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`Paper 7
`Filed: October 7, 2022
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`
`MYLAN PHARMACEUTICALS INC.,
`
`Petitioner,
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`v.
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`BAUSCH HEALTH IRELAND LIMITED,
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`Patent Owner.
`
`__________________
`
`Case IPR2022-01105
`U.S. Patent No. 9,925,231
`__________________
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`PATENT OWNER’S PRELIMINARY RESPONSE
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`
`
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`Case IPR2022-01105
`Patent No. 9,925,231
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`I.
`II.
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`TABLE OF CONTENTS
`INTRODUCTION ........................................................................................ 1
`BACKGROUND .......................................................................................... 4
`Claims of the ’231 Patent .................................................................... 4
`Grounds 1-5 of the Petition ................................................................. 6
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`Summary of the Asserted References .................................................. 7
`Shailubhai (EX1005) ................................................................ 8
`Remington (EX1006) ................................................................ 9
` Mihranyan (EX1007) ................................................................ 9
`2009 Abstract (EX1009) ......................................................... 10
`Doelker (EX1010) .................................................................. 10
`Aulton (EX1029) .................................................................... 11
`Zimmer (EX1011) .................................................................. 12
`Prosecution History........................................................................... 13
` Mylan’s Mischaracterization of Comiskey Declarations ................... 18
`III. The Board Should Deny Institution Under 35 U.S.C. § 325(d) ................... 23
`Legal Framework .............................................................................. 23
`The Petition Relies on the Same or Substantially the Same Art
`or Arguments Overcome During Prosecution .................................... 25
`Ground 1 – Shailubhai, Remington, and Mihranyan ............... 26
`Ground 3 – 2009 Abstract and Doelker ................................... 32
` Mylan Has Not Demonstrated That the Office Erred in a
`Manner Material to the Patentability of Challenged Claims .............. 37
`i
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`Case IPR2022-01105
`Patent No. 9,925,231
`IV. The Petition Should Be Denied Because Mylan Has Failed to
`Establish a Reasonable Likelihood That Any Challenged Claim Is
`Unpatentable ............................................................................................... 39
`Claim Construction ........................................................................... 40
`Priority Date ..................................................................................... 40
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`Person of Ordinary Skill in the Art (“POSA”) ................................... 40
` Ground 1: The Challenged Claims Would Not Have Been
`Obvious over Shailubhai, Remington, and Mihranyan ...................... 44
` Mylan Fails to Identify a Lead or Reference Composition
`from Shailubhai ...................................................................... 45
` Mylan’s Alleged Motivation to Combine the References
`Is Based on Hindsight ............................................................. 49
` Mylan Fails to Establish a Reasonable Expectation of
`Success ................................................................................... 52
`Ground 3: The Challenged Claims Would Not Have Been
`Obvious over the 2009 Abstract in view of Doelker .......................... 59
` Mylan Fails to Identify a Lead or Reference Composition
`from the 2009 Abstract ........................................................... 59
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`
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` Mylan’s Alleged Motivation to Combine the References
`Is Based on Hindsight ............................................................. 61
` Mylan Fails to Establish a Reasonable Expectation of
`Success ................................................................................... 63
`Grounds 2, 4 and 5: Dependent Claims Would Not Have Been
`Obvious ............................................................................................ 68
`Conclusion .................................................................................................. 69
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`V.
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`ii
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`TABLE OF AUTHORITIES
`
`Case IPR2022-01105
`Patent No. 9,925,231
`
` Page(s)
`
`Cases
`Advanced Bionics, LLC v. MED-EL Elektromedizinische Geräte
`GmbH,
`IPR2019-01469, Paper 6 (PTAB Feb. 13, 2020) ............................ 24, 25, 29, 38
`Becton, Dickinson & Co. v. B. Braun Melsungen AG,
`IPR2017-01586, Paper 8 (PTAB Dec. 15, 2017) ....................................... passim
`Best Med. Int’l, Inc. v. Elekta Inc.,
`46 F.4th 1346 (Fed. Cir. 2022) ......................................................................... 44
`Biocon Pharma Ltd. v. Novartis Pharms. Corp.,
`IPR2020-01263, Paper 12 (PTAB Feb. 16, 2021) ............................................ 29
`Boragen, Inc. v. Syngenta Participations AG,
`IPR2020-00124, Paper 18 (PTAB Aug. 10, 2020) ........................................... 39
`Edge Endo, LLC v. Michael Scianamblo,
`IPR2018-01321, Paper 15 (PTAB Jan. 14, 2019) ............................................. 39
`Eli Lilly & Co. v. Teva Pharms. Int’l GmbH,
`8 F.4th 1331 (Fed. Cir. 2021) ........................................................................... 30
`
`Insite Vision Inc. v. Sandoz, Inc.,
`783 F.3d 853 (Fed. Cir. 2015) .................................................................... 53, 64
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ................................................................................... 53, 64
`Kyocera Senco Indus. Tools Inc. v. ITC,
`22 F.4th 1369 (Fed. Cir. 2022) ................................................................... 43, 44
`Novartis Pharm. Corp. v. Watson Lab’ys, Inc.,
`611 F. App’x 988 (Fed. Cir. 2015) ............................................................. 51, 63
`In re Omeprazole Patent Litig.,
`536 F.3d 1361 (Fed. Cir. 2008) .................................................................. 46, 61
`
`iii
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`Patent No. 9,925,231
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`Ortho-McNeil Pharm. v. Mylan Lab’ys, Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) .................................................................. 58, 68
`Oxford Nanopore Techs. Ltd. v. Univ. of Wash.,
`IPR2014-00512, Paper 12 (PTAB Sept. 15, 2014) ..................................... 46, 61
`Procter & Gamble Co. v. Teva Pharm. USA, Inc.,
`566 F.3d 989 (Fed. Cir. 2009) .............................................................. 58, 59, 68
`Regeneron Pharms., Inc. v. Kymab Ltd.,
`IPR2019-01579, Paper 9 (PTAB Mar. 20, 2020) ............................................. 39
`Unigene Lab’ys, Inc. v. Apotex, Inc.,
`655 F.3d 1352 (Fed. Cir. 2011) .................................................................. 46, 61
`Federal Statutes
`35 U.S.C. § 102 .................................................................................................... 15
`35 U.S.C. § 103 .............................................................................................. 15, 16
`35 U.S.C. § 311 ...................................................................................................... 2
`35 U.S.C. § 314 .................................................................................................... 40
`35 U.S.C. § 325 .................................................................................... 2, 24, 30, 40
`
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`iv
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`Case IPR2022-01105
`Patent No. 9,925,231
`Patent Owner Bausch Health Ireland Limited (“Bausch” or “Patent Owner”)
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`submits this Preliminary Response to the Petition for Inter Partes Review of U.S.
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`Patent No. 9,925,231 (“the ’231 patent”) filed by Mylan Pharmaceuticals Inc.
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`(“Mylan” or “Petitioner”).
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`I.
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`INTRODUCTION
`Mylan challenges claims 1-12 of the ’231 patent, directed to oral dosage
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`formulations consisting of a sequence-defined peptide (hereinafter “plecanatide”),
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`an inert low moisture carrier, and a lubricant, wherein the plecanatide has a
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`chromatographic purity of no less than 91% after storage for at least three months.
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`Mylan’s Petition asserts that these claims would have been obvious over Shailubhai
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`in view of Remington and Mihranyan (Ground 1) or over the 2009 Abstract in view
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`of Doelker (Ground 3), adding Aulton to each combination for dependent claim 3
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`(Grounds 2 and 4, respectively), and Zimmer to the 2009 Abstract and Doelker for
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`dependent claim 7 (Ground 5). The Board should reject Mylan’s arguments and
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`deny institution for at least two independent reasons.
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`First, the ’231 patent is a continuation of U.S. Patent No. 9,616,097 (“the ’097
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`patent”), and Mylan’s asserted references and obviousness arguments are
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`substantially the same as those considered by the Office and overcome during
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`prosecution of the ’097 patent, recycling verbatim arguments made by the Examiner
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`in rejecting the claims as anticipated or obvious. In an effort to avoid discretionary
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`Patent No. 9,925,231
`denial, Mylan engages in unprofessional rhetoric and personal attacks, repeatedly
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`and wrongly alleging that “Bausch loaded the dice,” and “misled” and “misdirected”
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`the Examiner with “false impressions” and “bad science” by submitting the
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`Comiskey declarations, which compared differences in impurity levels between
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`formulations containing a regular-grade carrier (Avicel 102) and formulations
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`containing a low-moisture carrier (Avicel PH 112). Pet. at 1-2, 64-65. Mylan
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`effectively takes issue with the fact that the initial impurity levels of the formulations
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`varied. But contrary to Mylan’s allegations, the unexpected results are reflected in
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`the differences in impurity levels between the formulations initially and throughout
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`the duration of the test. Thus, the reduction in total impurities initially (39%) is
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`itself evidence of the unexpected superior stability of the claimed formulations as
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`set forth in the Comiskey Declarations. Stripped to its essence, Mylan’s Petition
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`amounts to an allegation of fraud, which is neither meritorious nor a proper ground
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`for an IPR petition. 35 U.S.C. § 311. The Board should therefore exercise discretion
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`under 35 U.S.C. § 325(d) and deny institution.
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`Second, Mylan’s obviousness arguments are fundamentally flawed and
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`thoroughly tainted by hindsight. Mylan begins by incorrectly characterizing its
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`primary references. Shailubhai (EX1005) is a patent directed to the active
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`pharmaceutical ingredient plecanatide itself, and Mylan has failed to identify any
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`particular formulation in Shailubhai that might constitute a “lead” formulation.
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`2
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`What Mylan calls “good reason” to make “simple direct-compression plecanatide
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`tablets” is based on Mylan’s improper general reliance on potential dosage forms.
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`Similarly, Mylan has failed to establish that the 2009 Abstract (EX1009), a one-
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`paragraph disclosure of a phase I clinical study administering an “oral, ascending
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`dose (0.1 mg to 48.6 mg),” discloses any “lead” formulation. Despite Mylan’s
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`repeated arguments that “tablets [were] a simple, conventional, and popular oral
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`dosage form providing many benefits,” the formulation used in the clinical study
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`described in the 2009 Abstract was a solution.
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`Mylan attempts to compensate for these deficiencies in its Petition by picking
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`and choosing isolated disclosures from multiple references, using the challenged
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`claims as a roadmap through the prior art. As but one example, Mylan asserts that a
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`person of ordinary skill in the art (“POSA”) would have had “good reason” to use a
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`low moisture carrier because, according to Mylan, peptides generally are moisture
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`sensitive. Pet. at 25. Yet Mylan’s Petition is completely devoid of any teaching or
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`suggestion that plecanatide is moisture sensitive, and the reference Mylan cites for
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`its argument that peptides are moisture-sensitive, in fact, recognizes that the effects
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`of moisture are not “widely reported or understood” and describes instances in which
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`peptides are less stable at lower moisture contents. EX1016, 492-94.
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`Mylan fails to establish that a POSA would have selected these isolated
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`disclosures, much less had a reasonable expectation of successfully combining the
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`Patent No. 9,925,231
`specific two types of inactive ingredients—an inert low moisture carrier and a
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`lubricant—as claimed in the ’231 patent. Mylan does not, and cannot, overcome the
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`well-known unpredictability and difficulties associated with preparing stable peptide
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`formulations that existed at the time of invention. The large number of potential
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`problems with formulating peptides, and even larger number of potential avenues to
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`address them, further diminished any reasonable expectation of successfully
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`achieving the claimed oral dosage formulation having an inert low moisture carrier
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`and a lubricant.
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`For each of these reasons, and as detailed below, denial of institution is
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`warranted.
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`II. BACKGROUND
`The ’231 patent covers Trulance® (3 mg tablets), a prescription medicine used
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`in adults to treat irritable bowel syndrome with constipation (IBS-C) and chronic
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`idiopathic constipation (CIC). The active pharmaceutical ingredient (“API”) in
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`Trulance® is plecanatide, a 16-amino acid peptide.
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` Claims of the ’231 Patent
`The claims of the ’231 patent are directed to oral dosage formulations of
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`plecanatide. The ’231 patent has one independent claim (claim 1) and eleven
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`dependent claims (claims 2-12).
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`Claim 1 recites:
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`1. An oral dosage formulation of a Guanylate Cyclase-C (GCC)
`agonist peptide consisting of SEQ ID NO:1, wherein said peptide
`is a (4,12; 7,15) bicycle, an inert low moisture carrier and a
`lubricant, wherein the peptide has a chromatographic purity of
`no less than 91% after storage for at least three months.
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`EX1001, claim 1. Mylan concedes, as it must, that the peptide recited in claim 1 of
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`the ’231 patent is plecanatide. Pet. at 1.
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`Claims 2-11 recite:
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`2. The oral dosage formulation of claim 1, wherein the GCC
`agonist peptide has a chromatographic purity of no less than 92%
`to 95%.
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`3. The oral dosage formulation of claim 1, wherein the
`formulation contains less than 0.2% inorganic acids and
`carboxylic acids.
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`4. The oral dosage formulation of claim 1, wherein the
`formulation is a solid formulation and the unit dose is a powder,
`granule, sachet, troche, tablet, or capsule.
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`5. The oral dosage formulation of claim 1, wherein the GCC
`agonist peptide is stabilized against degradation for a period of
`at least 18 months at 30° C. and 65% relative humidity, or at least
`18 months at 25° C. and 60% relative humidity, or at least 18
`months at 2-8° C.
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`Patent No. 9,925,231
`6. The oral dosage formulation of claim 1, wherein the
`formulation is in the form of a capsule or tablet.
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`7. The oral dosage formulation of claim 6, wherein the capsule
`or tablet is in a blister pack or strip.
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`8. The oral dosage formulation of claim 1, wherein the lubricant
`is magnesium stearate.
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`9. The oral dosage formulation of claim 1, wherein the lubricant
`is at 0.25% (w/w).
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`10. The oral dosage formulation of claim 1, wherein the inert
`carrier is microcrystalline cellulose.
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`11. The oral dosage formulation of claim 1, wherein the inert
`carrier is at least 96% (w/w).
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`12. The oral dosage formulation of claim 1, wherein the inert
`carrier has a particle size of from 50 to 900 microns.
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`EX1001, claims 2-12.
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` Grounds 1-5 of the Petition
`Mylan proposes five grounds of unpatentability, asserting that claims 1-12
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`would have been obvious over various combinations of references. With respect to
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`claim 1—the only independent claim of the ’231 patent—the Petition proposes only
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`two grounds of unpatentability (Grounds 1 and 3), asserting in Ground 1 obviousness
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`over Shailubhai in view of Remington and Mihranyan, and in Ground 3 obviousness
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`Patent No. 9,925,231
`over the 2009 Abstract in view of Doelker. Grounds 2 and 4 challenge only claim
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`3, which depends directly from claim 1. Ground 5 challenges only claim 7, which
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`depends indirectly from claim 1. Grounds 2, 4, and 5 do not raise any additional
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`arguments regarding the alleged obviousness of claim 1; rather, they address only
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`the additional elements that claims 3 and 7 recite.
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`Ground
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`Claims
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`1-2, 4-12
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`3
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`Obvious from the Combined Teachings of
`Shailubhai (EX1005), Remington (EX1006), and
`Mihranyan (EX1007)
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`Shailubhai, Remington, Mihranyan, and Aulton
`(EX1029)
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`1
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`2
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`3
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`4
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`5
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`1-2, 4-6, 8-12
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`2009 Abstract (EX1009), and Doelker (EX1010)
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`3
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`7
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`2009 Abstract, Doelker, and Aulton
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`2009 Abstract, Doelker, and Zimmer (EX1011)
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`Pet. at 6-7. Because the Petition fails to establish that claim 1 would have been
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`obvious for the reasons discussed below, the Petition necessarily fails to establish
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`that dependent claims 2-12 are obvious.
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`Summary of the Asserted References
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`Mylan relies on a combination of three references (Shailubhai, Remington,
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`and Mihranyan) in Ground 1 and two references (2009 Abstract and Doelker) in
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`Ground 3. In Grounds 2 and 4, Mylan additionally relies on Aulton, and in Ground
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`5, Mylan additionally relies on Zimmer.
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`Patent No. 9,925,231
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`Shailubhai (EX1005)
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`Shailubhai, which is Patent Owner’s patent, describes the novel peptide
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`plecanatide, which is the API in Trulance®. Shailubhai was filed in 2002, before the
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`September 15, 2011 priority date Mylan asserts for the ’231 patent claims.
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`While Shailubhai generally states that plecanatide can be “in a pharmaceutical
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`composition in unit dose form” (EX1005, 3:32-36), Shailubhai does not disclose any
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`specific formulation of plecanatide along the lines of those disclosed and claimed in
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`the ’231 patent. Instead, Shailubhai makes a general statement that:
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`in solutions,
`Peptide compositions may be administered
`powders, suspensions, emulsions, tablets, capsules, transdermal
`patches, ointments, or other formulations. Formulations and
`dosage forms may be made using methods well known in the art
`(see, e.g., Remington’s Pharmaceutical Sciences, 16th ed., A.
`Oslo ed., Easton, Pa. (1980)).
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`EX1005, 13:24-30. Mylan has not established that this general statement about
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`possible dosage forms would have provided a POSA any expectation of successfully
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`arriving at the invention recited in claim 1 of the ’231 patent:
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`An oral dosage formulation of a Guanylate Cyclase-C (GCC)
`agonist peptide consisting of [plecanatide], an inert low moisture
`carrier and a
`lubricant, wherein
`the peptide has a
`chromatographic purity of no less than 91% after storage for at
`least three months.
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`Patent No. 9,925,231
`EX1001, claim 1. Indeed, Shailubhai does not teach that plecanatide is moisture
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`sensitive. See generally EX1005.
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`Remington (EX1006)
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`Remington is a pharmaceutical sciences reference that discloses generalized
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`information regarding pharmaceutical formulations. Remington does not disclose
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`plecanatide, let alone formulations of plecanatide. Indeed, the formulation
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`information that Mylan cites from Remington is not directed to any specified protein;
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`it is merely generalized information.
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` Mihranyan (EX1007)
`Mihranyan is an article titled “Moisture sorption by cellulose powders of
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`varying crystallinity.” Mihranyan is not directed to any specified protein; instead, it
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`discloses generalized
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`information
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`regarding pharmaceutical
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`formulations.
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`Mihranyan does not disclose plecanatide, let alone formulations of plecanatide.
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`While Mihranyan states that “[f]or moisture sensitive drugs, low moisture grades of
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`MCC are available” (id., 433), Mylan has not established that, at the time of
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`invention, plecanatide was known to be moisture sensitive. Additionally, Mihranyan
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`cautions that “the structure of cellulose should be thoroughly considered when
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`manufacturing low moisture grades of MCC.” EX1007, 441.
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`2009 Abstract (EX1009)
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`Authored by an inventor of the ’231 patent, Shailubhai’s 2009 Abstract is a
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`one-paragraph disclosure of a phase I clinical trial
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`
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`which used a liquid solution of plecanatide as the test product. See infra § IV.E.1-
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`2 (citing EX2012, 42; EX2013, 5). The only ingredients in the liquid solution were
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`. EX1009, A-641, W1041. That the test
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`product used in the clinical trial was in the form of a liquid solution and
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` demonstrates the impermissible
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`hindsight in Mylan’s assertions that “direct-compression tablet[s]” were “a simple,
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`conventional, solid oral-dosage form.” See Pet. at 1.
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`Doelker (EX1010)
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`Doelker compares performance of the six Avicel PH grades. Doelker
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`illustrates “the main properties” of the listed five Avicel PH grades “evaluated
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`relative[] to the standard Avicel PH-101 product.” EX1010, 658-59. Doelker does
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`not teach that Avicel PH112 (a low moisture grade) has any superior properties
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`compared to other grades.
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`EX1010, 659. Doelker does not disclose plecanatide, let alone formulations of
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`plecanatide. Notably, the sample tablets disclosed in Doelker do not include any
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`APIs. Id. at 652-56. Instead, they include only inactive ingredients. Id.
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`Aulton (EX1029)
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`Aulton is a pharmaceutical sciences reference that discloses generalized
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`information regarding pharmaceutical dosage form design. Aulton does not disclose
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`plecanatide, let alone formulations of plecanatide.
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`Mylan mischaracterizes Aulton. EX1029. At the outset, Mylan points to a
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`membrane-controlled system in a section of Aulton titled “modified-release peroral
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`dosage form” (EX1029, 289), despite Mylan’s repeated characterization of “direct-
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`compression tablet[s]” as “a simple, conventional, solid oral-dosage form.” Mylan
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`has not established that a POSA would have considered this “membrane-controlled
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`system” to formulate “direct-compression tablets.” The membrane system is
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`comprised of “core” components in addition to “coating” components, which must
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`allow water to penetrate. EX1029 at 302. The membrane system is neither “simple”
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`nor “conventional.”
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`In particular, Mylan argues that “Aulton, a well-known pharmaceutical-
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`reference text, similarly teaches making compressed tablets consisting of (i) the
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`active drug, (ii) a filler (i.e., inert carrier); (iii) a lubricant/glidant; and, if necessary,
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`a solubilizer.” Pet. at 15 (citing EX1029, 302-03). According to Aulton (EX1029),
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`however, what Mylan cites as a “compressed tablet” is merely the “core”
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`components of “a membrane-controlled system.” Further, Aulton does not describe
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`the listed “filler or substrate” as a low-moisture carrier, and the listed lubricant and
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`glidant are two different types of excipients.
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`EX1029, 302 (emphasis added).
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`Zimmer (EX1011)
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`Zimmer is an international application, titled “Methods and Compositions for
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`the Treatment of Heart Failure and other Disorders” and discusses the heat stable
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`enterotoxin family (ST peptides) and various modified peptides. Zimmer does not
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`disclose plecanatide, let alone formulations of plecanatide. Mylan states that
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`Zimmer “teaches formulating orally-administered GCC-agonist peptides into tablets
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`for treating constipation and IBS.” Pet. at 20-21. But Zimmer in fact teaches various
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`dosage forms of peptides that are not plecanatide:
`
`For therapeutic and preventive treatment of disorders described
`herein, the peptides and agonists described herein can be
`administered orally, e.g., as a tablet or cachet containing a
`predetermined amount of the active ingredient, pellet, gel, paste,
`syrup, bolus, electuary, slurry, sachet; capsule; powder;
`lyophilized powder; granules; as a solution or a suspension in an
`aqueous liquid or a non-aqueous liquid; as an oil-in-water liquid
`emulsion or a water-in-oil liquid emulsion, via a liposomal
`formulation (see, e.g., EP 15 736299) or in some other form.
`
`EX1011, 66.
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`Prosecution History
`
`Mylan admits that prosecution history of the ’097 patent is directly applicable
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`to the patentability analysis of the ’231 patent. Pet. at 9 (“During the ’097 patent’s
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`examination Bausch alleged an unexpected discovery . . . .). Indeed, Mylan largely
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`discusses the prosecution history of the ’097 patent instead of the ’231 patent in the
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`“Prosecution History” section of the Petition. Pet. at 9-10.
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`Patent No. 9,925,231
`The application that ultimately issued as the ’097 patent underwent extensive
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`and thorough examination. The Examiner allowed the application only after four
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`rounds of substantive office actions and responses involving novelty and/or
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`obviousness issues. This highly substantive examination—from the first non-final
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`office action to allowance—took more than two and half years. The office actions
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`and responses involving novelty and/or obviousness issues are listed in the following
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`table:
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`Events
`Non-Final Office
`Action Dated
`August 19, 2014
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`Response Dated
`February 19, 2015
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`Brief Description of the Event
`Rejections under 35 U.S.C. § 102(b) over WO 02/078683
`(Shailubhai ’683) (EX2001)1
`Rejections under 35 U.S.C. § 103 over:
`(1) Shailubhai ’683 in view of WO 2010/027404
`(Fretzen); and
`(2) Shailubhai ’683 and Fretzen further in view of
`US2009/0253634 (Currie).
`
`• Amendments and Arguments/Remarks were filed with
`First Declaration of Stephen Comiskey including
`stability data.
`
`
`1 Shailubhai ’683 (EX2001) is in the same family as Shailubhai (EX1005).
`
`Shailubhai ’683 and Shailubhai have substantially the same specification, except for
`
`a few minor differences such as a reference list. Cf. EX2001 with EX1005.
`
`14
`
`
`
`Final Office Action
`Date May 20, 2015
`
`Response Dated
`November 20, 2015
`
`Non-Final Office
`Action Dated
`January 4, 2016
`Response Dated
`July 5, 2016
`
`Case IPR2022-01105
`Patent No. 9,925,231
`
`• Pending claim was amended to recite, “the
`formulation comprises an inert low moisture carrier.”
`Rejections under 35 U.S.C. § 103 over Shailubhai ’683,
`Currie, and Mihranyan (EX1007) in view of Avicel PH
`product instruction (FMC 2005).
`
`• Amendments and Arguments/Remarks were filed.
`• Applicant provided arguments that the pending claims
`would have been non-obvious over Shailubhai ’683,
`Currie, Mihranyan in view of Avicel PH product
`instruction (FMC 2005).
`Rejections under 35 U.S.C. § 103 over Shailubhai ’683,
`Mihranyan in view of US 2010/0048489 (Fretzen).
`
`• Amendments and Arguments/Remarks were filed.
`• Pending claim was amended to recite, “An oral dosage
`formulation comprising consisting of at least one
`Guanylate Cyclase C (GCC) agonist peptide, an inert
`low moisture carrier, and a lubricant.”
`
`Interview of
`September 14, 2016
`Supplemental
`Response Dated
`September 14, 2016
`
`• The Examiner discussed claim amendments with
`Applicant.
`
`• Amendments and Arguments/Remarks were filed.
`• Claims were re-arranged and amended to recite “per
`unit dose of 3.0 mg or 6.0 mg of a peptide.”
`
`15
`
`
`
`Case IPR2022-01105
`Patent No. 9,925,231
`
`Final Office Action
`Dated October 5,
`2016
`
`Rejections under 35 U.S.C. § 103 over Currie (WO
`2005/016244), FMC 2005, Fretzen, and in view of
`Shailubhai (Digestive Disease Week, San Diego, 2008)
`(Shailubhai Poster).
`
`Response Dated
`January 5, 2017
`
`• Amendments and Arguments/Remarks were filed with
`Second Declaration of Stephen Comiskey.
`• The Declaration effectively includes the same stability
`data that were filed on February 19, 2015.
`• Pending independent claim was not amended.
`
`• The Examiner discussed with Applicant regarding
`claim amendments.
`
`Interview of
`February 24, 2017
`Notice of Allowance
`Dated February 24,
`2017
`
`As shown in the table above, making four substantive novelty and obvious
`
`• The Examiner provided detailed reasons of allowance
`but did not mention the Comiskey Declarations and/or
`as a reason for her allowance.
`
`rejections, the Examiner generally cited a reference disclosing plecanatide as a
`
`primary reference, and combined it with references disclosing generalized
`
`information regarding pharmaceutical formulations, not specific to any active
`
`ingredient, as secondary references.2 To overcome the rejections, the Applicants
`
`
`2 While this is also what Mylan argued in this Petition, the Examiner made
`
`more robust arguments during prosecution, citing more detailed publications.
`
`16
`
`
`
`Case IPR2022-01105
`Patent No. 9,925,231
`argued that cited combinations of references would not have provided any
`
`reasonable expectation of success and also amended the claims. The Examiner
`
`eventually allowed the application, providing more than a page of her reasons for
`
`allowance for the ’097 patent. The reasons for allowance state that “to differentiate
`
`this instant invention from the prior art teachings,” the Applicants amended the
`
`claims “to be consisting of 3 mg or 6 mg of [plecanatide], an inert low moisture
`
`carrier, and a lubricant having a chromatographic purity of no less than 91% after
`
`storage for at least three months.” EX1022, 5104. The Examiner stated that
`
`“therefore, this instant invention is allowable.” Id.
`
`Mylan provides a one-paragraph summary of the prosecution history, mainly
`
`of the ’097 patent, focusing on the Comiskey declarations, without mentioning any
`
`of the office actions or responses. Mylan argues “[t]he examiner allowed the ’097
`
`patent claims after Bausch again submitted its purported ‘evidence’ of unexpected
`
`results.” Pet. at 9-10. But as shown in the above table, the second Comiskey
`
`Declaration (filed on January 5, 2017) includes overlapping data and arguments as
`
`compared to the first Comiskey Declaration (filed on February 19, 2015). After the
`
`first Comiskey Declaration was submitted, the Examiner issued three more
`
`substantive office actions before allowing the application. In allowing the
`
`application, the Examiner provided more than a page of reasons for allowance,
`
`including discussion of how the prior art was distinguishable from the claimed
`
`17
`
`
`
`Case IPR2022-01105
`Patent No. 9,925,231
`invention. Contrary to Mylan’s mischaracterizations, neither the Comiskey
`
`Declarations nor the unexpected results argued therein were mentioned in the
`
`Examiner’s reasons for allowance of the ’097 patent. EX1022, 5103-04.
`
` Mylan’s Mischaracterization of Comiskey Declarations
`Mylan further mischaracterizes the Comiskey Declarations by ignoring that
`
`the initial impurity levels (at 0 months) are themselves evidence of the unexpected
`
`superior stability of the claimed oral dosage formulations having an inert low
`
`moisture carrier. Pet. at 62-67. In particular, Mylan asserts that “what Bausch . . .
`
`characterized as a ‘dramatic’ 30-34% reduction in degradation during storage was
`
`a difference that existed before storage even began.” Pet. at 63 (emphasis added);
`
`see generally id. at 64-70 (repeatedly referring to “storage stability”). Mylan is
`
`wrong.
`
`First, the Applicants never limited the evidence of unexpected superior
`
`stability to stability following storage. Indeed, Mylan has improperly disregarded
`
`the initial impurity levels (at 0 months) in assessing the unexpected results set forth
`
`in the Comiskey Declarations.
`
` E.g., Pet. at 63.
`
` Contrary to Mylan’s
`
`characterizations, the unexpected results include the differences in impurity levels
`
`between formulations containing a regular-grade carrier (Avicel 102) and
`
`formulations containing a low-moisture carrier (Avicel PH 112) initially and
`
`throughout the duration of the test. Thus, the reduction in total impurities initially
`
`18
`
`
`
`Case IPR2022-01105
`Patent No. 9,925,231
`(39%) is itself evidence of the unexpected superior stability of the claimed oral
`
`dosage formulations as set forth in the Comiskey Declarations.
`
`Indeed, the percent reduction in impurities measured in the Comiskey
`
`Declarations confirms
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