Traiseiuspta. gov
`
`571-272-7822
`
`Paper 9
`Entered: October 2, 2023
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC. ,
`Petitioner,
`
`V.
`
`NOVO NORDISKA/S,
`Patent Owner.
`
`IPR2023-00722
`Patent 8,536,122 B2
`
`Before JOHN G. NEW, SUSAN L. C. MITCHELL, and
`ROBERT A. POLLOCK,Administrative Patent Judges.
`
`POLLOCK,Administrative Patent Judge.
`
`DECISION
`DenyingInstitution of/nter Partes Review
`35 US.C. $314
`
`
`
`571-272-7822
`
`Paper 9
`Entered: October 2, 2023
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC. ,
`Petitioner,
`
`V.
`
`NOVO NORDISKA/S,
`Patent Owner.
`
`IPR2023-00722
`Patent 8,536,122 B2
`
`Before JOHN G. NEW, SUSAN L. C. MITCHELL, and
`ROBERT A. POLLOCK,Administrative Patent Judges.
`
`POLLOCK,Administrative Patent Judge.
`
`DECISION
`DenyingInstitution of/nter Partes Review
`35 US.C. $314
`
`
`
`IPR2023-00722
`Patent 8,536,122 B2
`
`I.
`
`INTRODUCTION
`
`Petitioner, Mylan Pharmaceuticals Inc., filed a Petition for interpartes
`
`review of claims 1, 2, 4-11, 13, and 15 ofU.S. Patent No. 8,536,122 B2 (Ex.
`
`1001, “the ’122 patent’). Paper 1 (““Pet.”). Patent Owner, Novo Nordisk A/S,
`
`timely filed a Preliminary Response. Paper6 (“Prelim. Resp.”). Petitioner
`
`furtherfiled an authorized Reply to the Preliminary Response (Paper7,
`
`“Reply’’); Patent Ownerfiled a responsive Sur-Reply (Paper8, “Sur-reply”).
`
`For the reasons provided below, we determine Petitioner has not
`
`satisfied the threshold requirementset forth in 35 U.S.C. § 314(a). Because
`
`Petitioner has not demonstrated a reasonable likelihoodthat at least one
`
`claim ofthe ’122 patent is unpatentable, we do notinstitute an interpartes
`
`review on the Groundsraisedin the Petition. See SAS /nst., Inc. v. lancu,
`
`138 S. Ct. 1348, 1359-60 (2018); PGS Geophysical AS v. lancu, 891 F.3d
`
`1354, 1360 (Fed. Cir. 2018) (interpreting the statute to require “a simple yes-
`
`or-noinstitution choice respecting a petition, embracing all challenges
`
`included in the petition”); see also Guidance on the Impact of SAS on AIA
`
`Trial Proceedings (April 26, 2018). !
`
`A. Real Parties in Interest
`
`Petitioner identifies Mylan Pharmaceuticals Inc., Mylan Inc., and
`
`Viatris Inc. as the real parties-in-interest. Pet. 2. Patent Owneridentifies
`
`Novo Nordisk A/S and Novo Nordisk Inc. as real parties-in-interest. Paper4,
`
`1.
`
`' Available at https:/Avww.uspto.gov/patents-application-process/patent-
`trial-and-appeal-board/trials/guidance-impact-sas-aia-trial (“Guidance”).
`
`2
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`
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`IPR2023-00722
`Patent 8,536,122 B2
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`B. Related Matters
`
`In addition to the current matter, Petitioner challenges claims 1—6 of
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`U.S. Patent No. 8,129,343 B2 (Ex. 1002, “the ?343 patent”) in IPR2023-
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`00723. The ’122 patent is a continuation of application No. 11/908, 834 that
`
`issued as the °343 patent.
`
`Accordingto the parties, the *122 patentis at issue in the following
`
`pending actions involving the parties, among otherlitigations:
`
`Novo NordiskInc. v. Mylan Pharmaceuticals Inc. , No. 22-cv-
`01040-CFC (D. Del.);
`
`Novo NordiskInc. v. Viatris Inc., No. 1:23-cv-00013-TSK
`(N.D. W.Va.);
`
`Novo NordiskInc. v. Viatris Inc., No. 1:23-cv-00101-CFC (D.
`Del); and
`Inre: Ozempic (Semaglutide) PatentLitig., No. 22-md-3038-
`CFC (D. Del.).
`Pet. 2—3; Paper 4, 1-2.
`
`C. The ’122 Patent andRelevant Background
`
`The *122 patent, titled “Acylated GLP-1 Compounds,”is directed to
`
`modified analogs of glucagon-like peptide 1 (GLP-1). Ex. 1001, code (54),
`
`1:59-2:7. GLP-1? isa naturally-occurring insulinotropic peptide hormone
`
`derived from a37-amino acid precursor by the enzymatic removal of amino
`
`acids 1-6 and modification of aminoacids 8 and 26. See, e.g., id. at 3:27—30,
`
`Although the unprocessed peptide is sometimesreferred to as GLP-1 (see
`Pet. 17-18), we generally understand the term to refer to a processed form.
`See, e.g., Ex. 1002, 3:27—30. For additional specificity, GLP-1 peptides may
`be identified with reference to its amino acid sequence as comparedto the 37
`amino acid precursor form. For example, GLP-1(1—37) mayreferto the full-
`length parent molecule, and GLP-1(7—37) to a post-cleavage form in which
`amino acids 1—6 have been removed. See Prelim. Resp. 6, n.3.
`
`
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`IPR2023-00722
`Patent 8,536,122 B2
`
`Ex. 1011, 677.?:+ The structure ofa naturally-occurring mature form is
`
`shown below.
`
` GLP-1(7-37}
`
`Pet. 18; Prelim. Resp. 7.° Theabovefigureillustrates the structure ofGLP-
`
`1(7—37) including the modifications to the alanine 7 and lysine 26.
`
`In the body, GLP-1 1s rapidly degraded by dipeptidyl aminopeptidase
`
`IV (DPP-IV), such that “the natural hormoneis not very useful as a drug.”
`
`Ex. 1011, 677. According to the ’122 patent, the prior art discloses various
`
`“approaches... for modifying the structure of glucagon-like peptide 1
`
`(GLP-1) compoundsin order to provide a longer duration of action in vivo,”
`
`but indicates that, because ofthe short half-lives, prior art GLP-1
`
`compounds must be administeredat least once daily. See Ex. 1001, 1:23-43.
`
`The ’122 patent discloses improved GLP-1 analogs intended to allow
`
`for reduced dosing frequency whentreating type 2 diabetes. /d. at 1:52—2:7.
`
`In particular, the 122 patent describes GLP-1 analogs with modifications
`
`“of at least one non-proteogenic amino acid residue in positions 7 and/or 8
`
`relative to the sequence GLP-1(7-37) (SEQ ID No. 1), which is acylated
`
`3L. B. Knudsenetal., GLP-/ derivatives as novel compoundsfor the
`treatmentoftype 2 diabetes: selection ofNN2211for clinical development,
`26(7) DRUGS OF THE FUTURE 677-685 (2001). (“Knudsen 20017).
`+ We generally refer to the original page numbersofcited art rather than to
`the numbering assigned by the parties.
`> Naturally occurring GLP-1 also occurs as an amide, GLP-1(7-36) amide.
`See Ex. 1011, 677.
`
`
`
`IPR2023-00722
`Patent 8,536,122 B2
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`with a moiety to the lysine residue in position 26,” and wherein the moiety
`
`includesat least two acidic groups. /d. at 1:57—63, 4:4—16, Ex. 1011, 677.
`
`The non-proteogenic aminoacid residuein positions 7 and/or 8 protects the
`
`modified compounds from DPP-IV degradation as comparedto native GLP-
`
`1. See Ex. 1002, 4:4—-19; 6:18—25. The acylated GLP-1 analog binds to
`
`albumin and the GLP-1 receptor simultaneously. /d. at 5:4—6. Specifically,
`
`the acylated GLP-1 analog is acylated “with a lipophilic albumin binding
`
`moiety containing at least two free acidic chemical groups attached viaa
`
`non-natural aminoacid linkerto the lysine residue in position 26.” /d. at
`
`6:11-14.
`
`The ’122 patent discloses a numberof specific compounds, including
`
`semaglutide, N-e7°-[2-(2-[2+2-[2-(2-[4-(1 7-Carboxyheptadecanoylamino)-
`
`4(S)-carboxybutyrylaminoethoxy)ethoxyJacetylamino)ethoxy|ethoxy)
`
`acetyl|[Aib8,Arg34|GLP-1-(7-37)peptide. /d. at 57:1-58:37 (Example 4);
`
`Ex. 1020 § 100. The structure of semaglutide mayalso be illustrated as:
`
`
`
`Ex. 1020 4 100.
`
`D. Relevant Prosecution History
`
`The *122 patent wasfiled as Application No. 13/412,283 and claims
`
`priority as a continuation ofApplication no. 11/908,834, havingafiling date
`
`of March 20, 2006, that issuedas the *343 patent. Accordingly, we discuss
`
`the prosecution history both the ’343 and ’122 patents below.
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`
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`IPR2023-00722
`Patent 8,536,122 B2
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`1. The’343 Patent Prosecution History
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`In a first (and only) Office Action on the merits,° the Examiner
`
`rejected certain claims in view the Knudsen Patent’ and Larsen.* Ex. 1004,
`
`41-45. The Examiner found that the Knudsen Patent discloses a genus of
`
`GLP-1 analogs that encompassed the claimed genus. /d. at 41-42. The
`
`Examinerfurther found that the Knudsen Patent teaches attaching lipophilic
`
`substituents to the GLP-1 moiety to “obtain a satisfactory protracted profile
`
`of action.” /d. at 43. The lipophilic substituents may be attached by meansof
`
`a hydrophilic spacer. See id. The Examineralso found that Larsen teaches
`
`modifying GLP-1 with alpha-amino-isobutyric acid (Aib) at position 8 anda
`
`lipophilic substituent. /d. at 45. The Examiner determined that one of
`
`ordinary skill in the art would have been motivated to select GLP-1 analogs,
`
`spacers and lipophilic substituents taught by the Knudsen Patent, further
`
`modified with Larsen’s Aib aminoacid at position 8. /d. at 44-45.
`
`According to the Examiner, a person of ordinary skill in the art wouldhave
`
`been motivatedto make the modifications to produce analogs with increased
`
`stability and a satisfactory protracted profile of action. See id.
`
`In response, the Applicant cancelled the all claims andentered new
`
`claims that are substantially identical to those ofthe ’2 patent. Ex. 1004, 31—
`
`° Prior to this Office Action, Applicants engaged in an initial Examiner
`interview, submitted a preliminary amendment, and elected semaglutide for
`exam ination in response to a restriction requirement. See Ex. 1004, 68, 72,
`100-103.
`
`7L.B. Knudsenet al., US 6,268,343 B1, issuedJuly 31, 2001. (“Knudsen
`Patent’) (“Knudsen 2004”) (Ex. 1012).
`*P.J. Larsen et al., Systemic Administration ofthe Long-Acting GLP-1
`Derivative NN2211 Induces Lasting andReversible Weight Loss in Both
`Normal and Obese Rats, 50 DIABETES 2530 (2001) (“Larsen”) (Ex. 1086).
`
`
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`IPR2023-00722
`Patent 8,536,122 B2
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`33. The Applicant noted “that the new claimsare directed to the compound
`
`disclosed in Example 4.” /d. at 35. Following an Examiner’s amendmentto
`
`correct the sequence ofthe claimed formula, the Examinerissued a Notice of
`
`Allowance. See id. at 20-27.
`
`2. The’122 Patent Prosecution History
`
`In a first Action, the Examinerrequired election of species between
`
`claims directedto compounds(claims 1—26) and methodsofusing the
`
`compounds(claims 27—29). Ex. 1003, 88-89. The Examinerfurther required
`
`election ofa single disclosed species for prosecution on the merits. /d. at 90.
`
`In response, the Applicant cancelled the originally filed claims, and entered
`
`new claims 32-47,reciting a genus of GLP-1 analogs. /d. at 75—80. Within
`
`the genus, Applicant elected the compound ofExample 5 (semaglutide) as
`
`the species. /d. at 81-82.
`
`Following the Amendment, the Examiner issueda Notice of
`
`Allowance. See id. at 38-45.
`
`E.
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`Illustrative Claims
`
`Claim 1 is the only independent claim ofthe ’122 patent. See Ex.
`
`1001, 123:2-124:43. Ofthese, Petitioner challenges claims 1, 2, 4-11, 13,
`
`and 15. Pet. 1. There is no dispute that the challenged claims encompass
`
`semaglutide, the active ingredient in Patent Owner’s Ozempic, Rybelsus,
`
`and Wegovyproducts. See Prelim. Resp. 1,7—8; Pet. 2, 6, 67.
`
`Challenged claim 1 is reproduced below.
`
`
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`IPR2023-00722
`Patent 8,536,122 B2
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`1. A compound of formula II (SEQ ID No. 3):
`
`AtayAaee-CNu-Cly-Thy-Phe- Ther Sees-epNisag-Sees-Aas ceB69 jgAtay
`
`tt
`
`The NaasSagAleSais ooo Ny,
`
`~Sdier PiesTlisBkagae
`
`== a
`
`-Yip-Lass ~My yNailag-NMSsy 5POAds 7ANazg,
`
`wherein
`
`Xaaz 1s L-histidine, D-histidine, desamino-histidine,
`2-amino-histidine, B-hydroxy-histidine, homohistidine,
`N°-acetyl-histidine, a-fluoromethy]-histidine,
`a-methyl-histidine, 3-pyridylalanine, 2-pyridylalanine,or
`4-pyridylalanine;
`
`Xaas is Gly, Val, Leu, Ile, Lys, Aib, (1-aminocyclopropyl)
`carboxylic acid, (1-aminocyclobutyl) carboxylic acid,
`(1-aminocyclopenty1) carboxylic acid, (1-aminocyclohexy])
`carboxylic acid, (1-aminocycloheptyl) carboxylic acid, or
`(1-aminocyclooctyl) carboxylic acid;
`
`Xaaio is Val or Leu;
`
`Xaais 1s Ser, Lys, or Arg;
`
`Xaaig 1s Tyr or Gln;
`
`Xaayo 1s Leu or Met;
`
`Xaaz2 1s Gly, Glu, or Aib;
`
`Xaaz3 1s Gln, Glu, Lys, or Arg;
`
`Xaazs 1s Alaor Val;
`
`Xaaz7 1s Glu or Leu;
`
`
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`IPR2023-00722
`Patent 8,536,122 B2
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`Xaa3z3 1s Ala, Glu, or Arg;
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`Xaaz3 1s Val or Lys;
`
`Xaaza 1s Lys, Glu, Asn, or Arg;
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`Xaazs 1s Gly or Aib;
`
`Xaazo 1s Arg, Gly, Lys, or is absent;
`
`Xaaz7 1s Gly, Ala, Glu, Pro, Lys, oris absent;
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`Xaaszs 1s Lys, Ser, amide, or is absent; and
`
`where U is a spacer selected from
`
`
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`IPR2023-00722
`Patent 8,536,122 B2
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`vAAN
`
`and
`
`
`
`re!
`
`YL BF
`
`On
`
`ce
`
`where nis 12, 13, 14, 15, 16, 17, or 18,
`
`lis 12, 13, 14, 15, 16, 17, or 18,
`
`mis 0, 1,2, 3,4, 5, or 6,
`
`sis 0, 1,2, or 3,
`
`pis 3, 4,5, 6,7, 8,9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
`21,22, or 23; and
`
`where B 1s an acidic group selected from
`
`and
`
`ery
`
`oy
`
`G
`
`K
`
`woa
`
`o
`
`Ex. 1001, 1:2—124:43; Certificate of Correction 1.
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`With respect to the challenged dependentclaims, claims 2, and 4-11
`
`recite compoundswithin the genusof claim 1. See id. at 124:44—-126:41.
`
`Claim 13 recites a pharmaceutical compound comprising a compound of
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`claim 1. /d. at 131:16—18. Claim 15 recites a method oftreating
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`hyperglycemia and/or type 2 diabetes by administering a GLP-1 analog
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`according to claim 1. /d. at 131:22—132:17.
`
`10
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`
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`IPR2023-00722
`Patent 8,536,122 B2
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`F. Asserted Grounds ofUnpatentability
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`Petitionerasserts that claims 1, 2, 4-11, 13, and 15 would have been
`
`unpatentable on the following grounds:
`
`
`
`1,2,4-11,
`13,15
`
`103
`
`Knudsen 2004,”
`Knudsen Patent, Dong,'°
`Bridon!!
`
`13, 15
`
`13, 15
`
`Knudsen Patent, Dong, Bridon
`
`Knudsen Patent, Dong, Bridon
`
`Petitioner further relies, inter alia, on the Declarations ofPeter Flatt,
`
`Ph.D. (Ex. 1020), Christopher J. Soares, Ph.D. (Ex. 1022), Paul Dalby,
`
`° L. B. Knudsen, Glucagon-likePeptide-1: The Basis ofa New Class of
`Treatmentfor Type 2 Diabetes, 47 J. MED. CHEM.4128-4134 (2004). (Ex.
`1010).
`10 J. Z. Dong et al., Glucagon-LikePeptide-IAnalogs with Significantly
`Improved in vivo Activity, in PEPTIDES: THE WAVE OF THE FUTURE,
`PROCEEDINGS OF THE SECOND INTERNATIONAL AND THE SEVENTEENTH
`AMERICAN PEPTIDE SYMPOSIUM 670-671 (2001). (“Dong”) (Ex. 1013).
`'TT).P. Bridonet al., US 6,514,500 B1, issued Feb. 4, 2003. (“Bridon’’)
`(Ex. 1014).
`L. B. Knudsenetal., GLP-/ derivatives as novel compoundsfor the
`treatmentoftype 2 diabetes: selection ofNN2211for clinical development,
`26(7) DRUGS OF THE FUTURE 677-685 (2001). (Ex. 1011).
`'3 Petitioner casts Ground3 asdirected to “[o]bviousnessoverthe priorart
`and commondrug developmentprinciples.” Pet. 5. Insofar as Petitioner’s
`review of the “Scope and Content ofthe Prior Art,” addresses only Knudsen
`2004, Knudsen 2001, Knudsen Patent, Dong, and Bridon, weinfer that
`Ground3 is also limited to these five references. See id. at 19-26; see also
`Reply, 1 (Petitioner’s statement that “Ground 3 relies on the samepriorart
`as Grounds | and2.”).
`
`11
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`
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`IPR2023-00722
`Patent 8,536,122 B2
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`Ph.D. (Ex. 1024), and John Bantle, M.D. (Ex. 1026). Patent Owner’s
`
`Preliminary Response doesnotidentify the testimony of subject matter
`
`declarant(s).
`
`Il. ANALYSIS
`
`A. Legal Standards
`
`“Tn an [interpartes review], the petitioner has the burden from the
`
`onset to show with particularity why the patent it challengesis
`
`unpatentable.” Harmonic Inc. v. Avid Tech., Inc. , 815 F.3d 1356, 1363 (Fed.
`
`Cir. 2016) (citing 35 U.S.C. § 312(a)(3) (2012) (requiring interpartes
`
`review petitions to identify “with particularity . .. the evidence that supports
`
`the grounds for the challenge to each claim’’)). This burden ofpersuasion
`
`never shifts to Patent Owner. See Dynamic Drinkware, LLC v. Nat’]
`
`Graphics, Inc., 800 F.3d 1375, 1378 (Fed. Cir. 2015) (discussing the burden
`
`of proof in inter partes review).
`
`A claim is unpatentable under 35 U.S.C. § 103 if the differences
`
`between the claimed invention andthe priorart are such that the claimed
`
`invention as a whole would have been obviousbefore the effective filing
`
`date ofthe claimed invention to a person having ordinary skill in the art to
`
`whichthe claimed invention pertains. See KSR Int’] Co. v. Teleflex Inc. , 550
`
`U.S. 398, 406 (2007). The question of obviousnessis resolved on the basis
`
`of underlying factual determinations including: (1) the scope and content of
`
`the priorart; (2) any differences between the claimed subject matter and the
`
`prior art; (3) the level of ordinary skill in the art; and (4) objective evidence
`
`of nonobviousness, ifany. Graham v. John Deere Co., 383 U.S. 1, 17-18
`
`(1966).
`
`12
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`IPR2023-00722
`Patent 8,536,122 B2
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`In analyzing the obviousness of a combinationofprior art elements,it
`
`can be importantto identify a reason that wouldhave prompted one ofskill
`
`in the art “to combine. .
`
`. known elements in the fashion claimed by the
`
`patent at issue.” KSR, 550 U.S. at 418. A precise teaching directed to the
`
`specific subject matter ofa challenged claim is not necessary to establish
`
`obviousness. /d. Rather, “any need or problem known mnthefield of
`
`endeavorat the time of invention and addressed by the patent can provide a
`
`reason for combining the elements in the mannerclaimed.”/d. at 420.
`
`Accordingly, a party that petitions the Board for a determination of
`
`unpatentability based on obviousness must show that “a skilled artisan
`
`would have been motivated to combine theteachings ofthe prior art
`
`references to achieve the claimed invention, and that the skilled artisan
`
`would have had a reasonable expectation of success in doing so.” /n re
`
`Magnum Oil Tools Int’l, Ltd. , 829 F.3d 1364, 1381 (Fed. Cir. 2016) (internal
`
`quotations omitted).
`
`The Federal Circuit provides a two-prong analysis to determine
`
`whethera new chemical compoundis prima facie obviousoverparticular
`
`prior art. The fact finder first determines whether a chemist of ordinary skill
`
`would have selected one or moreprior art compounds as lead compounds,or
`
`starting points, for further developmentefforts. (Otsuka Pharm. Co.v.
`
`Sandoz Inc., 678 F.3d 1280, 1291 (Fed. Cir. 2012). The Court defines a lead
`
`compoundas “a compoundin the prior art that would be most promising to
`
`modify in order to improve upon its... activity and obtain a compound with
`
`better activity,” (Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd. , 492
`
`F.3d 1350, 1357 (Fed. Cir. 2007), or “a natural choice for further
`
`developmentefforts.” A/tana PharmaAG v. Teva Pharm. USA, Inc. , 566
`
`F.3d 999, 1008 (Fed. Cir. 2009). The second step involves determining
`
`13
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`Patent 8,536,122 B2
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`“whether the prior art would have supplied one ofordinary skill in the art
`
`with a reason or motivation to modify a lead compoundto make the claimed
`
`compound with a reasonable expectation of success.” Otsuka, 678 F.3d at
`
`1292 (citing Takeda, 492 F.3d at 1357).
`
`B. Level of Ordinary Skill in the Art
`
`In determining the level of skill in the art, we consider the type of
`
`problems encounteredin theart, the prior art solutions to those problems, the
`
`rapidity with which innovations are made, the sophistication ofthe
`
`technology, and the educationallevel of active workersin the field. See
`
`Custom Accessories, Inc. v. Jeffrey-Allan Industries, Inc. , 807 F.2d 955, 962
`
`(Fed. Cir. 1986); see also Orthopedic Equip. Co. v. United States, 702 F.2d
`
`1005, 1011 (Fed. Cir. 1983).
`
`In addressing the level of ordinary skill in the art, Petitioner contends
`
`that “[t]he claimed subject matter falls within the medicinal chemical and
`
`pharmacological arts and encompasses the skills, education, and expertise of
`
`a team ofindividuals working together to develop and formulate GLP-1
`
`analogsto treat patients having type-2 diabetes or related conditions.”Pet. 7.
`
`The persons of ordinary skill in the art (““POSA”) making up the team would
`
`have
`
`in chemistry,
`an M.D., Pharm.D., or doctoral degree(s)
`biochemistry, pharmaceutics, pharmaceutical sciences, chemical
`engineering, biochemical engineering or related fields, with at
`least two years of experience in developing therapeutic peptides
`or proteins, and experience with the development, design,
`manufacture, formulation, or administration of therapeutic
`peptides or proteins, and the literature concerning protein or
`peptide formulation and design or diabetes treatments.
`
`14
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`IPR2023-00722
`Patent 8,536,122 B2
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`Id. at 7-8 (citing Ex. 1020 9 26; Ex. 1022 4 26; Ex. 1024 4 20; Ex. 1026
`
`§ 24). 4 Patent Ownerdoesnotoffer a different level ofordinary skill in the
`
`art. See generally Prelim. Resp.
`
`On the current record, and for the purposes ofthis decision, we accept
`
`Petitioner’s proposed definition,as it appears consistent with the level of
`
`skill in the art reflected in the prior art ofrecord and the disclosure ofthe
`
`*122 Patent. See Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001)
`
`(“the priorart itself [may] reflect[] an appropriate level” as evidence ofthe
`
`ordinary level of skill in the art) (quoting Litton Indus. Prods., Inc. v. Solid
`
`State Sys. Corp., 755 F.2d 158, 163 (Fed. Cir. 1985)).
`
`C. Claim Construction
`
`Weinterpret a claim “using the sameclaim construction standard that
`
`would be used to construe the claim in a civil action under 35 U.S.C.
`
`282(b).” 37 C.F.R. § 42.100(b) (2020). Underthis standard, we construe the
`
`claim “in accordance with the ordinary and customary meaning of such
`
`claim as understood by one of ordinary skill in theart and the prosecution
`
`history pertaining to the patent.” /d. Moreover, “the specification ‘is always
`
`highly relevantto the claim construction analysis. Usually it is dispositive; it
`
`is the single best guide to the meaning of a disputed term.’” /n re Abbott
`
`Diabetes Care Inc., 696 F.3d 1142, 1149 (Fed. Cir. 2012) (quoting Phillips
`
`v. AWH Corp., 415 F.3d 1303, 1315 (Fed. Cir. 2005) (en banc)).
`
`The parties contend that no claim term requires construction.Pet. 16.
`
`Prelim. Resp. 16. Having considered the record, we determine that no
`
`express claim construction of any claim term is necessary to reach our
`
`'4 We need not considerPetitioner’s similar, but alternative, definitions. See
`id. at 8-9.
`
`15
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`
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`IPR2023-00722
`Patent 8,536,122 B2
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`decision. See Nidec Motor Corp. v. Zhongshan Broad Ocean MotorCo. Ltd.
`
`v. Matal, 868 F.3d 1013, 1017 (Fed. Cir. 2017) (“[W]e need only 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 ofAsserted References
`
`Petitioner’s Groundsare based on a combinations ofKnudsen 2004
`
`and/or Knudsen 2001 with Knudsen Patent, Dong, and Bridon, which we
`
`briefly address below.
`
`1.
`
`Knudsen 2004 (Ex. 1010)
`
`Knudsen 2004 provides an overview of GLP-1 based compoundsin
`
`development. Ex. 1010. By way ofbackground, Knudsen 2004 discloses that
`
`“GLP-1 wasdiscovered in 1984 and foundto be an importantincretin.It is a
`
`product ofthe preproglucagon gene andis released from the L-cells in the
`
`intestine upon food intake and potently releases insulin from the B-cells in
`
`the pancreas.” /d. at 4128. “GLP-1 exists in two equipotent naturally
`
`occurring forms, GLP-1(7-37)and GLP-1(7-36)amide, the former
`
`corresponding to proglucagon(78-108).” /d. Knudsen 2004 explains that
`
`[t]he numbering of GLP-1 starts with 7 becauseit wasoriginally believed
`
`that GLP-1(1-37) was theactive hormone.” The current numbering system
`
`began whenit was discovered that the active hormoneis formed upon
`
`removalofthe first 6 N-terminal amino acids. /d. The naturally-occurring
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`“hormoneis degraded rapidly by the enzyme dipeptidyl peptidase IV (DDP-
`
`IV) and cleared by the kidneysresulting in a half-life of less than 2 min after
`
`iv administration and a clearance higher than that ofthe normalcardiac
`
`output.” Jd.
`
`16
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`
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`IPR2023-00722
`Patent 8,536,122 B2
`
`Knudsen 2004 explains that because natural GLP-1 “has a very short
`
`half-life because of cleavage by DPP-I'Vand rapid clearance,”the challenge
`
`in making GLP-1 receptor peptide-therapeutics “is to makeastable
`
`compound with a long half-life.” /d. at 1429, 4130. In this respect, Knudsen
`
`2004 discloses that there are two subclasses of GLP-1 analogsin clinical
`
`developmentas treatments for Type 2 Diabetes: one based on natural GLP-1
`
`and the other based on exendin-4, a peptide agonist isolated from the venom
`
`of the lizard Heloderma Suspectum, which showsa53% structural
`
`homology to GLP-1. /d. at 4129.!° Knudsen 2004 notes that exendin-4is
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`moreresistant to proteolytic degradation than GLP-1, but that certain
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`modifications designed to further increase its stability “may... be at the
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`expense of an immunereaction to the peptide.” /d. at 4130.
`
`With respect to GLP-1, Knudsen 2004illustrates the structure-activity
`
`relationships of GLP-1(7—37)in Figure 3, reproduced below.
`
`'S We presume withoutdeciding that exendin-4 derivatives, such as
`exenatide, are GLP-1 analogs within the meaning ofthe ’122 patent.
`
`17
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`
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`IPR2023-00722
`Patent 8,536,122 B2
`
`
`
`
`cleavagesite e
`
`
`seems
`
`© S Sssantial for binding framAla-secan
`
`®& May be darivatioed with fong fatty acid
`® Consermad bebwaan GLP] and exendin~¢
`z
`yy
`ww \
`
`® May be modified for DPR-IY stabifity ~~
`
`
`Figure 3 is a color-coded representation of GLP-1 amino acids 7-37.
`
`Ex. 1010, 4130. According to Knudsen 2004, “it has been proposedthat the
`
`N-terminalpart ofthe peptide is responsible for the high-affinity binding to
`
`the core ofthe receptor, whereas the C-terminal is more responsible for the
`
`selectivity by interacting with the large N-terminal ofthe receptor.” /d. With
`
`respect to the individual amino acids shown in Figure 3, Knudson 2004
`
`discloses that Ala®, colored blue, may be modified for DPP-IV stability,
`
`whereas aminoacids Ser'®, GIn**, Lys”°, Glu’, Lys**, and Arg*®, colored
`
`green, may be derivatized with a long fatty acid. /d.
`
`Knudsen 2004 lists seven known GLP-1 analogs, but states that most
`
`of these compounds“are in the discovery phaseor in small-scale 2 phase
`
`clinical development”and“very little is published in peer-reviewed
`
`journals.” See Ex. 1010, 4129, 4131. In contrast, Knudsen 2004 discloses
`
`that Novo Nordisk completed phase2 clinical trials with liraglutide,(y-L-
`
`glutamyl(-a-hexadecanoyl))-Lys’®,Arg*4+-GLP-1(7-37) (NN2211). /d. at
`
`18
`
`
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`IPR2023-00722
`Patent 8,536,122 B2
`
`4130.'° Referencing “[s]everal preclinical and clinical studies,” Knudsen
`
`2004states that “Liraglutide 1s equipotent to GLP-1 and hasa half-life that is
`
`more than 10-fold larger that of exendin-4, 8 h vs 26 min after iv
`
`administration,[] respectively.” /d. “Liraglutideis part ofa series of acylated
`
`derivatives of GLP-1 that are aimed at being long-acting via two
`
`independent mechanisms, self-association and noncovalent binding to
`
`plasma albumin fatty acid bindingsites, resulting in a pharmacokinetic
`
`profile with slow absorption anda longhalf-life.” /d. Liraglutide in
`
`particular is acylated at Lysine 26 with ((y-L-glutamoyl(N-s-hexadecanoyl)).
`
`7d. Knudsen explainsthat acylation at different siteson GLP-1 may improve
`
`half-life while retaining potencyor, alternatively, destroy potency. See id.
`
`With respect to the latter, Knudsen 2004 cautionsthat “[a] potency-
`
`destroying SAR!'Ihas... been generated in which acylation in the N-
`
`terminus position 8 leads to a compoundabout 20 timesless potent than
`
`GLP-1,” whereas, “[a]cylation with two fatty acids on both naturally present
`
`lysines in positions 26 and 34 destroys potency.” /d.
`
`2. Knudsen 2001 (Ex. 1011)
`
`Knudsen 2001 explains that GLP-1’s mode of action suggests it would
`
`provide “the ideal treatment oftype 2 diabetes.” Ex. 1011, 679. However,
`
`GLP-1 is “metabolizedrapidly by DPP-IV”and “cleared very rapidly from
`
`the kidneys.” /d. To address the short physiological half-life, Knudsen 2001
`
`discloses GLP-1 derivativesfor treating type2 diabetes, specifically
`
`16 By way of context, liraglutide is now the active ingredient in Saxendaand
`Victoza commercial products. See Exs. 3002, 3003.
`17 “SAR”refers to Structure-Activity-Relationship. See Ex. 1020 § 80.
`
`19
`
`
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`IPR2023-00722
`Patent 8,536,122 B2
`
`NN2211, later named liraglutide. See id. at 677, 680 (Table 1, compound5).
`
`According to Knudsen 2001,
`
`[f]atty acid derivatization has been used successfully to
`protract the action ofinsulin by facilitating binding to plasma
`albumin. The same principle has been used to design
`derivatives of GLP-1 with half-lives longer than 10 h, thereby
`being optimalfor once-daily administration. Fatty acidsor fatty
`diacids, optionally extended with a “spacer” betweenthe
`epsilon-amino group ofthe lysine side chain and the carboxy]
`group ofthe fatty acid, were used. Acylation with simplefatty
`acids increasesthe net negative charge ofthe resulting molecule
`with one (by blocking the epsilon-aminogroupofthe lysine),
`whereaspeptides acylated with a L-glutamoyl-spacer or with
`diacids providesa further increase ofthe negative charge. The
`addition of a negative charge to the acylated molecule is
`expected to improvesolubility at physiological pH.
`
`Id. at 679 (internal citations omitted).
`
`Knudsen 2001 provides twenty-two examples of GLP-1 “derivatized
`
`on position 8, 18, 23, 26, 27, 34, 36 or 38 with fatty acids and optionally a
`
`spacer.” See, e.g., id. at 677, 680 (Table 1). “All compounds acylated witha
`
`fatty acid equalto or longer than 12 carbon atoms were considerabl[y]
`
`protracted compared to native GLP-1, which had a half-life afters.c.
`
`administration of only 1.2 h.” /d. Focusing on aset of examples derivatized
`
`with a y-Glu-C16 monoacid, Knudsen 2001 notes that “[m Jany different
`
`positions in the C-terminal part of GLP-1 could be derivatized with quite
`
`long fatty acids, visualized with compounds 3-9 (ECs 30-121 pM) without
`
`affecting the potency.”/d. at 680 (referencing compound numbersand
`
`potency data from Table 1). Focusing on a series of compoundsderivatized
`
`on lysine 26, however, Knudsenfurther notesthat, “[w]ithin the y-Glu
`
`spacer monoacid series (5, 16-18), derivatization with a C18 acid (16, 194
`
`pM ) led toa significant loss of activity comparedto C16 (5, 68 pM), C14
`
`20
`
`
`
`IPR2023-00722
`Patent 8,536,122 B2
`
`(17, 22 pm) and C12 (18, 27 pm). /d. Moreover, “[w]ithin the diacid series
`
`(14, 15), the diacid could be no longer than a C14 (15, 72 pM) before a loss
`
`in potency (14, 154 pM), compared to the y-Glu spacer monoacid series (17,
`
`18, 22-27 pM)wasseen.”/d.
`
`Of the twenty-two compoundslisted in Table 1, Knudsen 2001
`
`identifies compounds 4, 5, 7, 8, 18,20 and 21 as “very potent,” with
`
`compounds5, 7, and 8, showing “dramatic differences in plasma half-lives”
`
`as compared to naturally-occurring GLP-1. /d. at 679-680 (TableII).
`
`Knudsen 2001 explainsthat, although “[a] number of compounds were both
`
`very potent and had plasma half-lives above 10 h, making them suitableas
`
`drugs for the treatment oftype 2 diabetes using once-daily administration,”
`
`only liraglutide (compound 5) wasselected for clinical development. /d.at
`
`681-682. According to Knudsen 2001, liraglutide showed“equal potency to
`
`GLP-1”in in vitro testing, and its “mechanism ofprotraction involves
`
`binding to albumin, metabolic stability towards DPP-IV and slow release
`
`from the injection site.” /d. Knudsen 2001 further describes the specific
`
`attributes of liraglutide and the reasons for choosingit as the best compound
`
`for clinical development. /d. Knudsen 2001 reports, for example, that
`
`acylation of lysine 26 with a y-L-Glu spacer “gave the most potent” and
`
`“metabolically stable compound”with a half-life of20 hours. /d. Although
`
`“[a|mino acid substitutions in position 8 can give better metabolic stability
`
`against DPP-IV,” that was not neededfor liraglutide because “quitea
`
`substantial protection against DPP-IV was obtained by acylation alone, and
`
`since any aminoacid substitution poses arisk of immunogenicity.” /d.
`
`Knudsen 2001, concludes:
`
`[liraglutide] is ametabolically stable compound with potency
`equal to GLP-1. It has been characterized to act asa GLP-1
`
`21
`
`
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`IPR2023-00722
`Patent 8,536,122 B2
`
`compoundin several animal models, including the ability to
`lower body weight. [liraglutide] is currently the only GLP-1
`compoundin clinical developmentthat has been shown to
`possess pharmacokinetic properties applicable to once-daily
`administration. The only study carried out thus far in type 2
`diabetic patients has confirmed its efficacy. Ongoing phase 2
`clinicaltrials will reveal the potential of [liraglutide] as a
`promising new treatmentfor type 2 diabetes.
`Id. at 682.
`
`3. Knudsen Patent (Ex. 1012)
`
`Knudsen Patentis a U.S. Patent for “Derivatives of GLP-1 Analogs.”
`
`Ex. 1012, code (54). Knudsen Patent describes GLP-1 derivatives having a
`
`lipophilic substituent resulting in a protracted profile of action. /d. at
`
`code (57).
`
`Knudsen Patent describes various modifications to naturally occurring
`
`GLP-1. See Ex. 1012, 8:13—23. Knudsen Patent states, For example, “[tJhe
`
`GLP-1 derivatives ofthe present invention preferably have only one or two
`
`Lys wherein the g-amino groupofoneor both Lysis substituted with a
`
`lipophilic substituent.” /d. at 12:24—26. The lipophilic substituent may be
`
`attached viaa spacer, wherein suitable spacers are a, @-amino acids, such as
`
`“succinic acid, Lys, Glu or Asp, ora dipeptide such as Gly-Lys.”/d. at
`
`17:55—60. “Other preferred spacers are N¢-(y-L-glutamyl[)], N®-(B-L-
`
`asparagyl), N®-glycyl, and N-(a-(y-aminobutanoyl)[)].” /d. at 18:11—13.
`
`“The lipophilic substituents preferably comprises 4—40 carbon atoms... .
`
`The lipophilic substituent may be attached to an amino group ofthe GLP-1
`
`moiety by means of acarboxyl group.”/d. at 16:55—67. “In a further
`
`preferred embodiment, the lipophilic substituent is an acyl group ofthe
`
`formulaHOOC(CH2)nCO-, wherein m is an integer from 4 to 38.” /d. at
`
`19:17-19.
`
`22
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`
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`IPR2023-00722
`Patent 8,536,122 B2
`
`KnudsenPatent lists 100 different examples of GLP-1 analogs,
`
`including liraglutide(Example
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