UNITED STATES PATENT AND TRADEMARK OFFICE
`
`————————————————
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`————————————————
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`BAUSCH HEALTH IRELAND LIMITED,
`Patent Owner.
`
`————————————————
`Case IPR2022-01103
`Patent No. 9,616,097
`————————————————
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 9,616,097
`
`

`

`TABLE OF CONTENTS
`
`VI.
`
`I.
`II.
`
`Introduction ...................................................................................................... 1
`Rule 42.8 Notices ............................................................................................. 3
`A.
`Real Parties-in-Interest .......................................................................... 3
`B.
`Related Matters ...................................................................................... 4
`C.
`Counsel and Service Information .......................................................... 4
`III. Certifications .................................................................................................... 5
`IV. Overview of Challenges; Precise Relief Requested ........................................ 5
`V.
`The ’097 Patent ................................................................................................ 7
`A.
`Prosecution History ............................................................................... 9
`B.
`Priority Date ........................................................................................ 10
`C.
`Level of Ordinary Skill ....................................................................... 10
`D.
`Claim Construction.............................................................................. 12
`Prior Art Summary ........................................................................................ 13
`A.
`Technical Background ......................................................................... 13
`B.
`Asserted References ............................................................................ 17
`1.
`Shailubhai .................................................................................. 17
`2.
`Remington ................................................................................. 18
`3.
`Mihranyan ................................................................................. 18
`4.
`Aulton ........................................................................................ 19
`5.
`The 2009 Abstract ..................................................................... 19
`6.
`Doelker ...................................................................................... 20
`7.
`Zimmer ...................................................................................... 20
`VII. Ground 1: Claims 1-2 and 4-12 Were Obvious Over Shailubhai,
`Remington, and Mihranyan ........................................................................... 20
`A.
`Claim 1 ................................................................................................ 21
`1.
`Element 1.[a] ............................................................................. 21
`2.
`Element 1.[b] ............................................................................. 25
`-i-
`
`

`

`B.
`
`C.
`
`3.
`4.
`5.
`
`Element 1.[c] ............................................................................. 27
`Element 1.[d] ............................................................................. 28
`Reason to Combine and Reasonable Expectation of
`Success ...................................................................................... 32
`Conclusion ................................................................................ 34
`6.
`Dependent Claims 2 and 5 .................................................................. 35
`1.
`Claim 2 ...................................................................................... 35
`2.
`Claim 5 ...................................................................................... 36
`Dependent Claims 4 and 6-7 ............................................................... 37
`1.
`Claims 4 and 6 ........................................................................... 37
`2.
`Claim 7 ...................................................................................... 38
`Dependent Claims 8-9 ......................................................................... 39
`Dependent Claims 10-12 ..................................................................... 41
`1.
`Claims 10-11 ............................................................................. 41
`2.
`Claim 12 .................................................................................... 42
`VIII. Ground 2: Claim 3 Was Obvious Over Shailubhai, Remington,
`Mihranyan, and Aulton .................................................................................. 43
`IX. Ground 3: Claims 1-2, 4-6, and 8-12 Were Obvious Over 2009
`Abstract and Doelker ..................................................................................... 44
`A.
`Claim 1 ................................................................................................ 45
`1.
`Element 1.[a] ............................................................................. 45
`2.
`Element 1.[b] ............................................................................. 49
`3.
`Element 1.[c] ............................................................................. 50
`4.
`Element 1.[d] ............................................................................. 51
`5.
`Reason to Combine and Reasonable Expectation of
`Success ...................................................................................... 54
`Conclusion ................................................................................ 56
`6.
`Dependent Claims 2 and 5 .................................................................. 57
`1.
`Claim 2 ...................................................................................... 57
`
`D.
`E.
`
`B.
`
`-ii-
`
`

`

`C.
`D.
`E.
`
`Claim 5 ...................................................................................... 57
`2.
`Dependent Claims 4 and 6 .................................................................. 59
`Dependent Claims 8-9 ......................................................................... 59
`Dependent Claims 10-12 ..................................................................... 60
`1.
`Claims 10-11 ............................................................................. 60
`2.
`Claim 12 .................................................................................... 62
`Ground 4: Claim 3 Was Obvious Over the 2009 Abstract, Doelker,
`and Aulton ..................................................................................................... 62
`XI. Ground 5: Claim 7 Was Obvious Over the 2009 Abstract, Doelker,
`and Zimmer .................................................................................................... 64
`XII. No Secondary Considerations ....................................................................... 64
`XIII. Discretionary Denial is Unwarranted ............................................................ 71
`XIV. Conclusion ..................................................................................................... 74
`
`X.
`
`-iii-
`
`

`

`TABLE OF AUTHORITIES
`
`Cases
`
`Adapt Pharma Ops. v. Teva Pharms. USA, Inc., 25 F.4th 1354 (Fed. Cir.
`2022) ...................................................................................................................69
`Alcon Research, Ltd. v. Apotex Inc., 687 F.3d 1362 (Fed. Cir. 2012) .............. 29, 51
`Becton, Dickinson & Co. v. B. Braun Melsungen AG, IPR2017-01586,
`Paper 8 (2017) .....................................................................................................72
`ClearValue Inc. v. Pearl River Polymers Inc., 668 F.3d 1340 (Fed. Cir.
`2012) ........................................................................................................... passim
`Hospira, Inc. v. Fresenius Kabi USA, LLC, 946 F.3d 1322, 1329-30 (Fed.
`Cir. 2020) ..................................................................................................... 28, 51
`In re Harris, 409 F.3d 1339 (Fed. Cir. 2005) ..........................................................69
`In re Lohr, 317 F.2d 388 (CCPA 1963) ...................................................................68
`KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007) ............................. 21, 34, 45, 56
`Scientific Design Co., Inc. v. Shell Oil Co., IPR2022-00159, Paper 7
`(2022) ..................................................................................................................72
`Telemac Cellular Corp. v. Topp Telecom, Inc., 247 F.3d 1316 (Fed. Cir.
`2001) ............................................................................................................ 29, 51
`Tokai Corp. v. Easton Enters., Inc., 632 F.3d 1358 (Fed. Cir. 2011) .....................67
`Trend Micro Inc. v. Cupp Computing AS, IPR2021-01236, Paper 16
`(2022) ..................................................................................................................72
`
`-iv-
`
`

`

`Statutes
`
`35 U.S.C. §103 .............................................................................................. 6, 34, 56
`35 U.S.C. §316(b) .....................................................................................................74
`35 U.S.C. §325(d) ....................................................................................................73
`
`Regulations
`
`37 CFR §42.100(b) ...................................................................................................12
`
`-v-
`
`

`

`I.
`
`INTRODUCTION
`
`U.S. Patent No. 9,616,097 (“’097 patent,” EX1001), currently assigned to
`
`Bausch Health Ireland Limited (“Bausch”1), claims an oral-dosage formulation
`
`consisting of 3.0 or 6.0 mg of a known peptide (“plecanatide”), an “inert low
`
`moisture carrier,” and a lubricant, with stability limitations intrinsic to the
`
`composition.
`
`This petition relies both on references never before the examiner and
`
`references lost among hundreds in an IDS and never applied in a rejection. See
`
`§XIII. This prior art teaches a direct-compression tablet was one simple,
`
`conventional, solid oral-dosage form, commonly consisting of a unit dose of an
`
`active ingredient, an inert carrier (often microcrystalline cellulose (MCC)), and a
`
`lubricant (often magnesium stearate). It also taught peptides were susceptible to
`
`moisture-induced degradation, which a low-moisture inert carrier could
`
`successfully counteract. Thus, the challenged claims cover a simple, conventional
`
`solid oral-dosage form of a routine amount of prior-art plecanatide, and recite
`
`intrinsic stability properties of this conventional composition. This subject matter
`
`was obvious to a person of ordinary skill over the prior art.
`
`The challenged claims issued in error, at least partly because Bausch
`
`1 For simplicity, references to Bausch include its predecessors in interest.
`
`-1-
`
`

`

`misleadingly claimed unexpected results. During prosecution, Bausch alleged an
`
`unexpected discovery—the plecanatide peptide was “dramatic[ally]” more stable
`
`in storage (30-34%) when formulated with a low-moisture carrier than with a
`
`higher-moisture carrier. E.g., EX1022, 0369-86. The examiner allowed claims after
`
`Bausch again submitted its purported “evidence” of unexpected results. The
`
`evidence presented below demonstrates Bausch’s unexpected-results arguments are
`
`a mirage based on misleading data.
`
`Bausch’s characterization of its plecanatide stability data was materially
`
`misleading. What Bausch called a “dramatic” 30-34% reduction in degradation
`
`when using a low-moisture carrier, actually, largely results from a pre-existing
`
`difference in the plecanatide purity the patentee chose to use in the underlying
`
`experiments. In absolute terms, impurities in the two compared groups began at
`
`about 1.3% and 2.1%, respectively (a 39% difference). EX1022, 0385. Even when
`
`stored at high temperatures over six months, the difference in impurity amounts
`
`fluctuated somewhat over time but the purported “dramatic” 30-34% reduction in
`
`degradation over time never exceeded the 39% baseline difference in the starting
`
`materials’ respective purities when the experiments began. Put simply, Bausch
`
`made something out of nothing and misdirected the examiner.
`
`Nor is increased peptide stability an unexpected result of using a low-
`
`moisture carrier. It is precisely why the prior art used low-moisture carriers: to
`
`-2-
`
`

`

`avoid the same well-known, moisture-induced peptide degradation pathways. In
`
`the proper context—detailed below—a skilled artisan would have fully expected
`
`Bausch’s results, which represent at most a difference in degree, not in kind.
`
`Plecanatide’s stability properties were known, and claiming a prior-art compound’s
`
`intrinsic physical properties cannot justify extending a patent monopoly.
`
`Not only is this a problem on an individual patent basis, but Bausch created
`
`a patent thicket, with multiple patents featuring patentably-indistinct claims issued
`
`on the same erroneous bases. Petitions are thus being contemporaneously filed for
`
`inter partes review of four nearly-identical patents that never should have issued.
`
`Review should be instituted in each case to cancel the challenged claims.
`
`II.
`
`RULE 42.8 NOTICES
`
`A. Real Parties-in-Interest
`Petitioner Mylan Pharmaceuticals Inc. (“Mylan”) is a co-defendant with
`
`Mylan Laboratories Ltd., Mylan Inc., and Viatris Inc. in parallel litigation.
`
`Although Agila Specialties Inc. and Mylan API US LLC were also named as
`
`defendants in the administratively-closed Western District of Pennsylvania
`
`litigation (see below), they are not real parties-in-interest. They were dismissed
`
`from the case now in the Northern District of West Virginia and were the subject
`
`of a motion to dismiss when the Pennsylvania case was administratively closed.
`
`-3-
`
`

`

`B. Related Matters
`Mylan Pharmaceuticals Inc. v. Bausch Health Ireland Ltd., IPR2022-00722
`
`(PTAB); and Bausch Health Ireland Ltd. v. Mylan Laboratories Ltd., 1-22-cv-
`
`00020 (NDWV); 2-21-cv-00573 (WDPA (administratively closed)); and Bausch
`
`Health Ireland Ltd. v. MSN Laboratories Pvt. Ltd., 2-21-cv-10057 (DNJ).
`
`IPR2022-01102, IPR2022-01104, and IPR2022-01105 involve patents
`
`closely related to the challenged patent.
`
`C. Counsel and Service Information
`Lead:
`Jad Mills, Reg. No. 63,344.
`
`First Backup:
`
`Richard Torczon, Reg. No. 34,448.
`
`Backup:
`
`
`
`Nicole Stafford, Reg. No. 43,929;
`
`Dennis Gregory, Reg. No. 52,967.
`
`Postal Address:
`
`701 Fifth Avenue, Suite 5100, Seattle, WA 98104-7036.
`
`Telephone:
`
`206-883-2554.
`
`Facsimile:
`
`
`
`206-883-2699.
`
`Please direct all correspondence to the contact information above. Mylan consents
`
`to electronic-mail service at:
`
`jmills@wsgr.com,
`
`rtorczon@wsgr.com,
`
`nstafford@wsgr.com,
`
`-4-
`
`

`

`dgregory@wsgr.com, and
`
`4869-2213-2498@mail.vault.netdocuments.com.
`
`III. CERTIFICATIONS
`
`Mylan certifies the ’097 patent is available for review. Mylan is not barred
`
`or estopped from requesting review on these grounds.
`
`IV. OVERVIEW OF CHALLENGES; PRECISE RELIEF REQUESTED
`
`Mylan seeks cancellation of claims 1-12 for the reasons stated below,
`
`supported with exhibits, including declarations from Drs. Graham Buckton and
`
`Uwe Christians. EX1002, ¶¶11-16; EX1003; EX1004, ¶¶10-14; EX1033.
`
`The claims are unpatentable on these grounds:
`
`-5-
`
`

`

`Ground
`1
`
`Claims
`1-2, 4-12
`
`Obviousness (§103)2
`
`Shailubhai,3 Remington,4 and Mihranyan5
`
`Shailubhai, Remington, Mihranyan, and
`
`Aulton6
`
`3
`
`2
`
`3
`
`4
`
`1-2, 4-6, 8-12
`
`2009 Abstract7 and Doelker8
`
`3
`
`2009 Abstract, Doelker, and Aulton
`
`2 All statutory references are to pre-AIA 35 U.S.C. unless otherwise indicated.
`
`3 K. Shailubhai et al., Guanylate Cyclase Receptor Agonists for the Treatment of
`
`Tissue Inflammation and Carcinogenesis, U.S. Patent No. 7,041,786 (2006)
`
`(“Shailubhai,” EX1005).
`
`4 E. Rudnic, Chapter 45: Oral Solid Dosage Forms, REMINGTON: THE SCIENCE
`
`AND PRACTICE OF PHARMACY, 21st ed., 2005 (“Remington,” EX1006).
`
`5 A. Mihranyan et al., Moisture Sorption by Cellulose Powders of Varying
`
`Crystallinity, INT. J. PHARM., 269(2), 433-442 (2004) (“Mihranyan,” EX1007).
`
`6 M. Aulton, Pharmaceutics: The Science of Dosage Form Design, 2nd ed. (2001)
`
`(“Aulton,” EX1029).
`
`7 K. Shailubhai et al., SP-304 to Treat GI Disorders – Effects of a Single, Oral-
`
`Dose of SP-304 on Safety, Tolerability, Pharmacokinetics and Pharmacodynamics
`
`-6-
`
`

`

`5
`
`7
`
`2009 Abstract, Doelker, and Zimmer9
`
`V.
`
`THE ’097 PATENT
`
`The ’097 patent is entitled “Formulations of Guanylate Cyclase C Agonists
`
`and Methods of Use.” EX1001, Title. It states “[t]he invention provides low-dose
`
`formulations of guanylate cyclase-C (‘GCC’) agonist peptides and methods for
`
`their use.” EX1001, Abstract. The ’097 patent admits GCC-agonist peptides,
`
`including SEQ ID NO:1 (also “SP-304” and “plecanatide”), and methods for
`
`making them, were known in the prior art. EX1001, 3:54-60, 21:48-67, 25:58-66,
`
`27:18-28:44, 29:13-30:62; EX1002, ¶¶26-31. The ’097 patent also acknowledges
`
`GCC-agonist peptides’ mechanism of action was known. EX1001, 2:35-40;
`
`EX1004, ¶¶24-26; EX1002, ¶¶32-33.
`
`in Healthy Volunteers, GASTROENTEROL., 136(5), A641, Abstract W1041 (2009)
`
`(“2009 Abstract,” EX1009).
`
`8 E. Doelker et al., Morphological, Packing, Flow and Tableting Properties of New
`
`Avicel Types, DRUG DEV. IND. PHARM., 21(6), 643-661 (1995) (“Doelker,”
`
`EX1010).
`
`9 D. Zimmer et al., Methods and Compositions for the Treatment of Heart Failure
`
`and Other Disorders, WO 2008/106429 (2008) (“Zimmer,” EX1011).
`
`-7-
`
`

`

`Independent claim 1 recites an oral-dosage formulation of a GCC-agonist
`
`peptide consisting of 3.0 mg or 6.0 mg of plecanatide, an inert low-moisture
`
`carrier, and a lubricant. Claim 1 further recites “the peptide has a chromatographic
`
`purity of no less than 91% after storage for at least three months.” EX1002, ¶¶41-
`
`42, 50; EX1004, ¶¶27-28.
`
`The ’097 patent does not disclose any new process to achieve or maintain a
`
`chromatographic purity of 91% after three months of storage. The specification
`
`does not even provide stability data for any formulation with the claimed low-
`
`moisture carrier. Instead, the specification merely provides data for a plecanatide
`
`formulation using Avicel PH102 in combination with a well-known lubricant
`
`(magnesium stearate). EX1001, 99:29-102:20, Example 11 (capsule; batch 1528-
`
`2850-RD), Example 12 (tablet; batch 1528-2850B-RD). Yet Bausch disclaimed
`
`Avicel PH102 from the claimed low-moisture carrier during prosecution. EX1022,
`
`0382-86. Based on these experiments—using a formulation expressly outside the
`
`scope of its claims—the ’097 patent reports plecanatide’s “product stability in
`
`terms of HPLC or UPLC of total impurities as a function of time and storage
`
`condition.” EX1001, 99:22-24. That is, the ’097 patent identifies storage stability
`
`as an intrinsic physical property of the composition. As Dr. Buckton testifies,
`
`storage stability is an expected result of formulating plecanatide in this
`
`conventional manner, and at least as much storage stability (or more) would have
`
`-8-
`
`

`

`been expected using other conventional inert carriers, especially lower-moisture
`
`inert carriers (e.g., Avicel PH112). EX1002, ¶¶299-304, 353-354, 127-131, 223-
`
`226; see also EX1022, 0382-86 (asserting Avicel PH112 formulation is more
`
`stable than Avicel PH102 formulation). The remaining claims 2-12 also do not
`
`meaningfully distinguish the asserted art. EX1002, ¶¶41-42; EX1004, ¶¶29-30.
`
`Prosecution History
`A.
`During examination, Bausch alleged an unexpected discovery—that
`
`plecanatide was “dramatic[ally]” more stable in storage (30-34%) when formulated
`
`with a low-moisture carrier than with a higher-moisture carrier. E.g., EX1022,
`
`0369-86; EX1002, ¶¶57-61. Bausch further limited the claims to exclude other
`
`known peptide-stabilizing excipients and contended it was unexpected for a
`
`peptide to exhibit the observed stability without these additional stabilizing
`
`excipients. EX1022, 4973-77; EX1002, ¶¶62-66. The examiner allowed the ’097
`
`patent claims after Bausch again submitted its purported “evidence” of unexpected
`
`results. Id., 5079-89 (Applicants’ Remarks), 5090-94 (1.132 Declaration), 5098
`
`(Notice of Allowance); EX1002, ¶67.
`
`This petition provides new evidence and new arguments demonstrating the
`
`challenged claims never should have issued. See §XIII, below; EX1002, ¶¶68-71.
`
`-9-
`
`

`

`B. Priority Date
`The ’097 patent claims priority via a 2011 PCT application to three
`
`provisional applications filed in 2010. EX1001, cover; EX1025; EX1026; EX1027.
`
`During the ’097 patent’s examination, however, the examiner noted “none of the
`
`provisional applications…disclosed the amended claim 45.” EX1022, 4990. The
`
`examiner concluded that, because the provisional patent applications did not
`
`disclose the 91% chromatographic-purity limitation, the “date of this application is
`
`the effective filing date of PCT/US2011/0151805 (9/15/2011),” which is
`
`September 15, 2011. Id. The examiner made a similar comment in a related
`
`application, the priority date of which “would also be changed by the proposed
`
`amendment” that included the 91% chromatographic purity limitation. EX1021,
`
`0440-41; see also id., 0409-14 (amendment); EX1002, ¶¶51-55. The ’097 patent
`
`thus has an effective filing date no earlier than September 15, 2011.
`
`C. Level of Ordinary Skill
`Obviousness is determined from the perspective of a person of ordinary skill
`
`in the art (POSA), who is presumed to be aware of all pertinent art and possess
`
`common sense and ordinary creativity in the pertinent field. The challenged claims
`
`are directed to an oral-dosage formulation. By September 15, 2011, a POSA had
`
`the equivalent of a graduate degree in pharmaceutics or a related field, and
`
`knowledge and experience making oral-dosage formulations. EX1002, ¶¶81-84.
`
`-10-
`
`

`

`This individual could work with other specialists including, e.g., an M.D., clinical
`
`pharmacologist, and medicinal chemist. Id. This petition cites references, including
`
`background art, that further demonstrate a POSA’s knowledge and abilities. Id.;
`
`EX1004, ¶¶37, 39-40.
`
`Two eminently-qualified experts testify in support of this petition. Dr.
`
`Buckton is an Emeritus Professor of Pharmaceutics in the UCL School of
`
`Pharmacy of the University of London and was well-versed in formulating active
`
`pharmaceutical ingredients for oral administration at the relevant time. EX1002,
`
`¶¶1-10; EX1003. Dr. Buckton received his Ph.D. in Pharmaceutics from King’s
`
`College, University of London in 1985. Dr. Buckton’s work as a formulator in
`
`industry and in academia spanned 1988 to 2015 and focused on pharmaceutical
`
`formulation development, including materials characterization, pre-formulation,
`
`assay development, clinical trials, and manufacturing. His formulation projects
`
`have been funded by private industry (e.g., Pfizer, AstraZeneca, GSK, and
`
`Novartis) as well as government grants (e.g., Engineering and Physical Sciences
`
`Research Council). He publishes frequently about formulation in respected
`
`academic and industry journals, including Advanced Drug Delivery Reviews, the
`
`International Journal of Pharmaceutics, and the European Journal of
`
`Pharmaceutics and Biopharmaceutics. Because of his significant contributions, Dr.
`
`Buckton has received numerous awards and honors, including the Pfizer Award for
`
`-11-
`
`

`

`Excellence in Published Research, the Stig Sunner Award, and the Academy of
`
`Pharmaceutical Sciences Medal. Dr. Buckton is well qualified to testify regarding a
`
`POSA’s understanding and knowledge at the relevant time. EX1002, ¶¶83-84.
`
`Dr. Buckton’s testimony is further supported by the testimony of Dr.
`
`Christians, who is an M.D./Ph.D. and Professor of Medicine at the University of
`
`Colorado Health Sciences Center with experience in clinical pharmacology and
`
`toxicology. Dr. Christians has extensive experience designing and conducting
`
`clinical trials. EX1004, ¶¶1-9. Dr. Christians also has direct experience with
`
`uroguanylin peptides. Id., ¶5; EX1033. Dr. Christians is well qualified to testify
`
`based on his knowledge, training and experience regarding a POSA’s
`
`understanding and knowledge at the relevant time. EX1004, ¶¶1-9.
`
`D. Claim Construction
`This petition applies the claims’ ordinary and customary meaning as POSAs
`
`understood them, consistent with the specification. 37 CFR §42.100(b); EX1002,
`
`¶85; EX1004, ¶41. The claims do not require any constructions to apply the grounds.
`
`The term “inert low moisture carrier” appears in independent claim 1. The
`
`’097 patent expressly identifies Avicel PH112, an MCC-based carrier, as a “low
`
`moisture” carrier. EX1001, 9:35-38, 89:18-34. During examination, Bausch
`
`distinguished Avicel PH102 as a “regular grade carrier” as compared to “low-
`
`moisture” Avicel PH112. EX1022, 0382-86. Construction of “inert low moisture
`
`-12-
`
`

`

`carrier” is unnecessary for this petition because a POSA would have understood
`
`the claims to include at least Avicel PH112 as a prior-art “inert low moisture
`
`carrier.” EX1002, ¶¶86-88.
`
`VI. PRIOR ART SUMMARY
`
`Technical Background
`A.
`Plecanatide is the 16-amino acid peptide sequence:
`
`Asn1-Asp2-Glu3-Cys4-Glu5-Leu6-Cys7-Val8-Asn9-Val10-Ala11-Cys12-Thr13-Gly14-Cys15-Leu16
`
`EX1005, 5:4-16, 15:56-58; EX1002, ¶89; EX1004, ¶42.
`
`Before the critical date, plecanatide’s stability was well publicized. The prior
`
`art touted plecanatide’s “temperature and protease stability,” and its “biological
`
`activity at the physiologically favorable pH range (pH 6 to 7) in the large
`
`intestine.” EX1005, 5:16-23; see also EX1017, 1 (plecanatide “primarily exists in a
`
`single bioactive conformation”); EX1004, ¶45; EX1002, ¶90.
`
`Plecanatide was also known at the time to be a guanylate cyclase-C (GCC)
`
`agonist with anti-inflammatory effects useful for treating gastrointestinal (GI)
`
`disorders. EX1028, 73, 78; EX1002, ¶¶91-92, 105-107; EX1004, ¶¶44-48. As an
`
`agonist, when plecanatide binds to its receptor (GCC), its activity plateaus once the
`
`receptor is saturated. EX1004, ¶156. Dose increases above saturation will not
`
`provide additional therapeutic effects, but might increase adverse effects. Id.
`
`Consequently, low doses of agonists are conventional. Id. POSAs also knew
`
`-13-
`
`

`

`plecanatide “can be given orally, and is not systemically absorbed…, which means
`
`that the compound is likely to be very safe in clinical use.” EX1017, 1.
`
`POSAs further regarded plecanatide as a “small molecule.” EX1028, 78.
`
`Well before the critical date, POSAs knew conventional methods of formulating
`
`small molecules. EX1002, ¶¶92-97; see generally EX1006. “Although the
`
`differences in the physical and chemical properties between synthetic (small)
`
`molecules and protein biologics (peptide, antibodies, and recombinant proteins) are
`
`significant, the basic approach taken by the pharmaceutical scientist in formulating
`
`and delivery ha[d] become remarkably similar.” EX1020 (the “Protein
`
`Handbook”), 328; id., 330, 333.
`
`Skilled artisans further understood, “[w]hen the time comes to formulate
`
`either a biologic or a small molecule, the age-old rule of developing the simplest
`
`formulation possible should prevail. Excipients used should be justified with a
`
`reason for their inclusion.” EX1020, 331; EX1002, ¶94.
`
`Well before the critical date, POSAs knew “[t]ablets are the most widely
`
`used dosage form.” EX1029, 248. POSAs also understood “tablets can usually be
`
`prepared by direct compression,” where the active pharmaceutical ingredient is
`
`compressed with excipients. EX1029, 134; EX1002, ¶¶95-99. A 2008 published
`
`application, for example, teaches formulating peptides as direct-compression
`
`tablets in which the active drug ingredients is “mixed with a solid, pulverant carrier
`
`-14-
`
`

`

`such as…cellulose derivatives or gelatin, and mixtures thereof, as well as with an
`
`antifriction agent such as, for example, magnesium stearate[.]” EX1030, ¶167;
`
`EX1002, ¶98. Aulton, a well-known pharmaceutical-reference text, similarly
`
`teaches making compressed tablets consisting of (i) the active drug, (ii) a filler
`
`(i.e., inert carrier); (iii) a lubricant/glidant; and, if necessary, a solubilizer. EX1029,
`
`302-03; EX1002, ¶99. Thus, POSAs knew to formulate small molecules, including
`
`peptides, in direct-compression tablets consisting of the peptide, a carrier, and a
`
`lubricant.
`
`Aulton teaches MCC as a conventional filler for tablets:
`
`-15-
`
`

`

`EX1029, 136, Table 8.16, 302; see also EX1006, 891, 902-03; EX1002, ¶100;
`
`EX1001, 11:50-53 (carriers “also referred to as diluents”). POSAs knew MCC
`
`further provides “some lubricant and disintegrant properties that make it useful in
`
`tableting.” EX1008, 130; see also EX1006, 903; EX1002, ¶101. Thus, POSAs
`
`recognized MCC as a highly-preferred inert carrier for direct-compression tablets.
`
`EX1002, ¶¶100-101.
`
`POSAs also routinely used low-moisture MCC for moisture-sensitive
`
`materials. The Excipients Handbook teaches “[s]everal different grades of
`
`microcrystalline cellulose are commercially available” and “[l]ow-moisture grades
`
`are used with moisture-sensitive materials.” EX1008, 132; see also EX1007, 433
`
`(teaching low-moisture Avicel PH112 for formulating moisture-sensitive
`
`materials). Peptides were generally understood to be susceptible to water-induced
`
`degradation. EX1016, 489. Thus, POSAs recognized low-moisture MCC as a
`
`preferred inert carrier for direct-compression tableting of peptides. EX1002, ¶¶102,
`
`104.
`
`Lubricants had known utility for formulating direct-compression tablets by
`
`“prevent[ing] adhesion of the tablet material to the surface of the dies and punches,
`
`reduc[ing] interparticle friction,” and “facilitat[ing] the ejection of the tablets from
`
`the die cavity.” EX1006, 892; EX1002, ¶103. Magnesium stearate was a
`
`conventional lubricant for direct-compression tableting. EX1029, 136 (identifying
`
`-16-
`
`

`

`magnesium stearate as a preferred lubricant); EX1006, 892-93 (“magnesium
`
`stearate is one of the most widely used lubricants”); EX1008, 404; EX1002, ¶103.
`
`Asserted References
`B.
`The claims take a simple, conventional, and well-known tablet formulation
`
`and apply it to prior-art plecanatide. The discussion below summarizes certain
`
`prior-art publications illustrating the obviousness of each challenged claim.
`
`1.
`
`Shailubhai
`
`Shailubhai10 is a 2006 patent disclosing plecanatide. EX1005, 5:4-12;
`
`EX1002, ¶¶108-109. Shailubhai also discloses plecanatide’s pharmacological
`
`effect of increasing potassium and calcium ion influx and water transport into the
`
`GI tract. EX1005, 6:4-32, 15:25-17:5; EX1004, ¶43.
`
`Shailubhai teaches plecanatide “may be combined or formulated with
`
`various excipients” to make tablets, that plecanatide tablets “may be made using
`
`methods well known in the art” (citing well-known reference text Remington), and
`
`that the “selection of carriers” and “components suitable for use in compositions is
`
`well within the level of skill in this art.” EX1005, 13:18-52; EX1002, ¶110.
`
`10 Shailubhai is prior art under at least §102(b).
`
`-17-
`
`

`

`2.
`
`Remington
`
`Remington11 is the 21st edition (published in 2005) of a well-known,
`
`foundational reference text teaching the popularity of direct-compression tablets,
`
`which enable fewer excipients, lower cost, and greater automation. EX1006, 889-
`
`91, 901-03; EX1002, ¶¶111-112.
`
`Remington notes “[m]icrocrystalline cellulose (Avicel) usually is used as an
`
`excipient in direct compression formulas” and is the “excipient that has been
`
`studied extensively as a direct compression vehicle.” EX1006, 891, 902-03.
`
`Remington also teaches magnesium stearate is “one of the most widely used
`
`lubricants.” Id., 892-93; EX1002, ¶¶111-112.
`
`3.
`
`Mihranyan
`
`Mihranyan,12 a 2004 journal article, teaches, “[f]or moisture sensitive drugs,
`
`low moisture grades of MCC are available (1.5%, w/w, moisture in Avicel PH 112
`
`and 3%, w/w, moisture in Avicel PH 103, FMC Corp.).” EX1007, 433; EX1002,
`
`¶113.
`
`11 Remington is prior art under at least §102(b).
`
`12 Mihranyan is prior art under at least §102(b).
`
`-18-
`
`

`

`4.
`
`Aulton
`
`Aulton,13 a 2001 reference textbook, teaches standard pharmaceutical
`
`formulation and pre-formulation techniques. EX1029; EX1002, ¶¶114-115. More
`
`specifically, Aulton teaches pre-formulation drug characterization involving