IPR2023-00723
`U.S. Patent No. 8,129,343
`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 IPR2023-00723
`Patent 8,129,343
`______________________
`
`
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`UNDER 37 C.F.R. § 42.107
`
`
`
`
`
`
`
`
`
`
`
`

`

`Exhibit
`EX2001
`
`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)
`EX2005 WO98/32466
`EX2006
`U.S. Patent No. 6,528,486
`EX2007 WO00/69911
`EX2008
`Excerpt of Plaintiffs’ Initial Responses to Defendants’ Initial Invalidity
`Contentions, In re: Ozempic (Semaglutide) Patent Litigation, No. 1:22-
`cv-01040-CFC, (D. Del. Dec. 21, 2022)
`Declaration of Sayem Osman
`
`EX2002
`
`EX2003
`EX2004
`
`EX2009
`
`
`IPR2023-00723
`U.S. Patent No. 8,129,343
`
`LIST OF EXHIBITS
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`
`i
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`

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`IPR2023-00723
` U.S. Patent No. 8,129,343
` TABLE OF CONTENTS
`
`2.
`
`
`Introduction ...................................................................................................... 1
`I.
`Claims Are Directed To A Novel, Non-Obvious Invention ............................ 5
`II.
`III. Petitioner’s References Identify Thousands of Compounds and Potential
`Modifications ................................................................................................... 8
`A. Knudsen 2004 (EX1010) ....................................................................... 8
`B. Knudsen 2001 (EX1011) ....................................................................... 9
`C. Knudsen Patent (EX1012) ...................................................................11
`D. Dong (EX1013) ...................................................................................13
`E.
`Bridon (EX1014) .................................................................................14
`IV. Claim Construction ........................................................................................15
`§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 .............................................................................................15
`VI. Grounds 1-2: Petitioner’s Lead Compound Analysis Is
`Legally Deficient ...........................................................................................18
`A.
`Petitioner’s Lead Compound Analysis Fails .......................................19
`B.
`Even if Liraglutide Were Selected as a Lead, Petitioner Fails to
`Establish “Motivation To Combine” ...................................................23
`Petitioner Ignores The Numerous Types and Locations of
`1.
`Potential Modifications to Liraglutide Other than Those in
`Semaglutide ............................................................................... 24
`Even Focusing on the Types of Modifications Needed to Arrive
`at Semaglutide, Petitioner Ignores The Numerous Options for
`Implementing Them .................................................................. 27
`Petitioner Fails To Establish REOS In Creating Semaglutide ............43
`1.
`Petitioner Fails to Show REOS For Individual Modifications . 44
`2.
`Petitioner Fails to Show REOS For Its Argued Combination of
`Modifications ............................................................................ 47
`ii
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`C.
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`

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`IPR2023-00723
` U.S. Patent No. 8,129,343
`VII. Ground 3: Petitioner’s Obvious-To-Try Analysis Fails ...............................49
`VIII. Grounds 1-3: Objective Evidence of Non-Obviousness ...............................54
`1.
`The Results Were Unexpected .................................................. 54
`2.
`Long-Felt Need ......................................................................... 56
`Institution Should Be Denied Under §325(d) ................................................56
`A. Advanced Bionics Part One ................................................................58
`B. Advanced Bionics Part Two ................................................................64
`Conclusion .....................................................................................................71
`
`IX.
`
`X.
`
`
`
`
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`iii
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`

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`IPR2023-00723
` U.S. Patent No. 8,129,343
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`10X Genomics, Inc. v. Bio-Rad Labs., Inc.,
`IPR2021-00133, Pap.11 (May 14, 2021) ............................................................ 69
`Adaptics Ltd. v. Perfect Co.,
`IPR2018-01596, Pap.20 (Mar. 6, 2019) (informative) ................. 4, 15, 16, 17, 18
`Adidas AG v. Nike, Inc.,
`963 F.3d 1355 (Fed. Cir. 2020) .................................................................... 34, 37
`ADT LLC v. Vivint, Inc.,
`IPR2022-00634, Pap.7 (Oct. 4, 2022) .......................................................... 16, 17
`Advanced Bionics, LLC v. MED-EL Elektromedizinische Gerate
`GmbH,
`IPR2019-01469, Pap.6 (Feb. 13, 2020) (precedential) ................................passim
`Agrinomix, LLC v. Mitchell Ellis Prods., Inc.,
`IPR2017-00525, Pap.8 (June 14, 2017) .............................................................. 68
`Alarm.com, Inc. v. Vivint, Inc.,
`IPR2022-00728, Pap.6 (Nov. 1, 2022) ............................................................... 60
`Amgen Inc. v. Sandoz Inc.,
`66 F.4th 952 (Fed. Cir. 2023) ............................................................................. 54
`Apple Inc. v. Universal Secure Registry, LLC,
`IPR2018-00808, Pap.9 (Oct. 9, 2018) ................................................................ 49
`In re Applied Materials, Inc.,
`692 F.3d 1289 (Fed. Cir. 2012) .......................................................................... 47
`Aquestive Therapeutics, Inc. v. Neurelis, Inc.,
`IPR2019-00451, Pap.8 (Aug. 13, 2019) ............................................................. 63
`Autel Intelligent Tech. Corp. v. Orange Elec. Co.,
`IPR2021-01545, Pap.8 (Apr. 8, 2022) ................................................................ 60
`
`iv
`
`
`

`

`IPR2023-00723
` U.S. Patent No. 8,129,343
`Becton, Dickinson and Co. v. B. Braun Melsungen AG,
`IPR2017-01586, Pap.8 (Dec. 15, 2017) (precedential) .......................... 57, 58, 60
`Bioeq IP AG v. Genentech, Inc.,
`IPR2016-01608, Pap.11 (Feb. 22, 2017) .......................................... 29, 31, 33, 41
`In re Boesch,
`617 F.2d 272 (C.C.P.A. 1980) ............................................................................ 53
`CSL Behring LLC v. Bioverative Therapeutics Inc.,
`IPR2018-01313, Pap.10 (Jan. 9, 2019) ................................................... 31, 39, 41
`Cuozzo Speed Techs., LLC v. Lee,
`579 U.S. 261 (2016) ............................................................................................ 16
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) .......................................................................... 52
`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) .............................................................. 60
`Dish Network LLC v. Sound View Innovations, LLC,
`IPR2020-00969, Pap.20 (Nov. 25, 2020) ........................................................... 54
`EnergySource Minerals, LLC v. TerraLithium LLC,
`IPR2019-01607, Pap.10 (May 4, 2020) ........................................................ 16, 18
`Forest Lab’ys, LLC v. Sigmapharm Lab’ys, LLC,
`918 F.3d 928 (Fed. Cir. 2019) ............................................................................ 55
`Gator Bio, Inc. v. Sartorius Bioanalytical Instruments, Inc.,
`IPR2023-00215, Pap.19 (June 20, 2023) ............................................................ 63
`Gilead Scis., Inc. v. Regents of the Univ. of Minn.,
`IPR2017-01753, Pap.42 (Apr. 22, 2020) .......................................... 26, 31, 39, 41
`Google LLC v. Jawbone Innovations, LLC,
`IPR2022-00889, Pap.12 (Nov. 14, 2022) ..................................................... 29, 34
`
`v
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`

`

`IPR2023-00723
` U.S. Patent No. 8,129,343
`
`Google LLC v. Valtrus Innovations Ltd.,
`IPR2022-01197, Pap.9 (Jan. 3, 2023) ................................................................. 70
`Immunex Corp. v. Sandoz Inc.,
`964 F.3d 1049 (Fed. Cir. 2020) .................................................................... 31, 33
`Institut Pasteur & Universite Pierre Et Marie Curie v. Focarino,
`738 F.3d 1337 (Fed. Cir. 2013) .......................................................................... 47
`InVue Sec. Prods., Inc. v. Mobile Tech., Inc.,
`IPR2019-00078, Pap.7 (May 1, 2019) ................................................................ 16
`Ivantis, Inc. v. Sight Scis., Inc.,
`IPR2022-01533, Pap.14 (Mar. 27, 2023) ..................................................... 60, 70
`Jiangsu Sainty Sumex Tools Corp. v. Milwaukee Elec. Tool Corp.,
`IPR2021-00373, Pap.19 (July 6, 2021) .............................................................. 18
`John Crane, Inc. v. Finalrod IP, LLC,
`IPR2016-01827, Pap.6 (Jan. 31, 2017) ......................................................... 16, 18
`Keysight Techs., Inc. v. Centripetal Networks, Inc.,
`IPR2022-01421, Pap.9 (Mar. 22, 2023) ............................................................. 60
`KSR Int'l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 48, 52
`Leo Pharm. Prods., Ltd v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .......................................................................... 52
`Life Spine, Inc. v. Globus Med., Inc.,
`IPR2022-01603, Pap.8 (June 12, 2023) ........................................................ 29, 33
`Merck Sharp & Dohme Corp v. Genentech, Inc.,
`PGR2021-00039, Pap.10 (July 24, 2021) ........................................................... 53
`Microsoft Corp. v. AlmondNet, Inc.,
`IPR2022-01319, Pap.9 (Jan. 30, 2023) ................................................... 57, 65, 67
`Microsoft Corp. v. ThroughPuter, Inc.,
`IPR2022-00757, Pap.10 (Nov. 1, 2022) ............................................................. 62
`
`vi
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`

`IPR2023-00723
` U.S. Patent No. 8,129,343
`
`Millenium Pharms., Inc. v. Sandoz Inc.,
`862 F.3d 1356 (Fed. Cir. 2017) .......................................................................... 41
`Monolithic Power Sys., Inc. v. Volterra Semiconductor LLC,
`IPR2020-01348, Pap.19 (Mar. 4, 2021) ............................................................. 68
`Motorola Mobility LLC v. Maxell, Ltd.,
`IPR2022-01287, Pap.11 (Feb. 2, 2023) .............................................................. 57
`Mylan Pharms. Inc. v. AstraZeneca AB,
`IPR2015-01340, Pap.79 (Aug. 18, 2017) ............................................... 43, 48, 55
`Mylan Pharms. Inc. v. Nissan Chem. Indus., Ltd.,
`IPR2015-01069, Pap.24 (Oct. 20, 2015) ................................................ 24, 27, 48
`Mylan Pharms. Inc. v. UCB Pharma GmbH,
`IPR2016-00514, Pap.38 (July 19, 2017) ................................................ 24, 27, 48
`Otsuka Pharm. Co., v. Sandoz, Inc.,
`678 F.3d 1280 (Fed. Cir. 2012) ...................................................................... 2, 20
`Par Pharm. Inc. v. Novartis AG,
`IPR2016-00084, Pap.73 (Jan. 11, 2018) ................................................. 24, 27, 49
`Pfizer Inc. v. Teva Pharms. USA, Inc.,
`555 F. App’x 961 (Fed. Cir. 2014) ..................................................................... 44
`Proctor & Gamble Co. v. Teva Pharms. USA, Inc.,
`566 F.3d 989 (Fed. Cir. 2009) ...................................................................... 30, 53
`Sanofi-Aventis Deutschland GmbH v. Glenmark Pharms. Inc., USA,
`748 F.3d 1354 (Fed. Cir. 2014) .................................................................... 53, 56
`Sanofi-Aventis U.S., LLC v. Dr. Reddy’s Lab’ys, Inc.,
`933 F.3d 1367 (Fed. Cir. 2019) ...................................................................... 2, 23
`Sawai USA, Inc. v. Astellas Pharma Inc.,
`IPR2018-00079, Pap.7 (May 4, 2018) .........................................................passim
`Stryker Corp. v. KFX Med., LLC,
`IPR2019-00817, Pap.10 (Sept. 16, 2019) ........................................................... 54
`
`vii
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`

`

`IPR2023-00723
` U.S. Patent No. 8,129,343
`
`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) ............................................................................ 15
`Weatherford U.S., L.P. v. Eventure Global Technology, Inc.,
`IPR2020-01684, Pap.16 (Apr. 14, 2021) ............................................................ 68
`In re Wesslau,
`353 F.2d 238 (C.C.P.A. 1965) ...................................................................... 31, 39
`Xerox Corp. v. Bytemark, Inc.,
`IPR2022-00624, Pap.9 (Aug. 24, 2022) (precedential) ...................................... 48
`Yamanouchi Pharm. Co. v. Danbury Pharmacal, Inc.,
`231 F.3d 1339 (Fed. Cir. 2000) .......................................................................... 23
`Statutes
`35 U.S.C. §312(a)(3) .......................................................................................... 16, 17
`Other Authorities
`37 C.F.R. §42.104(b)(4) ........................................................................................... 16
`
`
`
`
`
`viii
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`

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`IPR2023-00723
` U.S. Patent No. 8,129,343
`
`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
`
`unpatentability, including by failing to articulate clearly the arguments and
`
`evidence on which Petitioner purports to rely, and failing to show liraglutide would
`
`have been a lead compound. Petitioner also fails to show obviousness of Claims 1-
`
`6 (“Challenged Claims”/“Claims”) of U.S. Pat. 8,129,343 (“’343 Patent”/“’343”).
`
`Petitioner concedes semaglutide (the GLP-1 analogue covered by the Claims) is
`
`novel, arguing only that semaglutide, the active ingredient in PO’s revolutionary
`
`once-weekly drug Ozempic®—which generated nearly $3 billion in 2021 sales and
`
`over $8.5 billion in 2022—was somehow obvious.
`
`Petitioner’s Grounds 1 and 2 rest on a flawed lead-compound analysis that
`
`ignores the wide array of therapeutic approaches and potential leads a skilled artisan
`
`would have had to choose from. Instead, Petitioner zeroes in on liraglutide—a
`
`decision based on a hindsight-driven search for compounds structurally similar to
`
`the claimed invention. This directly contravenes Federal Circuit precedent. E.g.,
`
`
`1 Unless stated, all statutory and regulatory citations are to 35 U.S.C./37 C.F.R., as
`
`context indicates, and all emphases/annotations are added.
`
`1
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`
`

`

`IPR2023-00723
` U.S. Patent No. 8,129,343
`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 start, 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.
`
`Petitioner itself acknowledges in litigation that “[n]umerous other GLP-1 derivatives
`
`would have been candidates,” EX2001, 5, conceding here “[m]any would have
`
`worked” as a starting point. Pet.31. This confirms Petitioner failed to demonstrate
`
`liraglutide is a lead because Petitioner failed to show POSITA “would have had a
`
`reason to select [liraglutide] over” these “[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).
`
`Even if liraglutide were shown to be a proper lead, Petitioner fails to address
`
`Petitioner’s own art, which contradicts Petitioner’s proposed rationale for modifying
`
`liraglutide, and ignores the innumerable other modifications available to POSITA.
`
`While Petitioner attempts to suggest POSITA would have selected “three” particular
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`substantive changes to liraglutide2 from a multitude of known alternatives (including
`
`
`2 What Petitioner tries to call “three” proposed changes (Pet.6) are at least four:
`
`Petitioner proposes modifying both the (1) length (from C16 to C18) and (2) type
`
`
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`2
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`IPR2023-00723
` U.S. Patent No. 8,129,343
`others Petitioner’s own art recommends) to “reach semaglutide” (Pet.42), this
`
`unsupported argument contradicts the teachings and data in Petitioner’s own art—
`
`which Petitioner simply ignores. At bottom, the art clearly demonstrates that each
`
`liraglutide modification Petitioner claims was obvious was, in fact, 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 unsupported assertion by
`
`its expert, entitled to no weight.
`
`Ultimately, Petitioner seeks to stitch together a patchwork of unrelated
`
`excerpts from a disparate collection of references in a hindsight-based effort to
`
`recreate semaglutide from the prior art. This improper mixing-and-matching of
`
`prior-art snippets to track Petitioner’s theory, ignoring those that don’t, is legally
`
`insufficient.
`
`And Petitioner’s purported “Ground 3”—“Obviousness over the prior art
`
`and common drug development principles”—is a breathtakingly impermissible
`
`catch-all that fails to identify what references it relies on, what limitations are
`
`allegedly disclosed in particular references, or how one reference is modified by
`
`
`(monoacid to diacid) of liraglutide’s fatty acid, incorrectly labeling two changes as
`
`one. Pet.6, 39-40.
`
`3
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`

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`IPR2023-00723
` U.S. Patent No. 8,129,343
`another (if at all). Pet.51-59. Instituting this Petition and forcing PO to respond to
`
`such a grab-bag of arguments with no meaningful notice of what it must defend
`
`against (or what Petitioner might later argue was supported by this vague catch-all)
`
`would be highly prejudicial and a denial of due process. The Board has made clear
`
`that including improper grounds like 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 the extent it is considered on any
`
`“merits,” Ground 3’s “obvious-to-try” theory clearly fails: even a small handful of
`
`Petitioner’s own references disclose, at minimum, millions of combinations of
`
`modifications, and Petitioner again offers merely a conclusory REOS assertion.
`
`Infra, §§VI.C-VII.
`
`Finally, the Board should deny institution under §325(d). Petitioner’s
`
`grounds, largely resting on references sharing common authorship, simply recycle
`
`art considered, or are cumulative of art considered, during prosecution. And in
`
`claiming “material error,” Petitioner merely asserts the Examiner—using the same
`
`liraglutide art—failed to make the precise obviousness argument Petitioner urges
`
`here. Petitioner has not shown entitlement to institution based on the same or
`
`substantially the same art and arguments.
`
`Institution should be denied.
`
`4
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`IPR2023-00723
` U.S. Patent No. 8,129,343
`II. Claims Are Directed To A Novel, Non-Obvious Invention
`Before ’343’s inventions, there were various approved type 2 diabetes
`
`treatments, but with significant disadvantages. For example, sulphonylureas,
`
`glinides, biguanides, and insulin sensitizers were approved, but had limited
`
`efficacy and side effects like weight gain. EX1011, 1. Insulin was very effective
`
`but required multiple doses per day and presented a serious hypoglycemia risk. Id.
`
`“GLP-1” (glucagon-like peptide 1) was discovered in 1983 and initially described
`
`as an “incretin” (“promoting glucose-dependent insulin release” upon food
`
`ingestion). Id. Later, GLP-1—“found to lower plasma glucagon in a glucose-
`
`dependent manner, decrease the rate of gastric emptying, [and] promote
`
`fullness/satiety and stimulate insulin biosynthesis, as well as proliferation of β-
`
`cells”—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.
`
`After years of work, multiple GLP-1 analogues with different structures and
`
`approaches were being clinically investigated—some for potential once-daily
`
`administration. EX1010, 2. One of these was PO’s compound, liraglutide (below).
`
`Id. But as of the priority date, none were FDA approved, a majority of each
`
`analogue’s clinical data was not yet public (see EX1010, 2-5), and researchers
`
`continued searching.
`
`5
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`

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`IPR2023-00723
` U.S. Patent No. 8,129,343
`The Claims of ’343, “Acylated GLP-1 Compounds” (claiming priority to a
`
`March 23, 2005 provisional), are directed to semaglutide, and formulations and
`
`methods of treatment with semaglutide. EX1002, 1, 66-70; Pet.10. Semaglutide is
`
`a “GLP-1(7-37)”3 analogue with multiple changes from native human GLP-1(7-
`
`37) (below). EX20024, 2, 5. Semaglutide has a non-natural amino acid,
`
`aminoisobutyric acid, substituted at position 8 (“Aib8”). Id. Semaglutide also has
`
`a complex structure modifying GLP-1’s lysine (“Lys”) at position 26, consisting of
`
`a di-aminoethylethanolamine (“di-AEEA”) spacer bonded to a gamma glutamic
`
`acid (“γ-Glu”), which is bonded to a “C18”5 dicarboxylic fatty acid. Id. In
`
`addition, semaglutide has an arginine (“Arg”) substituted for the native lysine at
`
`position 34. Id.
`
`
`
`
`3 “GLP-1(7-37)” reflects that amino acids at positions 1-6 were cleaved from the
`
`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.
`
`5 “x” in “Cx” identifies the number of carbons in a fatty-acid chain.
`
`6
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`
`

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`IPR2023-00723
` U.S. Patent No. 8,129,343
`
`
`
`
`
`Pet.32, 35.
`
`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 previously-
`
`attempted longer-acting GLP-1 analogues. Pet.18; EX2002, 1-2, 5. These
`
`differences from GLP-1 surprisingly allowed PO’s commercial products with
`
`semaglutide as the only active ingredient—Ozempic® for diabetes and Wegovy®
`
`for chronic weight management—to be dosed once-weekly in a lower dose than
`
`analogues (like liraglutide) delivered daily, while providing greater blood glucose
`
`control and weight loss than liraglutide. As a result, patients need to inject
`
`significantly less frequently, and with less GLP-1 analogue (1.0mg/week
`
`semaglutide for diabetes, versus 8.4mg/week (1.2mg/day) liraglutide) to achieve a
`
`better outcome. EX2003, Figs. 1-5.
`
`7
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`
`

`

`IPR2023-00723
` U.S. Patent No. 8,129,343
`’343’s Examiner initially rejected the pending genus 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.
`
`III. Petitioner’s References Identify Thousands of Compounds and
`Potential Modifications
`A. Knudsen 2004 (EX1010)
`Knudsen 2004—cited on ’343’s face—is an article by a Novo Nordisk
`
`researcher discussing several GLP-1-based compounds under 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, 2-4;
`
`EX1002, 1. Notably, Knudsen 2004 discloses that, e.g., CJC-1131 has a half-life
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`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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`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).
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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 semaglutide features), “led to a significant loss of activity compared to
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`C16…, C14… and C12.” EX1011, 4 (C18 analogue 3x less active than C16, which
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`is 3x less active than C14 and C12). Further, diacids, “could be no longer than a
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`C14… before a loss in potency… compared to the γ-Glu spacer monoacid series…
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`was seen.” Id. (C16 diacid 2x less active than C14 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 or with a GABA-spacer instead of γ-Glu,
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`yielding 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 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-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—with no N-terminus modification—for development over
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`analogues with N-terminus modifications. Id. Finally, while Petitioner urges a
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`position 8 substitution to protect against DPP-IV degradation, Knudsen 2001 chose
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`liraglutide because it already had substantial protection against DPP-IV cleaving
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`through acylation without needing any position 8 substitution. Id.
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`C. Knudsen Patent (EX1012)
`The Knudsen Patent, “Derivatives of GLP-1 Analogs” (issued July 31,
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`2001), is assigned to PO. It was expressly considered during examination, and
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`discloses thousands of GLP-1 analogues—describing each as a “preferred
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`embodiment” (e.g., EX1012, cols.20-167), and recognizing each could be further
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`modified, including with amino acid substitutions and/or acylation at multiple
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`positions, numerous fatty acid options for the acylation, and numerous spacer
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`options for linking the fatty and amino acids. E.g., EX1012, 9:21-19:59. The
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`Knudsen Patent discloses:
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`• multiple GLP-1 analogues with 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 more potent than liraglutide, including,
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`e.g., Exs.16, 26, 30, 38-40, and 43 (EX1012, 193:35-46).
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`
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`D. Dong (EX1013)
`Dong discloses testing of GLP-1(7-36)7 analogues designed and synthesized
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`to improve half-life. EX1013, 6. Dong states GLP-1 is cleaved in vivo in two
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`places—between positions 8-9 (by DPP-IV) and 34-35—reducing its half-life. Id.
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`Attempting to increase half-life, Dong synthesized GLP-1 analogues with
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`substitutions at position 8, 35, 26, 34 and/or 31. While Petitioner proposes
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`substitutions at position 8 but not positions 31 and 35 to reach semaglutide, Dong
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`reports half-life is improved when two to five substitutions are made together,
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`including the “representative analogue,” compound 4, which includes 2
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`substitutions: Aib8 and Aib35 (a combination of substitutions absent in
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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 (7-36) would translate
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`to (7-37). Pet.23-24, 36-37; infra, §VI.B.2.a.
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`semaglutide). Id. Dong also reports Aib8,35 results in a half-life of 9.76 hours,
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`whereas Aib8 alone (as in semaglutide) resulted in a poorer half-life of only 4.52
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`hours—the second shortest of any GLP-1(7-36) analogue Dong tested. Id. And
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`Dong’s conclusion notes compound 4, Aib8,35 (not found in semaglutide), was
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`“significantly more efficacious than hGLP-1” (native human GLP-1). Id., 7.
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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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`Related publication WO00/69911, claiming priority to the same provisional
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`(60/159,783) and sharing (in relevant part) Bridon’s specification, is cited on
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`’343’s face. EX1002, 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 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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`“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 dev