IPR2023-00722
` U.S. Patent No. 8,536,122
`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner
`
`v.
`NOVO NORDISK A/S,
`Patent Owner
`______________________
`Case IPR2023-00722
`Patent 8,536,122
`______________________
`
`
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`UNDER 37 C.F.R. § 42.107
`
`
`
`
`
`
`
`
`
`
`
`

`

`IPR2023-00722
` U.S. Patent No. 8,536,122
`LIST OF EXHIBITS
`
`
`Description
`Excerpt of Defendants’ Initial Invalidity Contentions, In re:
`Ozempic (Semaglutide) Patent Litigation, No. 1:22-cv-01040-
`CFC, (D. Del. Oct. 20, 2022)
`J. Lau, P. Bloch, et al., “Discovery of the Once-Weekly
`Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide,”
`Med. Chem., 58:7370-7380 (2015)
`U.S. Patent No. 10,335,462
`B. Furman, N. Pyne, P. Flatt & F. O’Harte, “Targeting B-cell
`cyclic adenosine monophosphate for the development of novel
`drugs for treating type 2 diabetes mellitus,” J. Pharmacy and
`Pharmacology, 56:1477-1492 (2004)
`WO98/32466
`U.S. Patent No. 6,528,486
`WO00/69911
`Declaration of Sayem Osman
`
`Exhibit
`EX2001
`
`EX2002
`
`EX2003
`EX2004
`
`EX2005
`EX2006
`EX2007
`EX2008
`
`
`
`i
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`

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`IPR2023-00722
` U.S. Patent No. 8,536,122
` TABLE OF CONTENTS
`
`
`Introduction ...................................................................................................... 1
`I.
`Challenged Claims Are Directed To A Novel, Non-Obvious Invention ........ 5
`II.
`III. Petitioner’s References Identify Thousands of Compounds and Potential
`Modifications ................................................................................................... 9
`A. Knudsen 2004 (EX1010) ....................................................................... 9
`B. Knudsen 2001 (EX1011) ....................................................................... 9
`C. Knudsen Patent (EX1012) ................................................................... 12
`D. Dong (EX1013) ................................................................................... 14
`E.
`Bridon (EX1014) ................................................................................. 15
`IV. Claim Construction ........................................................................................ 16
`§314(a) Discretionary Denial: Ground 3 Fails to Identify “With
`V.
`Particularity” Each Reference and Combination on Which the Challenge is
`Based, and Its Extraordinary, Prejudicial Impropriety Requires Denial ....... 16
`VI. Grounds 1-2: Petitioner’s Lead Compound Analysis Is Legally Deficient . 20
`A.
`Petitioner’s Lead Compound Analysis Fails ....................................... 20
`B.
`Even if Liraglutide Were Selected as a Lead Compound, Petitioner
`Fails to Establish “Motivation To Combine” ...................................... 25
`Petitioner Ignores The Numerous Types and Locations of
`1.
`Potential Modifications to Liraglutide Other than Those Found
`in Semaglutide ........................................................................... 26
`Even Focusing on the Types of Modifications Needed to Arrive
`at Semaglutide, Petitioner Ignores The Numerous Options for
`Implementing Those Modifications .......................................... 29
`Petitioner Fails To Establish A Reasonable Expectation Of Success In
`Creating Semaglutide .......................................................................... 46
`1.
`Petitioner Fails to Show REOS For Individual Modifications . 47
`2.
`Petitioner Fails to Show REOS For Its Argued
`Combination of Modifications .................................................. 51
`
`C.
`
`2.
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`ii
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`IPR2023-00722
` U.S. Patent No. 8,536,122
`VII. Ground 3: Petitioner’s Obvious-To-Try Analysis Fails ............................... 52
`VIII. Institution Should Be Denied Under 35 U.S.C. §325(d) ............................... 57
`A. Advanced Bionics Part One ................................................................ 59
`B. Advanced Bionics Part Two ................................................................ 66
`IX. Conclusion ..................................................................................................... 69
`
`
`iii
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`IPR2023-00722
` U.S. Patent No. 8,536,122
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Adaptics Ltd. v. Perfect Co.,
`IPR2018-01596, Pap.20 (Mar. 6, 2019) (informative) ................................. passim
`Adidas AG v. Nike, Inc.,
`963 F.3d 1355 (Fed. Cir. 2020) .................................................................... 36, 40
`ADT LLC v. Vivint, Inc.,
`IPR2022-00634, Pap.7 (Oct. 4, 2022) .......................................................... 17, 19
`Advanced Bionics, LLC v. MED-EL Elektromedizinische Gerate
`GmbH,
`IPR2019-01469, Pap.6 (Feb. 13, 2020) (precedential) ................................passim
`Alarm.com, Inc. v. Vivint, Inc.,
`IPR2022-00728, Pap.6 (Nov. 1, 2022) ............................................................... 62
`Apple Inc. v. Universal Secure Registry, LLC,
`IPR2018-00808, Pap.9 (Oct. 9, 2018) ................................................................ 53
`In re Applied Materials, Inc.,
`692 F.3d 1289 (Fed. Cir. 2012) .......................................................................... 50
`Autel Intelligent Tech. Corp. v. Orange Elec. Co.,
`IPR2021-01545, Pap.8 (Apr. 8, 2022) ................................................................ 62
`Becton, Dickinson and Co. v. B. Braun Melsungen AG,
`IPR2017-01586, Pap.8 (Dec. 15, 2017) (precedential) .......................... 58, 59, 61
`Bioeq IP AG v. Genentech, Inc.,
`IPR2016-01608, Pap.11 (Feb. 22, 2017) .......................................... 32, 34, 35, 45
`In re Boesch,
`617 F.2d 272 (C.C.P.A. 1980) ............................................................................ 57
`CSL Behring LLC v. Bioverative Therapeutics Inc.,
`IPR2018-01313, Pap.10 (Jan. 9, 2019) ................................................... 34, 42, 45
`
`iv
`
`
`

`

`IPR2023-00722
` U.S. Patent No. 8,536,122
`
`Cuozzo Speed Techs., LLC v. Lee,
`579 U.S. 261 (2016) ............................................................................................ 18
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) .......................................................................... 56
`Daiichi Sankyo Co. v. Matrix Lab’ys, Ltd.,
`619 F.3d 1346 (Fed. Cir. 2010) ...................................................................passim
`Darfon Elecs. Corp. v. Shipman,
`IPR2022-01008, Pap.11 (Dec. 2, 2022) .............................................................. 62
`EnergySource Minerals, LLC v. TerraLithium LLC,
`IPR2019-01607, Pap.10 (May 4, 2020) ........................................................ 17, 19
`Eyenovia, Inc. v. Sydnexis, Inc.,
`IPR2022-00963, Pap.7 (Nov. 8, 2022) ............................................................... 67
`Gilead Scis., Inc. v. Regents of the Univ. of Minn.,
`IPR2017-01753, Pap.42 (Apr. 22, 2020) .......................................... 29, 33, 42, 45
`Google LLC v. Jawbone Innovations, LLC,
`IPR2022-00889, Pap.12 (Nov. 14, 2022) ..................................................... 31, 36
`Google LLC v. Valtrus Innovations Ltd.,
`IPR2022-01197, Pap.9 (Jan. 3, 2023) ................................................................. 68
`Immunex Corp. v. Sandoz Inc.,
`964 F.3d 1049 (Fed. Cir. 2020) .................................................................... 34, 35
`Institut Pasteur & Universite Pierre Et Marie Curie v. Focarino,
`738 F.3d 1337 (Fed. Cir. 2013) .......................................................................... 51
`InVue Sec. Prods., Inc. v. Mobile Tech., Inc.,
`IPR2019-00078, Pap.7 (May 1, 2019) ................................................................ 17
`Ivantis, Inc. v. Sight Scis., Inc.,
`IPR2022-01533, Pap.14 (Mar. 27, 2023) ..................................................... 61, 68
`Jiangsu Sainty Sumex Tools Corp. v. Milwaukee Elec. Tool Corp.,
`IPR2021-00373, Pap.19 (July 6, 2021) .............................................................. 19
`
`v
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`

`

`IPR2023-00722
` U.S. Patent No. 8,536,122
`
`John Crane, Inc. v. Finalrod IP, LLC,
`IPR2016-01827, Pap.6 (Jan. 31, 2017) ......................................................... 17, 19
`Keysight Techs., Inc. v. Centripetal Networks, Inc.,
`IPR2022-01421, Pap.9 (Mar. 22, 2023) ............................................................. 61
`KSR Int'l Co. v. Teleflex Inc.,
`550 U.S. 398, 418 (2007) ........................................................................ 51, 56, 57
`Leo Pharm. Prods., Ltd v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .......................................................................... 56
`Life Spine, Inc. v. Globus Med., Inc.,
`IPR2022-01603, Pap.8 (June 12, 2023) ........................................................ 31, 36
`Microsoft Corp. v. AlmondNet, Inc.,
`IPR2022-01319, Pap.9 (Jan. 30, 2023) ......................................................... 66, 68
`Microsoft Corp. v. ThroughPuter, Inc.,
`IPR2022-00757, Pap.10 (Nov. 1, 2022) ....................................................... 65, 67
`Millenium Pharms., Inc. v. Sandoz Inc.,
`862 F.3d 1356 (Fed. Cir. 2017) .......................................................................... 44
`Miltenyi Biomedicine GmbH v. Tr. of the Univ. of Pa.,
`IPR2022-00853, Pap.11 (Oct. 11, 2022) ............................................................ 68
`Motorola Mobility LLC v. Maxell, Ltd.,
`IPR2022-01287, Pap.11 (Feb. 2, 2023) ............................................ 58, 59, 61, 67
`Mylan Pharms. Inc. v. AstraZeneca AB,
`IPR2015-01340, Pap.79 (Aug. 18, 2017) ............................................... 47, 51, 52
`Mylan Pharms. Inc. v. Nissan Chem. Indus., Ltd.,
`IPR2015-01069, Pap.24 (Oct. 20, 2015) ................................................ 26, 30, 52
`Mylan Pharms. Inc. v. UCB Pharma GmbH,
`IPR2016-00514, Pap.38 (July 19, 2017) ................................................ 26, 30, 52
`Netflix, Inc. v. DivX, LLC,
`IPR2020-00558, Pap.10 (Aug. 26, 2020) ........................................................... 62
`
`vi
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`

`

`IPR2023-00722
` U.S. Patent No. 8,536,122
`
`Otsuka Pharm. Co., v. Sandoz, Inc.,
`678 F.3d 1280 (Fed. Cir. 2012) ...................................................................... 2, 22
`Par Pharm. Inc. v. Novartis AG,
`IPR2016-00084, Pap.73 (Jan. 11, 2018) ................................................. 26, 30, 52
`Pfizer Inc. v. Teva Pharms. USA, Inc.,
`555 F. App’x 961 (Fed. Cir. 2014) ..................................................................... 47
`Proctor & Gamble Co. v. Teva Pharms. USA, Inc.,
`566 F.3d 989 (Fed. Cir. 2009) ...................................................................... 32, 56
`Sanofi-Aventis Deutschland GmbH v. Glenmark Pharms. Inc., USA,
`748 F.3d 1354 (Fed. Cir. 2014) .......................................................................... 56
`Sanofi-Aventis U.S., LLC v. Dr. Reddy’s Lab’ys, Inc.,
`933 F.3d 1367 (Fed. Cir. 2019) ...................................................................... 2, 25
`Sawai USA, Inc. v. Astellas Pharma Inc.,
`IPR2018-00079, Pap.7 (May 4, 2018) .........................................................passim
`Splunk Inc. v. Sable Networks, Inc.,
`IPR2022-00003, Pap.10 (Apr. 14, 2022) ............................................................ 67
`Takeda Chem. Indus. Ltd. v. Alphapharm Pty., Ltd.,
`492 F.3d 1350 (Fed. Cir. 2007) ...................................................................passim
`Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc.,
`200 F.3d 795 (Fed. Cir. 1999) ............................................................................ 16
`In re Wesslau,
`353 F.2d 238 (C.C.P.A. 1965) ...................................................................... 33, 42
`Xerox Corp. v. Bytemark, Inc.,
`IPR2022-00624, Pap.9 (Aug. 24, 2022) (precedential) ...................................... 52
`Yamanouchi Pharm. Co. v. Danbury Pharmacal, Inc.,
`231 F.3d 1339 (Fed. Cir. 2000) .......................................................................... 24
`Statutes
`35 U.S.C. §312(a)(3) .......................................................................................... 16, 18
`
`vii
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`

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`IPR2023-00722
` U.S. Patent No. 8,536,122
`
`Other Authorities
`37 C.F.R. §42.104(b)(4) ........................................................................................... 16
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`viii
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`IPR2023-00722
` U.S. Patent No. 8,536,122
`
`I.
`
`Introduction
`Patent Owner Novo Nordisk A/S (“PO”) submits this §42.1071 Preliminary
`
`Response to the above-captioned Petition (“Petition”/“Pet.”). The Board should
`
`deny institution because Petitioner fails to meet its burden to establish
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`unpatentability, including by failing to articulate clearly the arguments and
`
`evidence on which Petitioner purports to rely, and by failing to show liraglutide
`
`would have been a lead compound. Petitioner also fails to show obviousness of
`
`Claims 1-2, 4-11, 13, and 15 (“Challenged Claims”) of U.S. Pat. 8,536,122 (“’122
`
`Patent”/“’122”). Petitioner concedes semaglutide (a GLP-1 analogue covered by
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`the Challenged Claims) is novel, arguing only that semaglutide, the active
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`ingredient in PO’s revolutionary once-weekly drug Ozempic®—which generated
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`nearly $3 billion in sales in 2021 and over $8.5 billion in 2022—was somehow
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`obvious.
`
`Petitioner’s Grounds 1 and 2 rest on a flawed lead-compound analysis that
`
`ignores the wide array of potential leads that a skilled artisan would have had to
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`choose from. Instead, Petitioner zeroes in on liraglutide—a decision based on a
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`hindsight-driven search for compounds structurally similar to the claimed invention.
`
`
`1 Unless stated, all statutory and regulatory citations are to 35 U.S.C. or 37 C.F.R.,
`
`as context indicates, and all emphases/annotations are added.
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`1
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`IPR2023-00722
` U.S. Patent No. 8,536,122
`This directly contravenes Federal Circuit precedent. E.g., Otsuka Pharm. Co., v.
`
`Sandoz, Inc., 678 F.3d 1280, 1292 (Fed. Cir. 2012); Sanofi-Aventis U.S., LLC v. Dr.
`
`Reddy’s Lab’ys, Inc., 933 F.3d 1367, 1375 (Fed. Cir. 2019). To begin with,
`
`Petitioner asserts liraglutide would have been selected as the “lead compound”
`
`because of its half-life and efficacy, but ignores the multitude of other compounds
`
`in Petitioner’s own art with longer half-lives, greater potency, or both. And
`
`Petitioner itself acknowledges in copending litigation that “[n]umerous other GLP-
`
`1 derivatives would have been candidates.” EX2001, 5. And Petitioner
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`acknowledges that “[m]any would have worked” as a starting point. Pet.31. This
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`confirms Petitioner failed to demonstrate liraglutide is a lead because Petitioner
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`failed to show POSITA “would have had a reason to select [liraglutide] over” these
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`“[m]any” other GLP-1 analogue candidates. See, e.g., Daiichi Sankyo Co. v. Matrix
`
`Lab’ys, Ltd., 619 F.3d 1346, 1353-54 (Fed. Cir. 2010).
`
`And even if liraglutide were shown to be a proper lead compound, Petitioner
`
`fails to address Petitioner’s own art, which contradicts Petitioner’s proposed
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`rationale for modifying liraglutide, and ignores the innumerable other modifications
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`that would have been available to POSITA, belying Petitioner’s arguments. While
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`Petitioner attempts to suggest POSITA would have selected “three” particular
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`2
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`IPR2023-00722
` U.S. Patent No. 8,536,122
`substantive changes to liraglutide2 from a vast multitude of known alternatives
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`(including others Petitioner’s own art recommends) to “reach semaglutide” (Pet.46),
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`this unsupported argument contradicts the teachings and data in Petitioner’s own
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`prior art—which Petitioner simply ignores. At bottom, the art clearly demonstrates
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`that each liraglutide modification Petitioner claims was obvious was, in fact,
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`disfavored by the art, a mismatch for liraglutide, or, at most, one in a sea of potential
`
`alterations. Petitioner further fails to support its assertion about reasonable
`
`expectation of success (“REOS”) with anything beyond a conclusory and
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`unsupported assertion by its expert, which is entitled to no weight.
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`Ultimately, Petitioner seeks to stitch together a patchwork of unrelated
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`excerpts from a disparate collection of references in a hindsight-based effort to
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`recreate semaglutide out of the prior art. This improper mixing-and-matching of
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`snippets from the art to track Petitioner’s theory, ignoring all those that do not, is
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`legally insufficient.
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`2 What Petitioner tries to portray as “three” proposed changes (Pet.6) are actually
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`at least four: Petitioner proposes to modify both the (1) length (from C16 to C18)
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`and (2) type (from monoacid to diacid) of fatty acid in liraglutide, but purports to
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`label these two changes as one. Pet.6, 43.
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`3
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`

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`IPR2023-00722
` U.S. Patent No. 8,536,122
`And Petitioner’s purported “Ground 3”—“Obviousness over the prior art
`
`and common drug development principles”—is a breathtakingly-impermissible
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`catch-all that fails to identify what references it relies on, what limitations
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`Petitioner argues are disclosed in particular references, or even how one reference
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`is modified by another (if at all). Pet.56-65. Instituting this Petition and forcing
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`PO to respond to such a grab-bag of arguments with no meaningful notice of what
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`it must defend against (or what Petitioner might later argue was supported by this
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`vague catch-all) would be highly prejudicial and a denial of due process. The
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`Board has made clear that including improper grounds like Petitioner’s Ground 3
`
`provides sufficient reason to deny institution. Adaptics Ltd. v. Perfect Co.,
`
`IPR2018-01596, Pap.20, 15-19 (Mar. 6, 2019) (informative) (“Adaptics”). And to
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`the extent it is considered on any “merits,” Ground 3 relies on an “obvious-to-try”
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`theory that clearly fails: even a small handful of Petitioner’s own references
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`disclose, at minimum, millions of combinations of modifications, and Petitioner
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`again offers merely a conclusory assertion of reasonable expectation of success.
`
`Infra, §§VI.C-VII.
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`Finally, the Board should deny institution under §325(d). Petitioner’s
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`grounds, largely resting on references sharing common authorship, simply recycle
`
`art considered, or cumulative of art considered, during prosecution. And in
`
`claiming “material error,” Petitioner merely asserts the Examiner—using the same
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`4
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`IPR2023-00722
` U.S. Patent No. 8,536,122
`liraglutide art—failed to reject the claims in light of this art. Petitioner has not
`
`shown—and cannot show—it is entitled to institution based on the same or
`
`substantially the same art and arguments, merely in hopes the Board might now
`
`reach a different conclusion.
`
`The Petition should be denied.
`
`II. Challenged Claims Are Directed To A Novel, Non-Obvious Invention
`Prior to ’122’s inventions, there were various approved type 2 diabetes
`
`treatments, but they had significant disadvantages. For example, sulphonylureas,
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`glinides, biguanides, and insulin sensitizers were approved, but had limited
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`efficacy and side effects like weight gain. EX1011, 1. Insulin was very effective
`
`but required multiple doses per day and presented a risk of serious hypoglycemia.
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`Id. “GLP-1” (glucagon-like peptide 1) was discovered in 1983 and initially
`
`described as an “incretin” (“promoting glucose-dependent insulin release” upon
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`“ingestion of food”). Id. Later, GLP-1 was “found to [] lower plasma glucagon in
`
`a glucose-dependent manner, decrease the rate of gastric emptying, [and] promote
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`fullness/satiety and stimulate insulin biosynthesis, as well as proliferation of β-
`
`cells” and was being investigated, but it, too, presented challenges. Id. For
`
`example, GLP-1 had a half-life under two minutes, and was “metabolized by
`
`dipeptidyl peptidase IV (DPP-IV) and rapidly cleared by the kidneys.” Id.
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`After years of work, multiple analogues of GLP-1 with different structures
`
`5
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`IPR2023-00722
` U.S. Patent No. 8,536,122
`and approaches were being clinically investigated—some for potential once-daily
`
`administration. EX1010, 2. One of these was PO’s compound, liraglutide (shown
`
`below). Id. But as of the priority date, none were FDA approved and a majority of
`
`each analogue’s clinical data was not yet public (see EX1010, 2-5), and researchers
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`continued to search.
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`The Challenged Claims of ’122, “Acylated GLP-1 Compounds” (claiming
`
`priority to a March 23, 2005 provisional), are directed to specific GLP-1
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`compounds, including semaglutide, and formulations and methods of treatment
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`with them. EX1001, 1, 64-70; Pet.10. Semaglutide is a GLP-1(7-37)3 analogue
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`with multiple changes from native human GLP-1(7-37) (below). EX20024, 2, 5.
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`Semaglutide has a non-natural amino acid, aminoisobutyric acid, substituted at
`
`position 8 (“Aib8”). Id. Semaglutide also has a complex structure modifying GLP-
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`1’s lysine (“Lys”) at position 26, consisting of a di-aminoethylethanolamine (“di-
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`AEEA”) spacer bonded to a gamma glutamic acid (“γ-Glu”), which is bonded to a
`
`
`3 “GLP-1(7-37)” reflects that amino acids at positions 1-6 were cleaved from the
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`37-position parent, GLP-1(1-37). EX1010, 1. (GLP-1(7-37)’s first position is
`
`numbered “7.” Id.)
`
`4 EX2002 and EX2004 appear in regularly published journals.
`6
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`IPR2023-00722
` U.S. Patent No. 8,536,122
`5 dicarboxylic fatty acid. Id. In addition, semaglutide has an arginine (“Arg”)
`
`C18
`
`substituted for the native lysine at position 34. Id.
`
`
`
`
`
`
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`Pet.32, 35.
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`Semaglutide’s structural differences from native GLP-1 led to a greatly
`
`increased half-life—165 hours for semaglutide versus under 2 minutes for GLP-1
`
`and 8 hours for liraglutide—and far greater effectiveness over prior attempts for
`
`longer-acting GLP-1 analogues. Pet.20; EX2002, 1-2, 5. These differences from
`
`GLP-1 surprisingly allowed PO’s commercial products with semaglutide as the
`
`
`5 “x” in “Cx” identifies the number of carbons in a fatty-acid chain.
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`7
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`IPR2023-00722
` U.S. Patent No. 8,536,122
`only active ingredient—Ozempic® for diabetes and Wegovy® for chronic weight
`
`management, including in overweight patients with comorbid conditions such as
`
`type 2 diabetes—to be dosed once-weekly in a lower dose than analogues (such as
`
`liraglutide) delivered daily, while providing greater blood glucose control and
`
`weight loss than liraglutide. As a result, patients need to inject themselves
`
`significantly less frequently, and each needs less GLP-1 analogue (1.0mg/week
`
`semaglutide for diabetes treatment, compared to 8.4mg/week (1.2mg/day)
`
`liraglutide) to achieve a better treatment outcome. EX2003, Figs. 1-5.
`
`’122 is a continuation of an application that issued as U.S. Patent 8,129,343
`
`(“’343 Patent”/“’343”), both before the same Examiner. EX1001, 1; EX1002, 1.
`
`’343’s Examiner initially rejected the pending claims as obvious over the
`
`“Knudsen Patent”6 (EX1012) and Larsen. EX1004, 41-46. PO then returned to its
`
`conditionally elected species claims for semaglutide (EX1004, 32-33, 68), and the
`
`Examiner allowed ’343. EX1004, 25.
`
`’122 issued without any prior art rejections. As “Reasons for Allowance,”
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`the Examiner stated: “The closest prior art is that of Knudsen et al. [EX1012]
`
`which describes GLP-1 analogs… However Knudsen et al. do not teach the
`
`
`6 Knudsen—lead inventor of EX1012, a Ground 1-2 secondary reference—is an
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`author on both of Petitioner’s primary references (EX1010, EX1011).
`
`8
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`IPR2023-00722
` U.S. Patent No. 8,536,122
`instantly claimed U spacers required by the instant claimed products and methods,
`
`nor are they obvious over the prior art.” EX1003, 48.
`
`III. Petitioner’s References Identify Thousands of Compounds and
`Potential Modifications
`A. Knudsen 2004 (EX1010)
`Knudsen 2004—cited on ’122’s face—is an article by a Novo Nordisk
`
`researcher discussing several GLP-1-based compounds then in development with
`
`varying half-lives and dosing frequencies, including two exendin-4 analogues,
`
`exenatide (a.k.a. synthetic extendin-4) and ZP10, and natural GLP-1 analogues
`
`including liraglutide, CJC-1131, Albugon, and BIM-51077. EX1010, at 2-4;
`
`EX1001, 2. Notably, Knudsen 2004 discloses that, e.g., CJC-1131 has a half-life
`
`16-26 times longer than liraglutide’s (10-12 days versus 11-15 hours) and Albugon
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`has a half-life 4-6 times longer than liraglutide’s (3 days in monkeys versus 11-15
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`hours in humans). EX1010, 4.
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`B. Knudsen 2001 (EX1011)
`Knudsen 2001, co-authored by Knudsen, discusses GLP-1 analogues for
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`treating type 2 diabetes. EX1011, 1. Knudsen 2001 recognizes the significant
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`investigation still needed to identify and test GLP-1 analogues with the potential
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`for once-daily administration, and reports negative impacts of various potential
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`GLP-1 modifications. EX1011, 3-4. For example, although ignored by Petitioner,
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`Knudsen 2001 discloses compound 16, an analogue with a C18 acid and γ-Glu
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`spacer (two features of semaglutide), “led to a significant loss of activity compared
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`to C16…, C14… and C12.” EX1011, 4 (noting C18 analogue 3x less active than
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`C16, which is 3x less active than C14 and C12). Further, diacids, “could be no
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`longer than a C14… before a loss in potency… compared to the γ-Glu spacer
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`monoacid series… was seen.” Id. (noting C16 diacid 2x less active than C14
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`diacid).
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`Knudsen 2001 discloses, e.g.:
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`• at least two GLP-1 analogues (compounds 4, 20), modified at a
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`different amino acid with a GABA-spacer instead of γ-Glu, with a
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`substantially longer half-life than liraglutide (compound 5);
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`• at least six GLP-1 analogues (compounds 3, 4, 6, 8, 9, 17, 18) with
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`higher potency than liraglutide (a lower EC50 value indicates higher
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`potency); and
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`• at least one GLP-1 analogue (compound 4 (acylated at position 23))
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`with both a substantially longer half-life and higher potency than
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`
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`liraglutide.
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`EX1011, 4-5 (Tables I and II).
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`Lastly, while semaglutide has a position 8 Aib substitution at the N-
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`terminus, Knudsen 2001 recognizes that “[d]esamino His7 represents one of the
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`more potent suggestions to a modification giving metabolic stability,” that
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`“considerably more potent compounds could be obtained by not modifying the N-
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`terminus when a combination with acylation was desired,” and that “any amino
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`acid substitution poses a risk of immunogenicity.” EX1011, 4-5. Knudsen 2001
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`selected compound 5—which does not include an N-terminus modification—for
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`clinical development over analogues with N-terminus modifications. Id. Finally,
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`while Petitioner asserts the need for a position 8 substitution to protect against
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`DPP-IV degradation, Knudsen 2001 chose liraglutide because it already had
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`substantial protection against DPP-IV cleaving through acylation without needing
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`any position 8 substitution. Id.
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`C. Knudsen Patent (EX1012)
`The Knudsen Patent, “Derivatives of GLP-1 Analogs,” issued July 31, 2001,
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`and is assigned to PO. It was expressly considered during examination of ’122 and
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`its ’343 parent, and discloses thousands of GLP-1 analogues—describing each as
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`a “preferred embodiment” (e.g., EX1012, cols.20-167), and recognizing that each
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`could be further modified, including with amino acid substitutions at multiple
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`positions, acylation at multiple positions, numerous fatty acid options for the
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`acylation, and numerous spacer options for linking the fatty acid to the amino acid.
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`E.g., EX1012, 9:21-19:59. The Knudsen Patent discloses:
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`• multiple GLP-1 analogues with a greater half-life than liraglutide
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`(Example 37), including Exs.11-14, 32 and 34 (EX1012, 192:30-60
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`(Table 1));
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`and
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`• multiple GLP-1 analogues that were more potent than liraglutide,
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`including, e.g., Exs.16, 26, 30, 38-40, and 43 (EX1012, 193:35-46).
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`D. Dong (EX1013)
`Dong discloses testing of GLP-1(7-36)7 analogues that were designed and
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`synthesized to improve half-life. EX1013, 6. Dong states that GLP-1 is cleaved in
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`vivo in two places—between positions 8 and 9 by DPP-IV, and between positions
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`34 and 35—reducing its half-life. Id. To attempt to increase half-life, Dong
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`synthesized GLP-1 analogues with substitutions at position 8, 35, 26, 34 and/or 31.
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`While Petitioner proposes substitutions at position 8 but not positions 31 and 35 to
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`reach semaglutide, Dong reports that half-life is improved when two to five
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`substitutions are made together, including the “representative analogue,”
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`compound 4, which includes 2 substitutions: Aib8 and Aib35 (a combination of
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`substitutions absent in semaglutide). Id. Dong also reports that Aib8,35 results in a
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`half-life of 9.76 hours, whereas Aib8 alone (as in semaglutide) resulted in a poorer
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`half-life of only 4.52 hours—the second shortest half-life of any GLP-1(7-36)
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`analogue Dong tested. Id. And Dong’s conclusion notes that compound 4, Aib8,35
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`(not found in semaglutide), was “significantly more efficacious than hGLP-1,” the
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`unmodified human GLP-1 peptide. Id., 7.
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`7 Petitioner does not address that Dong’s data pertains to a different form of GLP-
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`1, (7-36), let alone explain why data and modifications from one form (7-36)
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`would translate to (7-37). Pet.23-24, 36-37; infra, §VI.B.2.a.
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`Bridon (EX1014)
`E.
`U.S. Patent 6,514,500, “Long Lasting Synthetic Glucagon Like Peptide”
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`(“Bridon,” issued February 4, 2003), is assigned to ConjuChem, Inc. EX1014, 1.
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`A related publication, WO00/69911, claiming priority to the same provisional as
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`Bridon (60/159,783) and sharing (in relevant part) Bridon’s specification, is cited
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`on ’122’s face. EX1001, 1; EX2007.
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`Bridon discloses analogues “capable of forming covalent bonds with one or
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`more blood components [such as albumin] to form a conjugate,” so that when
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`administered, they form a “peptidase stabilized therapeutic peptide.” EX1014, 1
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`(Abstract). Bridon explains that the covalent bond to albumin formed upon
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`administration (a bond not formed when liraglutide or semaglutide interacts with
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`albumin) extends “[t]he activity of the modified ITPs compound… for days to
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`weeks.” EX1014, 21:17-27.
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`Further, while Bridon discloses numerous GLP-1 analogues, it emphasizes
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`its “invention relates… especially [to] GLP-1(7-36) amide[s].” EX1014, 1:61-67,
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`51:1-68:6. Semaglutide is not a GLP-1(7-36) amide, nor does Petitioner contend it
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`is.8 EX2002, 5.
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`Bridon discloses numerous types of linker-reactive groups that could be used
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`to covalently bind blood components such as albumin, and further discloses that in
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`8 See also supra n.7.
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`“preferred embodiments,” the albumin-binding substituent attached to Bridon’s
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`linker is “a maleimido-containing group such as (GMBA or MPA)” (not a fatty
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`acid incapable of covalently binding albumin, as in liraglutide and semaglutide).
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`EX1014, 3:10-20, 9:15-18. And Bridon claimed only one GLP-1 analogue, which
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`had no linker, and instead was substituted directly on ε-position of Lys37 with
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`MPA. EX1014, cls.1-2.
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`IV. Claim Construction
`No terms require construction for considering institution. Vivid Techs., Inc.
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`v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999).
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`V.
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`§314(a) Discretionary Denial: Ground 3 Fails to Identify “With
`Particularity” Each Reference and Combination on Which the
`Challenge is Based, and Its Extraordinary, Prejudicial Impropriety
`Requires Denial
`Petitioner purports to identify “Ground 3” as “Obviousness over the prior
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`art and common drug development principles (under KSR).” Pet.5. But generally
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`invoking the “prior art” with unspecified “common drug development principles”
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`ignores the “particularity” petitions require (see, e.g., 35 U.S.C. §312(a)(3); 37
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`C.F.R. §42.104(b)(4)), and Petitioner’s extraordinarily overreaching attempt to
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`move forward to trial without specifying the prior art and arguments actually at
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`issue in “Ground 3” denies PO due