of intestinal absorption,” able to displace
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`ST binding, and may “act as a laxative and be useful in patients suffering from
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`constipation[.]” EX1005, 2:6-24. In contrast, STs are peptides from “[p]athogenic
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`strains of E. coli,” requiring three disulfide bridges “for full expression of
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`bioactivity,” that cause “secretory diarrhea” and potentially death, “particularly in
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`the infant population” and “domestic animals.” EX1005, 1:21-23, 1:31-44. Currie
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`thus suggests exploiting uroguanylin’s natural laxative effects and discloses
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`uroguanylin’s activity was desirable because it was effective but not as toxic as
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`enterotoxins. EX1063, ¶12; Pet., 22-24; EX1002, ¶¶88-90; EX1005, 6:11-15, Fig.
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`3A; EX1006, 45. Considering uroguanylin’s known properties and enterotoxins’
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`higher toxicity, uroguanylin was a natural GC-C ligand a POSA would have
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`selected for further modification.
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`Creating synthetic-peptide analogues to known hormones was a known
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`technique for studying their properties to understand their functionalities and
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`structure-activity relationships. Pet., 20-22, 24, 35-36, 38; EX1002, ¶¶66-67, 71,
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`80-81, 136 (routinely creating analogues to characterize their properties
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`(discussing EX1025, EX1028- EX1030)), 66-67 (synthesis was routine), 106, 130-
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`31 (Currie taught straightforward synthesis); EX1005, 1:47-63, 2:3-7, 3:8-45, 6:7-
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`18 (uroguanylin important to “medical science”); see also EX1063, ¶10-11, 14, 37-
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`38; EX2020, 229; EX2010, 230. Accordingly, ample reasons made uroguanylin a
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`very promising starting point. EX1063, ¶¶9-15.
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`1.
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`Bausch Fails to Show Maximizing Potency Would Lead
`Away from Modifying Uroguanylin.
`Bausch argues a desire to maximize potency without pH sensitivity would
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`teach away from selecting uroguanylin for modification. POR, 35-36. But Bausch
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`ignores prior-art teachings that maximizing potency beyond uroguanylin was not
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`necessarily desirable, as discussed above. Even a pharmaceutically-controlled
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`dosage can be too potent, resulting in diarrhea and potentially death. EX1063,
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`¶¶16-18; EX1064, ¶¶42-46; EX1062, 62:5-64:13, 76:13-79:20; EX1071. As Dr.
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`Peterson explains, toxins’ potency is dangerous precisely because small amounts
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`induce very powerful effects. EX1063, ¶19. Moreover, a POSA understood
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`replicating enterotoxin’s potency and lack of pH sensitivity might cause severe
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`diarrhea and even death. Id.; POR, 63; EX2025, ¶110 (potency in colon contributes
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`to diarrhea), 73 (proposing to ameliorate enterotoxin’s toxic potency). A POSA
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`would not have focused singularly on maximizing potency relative to enterotoxins.
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`EX1063, ¶¶19-22.
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`2.
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`Bausch Fails to Show Topoisomerism Led Away from
`Modifying Uroguanylin.
`Bausch argues “topoisomerism” was a “plague” that would have dissuaded a
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`POSA from making a uroguanylin analogue and instead choose an enterotoxin—an
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`actual plague. POR, 2, 29-31; EX1063, ¶¶23-24. But Bausch vastly overstates
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`topoisomerism’s extent and relevance. EX1063, ¶¶24-25; EX1064, ¶¶37-41.
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`Bausch argues uroguanylin was known as “freely convertible” at “acidic
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`pH,” such that 25% of each uroguanylin topoisomer interconverted to the other
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`within 24 hours at body temperature. POR, 1-2, 30. But this was observed only at
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`acidic pH of 4.5. EX2010, 236. As Drs. Peterson and Epstein explain, a POSA
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`normally would have expected oral uroguanylin not to be exposed to this low pH
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`for over an hour, with no more than 1% interconversion. EX1063, ¶¶25-26;
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`EX1064, ¶¶25-31, 39; EX2010, 236; EX1070. Uroguanylin was known as stable
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`and effective in vivo after oral administration. EX1063, ¶27; EX1018, G641-G642;
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`EX2021, 2:28-3:1. Moreover, most uroguanylin would be used and eliminated very
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`early in the small intestines where the receptors are concentrated, interconversion
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`at intestinal pH was slow and non-material, and outlier-patient pH environments
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`would not discourage modifying uroguanylin. EX1063, ¶¶29, 31-32; EX1065,
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`Abstract, 34-36; EX1006, 53; EX1064, ¶23-29, 40. Bausch’s in vivo
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`interconversion arguments are therefore misplaced.
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`Indeed, Bausch’s exhibits (Marx and Klodt) specifically teach uroguanylin
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`might not topoisomerically interconvert in the intestines, not all uroguanylins
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`inherently interconvert, and any interconversion can be modulated by modification.
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`EX1063, ¶¶29-30; EX2010, 236, 238-239; EX2020, 227-28. Moreover, if
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`interconversion arose in vivo and presented any concern, it was easily addressed
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`using routine, controlled-release formulations. EX1063, ¶¶27-28; EX1064, ¶32;
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`EX1002, ¶¶97-98, 112, 189, 193; EX1007, 39-40, 47; EX1046, 28-29; EX1047,
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`3708. Hyperbole against in vivo “stability” of the body’s natural ligand for
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`enhancing intestinal water content should be rejected.
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`Bausch speculates (POR, 32) that a POSA might consider uroguanylin
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`difficult to purify or store. EX1063, ¶¶34-37. But Drs. Davies and Peterson
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`testified purifying topoisomers was straightforward. EX1063, ¶¶34, 40; EX2010,
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`230-232 (“standard chromatography techniques”); EX1060, 114:19-116:10 (“You
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`would expect the topoisomers to run at different retention time[s] by HPLC, so you
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`would be purifying…one of them out of the rest.”). Again, Bausch’s Klodt and
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`Marx praised uroguanylin because its topoisomers could be separated and
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`characterized. EX1063, ¶¶36-37; EX2020, Abstract, 223 (“by HPLC”); EX2010,
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`Abstract (conformational interconversion “retarded significantly”), 236 (guanylins
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`“interconvert much more rapidly”). The evidence contradicts Bausch’s speculation.
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`Purifying and storing uroguanylin analogues would not have been
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`considered unduly burdensome. EX1063, ¶¶39-40. Bausch admits avoiding severe
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`diarrhea from enterotoxin required purification and special handling. POR, 36.
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`Moreover, the evidence undercuts Bausch’s arguments about storage instability.
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`“[S]low pH-dependent mutual isomerization” favored the active topoisomer and
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`was eliminated under common storage conditions. EX1063, ¶¶39-40; EX2010,
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`Abstract (“stable at low temperature”), 236 (“completely stable” at 0°C even under
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`acidic conditions; lyophilized uroguanylin isomers not converted after long-term
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`storage).3 Purification and storage were no obstacle to modifying uroguanylin.
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`EX1063, ¶35.
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`Bausch asserts potential topoisomerism taught away, but no reference rejects
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`uroguanylins: topoisomerism is just flagged for study as new analogues are made.
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`Indeed, Klodt and Marx reflect good reason to make (and success at making)
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`uroguanylin analogues. EX1063, ¶33; EX2020, 226 (Table 1); EX2010, 235
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`(advocating “systematic substitution of amino acids contained in uroguanylin and
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`3 Bausch’s self-serving, belated, hearsay letter from its supplier is not prior art.
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`guanylin”). They proposed additional ligand studies. EX1063, ¶¶37-38; EX2020,
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`229; EX2010, 230. The literature reflects artisans making uroguanylin analogues,
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`not paralyzing fear about FDA approval or manufacturing optimization. EX1063,
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`¶35.
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`If anything, uroguanylin topoisomerism provided additional reason to
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`synthesize uroguanylin analogues. EX1063, ¶¶41-42. For example, Klodt and
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`Marx suggest any naturally-occurring inactive topoisomer would provide a useful
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`ligand reservoir ready to convert into the thermodynamically-favored active
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`topoisomer over time. EX1063, ¶41; EX2010, 238 (“a storage form of isomer A”);
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`EX2020, 229 (“a storage form of the GC-C binding ligand”); EX1064, ¶38. The art
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`contradicts Bausch’s “plague” characterization.
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`Bausch also argues the active topoisomer amount might vary. POR, 30-32.
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`Yet, administering pharmaceuticals as mixtures of interconverting active and
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`inactive forms was common, e.g., racemic drugs like ibuprofen. EX1063, ¶42;
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`EX1066, Abstract. Bausch fails to prove a natural mixture of uroguanylin
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`topoisomers was seen as impure. A POSA would not have expected a natural
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`uroguanylin isoform (localized to the gastrointestinal tract) to have negative “off-
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`target effects.” EX1063, ¶¶42-44; EX1005, 1:46-67, 2:3-8; EX1064, ¶41. No
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`Bausch argument demonstrates topoisomerism would have discouraged
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`synthesizing a uroguanylin analogue. EX1063, ¶45; EX1064, ¶¶37-41.
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`The involved patent squarely contradicts Bausch’s allegations against
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`uroguanylin: known, natural uroguanylin properties are its sole basis for asserting
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`its utility. EX1063, ¶¶46-48; EX1001, 3:13, 6:33-40, 7:4-7, 7:25-31 (uroguanylin
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`natural GC-C agonist), 9:19-23 (“known to possess high biological activity”),
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`7:31-37 (“heat-resistant, acid-resistant, and proteolysis-resistant peptide”;
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`favorable for “oral or systemic administration” for being “effectively employed in
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`treatment methods”), 4:7-13, 6:25-32, 6:46-53 (“expected to eliminate or at least
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`retard the onset of inflammatory diseases of the GI tract”); EX1060, 95:11-97:19,
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`97:21-98:8, 99:2-100:3, 92:9-95:10, 86:7-87:8, 96:6-18. The patent’s admissions
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`that uroguanylin’s known properties made it useful for treatment contradict
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`Bausch’s lead-compound arguments. EX1063, ¶48.
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`Bausch’s Arguments Against [Glu3]-Substitution are Wrong.
`C.
`Good reasons existed to synthesize [Glu3]-uroguanylin with a reasonable
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`expectation of success. See, e.g., Pet., 21-22, 34-39; EX1002 ¶¶73-75
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`(conservative substitution likely to retain excellent GC-C activity), 132-136
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`(conserved in homologous species), ¶¶66-67 (routine synthesis and
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`characterization), ¶¶137-152 (Li narrows substitution choices at position 3 to acidic
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`Glu), 165-170 (fine tune pH response), 175-179 (eliminate pairings causing
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`aspartimide formation). This evidence shows good reason and reasonable
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`expectation of success for Glu3-substitution. EX1063, ¶¶50-51. None of Bausch’s
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`arguments undermine any of these rationales.
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`Potential Interconversion Provides Additional Motivation.
`1.
`Bausch argues a POSA would add a third disulfide bridge so uroguanylin
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`would “closely resemble[] heat stable E. Coli agonist” with decreased
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`topoisomerism. POR, 39-40; EX2010, 229-230. As discussed (§II.B.2), Bausch’s
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`topoisomerism arguments are misplaced. EX1063, ¶¶35, 54, 58; EX1064, ¶¶37-41.
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`Bausch overstates the amount and likelihood of interconversion, and ignores
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`contrary evidence. EX1063, ¶¶24-27, 29, 31-32, 58.
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`Interconversion does not teach away. EX1063, ¶¶29-30, 33, 36-38. Bausch
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`also ignores evidence that in vivo interconversion was easily addressed through
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`formulation and that purification was straightforward. EX1063, ¶¶27-28, 34-37,
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`39-40, 52; EX2011, 30; EX2025, ¶55; EX1064, ¶32. A POSA considering
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`topoisomeric interconversion had additional reason to synthesize uroguanylin
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`analogues to explore topoisomer storage forms or natural binding interactions.
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`EX1063, ¶¶41-43, 58; EX2010, 238; EX2020, 229; EX1064, ¶38. Thus,
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`topoisomerism is no better reason to ignore Glu3-substitution than it is to ignore
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`uroguanylin entirely.
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`Bausch argues a POSA would add a third disulfide bridge to make the
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`synthetic agonist pH-independent, like enterotoxin. POR, 55. This blunt approach
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`might work for pathogens, but does not lead away from the [Glu3]-modification.
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`EX1063, ¶55. Evolution concentrated GCC receptors where pH would activate the
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`natural ligand instead of evolving enterotoxins’ pathogenic approach. Id.; EX1062,
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`78:22-79:5; EX1064, ¶¶42-46. Regardless, even if another modification was also
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`obvious, a POSA had good reason to make [Glu3]-uroguanylin. EX1063, ¶¶50, 55.
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`Bausch incorrectly argues Marx proposed adding a third disulfide bridge to
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`uroguanylin. Marx evaluated a third bridge’s feasibility, but only to predict which
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`topoisomer better matches the enterotoxin conformation. EX1063, ¶57; EX2010,
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`234. Rather than add a third bridge, Marx proposed “systematic substitution of
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`amino acids contained in uroguanylin and guanylin.” EX2010, 236. The petition
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`provided just such a substitution, starting with one of the most conservative
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`possible choices. Bausch misunderstands Marx, which suggested a modification
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`different than a third bridge. EX1063, ¶56.
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`Bausch also argues “nothing in the art suggested” [Glu3]-substitution would
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`reduce interconversion. POR, 2, 27, 38-39. Yet Klodt observed the “sterical bulk”
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`of “other residues” far from the C-terminus may influence interconversion.
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`EX2020, 228. Marx observed “the ionization state of the isomeric molecules
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`strongly influences the kinetics of the transition,” and the ionizable side chains of
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`Asp2, Asp3, and Glu5 “may be involved in the control of stabilization of the two
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`isomers.” EX2010, 236, 238. Though extending the amino-terminal region does
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`not reduce topoisomerism, this does not contradict Marx’s teaching that ionizable
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`side-chains at positions 2-3 may affect topoisomerism. EX1063, ¶178. A POSA
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`considering topoisomeric conversion thus had additional reason for the [Glu3]-
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`substitution, an ionizable side-chain modification at position 3. EX1063, ¶¶50, 60.
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`2.
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`Bausch’s Exhibits Support Making the Conservative,
`Homologous [Glu3]-Substitution.
`Bausch simultaneously argues conservative substitutions have minimal
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`effect on biological activity but also are so unpredictable a POSA could have no
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`expectation regarding [Glu3]-substitution. POR, 22, 41-42. Yet Bausch’s exhibits
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`confirm Dr. Peterson’s testimony that [Glu3]-substitution was an obvious,
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`conservative modification expected to retain activity. EX1063, ¶62; EX2041, 37-
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`38 (“In the case of aspartic acid, the obvious replacement is glutamic acid…these
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`are certainly the only really conservative substitutions that would be possible.”);
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`EX2035, 397 (“In protein engineering the concept of conservative mutations is
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`frequently used.”). Reasonable expectation of success does not require guaranteed
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`success. Pfizer v. Apotex, 480 F.3d 1348, 1364 (Fed. Cir. 2007) (“obviousness
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`cannot be avoided simply by a showing of some degree of unpredictability”).
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`Bausch argues substituting Glu for Asp could affect certain peptide
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`structures. POR, 21, 50 (citing EX2036 out of context). Although Fiser found Asp
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`overrepresented in buried rings/loops, uroguanylin’s third position is not buried in
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`a ring/loop. EX1063, ¶¶63-65; EX2036, Abstract, 225-28; EX2010, 233, 235.
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`When an image of the peptide including position 3 is used, Bausch’s misstatement
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`of Fiser’s teachings is apparent. EX2010, Fig. 4 (details, Isomer A column,
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`showing unburied position 3, annotated with red coloring).
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`Bausch argues Jonson found an exception in a different peptide to the
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`“common belief that a Glu to Asp mutation is conservativ