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.
`
`IPR2022-01104
`Patent 9,919,024 B2
`
`
`
`
`
`
`
`
`
`Before SHERIDAN K. SNEDDEN, CYNTHIA M. HARDMAN, and
`MICHAEL A. VALEK, Administrative Patent Judges.
`SNEDDEN, 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
`
`
`
`
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`
`
`
`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.
`
`IPR2022-01104
`Patent 9,919,024 B2
`
`
`
`
`
`
`
`
`
`Before SHERIDAN K. SNEDDEN, CYNTHIA M. HARDMAN, and
`MICHAEL A. VALEK, Administrative Patent Judges.
`SNEDDEN, 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
`
`
`
`
`
`
`
`
`
`
`
`IPR2022-01104
`Patent 9,919,024 B2
`
`
`INTRODUCTION
`I.
`A. Background and Summary
`Mylan Pharmaceuticals, Inc. (“Petitioner”) filed a Petition requesting
`an inter partes review of claims 1–16 of U.S. Patent No. 9,919,024 B2 (“the
`’024 patent,” Ex. 1001). Paper 2 (“Pet.”). Bausch Health Ireland Limited
`(“Patent Owner”) filed a Preliminary Response to the Petition. Paper 7
`(“Prelim. Resp.”).
`To institute an inter partes review, we must determine that the
`information presented in the Petition shows “a reasonable likelihood that the
`petitioner would prevail with respect to at least 1 of the claims challenged in
`the petition.” 35 U.S.C. § 314(a) (2018). The Supreme Court has held that a
`decision to institute under 35 U.S.C. § 314 may not institute on less than all
`claims challenged in the petition. SAS Inst., Inc. v. Iancu, 138 S. Ct. 1348,
`1359–60 (2018). After considering the evidence and arguments presented in
`the Petition, we determine that Petitioner has not demonstrated a reasonable
`likelihood of success in proving that claims 1–16 of the ’024 patent are
`unpatentable.
`B. Real Parties-in-Interest
`Petitioner identifies itself, Mylan Laboratories Ltd., Mylan Inc., and
`Viatris Inc. as real parties-in-interest. Pet. 3.
`Patent Owner identifies itself and Salix Pharmaceuticals, Inc. as real
`parties-in-interest. Paper 3, 2.
`C. Related Matters
`Petitioner has filed petitions for inter partes review involving patents
`related to the ’024 patent in IPR2022-00722 (Patent 7,041,786), IPR2022-
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`01102 (Patent 9,610,321), IPR2022-01103 (Patent 9,616,097), and IPR2022-
`01105 (Patent 9,925,231). Pet. 4; Paper 3, 2–3.
`The parties state that the ’024 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.
`D. The ’024 patent (Ex. 1001)
`The ’024 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. 7,041,786.1 Ex. 1001, code (54), 1:30–32,
`3:19–20, 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 peptide[s] 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
`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
`
`1 U.S. Patent No. 7,041,786 appears in this record as Shailubhai, Ex. 1005.
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`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.
`E. Representative Claims
`Independent claims 1 and 3, reproduced below, are representative of
`the claims challenged in this proceeding.
`1. A method for treating chronic constipation in a human subject
`comprising
`orally administering to said human subject a composition
`consisting of SEQ ID NO:1
`wherein the peptide is a [4,12; 7,15] bicycle, an inert low
`moisture carrier, and a lubricant, and
`wherein the peptide has a chromatographic purity of no
`less than 91% after storage for at least three months.
`3. A method of treating or alleviating a symptom associated with
`chronic idiopathic constipation or irritable bowel syndrome in a
`human subject comprising
`orally administering to said human subject a composition
`consisting of SEQ ID NO:1
`wherein the peptide is a [4,12; 7,15] bicycle, an inert low
`moisture carrier, and a lubricant, and
`wherein the peptide has a chromatographic purity of no
`less than 91% after storage for at least three months.
`Ex. 1001, 227:47–53, 227:58–65.
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`Challenged dependent claims 2, 5–7, and 11–13 depend directly or
`indirectly from claim 1. Challenged dependent claims 4, 8–10, and 14–16
`depend directly or indirectly from claim 3.
`F. Asserted Grounds of Unpatentability
`Petitioner asserts that claims 1–16 are unpatentable on the following
`four grounds:
`
`Ground
`1
`
`Claim(s)
`35 U.S.C. §
`Challenged
`1–6, 8–9, 11–16 103(a)
`
`2
`
`3
`4
`
`7, 10
`
`1–4, 11–16
`5–10
`
`103(a)
`
`103(a)
`103(a)
`
`Reference(s)/Basis
`Shailubhai,2 Camilleri,3
`Remington,4 Mihranyan5
`Shailubhai, Camilleri,
`Remington, Mihranyan,
`Currie6
`2009 Abstract,7 Doelker8
`2009 Abstract, Doelker, Currie
`
`
`2 Shailubhai et al., U.S. Patent No. 7,041,786 B2, issued May 9, 2006
`(“Shailubhai,” Ex. 1005).
`3 Camilleri et al., Challenges to the Therapeutic Pipeline for Irritable Bowel
`Syndrome: End Points and Regulatory Hurdles, GASTROENTEROL., 135,
`1877–1891 (2008) (“Camilleri,” Ex. 1031).
`4 Rudnic, Chapter 45: Oral Solid Dosage Forms, in REMINGTON: THE
`SCIENCE AND PRACTICE OF PHARMACY 21st ed. (2005) (“Remington,”
`Ex. 1006).
`5 Mihranyan et al., Moisture Sorption by Cellulose Powders of Varying
`Crystallinity, 269(2) Int. J. Pharm. 433–442 (2004) (“Mihranyan,”
`Ex. 1007).
`6 Currie et al., U.S. Patent Application Publication No. 2005/0020811,
`published Jan. 27, 2005 (“Currie,” Ex. 1032).
`7 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).
`8 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).
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`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
`A. Level of Ordinary Skill in the Art
`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, a person of ordinary skill in the art
`(sometimes referred to herein as a “skilled artisan”) had an M.D.” or “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., a . . . clinical
`pharmacologist, and medicinal chemist.” Pet. 11 (citing Ex. 1002 ¶¶ 81–84).
`For the purposes of the Preliminary Response, Patent Owner does not
`dispute Petitioner’s proposal. Prelim. Resp. 41–42.
`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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`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. Patent Owner does not challenge the claim
`construction positions set forth in the Petition. See generally Prelim. Resp.
`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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`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,” SP304,9 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).
`
`
`9 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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`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 892–893.
`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
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`cellulose powders.” Ex. 1007, 433. Mihranyan was published in 2004, and
`thus is prior art to the challenged claims. Id.
`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. at A-641. 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
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`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
`(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.
`6. Camilleri (Ex. 1031)
`Camilleri is a review article, titled “Challenges to the Therapeutic
`Pipeline for Irritable Bowel Syndrome: End Points and Regulatory Hurdles.”
`Ex. 1031, 1877. Table 1 of Camilleri lists “[s]everal of the drugs in
`development that are in ongoing or planned clinical trials for [Irritable
`Bowel Syndrome (IBS)].” Id. at 1877–78. Guanilib (plecanatide) is
`indicated as in a phase I clinical trial. Id.
`Camilleri additionally discloses linaclotide, a related GCC-agonist
`peptide, for treating both chronic constipation and IBS given its ability to
`increase intestinal water and electrolyte secretion in the GI tract. Id. at 1879,
`Table 2.
`7. Currie (Ex. 1032)
`Currie discloses linaclotide, the active ingredient of Linzess. Currie
`discloses administering GCC-agonist peptides for the treatment of IBS and
`chronic constipation. Ex. 1032 ¶¶ 41, 97. Currie also discloses co-
`administration with other therapeutic agents, including laxatives and cGMP
`phosphodiesterase inhibitors (e.g., motapizone, zaprinast, suldinac sulfone).
`Id. ¶ 11.
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`E. Ground 1: Alleged Obviousness over Shailubhai, Camilleri, Remington,
`and Mihranyan
`For Ground 1, Petitioner asserts that claims 1–6, 8–9, and 11–16 are
`unpatentable as obvious over Shailubhai, Camilleri, Remington, and
`Mihranyan. Pet. 21–43. Patent Owner disputes Petitioner’s contentions.
`Prelim. Resp. 47–69.
`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, Camilleri, Remington, and Mihranyan. We focus
`our analysis on the recitation of “an inert low moisture carrier” in the
`independent claims.
`1. Brief Summary of Petitioner’s Arguments
`Petitioner argues that treating chronic constipation by orally
`administering plecanatide to a human subject would have been obvious in
`view of Shailubhai and Camilleri, which in combination disclose
`administering an oral-dosage form of a GCC-agonist peptide consisting of
`SEQ ID NO:1, where the peptide is a (4,12; 7,15) bicycle for the treatment
`of IBS with Constipation (IBS-C). Pet. 23–25 (citing Ex. 1005, 5:4–15,
`10:66–67, 35:8–25; Ex. 1031, 1878; Ex. 1002 ¶¶ 518, 412–413; Ex. 1004
`¶¶ 51–56).
`Petitioner also 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, for treating chronic constipation”
`to arrive at the method recited in independent claims 1 and 3. Pet. 21–22
`(claim 1), 36 (claim 3). In brief, Petitioner argues that Shailubhai teaches
`that plecanatide can be formulated as a tablet, and Remington teaches that
`most commercialized tablets are compressed tablets. Id. at 26–28 (citing,
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`e.g., Ex. 1005 (Shailubhai), 5:24–30; Ex. 1006 (Remington), 889, 891;
`Ex. 1002 ¶¶ 140–41; Ex. 1004 (Christians Decl.) ¶¶ 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 26 (citing, e.g., Ex. 1002 ¶ 101; Ex. 1006 (Remington),
`891–92, 903; Ex. 1007 (Mihranyan), 433); see also id. at 15–17 (citing, e.g.,
`Ex. 1029 (Aulton), 136, Table 8.16, 302; Ex. 1008 (Excipients Handbook),
`130).
`Regarding the independent claims’ 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), 27 (citing Ex. 1002 ¶ 145); Ex. 1001,
`claims 1, 3. 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; Ex. 1002
`¶¶ 102, 104); see also id. at 28 (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 Ex. 1002 ¶¶ 143–44, 146–47; Ex. 1016 (Lai), 489; Ex. 1006
`(Remington), 731); see also Pet. 36 (“The same combination discussed [with
`regard to claim 1] also rendered [claim 3] obvious.”).
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`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 independent claims 1 and 3.10
`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
`generally understood to be susceptible to water-induced degradation.”
`Pet. 17; see also id. at 27 (“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; Ex. 1002 ¶¶ 102, 104); see also id. at 27 (citing Ex. 1002 ¶¶ 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
`
`
`10 Claims 1 and 3 recite distinct methods of using the same composition. See
`supra § I.E.; see also Pet. 54 (“Independent claim 3 differs from claim 1
`only in the claim preamble.”). As our analysis primarily addresses the
`sufficiency of Petitioner’s challenge with regard to the recited composition,
`we focus, for brevity, our analysis on claim 1 given the relevant overlap in
`the scope and subject matter recited in independent claims 1 and 3.
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`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
`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 Ex. 1002 ¶ 143 (quoting same); Pet. 27 (citing
`same). Similarly, Aulton states: “In general, drug substances decompose as
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`a result of the effects of heat, oxygen, light and moisture.” Ex. 1029
`(Aulton), 9; see also Ex. 1002 ¶ 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
`degradation during storage.” Pet. 27. 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, 54.
`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. 53 (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
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`IPR2022-01104
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`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
`demonstrates 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
`significance of the evidence.” 37 C.F.R. § 42.22(a)(2) (emphasis added); see
`also 35 U.S.C. § 312(a)(3) (the 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
`particular are generally subject to degradation from moisture during
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`storage,” without explaining how Lai supports that conclusion. Ex. 1002
`¶ 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.”);
`Velander v. Garner, 348 F.3d 1359, 1371 (Fed. Cir. 2003) (noting that the
`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, Camilleri,
`Remington, and Mihranyan. Dependent claims 2, 4–6, 8–9, and 11–16
`incorporate all of the limitations of independent claims 1 and 3. Petitioner’s
`arguments and evidence for these dependent claims do not remedy the
`deficiencies discussed above for claims 1 and 3. See Pet. 35–42.
`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 1–4 and 11–16 are
`unpatentable under 35 U.S.C. § 103(a) as obvious over the 2009 Abstract
`
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`IPR2022-01104
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`and Doelker. Pet. 43–57. Patent Owner disputes Petitioner’s contentions.
`Prelim. Resp. 62–69.
`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 the recitation of “an inert low moisture carrier” in independent claims 1
`and 3.
`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 administering 2009
`Abstract’s peptide, formulated as Doelker taught, for treating chronic
`constipation.” Pet. 43. In brief, Petitioner argues that the 2009 Abstract
`teaches oral administration of SP-304 (plecanatide) for treating chronic
`constipation, while Doelker teaches direct-compression tablets consisting of
`the inert low-moisture carrier Avicel PH112 and the lubricant magnesium
`stearate. See, e.g., Pet. 44–47. 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
`storage.” Id. at 46 (citing Ex. 1002 ¶¶ 236–38; 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; Ex. 1002 ¶¶ 102, 104).
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`2. Analysis
`For the same reasons discussed above for
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