Trials@uspto.gov
`571-272-7822
`
`Paper No. 78
`Date: September 8, 2023
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`MYLAN PHARMACEUTICALS, INC., MSN LABORATORIES
`PRIVATE LTD. and MSN PHARMACEUTICALS INC.,
`Petitioners,
`
`v.
`
`BAUSCH HEALTH IRELAND LIMITED,
`Patent Owner.
`
`IPR2022-007221
`Patent 7,041,786 B2
`
`
`
`
`
`
`
`
`
`
`Before TINA E. HULSE, CYNTHIA M. HARDMAN, and
`MICHAEL A. VALEK, Administrative Patent Judges.
`
`VALEK, Administrative Patent Judge.
`
`
`
`JUDGMENT
`Final Written Decision
`Determining No Challenged Claims Unpatentable
`35 U.S.C. § 318(a)
`Granting-in-Part Patent Owner’s Motion to Exclude
`Denying Petitioner’s Motion to Exclude
`37 C.F.R. § 42.64(c)
`
`
`
`
`
`1 IPR2023-00016 has been joined with this proceeding.
`
`
`
`
`571-272-7822
`
`Paper No. 78
`Date: September 8, 2023
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`MYLAN PHARMACEUTICALS, INC., MSN LABORATORIES
`PRIVATE LTD. and MSN PHARMACEUTICALS INC.,
`Petitioners,
`
`v.
`
`BAUSCH HEALTH IRELAND LIMITED,
`Patent Owner.
`
`IPR2022-007221
`Patent 7,041,786 B2
`
`
`
`
`
`
`
`
`
`
`Before TINA E. HULSE, CYNTHIA M. HARDMAN, and
`MICHAEL A. VALEK, Administrative Patent Judges.
`
`VALEK, Administrative Patent Judge.
`
`
`
`JUDGMENT
`Final Written Decision
`Determining No Challenged Claims Unpatentable
`35 U.S.C. § 318(a)
`Granting-in-Part Patent Owner’s Motion to Exclude
`Denying Petitioner’s Motion to Exclude
`37 C.F.R. § 42.64(c)
`
`
`
`
`
`1 IPR2023-00016 has been joined with this proceeding.
`
`
`
`
`
`IPR2022-00722
`Patent 7,041,786 B2
`
`I.
`
`INTRODUCTION
`
`Mylan Pharmaceuticals Inc. (“Mylan”) filed a Petition (Paper 1,
`
`“Pet.”), seeking inter partes review of claims 1–6 of U.S. Patent
`
`No. 7,041,786 B2 (Ex. 1001, “the ’786 patent”). We instituted trial on all of
`
`the grounds in the Petition. Paper 16, 32.
`
`Following institution, MSN Laboratories Private Ltd. and MSN
`
`Pharmaceuticals Inc. (collectively “MSN”) filed a substantially identical
`
`petition in IPR2023-00016. That proceeding was instituted and joined with
`
`this one. See Paper 25 (granting joinder). Herein, we refer to Mylan and
`
`MSN collectively as “Petitioner.”2
`
`Bausch Health Ireland Limited (“Patent Owner”) then filed a
`
`Response (Paper 70,3 “Resp.”), Petitioner filed a Reply (Paper 38, “Reply”),
`
`and Patent Owner filed a Sur-reply (Paper 71, “Sur-reply”). We held a
`
`hearing on June 14, 2023, and a transcript is of record. Paper 75 (“Tr.”). In
`
`addition, both Parties have filed motions to exclude certain exhibits. Paper
`
`53 (“PO MTE”); Paper 67 (“Pet. MTE”).
`
`After considering the parties’ arguments and evidence, we find that
`
`Petitioner has not shown by a preponderance of the evidence that the
`
`challenged claims of the ’786 patent are unpatentable. See 35 U.S.C.
`
`§ 316(e). Moreover, as explained below, we grant Patent Owner’s motion to
`
`exclude in part and deny Petitioner’s motion to exclude.
`
`
`2 MSN has agreed to an “understudy role” in this proceeding. See
`IPR2023-00016, Paper 14.
`3 Portions of Patent Owner’s Response and Sur-reply were initially filed
`under seal. See Papers 28 and 51. Patent Owner has since filed unredacted
`versions that we refer to herein. See Paper 73 (Patent Owner agreeing to
`make these papers public).
`
`2
`
`
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`IPR2022-00722
`Patent 7,041,786 B2
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`II. BACKGROUND
`
`A. Real Parties in Interest
`
`In addition to itself, Mylan identifies the following real parties in
`
`interest (“RPI”): Mylan Inc. and Viatris Inc. See Paper 9, 2 (identifying
`
`these entities as parent companies); Paper 16, 31 (accepting Petitioner’s
`
`representation that these entities are RPI). MSN identifies MSN Laboratories
`
`Private Limited and MSN Pharmaceuticals, Inc. as RPI. IPR2023-00016,
`
`Paper 16, 2. Patent Owner identifies itself and Salix Pharmaceuticals, Inc. as
`
`RPI. Paper 4, 2.
`
`B. The ’786 Patent
`
`The ’786 patent issued on May 9, 2006, from a utility application filed
`
`on March 28, 2002, and claims priority to a provisional application filed on
`
`January 17, 2002. Ex. 1001, codes (22), (45), (60).
`
`The ’786 patent is titled “Guanylate Cyclase Receptor Agonists for
`
`the Treatment of Tissue Inflammation and Carcinogenesis.” Ex. 1001, code
`
`(54). According to the Specification,
`
`[t]he present invention relates to the therapeutic use of
`guanylate cyclase receptor agonists as a means for enhancing
`the intracellular production of cGMP. The agonists may be used
`either alone or in combination with inhibitors of cGMP-specific
`phosphodiesterase to prevent or treat cancerous, pre-cancerous
`and metastatic growths, particularly in the gastrointestinal tract
`and lungs. In addition, the agonists may be used in the
`treatment of inflammatory disorders such as ulcerative colitis
`and asthma.
`
`Id. at 1:14–23.
`
`The Specification explains that “[u]roguanylin, guanylin and bacterial
`
`ST [i.e., heat-stable enterotoxin] peptides are structurally related peptides
`
`3
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`
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`IPR2022-00722
`Patent 7,041,786 B2
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`that bind to a guanylate cyclase receptor and stimulate intracellular
`
`production of cyclic guanosine monophosphate (cGMP).” Ex. 1001, 1:26–
`
`30. “This results in the activation of the cystic fibrosis transmembrane
`
`conductance regulator (CFTR),” which in turn “leads to stimulation of
`
`sodium and water secretion into the intestinal lumen.” Id. at 1:30–36.
`
`“Therefore, by serving as paracrine regulators of CFTR activity, cGMP
`
`receptor agonists,” such as uroguanylin, guanylin, and bacterial ST peptides,
`
`“regulate fluid and electrolyte transport in the GI tract.” Id. at 1:36–39.
`
`“The present invention is based upon the development of new agonists
`
`of guanylate cyclase receptor” that “are analogs of uroguanylin.” Ex. 1001,
`
`3:3–6. The Specification describes the sequence for its “most preferred”
`
`uroguanylin analog in SEQ ID NO:20, which is reproduced below.
`
`
`
`Id. at 5:7–12. SEQ ID NO:20 provides the primary structure of a 16-amino
`
`acid long peptide. The sequence in SEQ ID NO:20 differs from that of the
`
`“Parent compound: uroguanylin” (shown in SEQ ID NO: 1) in that it has a
`
`“Glu3,” i.e., a glutamic acid (Glu) at position 3 in the peptide sequence,
`
`whereas human uroguanylin has an “Asp3,” i.e., an aspartic acid (Asp) at
`
`that position.4 See id. at 11 (Table 2). This is the only difference between the
`
`
`4 Both parties use a superscript to denote the position of the residue in an
`amino acid sequence. See, e.g., Pet. 1, 38; Resp. 2 (referring to “Glu3” and
`“Asp3”). In addition to Glu, other synonyms for glutamic acid appearing in
`the record include “glutamate” and the letter “E” from the single-letter code
`for amino acids. In addition to Asp, other synonyms for aspartic acid include
`“aspartate” and the letter “D.”
`
`4
`
`
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`IPR2022-00722
`Patent 7,041,786 B2
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`sequence in SEQ ID NO:20 and the naturally–occurring human uroguanylin
`
`sequence in SEQ ID NO:1. Id.; see also Ex. 1002 ¶¶ 24–25.
`
`According to the Specification, the peptide of SEQ ID NO:20
`
`has been found to have enhanced biological activity as an
`agonist of cGMP production due to its enhanced binding
`constant for the guanylate cyclase receptor, and is superior to
`uroguanylin with regard to temperature and protease stability
`and with regard to its biological activity at the physiologically
`favorable pH range (pH 6 to 7) in the large intestine.
`
`Ex. 1001, 5:16–23. Table 4, reproduced below, shows data from a “T84 cell-
`
`based assay for determining the intracellular levels of cGMP.” Id. at 15:35–
`
`36.
`
`“As shown in Table 4, SP304 (SEQ ID NO:20) gave the greatest
`
`enhancement of intracellular cGMP of all the” peptides tested. Id. at 15:53–
`
`58.
`
`5
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`IPR2022-00722
`Patent 7,041,786 B2
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`C. Challenged Claims
`
`The Petition challenges claims 1–6. Claims 1–3 and 6 are independent
`
`claims. They provide as follows:
`
`1. A peptide consisting of the amino acid sequence of SEQ ID
`NO:20.
`
`2. A composition in unit dose comprising a guanylate cyclase
`receptor agonist peptide consisting of the amino acid sequence
`of SEQ ID NO:20.
`
`
`
`
`3. A composition in unit dose form comprising:
`a) a guanylate cyclase receptor agonist peptide consisting
`of the amino acid sequence of SEQ ID NO: 20; and
`b) at least one compound selected from the group
`consisting of: a cGMP-dependent phosphodiesterase inhibitor,
`an anti-inflammatory agent, an antiviral agent and an anticancer
`agent.
`
`6. A peptide conjugate comprising polyethylene glycol (PEG)
`attached to a peptide consisting of the amino acid sequence
`SEQ ID NO:20.
`
`Ex. 1001, 37:1–12, 38:7–9. Claims 4 and 5 additionally limit the
`
`compositions of either claim 2 or 3 to a “dose form . . . selected from the
`
`group consisting of a tablet, a capsule, a solution and an inhalation
`
`formulation” (claim 4) and to further comprise “one or more excipients”
`
`(claim 5). Id. at 38:1–6.
`
`Claim 1 is directed to a peptide with the sequence of SEQ ID NO:20.
`
`The parties’ papers and exhibits refer to this peptide by several names,
`
`including [Glu3]-human uroguanylin, [Glu3]-UG, plecanatide, and SP-304.
`
`See, e.g., Pet. 5 (noting that Patent Owner “markets [Glu3]-human
`
`uroguanylin as TRULANCE® (plecanatide)”); Resp. 1; Ex. 1001, 10:42–63
`
`6
`
`
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`IPR2022-00722
`Patent 7,041,786 B2
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`(referring to the Glu3-substituted analog of human uroguanylin as SP304).
`
`Plecanatide “is the active pharmaceutical ingredient in Trulance®, which is
`
`FDA-approved for the treatment of chronic idiopathic constipation . . . and
`
`irritable bowel syndrome with constipation.” Resp. 1; see also Pet. 5.
`
`(similar); Ex. 1055 (prescribing information for “TRULANCE (plecanatide)
`
`tablets”).
`
`D. Asserted Grounds of Unpatentability
`
`Petitioners assert the following grounds of unpatentability:
`
`Claim(s) Challenged 35 U.S.C. §5
`1
`103(a)
`2, 4, 5
`103(a)
`3–5
`103(a)
`6
`103(a)
`
`Reference(s)/Basis
`Currie6, Li7
`Currie, Li, Narayani8
`Currie, Li, Narayani, Campieri9
`Currie, Li, Ekwuribe10
`
`
`
`In support of these grounds, Petitioner relies on declarations from
`
`Blake R. Peterson, Ph.D. submitted with the Petition (Ex. 1002) and Reply
`
`(Ex. 1063) and a declaration from Michael S. Epstein, M.D. (Ex. 1064).
`
`
`5 The Leahy-Smith America Invents Act, Pub. L. No. 112–29, 125 Stat. 284
`(2011) (“AIA”), included revisions to 35 U.S.C. § 103 that became effective
`after the filing of the application that led to the ’786 patent. Therefore, we
`apply the pre-AIA version of 35 U.S.C. § 103.
`6 U.S. Pat. 5,489,670, issued Feb. 6, 1996 (Ex. 1005) (“Currie”).
`7 Z. Li et al., Purification, cDNA Sequence, and Tissue Distribution of Rat
`Uroguanylin, 68 Regulatory Peptides 45–56 (1997) (Ex. 1006) (“Li”).
`8 R. Narayani et al., Polymer-coated Gelatin Capsules as Oral Delivery
`Devices and their Gastrointestinal Tract Behavior in Humans, 7 J.
`Biomater. Sci. Polymer Edn. 39–48 (1995) (Ex. 1007) (“Narayani”).
`9 M. Campieri et al., Oral Budesonide is as Effective as Oral Prednisolone
`in Active Crohn’s Disease, 41 Gut 209–214 (1997) (Ex. 1008) (“Campieri”).
`10 U.S. Pat. 5,359,030, issued Oct. 25, 1994 (Ex. 1009) (“Ekwruibe”).
`
`7
`
`
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`IPR2022-00722
`Patent 7,041,786 B2
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`Patent Owner relies on declarations from Kunwar Shailubhai (Ex. 2023,
`
`Ex. 2066), Stephen G. Davies (Ex. 2024), and Scott A. Waldman (Ex. 2025).
`
`III. ANALYSIS OF THE ASSERTED GROUNDS
`
`A. Legal Standards
`
`Under pre-AIA § 103(a), a claim is unpatentable for obviousness if, to
`
`one of ordinary skill in the pertinent art, “the differences between the subject
`
`matter sought to be patented and the prior art are such that the subject matter
`
`as a whole would have been obvious at the time the invention was made.”
`
`35 U.S.C. § 103(a) (2006); see also KSR Int’l Co. v. Teleflex Inc., 550 U.S.
`
`398, 406 (2007). The question of obviousness is resolved on the basis of
`
`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) when in evidence,
`
`objective evidence of nonobviousness. Graham v. John Deere Co., 383 U.S.
`
`1, 17–18 (1966).
`
`B. Level of Ordinary Skill in the Art
`
`
`
`Relying on the testimony of its declarant, Dr. Peterson, Petitioner
`
`contends that as of January 17, 2002:
`
`A skilled artisan would have been familiar with signaling
`peptides and their biochemistry, as the accompanying exhibits
`prove. The specification admits an artisan would also have
`known how to choose and prepare various dosage forms when
`it notes the use of known alternatives without further guidance
`on when and how to use them. A Ph.D. in peptide chemistry,
`protein engineering, or a related field, or alternatively, a
`master’s degree in one of these fields plus two to five years of
`experience in drug development would represent typical
`education and experience for a skilled artisan. EX1002,
`
`8
`
`
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`IPR2022-00722
`Patent 7,041,786 B2
`
`¶¶40-43. This individual would have worked in consultation
`with a team including, e.g., a pharmaceutical chemist and/or a
`pharmacist familiar with formulating peptides for
`administration.
`
`Pet. 13.
`
`
`
`Patent Owner contends that a person of ordinary skill in the art
`
`(“POSA”)
`
`would have a B.S. degree in chemistry or a related field and 2-5
`years of experience in drug development that could include
`experience with peptide chemistry and/or peptide engineering.
`The POSA could also include individuals having a master’s
`degree or Ph.D. in chemistry or a related field with
`comparatively less experience in drug development involving
`peptide chemistry and/or peptide engineering. The POSA could
`have worked in consultation with individuals with knowledge
`and experience with the target drug receptor and of the disease
`condition to be treated. In particular, this team could include a
`clinical pharmacologist with experience with the target drug
`receptor (here, GCC receptors) or a medical doctor with
`experience in treating GI disorders, who may also have
`experience designing and running clinical trials, or a
`pharmaceutical formulator.
`
`Resp. 25–26 (citing Ex. 2024 ¶¶ 30–32). However, Patent Owner’s
`
`expert states his analysis and conclusion would be the same under
`
`Petitioner’s definition of a POSA. Ex. 2024 ¶ 32.
`
`
`
`The parties’ descriptions of a POSA are substantially similar.
`
`Indeed, neither side identifies any meaningful distinction between the
`
`two. Because we find Petitioner’s description of the level of ordinary
`
`skill in the art to be sufficiently supported by the record, we apply it
`
`for our analysis. That said, if we applied Patent Owner’s description,
`
`all of our findings and conclusions would be the same.
`
`9
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`IPR2022-00722
`Patent 7,041,786 B2
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`C. Claim Construction
`
`Petitioner asserts that “[t]he claim terms do not require construction to
`
`apply the grounds.” Pet. 14. Patent Owner does not respond to this
`
`contention, or otherwise address claim construction in its Response.
`
`Accordingly, neither party has identified any claim term for construction.
`
`We agree that no formal claim construction is necessary for purposes
`
`of our Decision. See Nidec Motor Corp. v. Zhongshan Broad OceanMotor
`
`Co., 868 F.3d 1013, 1017 (Fed. Cir. 2017) (explaining that it is only
`
`necessary to “construe 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))).
`
`D. Overview of the Cited References
`
`i. Currie
`
`
`
`Currie is a United States Patent that was issued on February 6, 1996.
`
`Ex. 1005, code (45). Petitioner contends, and Patent Owner does not dispute,
`
`that Currie qualifies as prior art under 35 U.S.C. § 102(b). Pet. 22.
`
`Currie describes human uroguanylin. Ex. 1005, 1:47–63. Currie
`
`discloses the amino acid sequence for human uroguanylin in SEQ ID NO:1,
`
`which is reproduced below.
`
`Id. at 1:50–55. The peptide shown in SEQ ID NO:1 of Currie is 16 amino
`
`acids long and has an Asp3.
`
`
`
`10
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`
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`IPR2022-00722
`Patent 7,041,786 B2
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`
`
`Currie teaches that human uroguanylin “is an endogenous stimulator
`
`of intestinal guanylate cyclase” and “has been found to stimulate increases in
`
`cyclic GMP levels in a manner similar to guanylin and the STs.”11 Ex. 1005,
`
`2:6–8. Currie describes tests in which human uroguanylin “caused a
`
`concentration-dependent increase in T84 cell cyclic GMP” and “appeared to
`
`be more potent than human guanylin, but less potent than ST.” Id. at 6:11–
`
`14, Fig. 3A.12 Currie also describes the results of a “competitive binding
`
`assay” showing “ST and human uroguanylin had similar affinities for the
`
`receptors on T84 cells and human guanylin had a much lower affinity.” Id. at
`
`6:16–19, Fig. 3B. According to Currie these and other results described
`
`therein, suggest “human uroguanylin may . . . act as a laxative and be useful
`
`in patients suffering from constipation, e.g., cystic fibrosis patients who
`
`suffer severe intestinal complications from constipation.” Id. at 2:20–24.
`
`ii.
`
`Li
`
`Li is an article from a scientific journal bearing a 1997 publication
`
`date. Ex. 1006, 45. Petitioner contends, and Patent Owner does not dispute,
`
`that Li qualifies as prior art under 35 U.S.C. § 102(b). Pet. 24.
`
`Li describes the amino acid sequence for rat uroguanylin, explaining it
`
`has “high homology with uroguanylin” from humans and opossum
`
`uroguanylin. Ex. 1006, Abstr. Figure 6a of Li, reproduced below, is a
`
`
`11 Currie explains that “STs” are a “family of heat stable enterotoxins”
`produced by E. coli and other bacteria “that activate intestinal guanylate
`cyclase” and “cause secretory diarrhea.” Ex. 1005, 1:31–39.
`12 Although it refers to “Fig. 4a” and “Fig. 4b,” the results Currie describes
`appear to be those shown in Figures 3A and 3B. Compare Ex. 1005, 6:11–
`22, with id. at Figs. 3A–B.
`
`11
`
`
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`sequence alignment comparing the amino acid sequences of uroguanylins,
`
`guanylins and ST from different species.
`
`
`
`Id. at 52. Figure 6a shows the sequence for rat uroguanylin (first row)
`
`aligned with the sequences for opossum uroguanylin (second row) and
`
`human uroguanylin (third row), with shading added to indicate “amino acid
`
`identities” (i.e., positions where the sequences have the same amino acid).
`
`Id. The alignment in Figure 6a shows that human and opossum uroguanylin
`
`have an aspartic acid (D) residue at position 3 in those sequences, whereas
`
`rat uroguanylin has a glutamic acid (E) at the corresponding position. Figure
`
`6a also depicts “stippled arrowheads,” i.e., gray triangles, above the residues
`
`at positions 2 and 3 and a “solid arrowhead,” i.e., a black triangle, above the
`
`residue at position 9. See id. at 54 (left column). Li explains that these
`
`“arrowheads denote structural features described in the text.”
`
`
`
`Li teaches that
`
`[t]he affinity of GCC [i.e., guanylate cyclase type C
`
`receptor] for uroguanylin (opossum or human) is about 10-fold
`higher than its affinity for guanylin (rat or human). Thus,
`features that are found in uroguanylin, but not in guanylin, offer
`information about structural elements that specify the strength
`of the ligand/receptor interaction. Of particular interest are two
`residues that are basic or uncharged in guanylin but acidic in
`uroguanylin (stippled arrowheads), and one residue that
`contains an aromatic ring in guanylin but an acidic amide in
`uroguanylin (solid arrowhead).
`
`12
`
`
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`IPR2022-00722
`Patent 7,041,786 B2
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`Ex. 1006, 54 (left column). Li explains that rat uroguanylin “follows the
`
`consensus sequence of uroguanylin rather than that of guanylin” “[a]t all
`
`three positions” denoted by the arrowheads in Figure 6a “and thus we would
`
`expect its affinity to be comparable to that of opossum or human
`
`uroguanylin.” Id.
`
`iii. Narayani
`
`Narayani is an article from a scientific journal bearing a 1995
`
`publication date. Ex. 1007, 39. Petitioner contends, and Patent Owner does
`
`not dispute, that Narayani qualifies as prior art under 35 U.S.C. § 102(b).
`
`Pet. 26.
`
`Narayani describes tests of polymer-coated gelatin capsules. Ex. 1007,
`
`Abstr. Narayani explains that
`
`[g]elatin capsules were coated with various concentrations of
`sodium alginate and cross-linked with appropriate
`concentrations of calcium chloride and tested in vitro for
`resistance to gastric and intestinal medium. Gelatin capsules
`coated with 20% w/v of the polymer which gave the most
`promising result in vitro were evaluated in human volunteers
`for their in vivo gastro intestinal tract behavior.
`
`Id. Narayani teaches that “the alginate coated gelatin capsules remained
`
`intact as long as they were retained in the stomach (up to 3 h) and then
`
`migrated to the ileocecal region of the intestine and disintegrated.” Id.
`
`According to Narayani,
`
`[t]he results of this study clearly suggested that alginate-coated
`gelatin capsules are safe candidates as oral delivery devices to
`carry microspheres containing bioactive peptides and proteins
`and dump them selectively in the large intestine where
`therapeutic action or drug absorption is desired. The
`
`13
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`polymer-coated gelatin capsules will facilitate the routine use of
`the oral route of drug delivery for protein and peptide drugs.
`
`Id. at 47.
`
`iv. Campieri
`
`Campieri is an article from a scientific journal bearing a 1997
`
`publication date. Ex. 1008, 209. Petitioner contends, and Patent Owner does
`
`not dispute, that Campieri qualifies as prior art under 35 U.S.C. § 102(b).
`
`Pet. 27.
`
`Campieri describes a clinical study involving the oral administration
`
`of certain steroids, i.e., prednisolone and budesonide, to treat Crohn’s
`
`disease. Ex. 1008, Abstr. Campieri teaches that budesonide in “controlled
`
`ileal release (CIR) capsules . . . administered at 9 mg once daily or 4.5 mg
`
`twice daily, is comparable to prednisolone in inducing remission in active
`
`Crohn’s disease.” Id.
`
`v.
`
`Ekwuribe
`
`Ekwuribe is a United States Patent that issued on October 25, 1994.
`
`Ex. 1009, code (45). Petitioner contends, and Patent Owner does not dispute,
`
`that Ekwuribe qualifies as prior art under 35 U.S.C. § 102(b). Pet. 28.
`
`Ekwuribe discloses “[a] stabilized conjugated peptide complex
`
`comprising a peptide conjugatively coupled to a polymer including
`
`lipophilic and hydrophilic moieties.” Ex. 1009, Abstr. Ekwuribe discloses
`
`examples that incorporate polyethylene glycol (PEG) into the polymer. See
`
`id. at 13:4–52. Ekwuribe teaches that “[t]he presence of these PEG residues
`
`will impart hydrophilic properties to the polymer and to the corresponding
`
`polymer-peptide conjugates.” Id. at 12:41–43; 14:50–55.
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`14
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`IPR2022-00722
`Patent 7,041,786 B2
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`E. Ground 1: Obviousness over Currie and Li
`
`
`
`Petitioner contends that claim 1 would have been obvious over the
`
`combination of Currie and Li. See Pet. 32–39. More specifically, Petitioner
`
`contends that Currie discloses the amino acid sequence for human
`
`uroguanylin, which differs from the claimed SEQ ID. NO:20 in only respect.
`
`That is, in the human uroguanylin sequence there is an aspartic acid residue
`
`at position 3 (“Asp3”), whereas SEQ ID NO:20 has a glutamic acid residue at
`
`positions 3 (“Glu3”). Petitioner contends that it would have been obvious to
`
`modify uroguanylin by substituting glutamic acid for the aspartic acid at
`
`position 3 (i.e., “the Glu3 substitution”), thereby resulting in the peptide of
`
`claim 1.
`
`Patent Owner does not dispute that the only difference between the
`
`uroguanylin sequence disclosed in Currie and the peptide of claim 1 is that
`
`uroguanylin has an Asp3, whereas the recited peptide has a Glu3. Rather,
`
`Patent Owner argues that it would not have been obvious to modify Currie’s
`
`uroguanylin sequence as Petitioner contends. See Resp. 26–66.
`
`The parties’ disputes are focused on three issues: (1) whether it would
`
`have been obvious to select uroguanylin as a lead compound for
`
`modification; (2) assuming uroguanylin was selected as a lead, whether it
`
`would have been obvious to make the Glu3 substitution; and (3) Patent
`
`Owner’s unexpected results showing, which it offers as objective evidence
`
`of the alleged non-obviousness of the recited peptide. We address each of
`
`these issues below before reaching an ultimate conclusion on obviousness.
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`15
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`Patent 7,041,786 B2
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`i. Whether a POSA would have had a reason to select human
`uroguanylin as a lead compound
`
`
`
`Petitioner contends that a POSA would have recognized uroguanylin
`
`“as a good candidate for oral administration for delivery to the intestines to
`
`treat constipation” and therefore selected it as a lead compound for further
`
`modification. See Pet. 19 (citing Ex. 1002 ¶¶ 59–61, 82–86, 89–93, 107).
`
`Patent Owner responds to Petitioner’s contentions, arguing that “a
`
`POSA would not have selected human uroguanylin as a lead compound over
`
`heat-stable enterotoxins.” Resp. 29. Patent Owner explains that “[h]eat
`
`stable enterotoxins (STs) are secretory peptides produced by some bacterial
`
`strains, such as enterotoxigenic E. coli.” Id. at 13. According to Patent
`
`Owner, STs were known to be more stable than other GCC agonist peptides
`
`and “exhibited a potency and binding affinity that surpassed uroguanylin and
`
`guanylin in the acidic and alkaline pHs of both the small and large
`
`intestines.” Id. at 14.
`
`In addition, Patent Owner asserts that “human uroguanylin was
`
`plagued by isomeric instability,” i.e., it “was known to have two topological
`
`interconverting isomers: Isomer A, which was known to be biologically
`
`active, and Isomer B, which was known to be biologically inactive.” Resp.
`
`29 (citing Ex. 2011, 27; Ex. 2020, 223). According to Patent Owner,
`
`[b]ecause of human uroguanylin’s known
`interconversion/topoisomerism dilemma and its attendant
`problems with manufacture, formulation, storage and in vivo
`unpredictability, a POSA would not have selected human
`uroguanylin as a lead compound. Instead . . . the heat-stable
`enterotoxins would have been a far more promising option, for
`they were not afflicted with topoisomerism, were more
`biologically effective, and were pH-independent, giving them
`greater versatility throughout the small intestine and colon.
`
`16
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`IPR2022-00722
`Patent 7,041,786 B2
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`Id. at 32–33.
`
`Petitioner disputes Patent Owner’s arguments against the selection of
`
`human uroguanylin as a lead compound for developing synthetic analogues.
`
`See Reply 4–11. According to Petitioner, “[u]roguanylin’s known properties
`
`were very promising for synthesizing an analogue” and “Currie
`
`acknowledged enterotoxins’ higher potency yet identified uroguanylin as a
`
`very promising lead compound for further modification.” Id. at 4–5 (citing
`
`Ex. 1063 ¶¶ 10–12). Petitioner contends that a POSA would have
`
`understood that “maximizing potency beyond uroguanylin was not
`
`necessarily desirable” because “replicating enterotoxin’s potency and lack of
`
`pH sensitivity might cause severe diarrhea and even death.” Id. at 6–7 (citing
`
`Ex. 1063 ¶¶ 16–18; Ex. 1064 ¶¶ 42–46; Ex. 1062, 62:5–64:13, 76:13–79:20;
`
`Ex. 1071).
`
`Petitioner also asserts that topoisomerism would not have led a POSA
`
`away from selecting uroguanylin as a lead compound. See Reply 7–11.
`
`According to Petitioner, uroguanylin was known to freely covert between
`
`topoisomers at acidic pH of 4.5, but a POSA “would have expected oral
`
`uroguanylin not to be exposed to this low pH for over an hour, with no more
`
`than 1% interconversion” and therefore “[u]roguanylin was known as stable
`
`and effective in vivo after oral administration.” Id. at 7 (citing Ex. 1063 ¶ 27;
`
`Ex. 1018, G641–G642; Ex. 2021, 2:28–3:1). Moreover, Petitioner asserts
`
`that Patent Owner’s arguments about potential purification and storage
`
`problems are overstated because “purifying topoisomers was
`
`straightforward” and “administering pharmaceuticals as mixtures of
`
`interconverting active and inactive forms was common, e.g., racemic drugs
`
`like ibuprofen.” Id. at 8–10 (citing Ex. 1063 ¶¶ 34, 40, 42).
`
`17
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`IPR2022-00722
`Patent 7,041,786 B2
`
`In its Sur-reply, Patent Owner disputes Petitioner’s evidence that
`
`uroguanylin would only be expected to spend an hour exposed to pH 4.5 in
`
`vivo because it is based “on gastrointestinal pHs and transit times in healthy
`
`patients, not constipated patients.” Sur-reply 3. According to Patent Owner,
`
`“Petitioner also downplays the difficulties with purifying, formulating, and
`
`storing human uroguanylin––difficulties a POSA would have considered
`
`when selecting a lead compound.” Id. at 4–5. Thus, Patent Owner contends
`
`that uroguanylin’s “topoisomeric instability” and “inferior potency”
`
`presented unnecessary challenges, which a POSA would have avoided by
`
`instead selecting a heat-stable enterotoxin as a lead compound. See id. 2–3.
`
`We find that Petitioner has the better argument on this issue. As
`
`Petitioner points out, it “need only identify ‘some reason’ that would have
`
`sufficed for a chemist to modify” human uroguanylin. Reply 3 (quoting
`
`Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc., 752 F.3d 967, 973
`
`(Fed. Cir. 2014)); see also Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d
`
`1280, 1292 (Fed. Cir. 2012) (“In determining whether a chemist would have
`
`selected a prior art compound as a lead, the analysis is guided by evidence of
`
`the compound’s pertinent properties.”).
`
`Here, Currie itself provides that reasoning. Currie specifically
`
`identifies uroguanylin as a potential “laxative” that may “be useful in
`
`patients suffering from constipation, e.g. cystic fibrosis patients who suffer
`
`with severe intestinal complications from constipation.” Ex. 1005, 2:20–24.
`
`Currie also teaches that STs affect the same biological pathway, but are
`
`derived from pathogenic bacteria and are dangerous. Id. at 1:30–44. Thus,
`
`Currie’s teachings and data showing that uroguanylin exhibits activity that is
`
`intermediate between the higher activity associated with STs and the lower
`
`18
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`IPR2022-00722
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`activity associated with guanylin (see, e.g., id. at Figs. 3A–B) support
`
`Dr. Peterson’s testimony that a POSA would have recognized uroguanylin as
`
`a candidate for “treating constipation using a more controlled version” of the
`
`same pathway targeted by STs. Ex. 1002 ¶¶ 59–60. This evidence is
`
`sufficient to show that a POSA would have been motivated to select human
`
`uroguanylin as a lead compound.
`
`Patent Owner’s evidence that topoisomerism was a known concern
`
`with human uroguanylin does not negate Petitioner’s rationale for selecting
`
`uroguanylin as a lead compound. See Resp. 29–32 (citing Ex. 2010, 236; Ex.
`
`2011, 27, 30; Ex. 2020, 223; Ex. 2024 ¶¶ 49–60, 127–34). Rather, it
`
`suggests that isomeric instability was a challenge, but not one that would
`
`discourage further investigation of uroguanylin analogues. In this regard, we
`
`credit the testimony of Petitioner’s declarants that a POSA would have
`
`understood that the negative effects caused by in vivo interconversion could
`
`be mitigated by using known techniques, e.g., formulating a tablet to target
`
`release in the higher pH environment of the intestines as opposed to the
`
`lower pH environment of the stomach. See Ex. 1063 ¶¶ 24–29; Ex. 1064
`
`¶¶ 24–32 (explaining, inter alia, that the “GCC receptor that uroguanylin
`
`activates is concentrated in the proximal small intestines,” an “enteric
`
`coating” can be used to “protect[] the tablet from the stomach fluids,” and
`
`that “if exposure to prolonged acidic conditions were a concern there were
`
`routine approaches” that could be taken to address such).
`
`Finally, Patent Owner’s argument that STs would have been viewed
`
`as a better choice for a lead compound does not overcome Petitioner’s
`
`showing that human uroguanylin would also have been a “natural choice for
`
`further development efforts.” See Bristol-Myers, 752 F.3d at 973 (quoting
`
`19
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`IPR2022-00722
`Patent 7,041,786 B2
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`Altana Pharma AG v. Teva Pharms. USA, Inc., 566 F.3d 999, 1008 (Fed.
`
`Cir. 2009)). The Federal Circuit has cautioned that it would be overly
`
`restrictive to view the “lead compound test” to require “that the prior art
`
`must point to only a single lead compound for further development.” Altana,
`
`566 F.3d at 1008. Here, Petitioner articulates reasoning supported by
`
`evidence to explain why a POSA would have selected uroguanylin for
`
`further development in view of both its advantages and disadvantages
`
`relative to STs. See Ex. 1002 ¶¶ 59–61, 89–90; Ex. 1005, 1:30–44, 2:20–24;
`
`Ex. 1063 ¶¶ 16–21. We find Petitioner’s showing sufficient to meet its
`
`burden even if a POSA might also have viewed STs as another class of
`
`promising lead compounds.
`
`ii. Whether it would have been obvious to make the Glu3 substitution
`
`Petitioner argues that it would have been obvious to make the Glu3
`
`substitution to human uroguanylin. More specifically, Petitioner, relying on
`
`testimony from Dr. Peterson, asserts that: (1) aspartic
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