Trials@uspto.gov
`571-272-7822
`
`Paper 15
`Date: January 4, 2023
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`v.
`BAUSCH HEALTH IRELAND LIMITED,
`Patent Owner.
`
`IPR2022-01105
`Patent 9,925,231 B2
`
`
`
`
`
`
`
`
`
`Before SHERIDAN SNEDDEN, CYNTHIA M. HARDMAN, and
`MICHAEL A. VALEK, Administrative Patent Judges.
`HARDMAN, Administrative Patent Judge.
`
`DECISION
`Denying Institution of Inter Partes Review
`35 U.S.C. § 314
`Granting Patent Owner’s Motion to Seal and Enter Default Protective Order
`37 C.F.R. §§ 42.14, 42.54
`
`
`
`
`
`
`
`
`571-272-7822
`
`Paper 15
`Date: January 4, 2023
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`v.
`BAUSCH HEALTH IRELAND LIMITED,
`Patent Owner.
`
`IPR2022-01105
`Patent 9,925,231 B2
`
`
`
`
`
`
`
`
`
`Before SHERIDAN SNEDDEN, CYNTHIA M. HARDMAN, and
`MICHAEL A. VALEK, Administrative Patent Judges.
`HARDMAN, Administrative Patent Judge.
`
`DECISION
`Denying Institution of Inter Partes Review
`35 U.S.C. § 314
`Granting Patent Owner’s Motion to Seal and Enter Default Protective Order
`37 C.F.R. §§ 42.14, 42.54
`
`
`
`
`
`
`
`
`
`IPR2022-01105
`Patent 9,925,231 B2
`
`I.
`INTRODUCTION
`Petitioner Mylan Pharmaceuticals Inc. requests inter partes review of
`claims 1–12 of U.S. Patent No. 9,925,231 B2 (“the ’231 patent,” Ex. 1001).
`Paper 2 (“Pet.”). Patent Owner Bausch Health Ireland Limited filed a
`Preliminary Response. Paper 7 (“Prelim. Resp.”); Paper 3, 1. The parties
`also filed authorized additional briefing concerning discretionary denial
`under 35 U.S.C. § 325(d). Papers 12, 14.
`Considering the arguments and evidence of record, we determine that
`the Petition does not demonstrate “a reasonable likelihood that [P]etitioner
`would prevail with respect to at least 1 of the claims challenged in the
`petition.” 35 U.S.C. § 314(a). Accordingly, we do not institute an inter
`partes review.
`A.
`Real Parties in Interest
`Petitioner identifies itself, Mylan Laboratories Ltd., Mylan Inc., and
`Viatris Inc. as real parties in interest. Pet. 3–4.
`Patent Owner identifies itself and Salix Pharmaceuticals, Inc. as real
`parties in interest. Paper 3, 1.
`B.
`Related Matters
`The parties state that the ’231 patent is involved in Bausch Health
`Ireland Ltd. v. Mylan Laboratories Ltd., 1-22-cv-00020 (N.D. W.Va.); 2-21-
`cv-00573 (W.D. Pa. (administratively closed)); and Bausch Health Ireland
`Ltd. v. MSN Laboratories Pvt. Ltd., 2-21-cv-10057 (D.N.J.). Pet. 4; Paper 3,
`2–3. Patent Owner additionally identifies Bausch Health Ireland Ltd. v.
`Mylan Laboratories Ltd., 1-21-cv-00611 (D. Del.) (closed), and 2:21-cv-
`10403 (D.N.J.) (transferred to N.D. W.Va.). Paper 3, 2–3.
`Patent Owner also identifies the following inter partes reviews
`involving patents related to the ’231 patent: IPR2022-00722 (U.S. Patent
`
`2
`
`
`
`IPR2022-01105
`Patent 9,925,231 B2
`No. 7,041,786 B2); IPR2022-01102 (U.S. Patent No. 9,610,321 B2);
`IPR2022-01103 (U.S. Patent No. 9,616,097 B2); and IPR2022-01104 (U.S.
`Patent No. 9,919,024 B2).
`C.
`The ’231 Patent1
`The ’231 patent, titled “Formulations of Guanylate Cyclase C
`Agonists and Methods of Use,” relates to pharmaceutical formulations
`containing guanylate cyclase-C (“GCC”) agonist peptides, including those
`described in U.S. Patent No. 7,041,786.2 Ex. 1001, code (54), 1:30–32,
`3:20–22, 7:15–16. According to the Specification, formulating “peptides for
`pharmaceutical delivery presents a number of special problems,” including
`chemical and physical stability problems due to the peptides degrading by a
`variety of mechanisms. Id. at 3:24–29.
`The Specification describes exemplary pharmaceutical formulations
`containing “GCC agonist peptides formulated with one or more excipients
`such that the peptide is stabilized against chemical degradation.” Id. at
`8:34–36. “The ideal excipient or combination of excipients will be non-
`hygroscopic, have few or no reducing sugars, and be substantially free of
`
`
`1 The ’231 patent claims priority to a series of applications, including
`PCT/US2011/051805, filed September 15, 2011, and three provisional
`applications filed in 2010. Ex. 1001, codes (63), (60). Petitioner asserts that
`during prosecution, the Examiner concluded that the provisional applications
`did not disclose all claim limitations, and that effective filing date of the
`claims under examination was September 15, 2011, the filing date of the
`PCT application. Pet. 10–11. Here, Petitioner assumes, and Patent Owner
`does not dispute, that the priority date of the challenged claims is September
`15, 2011. Id.; Prelim. Resp. 40. We similarly assume that the priority date
`of the challenged claims is September 15, 2011.
`2 U.S. Patent No. 7,041,786 appears in this record as Shailubhai, Ex. 1005.
`
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`IPR2022-01105
`Patent 9,925,231 B2
`contaminants.” Id. at 8:39–42. Excipients may include carriers and
`lubricants. Id. at 9:33–65, 12:10–14, 13:3. One example formulation
`includes a GCC agonist peptide, an inert carrier, e.g., low-moisture
`microcrystalline cellulose (Avicel PH 112), and a lubricant, e.g., magnesium
`stearate. Id. at 18:13–30, 94:20–33 (Example 14).
`The exemplary formulations include the GCC agonist peptide
`designated SP-304. Id. at 94:10. SP-304, also known as plecanatide, has the
`amino acid sequence shown in SEQ ID NO:1. Id. at 6:63–64, 7:21–25,
`21:37, 23:20–23.
`D.
`The Challenged Claims
`Petitioner challenges all 12 claims of the ’231 patent. Claim 1, the
`only independent claim, reads:
`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.
`Ex. 1001, 249:31–36.
`
`Challenged dependent claims 2–12 depend directly from claim 1 and
`recite additional features. For example, claims 2, 3, and 5 add limitations
`regarding purity, stability, and excluding acids. Id. at 249:37–42, 249:46–
`250:32. Claims 4, 6, and 7 further limit the formulation and its packaging.
`Id. at 249:43–45, 250:33–36. Claims 8–9 and 10–12 further limit the
`lubricant and inert carrier, respectively. Id. at 250:37–46.
`E.
`The Asserted Grounds of Unpatentability
`Petitioner asserts that claims 1–12 are unpatentable on the following
`five grounds:
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`4
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`IPR2022-01105
`Patent 9,925,231 B2
`Claim(s)
`Challenged
`1, 2, 4–12
`
`Ground
`1
`
`2
`
`3
`4
`5
`
`3
`
`1, 2, 4–6, 8–12
`3
`7
`
`35 U.S.C.
`§3
`103(a)
`
`103(a)
`
`103(a)
`103(a)
`103(a)
`
`Reference(s)/Basis
`Shailubhai,4 Remington,5
`Mihranyan6
`Shailubhai, Remington,
`Mihranyan, Aulton7
`2009 Abstract,8 Doelker9
`2009 Abstract, Doelker, Aulton
`2009 Abstract, Doelker,
`Zimmer10
`
`
`3 The Leahy-Smith America Invents Act, Pub. L. No. 112-29, 125 Stat. 284
`(2011) (“AIA”), amended several provisions of 35 U.S.C., including § 103.
`Because the assumed priority date for the challenged claims of September
`15, 2011 (see supra n.1) is before the effective date of the applicable AIA
`amendments, we refer to the pre-AIA version of 35 U.S.C. § 103.
`4 Shailubhai et al., U.S. Patent No. 7,041,786 B2, issued May 9, 2006
`(“Shailubhai,” Ex. 1005).
`5 Rudnic, Chapter 45: Oral Solid Dosage Forms, in REMINGTON: THE
`SCIENCE AND PRACTICE OF PHARMACY 21st ed. (2005) (“Remington,”
`Ex. 1006).
`6 Mihranyan et al., Moisture Sorption by Cellulose Powders of Varying
`Crystallinity, 269(2) Int. J. Pharm. 433–442 (2004) (“Mihranyan,”
`Ex. 1007).
`7 Aulton, Pharmaceutics: The Science of Dosage Form Design (2nd ed.
`2001) (“Aulton,” Ex. 1029).
`8 Shailubhai et al., SP-304 to Treat GI Disorders – Effects of a Single, Oral-
`Dose of SP-304 on Safety, Tolerability, Pharmacokinetics and
`Pharmacodynamics in Healthy Volunteers, 136(5) Gastroenterol. A641,
`Abstract W1041 (2009) (“2009 Abstract,” Ex. 1009).
`9 Doelker et al., Morphological, Packing, Flow and Tableting Properties of
`New Avicel Types, 21(6) Drug Dev. Ind. Pharm. 643–661 (1995) (“Doelker,”
`Ex. 1010).
`10 Zimmer et al., WO 2008/106429, published Sept. 4, 2008 (“Zimmer,”
`Ex. 1011).
`
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`IPR2022-01105
`Patent 9,925,231 B2
`Pet. 6–7. Petitioner supports its contentions with the Declarations of
`Graham Buckton, Ph.D. (Ex. 1002, “Buckton Decl.”) and Uwe Christians,
`M.D., Ph.D. (Ex. 1004), among other evidence.
`II. ANALYSIS
`Level of Ordinary Skill in the Art
`A.
`We consider the grounds of unpatentability in view of the
`understanding of a person of ordinary skill in the art at the time of the
`invention. Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966). Petitioner
`contends that as of September 15, 2011 (see supra n.1), a person of ordinary
`skill in the art (sometimes referred to herein as a “skilled artisan”) “had the
`equivalent of a graduate degree in pharmaceutics or a related field, and
`knowledge and experience making oral-dosage formulations. This
`individual could work with other specialists including, e.g., an M.D., clinical
`pharmacologist, and medicinal chemist.” Pet. 11 (citing Buckton Decl.
`¶¶ 81–84). For the purposes of the Preliminary Response, Patent Owner
`does not dispute Petitioner’s proposal. Prelim. Resp. 40–41.
`Because Petitioner’s proposed level of ordinary skill in the art appears
`to be consistent with the cited prior art and is undisputed on this record, we
`adopt it for purposes of this Decision.
`B.
`Claim Construction
`In AIA proceedings we interpret a claim “using the same claim
`construction standard that would be used to construe the claim in a civil
`action under 35 U.S.C. 282(b).” 37 C.F.R. § 42.100(b). In particular, we
`construe the claim “in accordance with the ordinary and customary meaning
`of such claim as understood by one of ordinary skill in the art and the
`prosecution history pertaining to the patent.” Id.
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`IPR2022-01105
`Patent 9,925,231 B2
`Petitioner asserts that the claims do not require any construction, but
`also states that a person of ordinary skill in the art would have understood
`the term “inert low moisture carrier,” which appears in claim 1, to include
`Avicel PH112. Pet. 13. For purposes of the Preliminary Response, Patent
`Owner “does not challenge the claim construction positions set forth in the
`Petition.” Prelim. Resp. 40.
`For purposes of this Decision, we determine that we need not construe
`any claim term. See Realtime Data, LLC v. Iancu, 912 F.3d 1368, 1375
`(Fed. Cir. 2019) (“The Board is required to construe ‘only those terms . . .
`that are in controversy, and only to the extent necessary to resolve the
`controversy.’”) (quoting Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200
`F.3d 795, 803 (Fed. Cir. 1999)).
`C. Obviousness: Legal Standard
`A claim is unpatentable as obvious under 35 U.S.C. § 103(a) if the
`differences between the claimed subject matter and the prior art are such that
`the subject matter, as a whole, would have been obvious at the time the
`invention was made to a person having ordinary skill in the art to which said
`subject matter pertains. See also KSR Int’l Co. v. Teleflex Inc., 550 U.S.
`398, 406 (2007); 35 U.S.C. § 103(a) (2006). The question of obviousness is
`resolved based on underlying factual determinations including: (1) the scope
`and content of the prior art; (2) any differences between the claimed subject
`matter and the prior art; (3) the level of ordinary skill in the art; and (4) any
`objective indicia of nonobviousness. Graham, 383 U.S. at 17–18. An
`obviousness determination requires finding a reason to combine
`accompanied by a reasonable expectation of achieving what is claimed in the
`patent-at-issue. Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821
`F.3d 1359, 1367 (Fed. Cir. 2016). “[A]ny need or problem known in the
`
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`IPR2022-01105
`Patent 9,925,231 B2
`field of endeavor at the time of invention and addressed by the patent can
`provide a reason for combining the elements in the manner claimed.” KSR,
`550 U.S. at 419–20.
`D. Overview of Asserted Prior Art
`1.
`Shailubhai (Ex. 1005)
`Shailubhai is a U.S. patent titled “Guanylate Cyclase Receptor
`Agonists for the Treatment of Tissue Inflammation and Carcinogenesis.”
`Ex. 1005, code (54), 1:14–22. Shailubhai issued on May 9, 2006, and thus is
`prior art to the challenged claims. Id. at code (45).
`Shailubhai discloses peptide agonists of guanylate cyclase receptors
`and their use in treating gastrointestinal inflammatory disorders such as
`Crohn’s disease and ulcerative colitis. Id. at 4:43–61. Shailubhai discloses
`that “[t]he most preferred peptide,” SP304,11 is “defined by SEQ ID NO:20”
`and “gave the greatest enhancement of intracellular cGMP of all the analogs
`tested.” Id. at 5:4–5, 15:57–58.
`Shailubhai discloses that the peptides may be “formulated with
`various excipients,” and “may be administered in solutions, powders,
`suspensions, emulsions, tablets, capsules, transdermal patches, ointments, or
`other formulations” that are “made using methods well known in the art.”
`Id. at 5:24–26, 13:19–30. Shailubhai claims unit dose forms, selected from a
`tablet, capsule, solution, or inhalation formulation, comprising SP304 and
`one or more excipients. Id. at 37:4–6, 38:1–6 (claim 5).
`
`
`11 Petitioner contends, and Patent Owner does not dispute, that SP304 is also
`known as plecanatide. See, e.g., Pet. 7, 22, 45.
`
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`IPR2022-01105
`Patent 9,925,231 B2
`2.
`Remington (Ex. 1006)
`Remington, titled “The Science and Practice of Pharmacy,” is a
`“textbook and reference work for pharmacists, physicians, and other
`practitioners of the pharmaceutical and medical sciences.” Ex. 1006, i, iii.
`Remington was published in 2005, and thus is prior art to the challenged
`claims. Id. at iii.
`Remington explains that “[d]rug substances most frequently are
`administered orally by means of solid dosage forms such as tablets and
`capsules.” Id. at 889. Tablets may be manufactured by direct compression,
`which “consists of compressing tablets directly from powdered material
`without modifying the physical nature of the material itself.” Id. at 901.
`Remington describes microcrystalline cellulose (“MCC,” sold under the
`brand name Avicel) as a common excipient in direct-compression
`formulations. Id. at 891. MCC is water-insoluble but can draw fluid into a
`tablet by capillary action. Id. at 903.
`Remington also teaches that lubricants such as magnesium stearate
`“have a number of functions in tablet manufacture,” including that they
`“prevent adhesion of the tablet material to the surface of the dies and
`punches, reduce interparticle friction, facilitate the ejection of the tablets
`from the die cavity, and may improve the rate of flow of the tablet
`granulation.” Id. at 893.
`3. Mihranyan (Ex. 1007)
`Mihranyan, an article titled “Moisture sorption by cellulose powders
`of varying crystallinity,” describes a study designed “to investigate the
`influence of crystallinity and surface area on the uptake of moisture in
`cellulose powders.” Ex. 1007, 433. Mihranyan was published in 2004, and
`thus is prior art to the challenged claims. Id.
`
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`IPR2022-01105
`Patent 9,925,231 B2
`In its Introduction section, Mihranyan notes that MCC is one of the
`most common tableting excipients and states that “[o]rdinary MCC is
`manufactured with 4–5% (w/w) moisture content (European Pharmacopoeia,
`2002). For 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.).” Id.
`4.
`2009 Abstract (Ex. 1009)
`The 2009 Abstract is titled “SP-304 to Treat GI Disorders - Effects of
`a Single, Oral-Dose of SP-304 On Safety, Tolerability, Pharmacokinetics
`and Pharmacodynamics in Healthy Volunteers.” Ex. 1009, A-641. The
`2009 Abstract was published in 2009, and thus is prior art to the challenged
`claims. Id. at cover page.
`SP-304 is “a synthetic analog of uroguanylin . . . that regulates ion and
`fluid transport in the GI tract.” Id. The 2009 Abstract describes a clinical
`trial wherein a single oral ascending dose of SP-304 was administered to
`healthy volunteers. Id.
`5.
`Doelker (Ex. 1010)
`Doelker is an article titled “Morphological, Packing, Flow and
`Tableting Properties of New Avicel Types.” Ex. 1010, 643. Doelker was
`published in 1995, and thus is prior art to the challenged claims. Id.
`Doelker compares “classical” grades of Avicel MCC to new grades,
`including Avicel PH-112. Id. The products differ in their nominal particle
`size and moisture content. Id. Doelker determines the basic properties of
`the products, then evaluates their compactibility “and the effect of adding a
`hydrophobic lubricant (0.5% magnesium stearate) on the compact strength.”
`Id. Doelker explains that Avicel PH-112 has “the typical particle size
`specifications of Avicel PH-102 (100 μm) but very low moisture content
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`IPR2022-01105
`Patent 9,925,231 B2
`(max. 1.5%) which makes it an ideal excipient for moisture-sensitive
`substances.” Id. at 645. Doelker describes conventional grades of Avicel
`(with the exception of Avicel PH-103) as having too-high water content for
`tablets containing water-sensitive drugs. Id.
`E. Ground 1: Alleged Obviousness over Shailubhai, Remington,
`and Mihranyan
`For Ground 1, Petitioner asserts that claims 1, 2, and 4–12 are
`unpatentable as obvious over Shailubhai, Remington, and Mihranyan.
`Pet. 21–42. Patent Owner disputes Petitioner’s contentions. Prelim. Resp.
`44–58.
`On this record Petitioner has not shown a reasonable likelihood of
`establishing that at least one of the challenged claims is unpatentable as
`obvious over Shailubhai, Remington, and Mihranyan. We focus our analysis
`on claim 1’s recitation of “an inert low moisture carrier.”
`1.
`Brief Summary of Petitioner’s Arguments
`Petitioner argues that a person of ordinary skill in the art would have
`had “good reason” to formulate “Shailubhai’s plecanatide consistent with
`Remington and Mihranyan” to arrive at the formulation recited in claim 1.
`Pet. 21. In brief, Petitioner argues that Shailubhai that teaches plecanatide
`can be formulated as a tablet, and Remington teaches that most
`commercialized tablets are compressed tablets. Id. at 24–25 (citing, e.g.,
`Ex. 1005 (Shailubhai), 5:24–30; Ex. 1006 (Remington), 889, 891; Buckton
`Decl. ¶¶ 139–47; Ex. 1004 (Christians Decl.) ¶¶ 159–60, 64–65). Petitioner
`further argues that a person of ordinary skill in the art would have had good
`reason to use MCC in the tablet, including because it was common excipient
`in compressed tablets, acts as both a carrier and binder, and is partially self-
`lubricating. Id. at 25 (citing, e.g., Buckton Decl. ¶ 101; Ex. 1006
`
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`(Remington), 891–92, 903; Ex. 1007 (Mihranyan), 433); see also id. at 15–
`16 (additionally citing, e.g., Ex. 1029 (Aulton), 136, Table 8.16, 302;
`Ex. 1008 (Excipients Handbook), 130).
`Regarding claim 1’s recitation of “an inert low moisture carrier,”
`Petitioner contends skilled artisans “routinely used low-moisture MCC,”
`such as the Avicel PH 112 taught in Mihranyan, “for moisture-sensitive
`materials.” Id. at 16–17 (citing, e.g., Ex. 1008 (Excipients Handbook), 132
`(disclosing “[s]everal different grades” of MCC); Ex. 1007 (Mihranyan),
`433); id. at 25 (additionally citing Buckton Decl. ¶ 145). Petitioner asserts
`that skilled artisans “recognized low-moisture MCC as a preferred inert
`carrier for direct-compression tableting of peptides” because “[p]eptides
`were generally understood to be susceptible to water-induced degradation.”
`Id. at 17 (citing Ex. 1016 (Lai), 489; Buckton Decl. ¶¶ 102, 104); see also id.
`at 25–26 (arguing that skilled artisans “had good reason to use a low-
`moisture MCC carrier (e.g., Mihranyan’s Avicel PH112) to reduce
`plecanatide’s moisture exposure from tablet excipients because peptides
`generally are subject to moisture-based degradation during storage”) (citing
`Buckton Decl. ¶¶ 143–44, 146–47; Ex. 1016 (Lai), 489; Ex. 1006
`(Remington), 731).
`2.
`Analysis
`Petitioner has not shown a reasonable likelihood of prevailing on
`Ground 1, at least because Petitioner has not sufficiently shown that the cited
`prior art taught or suggested use of “an inert low moisture carrier,” as recited
`in claim 1.
`As an initial matter, we note that Petitioner does not cite any evidence
`suggesting that plecanatide was known to be a moisture-sensitive material.
`See Prelim. Resp. 3. Rather, Petitioner argues that “[p]eptides were
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`generally understood to be susceptible to water-induced degradation.”
`Pet. 17; see also id. at 25 (“peptides generally are subject to moisture-based
`degradation during storage”). To support this contention, Petitioner cites
`Lai, Dr. Buckton’s testimony, and Remington. See id. at 17 (citing Ex. 1016
`(Lai), 489; Buckton Decl. ¶¶ 102, 104); see also id. at 25–26 (additionally
`citing Buckton Decl. ¶¶ 143–44, 146–47; Ex. 1006 (Remington), 731).
`Lai, a review article published in 1999, “summarizes the major
`chemical reactions affecting proteins and peptides in the solid-state” and
`discusses factors that influence these reactions, including “temperature,
`moisture content, excipients, and the physical state of the formulation
`(amorphous vs crystalline).” Ex. 1016 (Lai), Abstr. Petitioner and
`Dr. Buckton do not quote from Lai or indicate any specific portion of Lai
`that supports their positions beyond a bare citation to page 489. That page
`states, among other things, that “[f]actors that may impact the chemical
`stability of proteins and peptides in the solid-state include residual moisture
`and the excipient(s) used in a formulation.” Id. at 489.
`On this record, we find that Petitioner’s reliance on Lai is insufficient
`to carry its burden for institution. Petitioner and Dr. Buckton generically
`cite Lai’s first page (page 489), but fail to articulate any specific reason why
`a skilled artisan would have been motivated to use a low-moisture MCC
`carrier in a peptide formulation (let alone in the claimed plecanatide
`formulation). At most, Lai page 489 is equivocal about the impact of
`moisture on peptides, stating only that, among other factors, moisture “may
`impact the chemical stability of proteins and peptides in the solid-state.” Id.
`(emphasis added). Neither Petitioner nor Dr. Buckton adequately explains
`how this teaching (or any other teaching in Lai) would have informed a
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`person of ordinary skill in the art that peptides were moisture-sensitive,
`thereby motivating use of a low-moisture MCC carrier.
`To be sure, Lai page 489 teaches that moisture content is one of
`several factors (along with temperature, excipients, and the physical state of
`the formulation) that influences chemical reactions affecting peptides in the
`solid state. Id. at Abstr. But other evidence Petitioner cites reflects that
`moisture content is a factor that influences degradation of all drug
`formulations, whether they comprise small molecules or peptides. For
`example, in the context of drug formulations generally, Remington teaches
`that the “presence or absence of moisture is one of the most important
`environmental factors that can affect solid-state stability.” Ex. 1006
`(Remington), 731; see also Buckton Decl. ¶ 143 (quoting same); Pet. 25–26
`(citing same). Similarly, Aulton states: “In general, drug substances
`decompose as a result of the effects of heat, oxygen, light and moisture.”
`Ex. 1029 (Aulton), 9; see also Buckton Decl. ¶ 104 (citing same). Despite
`this global concern with moisture, the record does not suggest the use of
`low-moisture MCC in every tablet formulation, but rather only for moisture-
`sensitive drugs. See Ex. 1007 (Mihranyan), 433 (“Ordinary MCC is
`manufactured with 4-5% (w/w) moisture content,” but “[f]or moisture
`sensitive drugs, low moisture grades of MCC are available.”); Ex. 1010
`(Doelker), 660 (“Avicel PH-112 is indicated for moisture-sensitive drugs”).
`Petitioner has not sufficiently shown that one of ordinary skill in the art
`would have understood plecanatide, or GCC agonist peptides more
`generally, to be moisture-sensitive drugs.
`Indeed, various portions of Lai not cited by Petitioner undercut
`Petitioner’s blanket assertion that the ordinarily skilled artisan would have
`understood that “peptides generally are subject to moisture-based
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`IPR2022-01105
`Patent 9,925,231 B2
`degradation during storage.” Pet. 25. First, Lai recognizes that as compared
`to the solid-state stability of small molecules, the effect of moisture “on the
`solid-state chemical stability of proteins and peptides [is] not as widely
`reported or understood.” Ex. 1016 (Lai), 493; see also Prelim. Resp. 3, 50.
`Second, although Lai states that “[r]esidual moisture is often thought to be
`responsible for protein and peptide chemical instability in the solid-state”
`(Ex. 1016 (Lai), 494), it also “describes instances in which peptides are less
`stable at lower moisture contents” (Prelim. Resp. 50–51 (citing Ex. 1016
`(Lai), 492, 494). Indeed, Lai reports instances in which solid state
`degradation “is accelerated in the low moisture range” (Ex. 1016, 492),
`conditions in which “residual water . . . can suppress a chemical reaction”
`that might otherwise cause degradation (id. at 494), as well as “other types
`of chemical instabilities” that exhibit a “bell-shaped relationship between
`degradation kinetics and moisture content” (id.). Thus, Lai suggests that
`moisture may have a variety of effects depending on the peptide and the
`circumstances of its formulation.
`Given Lai’s more nuanced teachings about the varying effects of
`moisture (which Petitioner does not address), coupled with Petitioner’s
`unexplained, superficial citation to Lai, Petitioner does not sufficiently
`demonstrate for purposes of institution that a skilled artisan would have
`understood plecanatide to be a moisture-sensitive material such that they
`would have been motivated to formulate it with a low-moisture MCC
`carrier. See, e.g., Novartis Pharm. Corp. v. Watson Labs., Inc., 611 F.
`App’x 988, 995–96 (Fed. Cir. 2015) (affirming finding of no motivation to
`add an antioxidant to a formulation where the prior art did not
`unambiguously identify the subject drug as susceptible to oxidative
`degradation). A petition must include “a detailed explanation of the
`
`15
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`IPR2022-01105
`Patent 9,925,231 B2
`significance of the evidence.” 37 C.F.R. § 42.22(a)(2) (emphasis added); see
`also 35 U.S.C. § 312(a)(3) (petition must identify “with particularity . . . the
`evidence that supports the grounds for the challenge to each claim”)
`(emphasis added). Here, the Petition fails to sufficiently explain how Lai
`supports Petitioner’s assertion that “[p]eptides were generally understood to
`be susceptible to water-induced degradation,” particularly given the
`equivocal and sometimes contrary teachings in Lai that the Petition ignores.
`Pet. 17.
`Dr. Buckton’s testimony does not provide the missing explanation.
`He merely repeats the Petition’s statement that Lai teaches “peptides in
`particularly are generally subject to degradation from moisture during
`storage,” without explaining how Lai supports that conclusion. Buckton
`Decl. ¶ 104; see also id. ¶ 144. Dr. Buckton also cites Aulton, but again
`fails to indicate exactly what in Aulton indicates that peptides generally,
`much less plecanatide specifically, are moisture-sensitive. Id. ¶ 144.
`Indeed, the cited page of Aulton does not mention peptides at all. See Ex.
`1029 (Aulton), 9. On this record, Dr. Buckton’s testimony lacks sufficient
`explanation and is not persuasive to support Petitioner’s burden for
`institution. See 37 C.F.R. § 42.65(a) (“Expert testimony that does not
`disclose the underlying facts or data on which the opinion is based is entitled
`to little or no weight.”); Verlander v. Garner, 348 F.3d 1359, 1371 (Fed. Cir.
`2003) (noting that Board has discretion to accord little weight to expert’s
`“broad conclusory statements that it determined were unsupported by
`corroborating references”).
`For at least the reasons discussed above, on this record we are not
`persuaded that Petitioner has shown a reasonable likelihood of establishing
`that claim 1 is unpatentable as obvious over Shailubhai, Remington, and
`
`16
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`IPR2022-01105
`Patent 9,925,231 B2
`Mihranyan. Dependent claims 2 and 4–12 incorporate all of the limitations
`of independent claim 1. Petitioner’s arguments and evidence for these
`dependent claims do not remedy the deficiencies discussed above for
`claim 1. See Pet. 33–42. Accordingly, Petitioner has not demonstrated a
`reasonable likelihood of prevailing on Ground 1.
`F. Ground 3: Alleged Obviousness over 2009 Abstract and
`Doelker
`For Ground 3, Petitioner asserts that claims 1, 2, 4–6, and 8–12 are
`unpatentable under 35 U.S.C. § 103(a) as obvious over the 2009 Abstract
`and Doelker. Pet. 43–59. Patent Owner disputes Petitioner’s contentions.
`Prelim. Resp. 59–68.
`On this record Petitioner has not shown a reasonable likelihood of
`establishing that at least one of the challenged claims is unpatentable as
`obvious over the 2009 Abstract and Doelker. We again focus our analysis
`on claim 1’s recitation of “an inert low moisture carrier.”
`1.
`Brief Summary of Petitioner’s Arguments
`Petitioner argues that a person of ordinary skill in the art “had good
`reason and reasonable expectation of success for formulating the 2009
`Abstract’s peptide into an oral-dosage form as Doelker taught.” Pet. 21–33.
`In brief, Petitioner argues that the 2009 Abstract teaches oral administration
`of SP-304 (plecanatide), while Doelker teaches direct-compression tablets
`consisting of the inert low-moisture carrier Avicel PH112 and the lubricant
`magnesium stearate. See, e.g., Pet. 48, 51. Petitioner reiterates its argument
`from Ground 1 that a person of ordinary skill in the art would have had
`“good reason to use a low-moisture MCC carrier (e.g., Doelker’s Avicel
`PH112) to reduce plecanatide’s moisture exposure from tablet excipients
`because peptides generally are subject to moisture-based degradation during
`
`17
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`IPR2022-01105
`Patent 9,925,231 B2
`storage.” Id. at 47 (citing Buckton Decl. ¶¶ 236–37; Ex. 1016 (Lai), 489;
`Ex. 1006 (Remington), 731); see also id. at 17 (arguing that “[p]eptides were
`generally understood to be susceptible to water-induced degradation” and
`that skilled artisans “recognized low-moisture MCC as a preferred inert
`carrier for direct-compression tableting of peptides”) (citing Ex. 1016 (Lai),
`489; Buckton Decl. ¶¶ 102, 104).
`2.
`Analysis
`For the same reasons discussed above for Ground 1, Petitioner has not
`sufficiently shown that the cited prior art taught or suggested use of “an inert
`low moisture carrier,” as recited in claim 1. Petitioner relies on the same
`rationale already discussed above, namely that a person of ordinary skill in
`the art “had good reason to use a low-moisture MCC carrier . . . because
`peptides generally are subject to moisture-based degradation during
`storage,” and cites the same evidence in support, namely Lai, Dr. Buckton’s
`testimony12, and the general proposition that “moisture is one of the most
`important environmental factors that can effect solid-state stability.”
`Pet. 25–26 (quoting Ex. 1006 (Remington), 731).
`Petitioner’s arguments and evidence are not sufficient for institution
`for the same reasons discussed above for Ground 1. See supra Section
`II.E.2. Petitioner’s arguments and evidence for dependent claims 2, 4–6,
`
`
`12 For the proposition that “peptides generally are subject to moisture-based
`degradation during storage,” Petitioner cites different paragraphs of
`Dr. Buckton’s Declaration for Grounds 1 and 3. See Pet. 25 (citing ¶¶ 143,
`144 for Ground 1), 47 (citing ¶¶ 236, 237 for Ground 3). The citation to
`different paragraphs in the different grounds is immaterial to our analysis,
`because the paragraphs regarding the alleged moisture-based degradation of
`peptides offer the substantially the same opinion and cite the same
`supporting evidence. Compare Buckton Decl. ¶ 144, with id. ¶ 236.
`
`18
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`IPR2022-01105
`Patent 9,925,231 B2
`and 8–12 do not cure the deficiencies discussed above for claim 1. See
`Pet. 54–59. Accordingly, Petitioner has not demonstrated a reasonable
`likelihood of prevailing on Ground 3.
`G. Grounds 2, 4, and 5
`For Grounds 2, 4, and 5, Petitioner respectively asserts that
`(1) dependent claim 3 is unpatentable as obvious over Shailubhai,
`Remington, Mihranyan, and Aulton; (2) dependent claim 3 is unpatentable
`as obvious over the 2009 Abstract, Doelker, and Aulton; and (3) dependent
`claim 7 is unpatentable as
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