Paper No. 49
`Filed: May 15, 2023
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`————————————————
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`————————————————
`
`MYLAN PHARMACEUTICALS INC.,
`MSN LABORATORIES PRIVATE LTD.,
`and MSN PHARMACEUTICALS INC.,
`
`Petitioners,
`
`v.
`
`BAUSCH HEALTH IRELAND LIMITED,
`
`Patent Owner.
`
`————————————————
`Case IPR2022-00722
`Patent 7,041,786
`————————————————
`
`PATENT OWNER’S SUR-REPLY
`
`1 IPR2023-00016 has been joined with this proceeding.
`
`

`

`
`
`TABLE OF CONTENTS
`
`Case IPR2022-00722
`Patent No. 7,041,786
`
`
`
`
`
`I.
`
`B.
`
`Petitioner’s Attempt to Divorce the Claimed Compound from Its
`Properties Is Legally Improper ........................................................................ 1
`II. A POSA Would Not Have Selected Human Uroguanylin as a Lead
`Compound ........................................................................................................ 2
`A. Human Uroguanylin’s Topoisomeric Instability Presented
`Unnecessary Challenges ........................................................................ 3
`Petitioner’s Criticism of Heat-Stable Enterotoxins Is Inconsistent
`with the Literature and Its Alleged Motivation to Modify Human
`Uroguanylin ........................................................................................... 6
`III. A POSA Would Not Have Been Motivated to Substitute Asp3 with
`Glu3 with Any Reasonable Expectation of Success ........................................ 9
`A.
`Petitioner’s New Alleged Motivation Based on Topoisomerism
`Is Misplaced ........................................................................................ 10
`Petitioner’s “Conservative Substitution” Arguments Are
`Unpersuasive ....................................................................................... 12
`C. Dr. Peterson Admitted that Asp3 Was Required to Maintain
`Activity ................................................................................................ 14
`Petitioner’s Alleged Motivation Based on Protonation Ignores
`the Effect of Intrachain Hydrogen Bonding on pKa ........................... 15
`Petitioner’s Alleged Motivation Based on Acetamide Formation
`Is Unavailing ....................................................................................... 17
`IV. Patent Owner’s Unexpected Results Are Supported ..................................... 18
`A.
`Patent Owner’s Unexpected Results Are Commensurate with the
`Scope of the Challenged Claims and Are Versus the Closest Prior
`Art ........................................................................................................ 18
`Currie’s Data Should Be Afforded No Weight ................................... 21
`1.
`Figures 1 and 2 are internally inconsistent ............................... 21
`
`B.
`
`D.
`
`E.
`
`B.
`
`i
`
`

`

`2.
`
`3.
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`Case IPR2022-00722
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`Patent No. 7,041,786
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`The levels of cGMP produced are inconsistent with the
`levels reported in the literature ................................................. 21
`Drs. Peterson and Epstein are not qualified to assess the
`reliability of the data submitted ................................................ 23
`Petitioner Mischaracterizes Patent Owner’s Data, Which
`Demonstrate a Difference in Kind ...................................................... 23
`Conclusion ..................................................................................................... 26
`
`
`
`
`V.
`
`
`C.
`
`
`
`
`
`ii
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`

`

`
`
`
`
`
`TABLE OF AUTHORITIES
`
`Case IPR2022-00722
`Patent No. 7,041,786
`
` Page(s)
`
`Cases
`Daiichi Sankyo Co. v. Matrix Lab’ys, Ltd.,
`619 F.3d 1346 (Fed. Cir. 2010) ............................................................................ 3
`Genetics Institute, LLC v. Novartis Vaccines & Diagnostics, Inc.,
`655 F.3d 1291 (Fed. Cir. 2011) .......................................................................... 18
`Institut Pasteur & Universite Pierre Et Marie Curie v. Focarino,
`738 F.3d 1337 (Fed. Cir. 2013) ........................................................................ 2, 8
`In re Merchant,
`575 F.2d 865 (C.C.P.A. 1978) .................................................................... 1-2, 18
`Millennium Pharms., Inc. v. Sandoz Inc.,
`862 F.3d 1356 (Fed. Cir. 2017) .......................................................................... 26
`In re Omeprazole Patent Litig.,
`536 F.3d 1361 (Fed. Cir. 2008) ........................................................................ 1, 9
`Otsuka Pharm. Co. v. Sandoz, Inc.,
`678 F.3d 1280 (Fed. Cir. 2012) ...................................................................... 2, 12
`In re Papesch,
`315 F.2d 381 (C.C.P.A. 1963) .............................................................................. 1
`Rohm & Haas Co. v. Brotech Corp.,
`127 F.3d 1089 (Fed. Cir. 1997) .......................................................................... 26
`Sanofi-Synthelabo v. Apotex, Inc.,
`550 F.3d 1075 (Fed. Cir. 2008) ............................................................................ 1
`Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd.,
`492 F.3d 1350 (Fed. Cir. 2007) ............................................................................ 9
`
`
`
`
`
`
`
`iii
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`

`

`
`
`
`Case IPR2022-00722
`
`Patent No. 7,041,786
`
`Patent Owner respectfully submits this Sur-Reply in response to Petitioner’s
`
`Reply.
`
`I.
`
`Petitioner’s Attempt to Divorce the Claimed Compound from Its
`Properties Is Legally Improper
`Petitioner attempts to divorce the claimed compound, plecanatide, from its
`
`properties, arguing that Patent Owner’s “arguments are not commensurate with its
`
`claims” because the claims do not recite “any level of potency or topoisomerism.”
`
`Reply, 2. Petitioner misses the point. The question of obviousness is assessed based
`
`on what a POSA would have done, not could have done. In re Omeprazole Patent
`
`Litig., 536 F.3d 1361, 1379-81 (Fed. Cir. 2008). The relevant art pertains to
`
`constipation, and a POSA seeking to make a better anti-constipation drug would
`
`have considered the properties of various prior-art compounds and would not have
`
`ignored human uroguanylin’s middling potency or problematic topoisomeric
`
`instability in selecting a lead compound. Patent Owner’s Response (“POR”), 28-37.
`
`Moreover, plecanatide’s properties, including its unexpectedly superior potency and
`
`topoisomeric stability, cannot be ignored. Id., 58-64. “From the standpoint of patent
`
`law, a compound and all of its properties are inseparable; they are one and the same
`
`thing.” In re Papesch, 315 F.2d 381, 391 (C.C.P.A. 1963); see also Sanofi-
`
`Synthelabo v. Apotex, Inc., 550 F.3d 1075, 1086 (Fed. Cir. 2008); In re Merchant,
`
`1
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`Case IPR2022-00722
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`Patent No. 7,041,786
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`575 F.2d 865, 869 (C.C.P.A. 1978) (holding unexpected results need not be
`
`claimed). Petitioner’s arguments otherwise should be rejected.
`
`Petitioner’s argument that a POSA need only have a reasonable expectation
`
`of successfully synthesizing the claimed compound also should be rejected.
`
`Petitioners’ Reply (“Reply”), 2. Reasonable expectation is tied to the proposed
`
`motivation. Institut Pasteur & Universite Pierre Et Marie Curie v. Focarino, 738
`
`F.3d 1337, 1346 (Fed. Cir. 2013). It is not a question of whether one could make
`
`the claimed compound, as Petitioner incorrectly argues, but whether one would have
`
`done so based on some proposed motivation and reasonably expected it to succeed
`
`for the proposed objective. For a claimed compound, the proper analysis requires
`
`selection of “a compound in the prior art that would be most promising to modify in
`
`order to improve upon its . . . activity and obtain a compound with better activity.”
`
`Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1291 (Fed. Cir. 2012) (citations
`
`omitted) (emphasis added).
`
`II. A POSA Would Not Have Selected Human Uroguanylin as a Lead
`Compound
`Petitioner does not dispute that human uroguanylin is unstable and far less
`
`potent than the heat-stable enterotoxins. Reply, 4-11. Instead, Petitioner endeavors
`
`to minimize human uroguanylin’s widely recognized instability, characterize the
`
`heat-stable enterotoxins’ excellent potency as detrimental, and recast Patent Owner’s
`
`2
`
`

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`Case IPR2022-00722
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`Patent No. 7,041,786
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`arguments as requiring a single lead compound. Patent Owner does not contend that
`
`there can be only one “most promising candidate.”2 Here, however, a POSA would
`
`not have selected human uroguanylin as a lead compound in view of its recognized
`
`topoisomeric instability and inferior potency. Petitioner’s use of hindsight to rewrite
`
`the prior art and ignore these issues must be rejected. Daiichi Sankyo Co. v. Matrix
`
`Lab’ys, Ltd., 619 F.3d 1346, 1354 (Fed. Cir. 2010).
`
`A. Human Uroguanylin’s Topoisomeric Instability Presented
`Unnecessary Challenges
`Petitioner does not dispute
`
`that human uroguanylin suffered from
`
`topoisomeric instability. Reply, 7-11. Instead, Petitioner argues that a POSA would
`
`have accommodated—or even embraced—this
`
`instability because human
`
`uroguanylin is a “natural ligand.” Id. Not so.
`
`Petitioner focuses largely on in vivo interconversion, contending that human
`
`uroguanylin would only spend an hour exposed to pH 4.5 and undergo “no more
`
`than 1% interconversion.” Id., 7. But Petitioner bases its contention on
`
`gastrointestinal pHs and transit times in healthy patients, not constipated patients.
`
`Id.; Ex. 2070 at 45:18-47:7 (conceding transit times would be longer in constipated
`
`patients), 38:6-22. Further, Petitioner cites no literature to support its suggestion
`
`
`2 STa is a family of heat-stable enterotoxins, not a single peptide. Ex. 1062 at 68:13-
`
`20.
`
`3
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`Case IPR2022-00722
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`that some level of interconversion would have been acceptable to a POSA. This is
`
`especially problematic given the literature’s recognition that biological properties of
`
`human uroguanylin’s inactive topoisomer were “completely unknown.” Ex. 2020 at
`
`229; Ex. 2069 at 106:9-19. Petitioner’s speculation that a POSA would not have
`
`expected a “natural uroguanylin isoform” to have negative off-target effects is
`
`wholly unsupported. Reply, 10. Drs. Epstein and Peterson recognized that any
`
`compound, including those produced in the human body, can be toxic if administered
`
`at high doses. Ex. 2070 at 35:19-36:13.
`
`Petitioner also downplays the difficulties with purifying, formulating, and
`
`storing human uroguanylin—difficulties a POSA would have considered when
`
`selecting a lead compound. As an initial matter, Dr. Peterson admitted that
`
`purification by HPLC is not cost-effective on a manufacturing scale, undermining
`
`any assertion that purifying topoisomers was straightforward. Ex. 2069 at 22:14-
`
`23:4, 28:5-12. Moreover, Patent Owner never “admit[ed]” that heat-stable
`
`enterotoxins would require “special handling”; to the contrary, Patent Owner
`
`explained that their superior stability would have made them far more attractive lead
`
`compounds. Additionally, Petitioner states that human uroguanylin’s isomerization
`
`“was eliminated under common storage conditions”; however, the “common storage
`
`conditions” Petitioner cites are 0 and -20 °C. Reply, 9; Ex. 2010 at 236. Such
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`extreme storage conditions are hardly “common” and practically speaking would
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`4
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`have dissuaded a POSA from selecting human uroguanylin as a lead compound.
`
`That Marx and Klodt studied the structure-function relationship of the isomers does
`
`not suggest otherwise. Reply, 9-10.
`
`Petitioner next argues that “uroguanylin topoisomerism provided additional
`
`reason to synthesize uroguanylin analogues” because “any naturally-occurring
`
`inactive topoisomer would provide a useful ligand reservoir.” Reply, 10. But
`
`Petitioner’s cropped quotes do not tell the full story. Klodt in fact states:
`
`[T]here are three obvious possibilities for the other
`isoform: (a) it represents another ligand with binding
`specificity to another receptor that is not yet discovered,
`(b) it represents a storage form of the GC-C-binding ligand
`or (c) it has no biological significance at all.
`
`Ex. 2020 at 229. Marx likewise postulates that although uroguanylin isomer B may
`
`“function as a storage form of isomer A, a distinct functional role of the B-type
`
`isomers cannot be excluded.” Ex. 2010 at 239; see also Ex. 2069 at 50:18-24, 106:9-
`
`19. Read in context, Klodt and Marx underscore the uncertainty surrounding the
`
`biological activity of human uroguanylin’s inactive topoisomer.
`
`Such uncertainty is only reinforced by Petitioner’s reliance on Evans’
`
`discussion of ibuprofen. Reply, 10. Consistent with the interpatient variability
`
`concerns Dr. Davies discussed, Evans explains that “the extent of [ibuprofen’s]
`
`chiral inversion varies between individuals.” Ex. 1066 at 11 (citing 35-85%
`
`5
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`variability). Also consistent with the off-target effects Dr. Davies discussed, Evans
`
`explains
`
`that
`
`ibuprofen’s
`
`inactive
`
`isomer “interfere[s] with normal
`
`lipid
`
`metabolism,” the consequences of which are unknown. Id. Additionally, Evans
`
`identifies unexpected unpredictability in differences between dosing of the active
`
`isomer and the racemate. Id. at 12 (reporting that 200 mg of active isomer provided
`
`a more rapid onset of action and better pain relief than 400 mg of the racemate).
`
`Evans also identifies a range of advantages of administering enantiomerically pure
`
`preparations, including reduced metabolic load, reduced chance of pharmacokinetic
`
`interactions with other drugs, avoidance of off-target effects, and the use of smaller
`
`doses. Id. at 13. Evans thus supports Patent Owner’s position. Ex. 2069 at 55:17-
`
`24.
`
`B.
`
`Petitioner’s Criticism of Heat-Stable Enterotoxins Is Inconsistent
`with the Literature and Its Alleged Motivation to Modify Human
`Uroguanylin
`Petitioner does not dispute that the heat-stable enterotoxins lacked human
`
`uroguanylin’s topoisomerism problem; had greater stability, higher potency, and
`
`higher binding affinity than human uroguanylin; and were pH-independent allowing
`
`them to work well throughout the small intestine and colon where constipation was
`
`treated. Petitioner cites Currie, but Currie nowhere suggests a preference for human
`
`uroguanylin over heat-stable enterotoxins. Compare Reply, 4-6, with Ex. 1005.
`
`Currie, filed in 1993, concerns the identification, synthesis, purification, and
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`characterization of what was then a novel peptide, human uroguanylin. See
`
`generally Ex. 1005.
`
`Petitioner highlights Currie’s statement that heat-stable enterotoxins cause
`
`diarrhea in developing countries, particularly in infants and domestic animals. Ex.
`
`1005 at 1:21-23, 1:31-44, 2:6-9; Reply, 5-6. As an initial matter, infants and
`
`domestic animals would not have been the target of these agonists. Ex. 2070 at 64:2-
`
`14, 65:14-18; Ex. 2069 at 28:14-29:11. By the time of the invention, moreover,
`
`POSAs were not studying heat-stable enterotoxins produced at uncontrolled rates by
`
`pathogenic strains of E. coli; they were studying commercially purified heat-stable
`
`enterotoxins. E.g., Ex. 1006 at 51. Indeed, Dr. Peterson admitted that toxicity is
`
`dose-dependent, candidly conceding that “any compound can be toxic at a high
`
`enough dose” and that lowering the dose of an active ingredient generally decreases
`
`side effects. Ex. 2069 at 18:3-6, 19:4-7, 21:3-9; see also Ex. 2070 at 27:10-15,
`
`60:15-21 (conceding that he was unable to identify any constipation treatment that
`
`did not list diarrhea as a potential side effect). Further, as Dr. Peterson admits, it is
`
`undisputed that Dr. Currie, despite having discovered human uroguanylin, selected
`
`a heat-stable enterotoxin from the prior art and modified it to obtain linaclotide.
`
`POR, 37; Ex. 2069 at 16:3-6.
`
`7
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`Petitioner now argues that maximizing potency without pH sensitivity would
`
`not have been desirable. Reply, 6-7. This about-face runs contrary to the arguments
`
`in the Petition:
`
`[T]he [Glu3]-substitution would have been expected to
`result in a protonated glutamate at a higher pH (pKa = 4.25
`rather than aspartic acid’s 3.65) for better activity in the
`less acidic environment of the intestinal lumen further
`away from the stomach. . . . In this way, the substitution
`would have been expected to apply the enhanced activity
`of human uroguanylin (relative to guanylin) more broadly
`to the intestines instead of being localized only proximate
`to the more acidic environment near the stomach.
`
`Pet., 36 (emphasis added); see also id., 18-20. Despite having touted potency and
`
`pH independence as alleged motivations to select and modify human uroguanylin,
`
`Petitioner now argues that a POSA would have sought to partially optimize these
`
`properties. Institut Pasteur, 738 F.3d at 1346 (“[T]he expectation-of-success
`
`analysis must match the highly desired goal, not switch to a different goal that may
`
`be a less challenging.”). This transparent attempt to avoid the far superior heat-
`
`stable enterotoxins is nothing more than hindsight.
`
`Further, Petitioner wholly ignores that the colon was universally accepted as
`
`a necessary site of action for treating constipation. Ex. 2025 ¶ 38; Ex. 2070 at 50:4-
`
`10. In particular, Petitioner argues that GCC receptors were expressed “with higher
`
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`density in the proximal small intestine,” providing a reason to select human
`
`uroguanylin as a lead compound. Reply, 4. While Petitioner does not assert the
`
`difference in expression was meaningful, Petitioner nonetheless provides no
`
`rationale for targeting the small intestine. Indeed, Dr. Epstein candidly conceded
`
`that he was not aware of any pharmacologic therapies available as of 2002 that acted
`
`only in the small intestine. Ex. 2070 at 52:6-16. Accordingly, that GCC receptors
`
`were expressed with higher density in the small intestine would not have provided a
`
`motivation to select human uroguanylin as a lead compound.
`
`III. A POSA Would Not Have Been Motivated to Substitute Asp3 with Glu3
`with Any Reasonable Expectation of Success
`Petitioner argues that “[o]ther obvious compounds and modifications . . . do
`
`not render the proposed compound nonobvious.” E.g., Reply, 2-4. Again, Petitioner
`
`misses the point. Obviousness concerns not what the POSA could have done, but
`
`what the POSA would have done in view of what was taught and suggested by the
`
`prior art. Omeprazole Patent Litig., 536 F.3d at 1379-81. Here, plecanatide is
`
`nonobvious because, inter alia, a POSA would not have been motivated to make the
`
`“specific molecular modifications” to human uroguanylin with a reasonable
`
`expectation of achieving plecanatide. Takeda Chem. Indus., Ltd. v. Alphapharm
`
`Pty., Ltd., 492 F.3d 1350, 1356-57 (Fed. Cir. 2007). Patent Owner’s identification
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`9
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`of other avenues taught by the prior art only reinforces why a POSA would not have
`
`had the requisite motivation and reasonable expectation of success.
`
`A.
`
`Petitioner’s New Alleged Motivation Based on Topoisomerism Is
`Misplaced
`To the extent a POSA would have selected human uroguanylin as a lead
`
`compound, which Petitioner has not established, Petitioner admits that a POSA
`
`would have sought to address human uroguanylin’s topoisomeric instability. Reply,
`
`12-14. Petitioner argues, however, that human uroguanylin’s topoisomeric
`
`instability would have motivated the Glu3 substitution. Id. Petitioner is incorrect.
`
`At the outset, Petitioner argues that “in-vivo interconversion was easily
`
`addressed through formulation and that purification was straightforward.” Id., 12
`
`(emphasis added); Ex. 2069 at 33:24-34:4. According to Petitioner, a POSA would
`
`have pursued these allegedly straightforward solutions rather than the Glu3
`
`substitution. Such straightforward solutions would not have resulted in
`
`plecanatide; they would have resulted in enterically coated human uroguanylin, as
`
`Dr. Peterson admitted. Id.
`
`Petitioner does not dispute that “add[ing] a third disulfide bridge” would have
`
`been a viable approach to developing a synthetic agonist. Reply, 12-13.
`
`Nevertheless, Petitioner misconstrues the teachings of Marx to suggest that they
`
`support the Glu3 substitution. Not so. Petitioner contends that Marx evaluated a
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`third disulfide bridge “only to predict which topoisomer better matches the
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`enterotoxin conformation.” Reply, 13. But “close resembl[ance]” to the structure
`
`of the heat-stable enterotoxins was known to result in high potency, motivating a
`
`different modification to human uroguanylin than Petitioner proposes. Ex. 1063
`
`¶ 57. Petitioner also contends that “Marx proposed systematic substitution of amino
`
`acids contained in uroguanylin and guanylin.” Reply, 13 (emphasis added). But Dr.
`
`Peterson admitted that these types of screening approaches are not rational. Ex. 2069
`
`at 15:5-8.
`
`Petitioner also cites Klodt to argue that “sterical bulk” of “other residues” far
`
`from C-terminus may influence interconversion. Reply, 13. But Klodt points
`
`specifically to the residues “between the inner cystine residues,” which do not
`
`include Asp3. Ex. 2020 at 228. Klodt therefore does not support Petitioner’s
`
`argument.
`
`Petitioner asserts that the Glu3 substitution “does not contradict” Marx’s
`
`alleged
`
`teaching
`
`that “ionizable side-chains at positions 2-3 may affect
`
`topoisomerism.” Reply, 13-14 (emphasis added). Marx states that these side chains
`
`“may be involved in the control of stabilization of the two isomers.” Ex. 2010 at 236
`
`(emphasis added). Marx immediately thereafter states that its “results clearly
`
`demonstrate that the isomerization is not affected by the amino-terminal region of
`
`uroguanylin.” Id.; Ex. 2024 ¶ 147. Reading these passages together, a POSA would
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`not have been motivated to modify the residues at positions 2-3 but would have
`
`retained those residues and attempted, if anything, Marx’s compelling suggestion of
`
`a third disulfide bridge.
`
`B.
`
`Petitioner’s “Conservative Substitution” Arguments Are
`Unpersuasive
`A lead compound is “a compound in the prior art that would be most
`
`promising to modify in order to improve upon its . . . activity and obtain a compound
`
`with better activity.’” Otsuka, 678 F.3d at 1291-93 (citations omitted) (emphasis
`
`added). Petitioner concedes, however, that a POSA would not have had a reasonable
`
`expectation of successfully improving activity via Glu3 substitution, for it
`
`acknowledged that Glu3 substitution was merely “expected to retain activity.”
`
`Reply, 14. Dr. Peterson likewise conceded that a “conservative substitution” would
`
`not be expected to enhance functionality because it generally “has a minimal effect
`
`on biological activity.” Ex. 2026 at 47:3-14.
`
`Petitioner’s attempts to distinguish Jonson and Fiser are unpersuasive.
`
`Contrary to Petitioner’s assertions, Johnson did not merely find “an exception in a
`
`different peptide to the ‘common belief that a Glu to Asp mutation is conservative.’”
`
`Reply, 15 (quoting Ex. 2035 at 400). Rather, Jonson’s conclusions were the result
`
`of a systematic study of 1,415,986 amino acid residues across 8,379 aligned
`
`sequences. Ex. 2035 at 397. Petitioner’s assertions that Fiser is limited to “buried
`
`12
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`rings/loops” and that Asp3 is not buried in a ring/loop are likewise incorrect. Reply,
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`14. The Marx figure Petitioner cites is not meant to depict intra-chain hydrogen
`
`bonding, let alone the carboxylic acid side chains of Asp3.
`
`Further, despite Petition’s assertion that Li “provided a concrete and sensible
`
`design plan,” Dr. Peterson admitted that “Li cannot be used to make cross-peptide
`
`activity comparisons.” Ex. 2069 at 84:18-20. Dr. Peterson also admitted that Li
`
`does “not permit comparison of the affinity or potency of rat uroguanylin to human
`
`uroguanylin or opossum uroguanylin.” Id. at 81:20-24; see also id. at 80:23-81:15,
`
`84:8-12. Given the foregoing,3 Petitioner articulates no rationale why a POSA
`
`would have combined Li with Currie to modify human uroguanylin in view of rat
`
`uroguanylin, let alone as opposed to opossum uroguanylin or any of the other listed
`
`GCC receptor agonists. Ex. 1006 at 52, Fig. 6. Indeed, Petitioner identifies no
`
`
`3 Petitioner’s assertion that “Li does not even use identical amounts in each assay”
`
`is unsupported. Reply at 18. Li is silent on this point. Ex. 1006. Additionally, that
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`Li evaluated whether preincubation enhanced activity of the peptides does not
`
`foreclose the direct comparison of the peptides’ potency, which demonstrates rat
`
`uroguanylin was far inferior to opossum uroguanylin. Id. at 49, Fig. 3; see also Ex.
`
`2069 at 86:9-13 (acknowledging that Hamra 1993 evaluates a truncated opossum
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`uroguanylin peptide, not opossum uroguanylin).
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`reason why substituting Asp3 with Glu3 in the human sequence would have been
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`advantageous.
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`C. Dr. Peterson Admitted that Asp3 Was Required to Maintain
`Activity
`Petitioner argues that “Asp3 was not required to maintain activity,” asserting
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`that “Hamra 1997 indicates only Glu can replace Asp3 while retaining this enhanced
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`activity.” Reply, 16-17. Contrary to Petitioner’s assertion, Hamra 1997 explicitly
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`states that “N-terminal acidic residues of uroguanylin are required for the increased
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`binding affinities.” Ex. 1021 at 2709. Moreover, Dr. Peterson testified that “[b]ased
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`on Hamra 1997, it is [his] opinion that the N-terminal amino acid residues of human
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`uroguanylin are required for the increased binding affinities and enhanced potency
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`for activation of receptors under acidic conditions.” Ex. 2069 at 89:13-18 (emphasis
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`added). Hamra 1997 nowhere indicates that Glu can replace Asp3 while retaining
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`enhanced activity. Ex. 1021.
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`Petitioner also argues that WO ’266 “identifies residues it believes are
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`essential for activity (i.e., those labeled in bold italics in Fig. 7) [and that] Asp2 and
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`Asp3 are not among them.” Reply, 19.
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`But as Dr. Peterson admitted, “WO ’266 identifies the aspartate residues at positions
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`2 and 3 in human uroguanylin as important for regulating the functional activity of
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`uroguanylin in the acidic environment of intestinal mucosa.” Ex. 2069 at 89:24-
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`90:7 (emphasis added); Ex. 2021 at 7-8.
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`Petitioner does not dispute that Klodt reported that deleting Asp3 reduced
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`activity. Reply, 16-17. Contending that “deleting Asp3 is not the same as
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`substituting Glu3,” Petitioner faults Patent Owner for not identifying “any reference
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`teaching Glu3-substitution would impair uroguanylin’s favorable potency.” Reply,
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`16-17. But Petitioner bears the burden of proving that a POSA would have been
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`motivated to substitute Asp3, not the other way around. Notably, and as discussed
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`above, Patent Owner identified at least Hamra 1997 and WO ’266, which state in no
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`uncertain terms that Asp3 was required for human uroguanylin’s activity.
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`D.
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`Petitioner’s Alleged Motivation Based on Protonation Ignores the
`Effect of Intrachain Hydrogen Bonding on pKa
`Based on Marx’s figures, Petitioner classifies human uroguanylin’s residues
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`as “buried” or “exposed” and asserts that the “relative difference between the pKas
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`[for solvent-exposed residues] would be very similar to the difference in the free
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`amino acids.” Reply, 14-15, 20. But Marx does not depict, inter alia, intra-chain
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`hydrogen bonding, which Dr. Peterson agrees can affect pKa values of the involved
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`amino acids. Ex. 2069 at 96:19-97:2, 97:19-98:22. Asp3 contains an ionizable
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`carboxylic acid side chain, which was known to be involved in intra-chain hydrogen
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`bonding due its ability to ionize. See, e.g., Reply, 14 (noting “an ionizable side-
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`chain modification at position 3”); see also Ex. 2010 at 236.
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`Substituting Asp3 with Glu3 would have affected this intra-chain hydrogen
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`bonding and, consequently, the involved amino acids’ pKa values, including in
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`unpredictable ways. Ex. 2069 at 90:16-22 (acknowledging that any “prediction as
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`to the pKa of the carboxylic acid on the side chain . . . would require accounting for
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`the environment in which these residues are found when incorporated into a peptide
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`chain”). Contrary to Petitioner’s unsupported opinion that the pKa values would be
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`predictable, Harms’ systematic study shows that the pKa values can vary
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`unpredictably when incorporated into a peptide chain and that Asp can even have a
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`higher pKa value than Glu. Ex. 2045 at 37, Table 1. Thus, contrary to Petitioner’s
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`argument, the pKa change would have been unpredictable.
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`Petitioner also mischaracterizes Patent Owner’s argument regarding retention
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`of the acidic residues. Reply, 20. While Petitioner’s protonation arguments are
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`fundamentally flawed for the reasons set for above and in Patent Owner’s Response,
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`even if one were to accept Petitioner’s faulty premise, Petitioner’s protonation
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`arguments are nonetheless inconsistent with Petitioner’s assertion that a POSA
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`would have been motivated to keep acidic residues at positions 2 and 3. In particular,
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`if a POSA would have sought to make a uroguanylin analog that was more active in
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`less acidic environments—as Petitioner suggests—then the POSA would not have
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`retained the acidic residues. Petitioner’s suggestion that Patent Owner “argue[d] a
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`POSA would have eliminated uroguanylin’s acidic amino acids at positions 2 and
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`3” mischaracterizes the issue. Id.; Ex 2024 ¶¶ 192-94.
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`E.
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`Petitioner’s Alleged Motivation Based on Acetamide Formation Is
`Unavailing
`Petitioner does not dispute that “aspartimide formation” can be reduced using
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`protecting groups or removed through purification. Indeed, Dr. Peterson conceded
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`that a POSA “can limit the undesired pathways that lead to undesired products” and
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`further admitted that a POSA “can reduce side reactions in chemical synthesis in
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`general by using protecting groups.” Ex. 2069 at 22:3-12. Dr. Peterson likewise
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`admitted that a POSA can separate aspartimide impurities from the desired product
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`by HPLC. Ex. 2069 at 21:20-22:1.
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`Petitioner’s assertion that the use of protecting groups and purification
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`techniques “cannot teach away from an otherwise-favorable substitution” is
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`unavailing. Reply, 21. Reduction of aspartimide formation does not provide
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`Petitioner’s alleged motivation. Notably, Petitioner attempts to distance itself from
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`its own cited aspartimide references by characterizing them as “Bausch’s
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`references.” Reply, 21. Petitioner baldly asserts that these “references identify
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`limitations” for the use of protecting groups, yet Petitioner fails to identify any such
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`limitations. Id.
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`IV. Patent Owner’s Unexpected Results Are Supported
`A.
`Patent Owner’s Unexpected Results Are Commensurate with the
`Scope of the Challenged Claims and Are Versus the Closest Prior
`Art
`Petitioner argues that Patent Owner’s evidence of unexpected results is not
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`commensurate with the scope of the challenged claims. Reply, 22-23. But “absolute
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`identity of scope” is not required. Genetics Institute, LLC v. Novartis Vaccines &
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`Diagnostics, Inc., 655 F.3d 1291, 1308 (Fed. Cir. 2011); Merchant, 575 F.2d at
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`869. Although Petitioner speculates that plecanatide has numerous topoisomers,
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`Petitioner identifies but one.4 Reply, 22. Patent Owner’s evidence of unexpected
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`results is plainly commensurate with the scope of the challenged claims.
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`4 Petitioner also conflates the 7-fold difference in the activity of human
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`uroguanylin’s topoisomers with plecanatide’s. Compare Reply, 22-23, with Ex.
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`1067 at 102.
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`Petitioner also argues that Patent Owner’s evidence of u