Trials@uspto.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 NORDISK A/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
`Denying Institution of Inter Partes Review
`35 U.S.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 NORDISK A/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
`Denying Institution of Inter Partes Review
`35 U.S.C. § 314
`
`
`
`
`
`
`
`
`
`IPR2023-00722
`Patent 8,536,122 B2
`
`INTRODUCTION
`I.
`Petitioner, Mylan Pharmaceuticals Inc., filed a Petition for inter partes
`review of claims 1, 2, 4–11, 13, and 15 of U.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. Paper 6 (“Prelim. Resp.”). Petitioner
`further filed an authorized Reply to the Preliminary Response (Paper 7,
`“Reply”); Patent Owner filed a responsive Sur-Reply (Paper 8, “Sur-reply”).
`For the reasons provided below, we determine Petitioner has not
`satisfied the threshold requirement set forth in 35 U.S.C. § 314(a). Because
`Petitioner has not demonstrated a reasonable likelihood that at least one
`claim of the ’122 patent is unpatentable, we do not institute an inter partes
`review on the Grounds raised in the Petition. See SAS Inst., Inc. v. Iancu,
`138 S. Ct. 1348, 1359–60 (2018); PGS Geophysical AS v. Iancu, 891 F.3d
`1354, 1360 (Fed. Cir. 2018) (interpreting the statute to require “a simple yes-
`or-no institution 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). 1
`A. Real Parties in Interest
`Petitioner identifies Mylan Pharmaceuticals Inc., Mylan Inc., and
`Viatris Inc. as the real parties-in-interest. Pet. 2. Patent Owner identifies
`Novo Nordisk A/S and Novo Nordisk Inc. as real parties-in-interest. Paper 4,
`1.
`
`
`
`
`1 Available at https://www.uspto.gov/patents-application-process/patent-
`trial-and-appeal-board/trials/guidance-impact-sas-aia-trial (“Guidance”).
`
`2
`
`
`
`IPR2023-00722
`Patent 8,536,122 B2
`B. Related Matters
`In addition to the current matter, Petitioner challenges claims 1–6 of
`U.S. Patent No. 8,129,343 B2 (Ex. 1002, “the ’343 patent”) in IPR2023-
`00723. The ’122 patent is a continuation of application No. 11/908,834 that
`issued as the ’343 patent.
`According to the parties, the ’122 patent is at issue in the following
`pending actions involving the parties, among other litigations:
`Novo Nordisk Inc. v. Mylan Pharmaceuticals Inc., No. 22-cv-
`01040-CFC (D. Del.);
`Novo Nordisk Inc. v. Viatris Inc., No. 1:23-cv-00013-TSK
`(N.D. W. Va.);
`Novo Nordisk Inc. v. Viatris Inc., No. 1:23-cv-00101-CFC (D.
`Del); and
`In re: Ozempic (Semaglutide) Patent Litig., No. 22-md-3038-
`CFC (D. Del.).
`Pet. 2–3; Paper 4, 1–2.
`C. The ’122 Patent and Relevant 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-12 is a naturally-occurring insulinotropic peptide hormone
`derived from a 37-amino acid precursor by the enzymatic removal of amino
`acids 1–6 and modification of amino acids 8 and 26. See, e.g., id. at 3:27–30,
`
`
`2 Although the unprocessed peptide is sometimes referred 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 compared to the 37
`amino acid precursor form. For example, GLP-1(1–37) may refer to 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.
`
`
`3
`
`
`
`IPR2023-00722
`Patent 8,536,122 B2
`Ex. 1011, 677. 3, 4 The structure of a naturally-occurring mature form is
`shown below.
`
`
`
`Pet. 18; Prelim. Resp. 7. 5 The above figure illustrates the structure of GLP-
`1(7–37) including the modifications to the alanine 7 and lysine 26.
`In the body, GLP-1 is rapidly degraded by dipeptidyl aminopeptidase
`IV (DPP-IV), such that “the natural hormone is 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) compounds in order to provide a longer duration of action in vivo,”
`but indicates that, because of the short half-lives, prior art GLP-1
`compounds must be administered at least once daily. See Ex. 1001, 1:23–43.
`The ’122 patent discloses improved GLP-1 analogs intended to allow
`for reduced dosing frequency when treating type 2 diabetes. Id. 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
`
`
`3 L. B. Knudsen et al., GLP-1 derivatives as novel compounds for the
`treatment of type 2 diabetes: selection of NN2211 for clinical development,
`26(7) DRUGS OF THE FUTURE 677–685 (2001). (“Knudsen 2001”).
`4 We generally refer to the original page numbers of cited art rather than to
`the numbering assigned by the parties.
`5 Naturally occurring GLP-1 also occurs as an amide, GLP-1(7-36) amide.
`See Ex. 1011, 677.
`
`4
`
`
`
`IPR2023-00722
`Patent 8,536,122 B2
`with a moiety to the lysine residue in position 26,” and wherein the moiety
`includes at least two acidic groups. Id. at 1:57–63, 4:4–16, Ex. 1011, 677.
`The non-proteogenic amino acid residue in positions 7 and/or 8 protects the
`modified compounds from DPP-IV degradation as compared to 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. Id. 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 via a
`non-natural amino acid linker to the lysine residue in position 26.” Id. at
`6:11–14.
`The ’122 patent discloses a number of specific compounds, including
`semaglutide, N-ε26-[2-(2-[2-(2-[2-(2-[4-(17-Carboxyheptadecanoylamino)-
`4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)
`acetyl][Aib8,Arg34]GLP-1-(7-37)peptide. Id. at 57:1–58:37 (Example 4);
`Ex. 1020 ¶ 100. The structure of semaglutide may also be illustrated as:
`
`
`
`Ex. 1020 ¶ 100.
`D. Relevant Prosecution History
`The ’122 patent was filed as Application No. 13/412,283 and claims
`priority as a continuation of Application no. 11/908,834, having a filing date
`of March 20, 2006, that issued as the ’343 patent. Accordingly, we discuss
`the prosecution history both the ’343 and ’122 patents below.
`
`5
`
`
`
`IPR2023-00722
`Patent 8,536,122 B2
`1. The ’343 Patent Prosecution History
`In a first (and only) Office Action on the merits,6 the Examiner
`rejected certain claims in view the Knudsen Patent7 and Larsen.8 Ex. 1004,
`41–45. The Examiner found that the Knudsen Patent discloses a genus of
`GLP-1 analogs that encompassed the claimed genus. Id. at 41–42. The
`Examiner further found that the Knudsen Patent teaches attaching lipophilic
`substituents to the GLP-1 moiety to “obtain a satisfactory protracted profile
`of action.” Id. at 43. The lipophilic substituents may be attached by means of
`a hydrophilic spacer. See id. The Examiner also found that Larsen teaches
`modifying GLP-1 with alpha-amino-isobutyric acid (Aib) at position 8 and a
`lipophilic substituent. Id. 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 amino acid at position 8. Id. at 44–45.
`According to the Examiner, a person of ordinary skill in the art would have
`been motivated to 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 and entered new
`claims that are substantially identical to those of the ’2 patent. Ex. 1004, 31–
`
`
`6 Prior to this Office Action, Applicants engaged in an initial Examiner
`interview, submitted a preliminary amendment, and elected semaglutide for
`examination in response to a restriction requirement. See Ex. 1004, 68, 72,
`100–103.
`7 L.B. Knudsen et al., US 6,268,343 B1, issued July 31, 2001. (“Knudsen
`Patent”) (“Knudsen 2004”) (Ex. 1012).
`8 P.J. Larsen et al., Systemic Administration of the Long-Acting GLP-1
`Derivative NN2211 Induces Lasting and Reversible Weight Loss in Both
`Normal and Obese Rats, 50 DIABETES 2530 (2001) (“Larsen”) (Ex. 1086).
`
`6
`
`
`
`IPR2023-00722
`Patent 8,536,122 B2
`33. The Applicant noted “that the new claims are directed to the compound
`disclosed in Example 4.” Id. at 35. Following an Examiner’s amendment to
`correct the sequence of the claimed formula, the Examiner issued a Notice of
`Allowance. See id. at 20–27.
`2. The ’122 Patent Prosecution History
`In a first Action, the Examiner required election of species between
`claims directed to compounds (claims 1–26) and methods of using the
`compounds (claims 27–29). Ex. 1003, 88–89. The Examiner further required
`election of a single disclosed species for prosecution on the merits. Id. at 90.
`In response, the Applicant cancelled the originally filed claims, and entered
`new claims 32–47, reciting a genus of GLP-1 analogs. Id. at 75–80. Within
`the genus, Applicant elected the compound of Example 5 (semaglutide) as
`the species. Id. at 81–82.
`Following the Amendment, the Examiner issued a Notice of
`Allowance. See id. at 38–45.
`E. Illustrative Claims
`Claim 1 is the only independent claim of the ’122 patent. See Ex.
`1001, 123:2–124:43. Of these, 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 Wegovy products. See Prelim. Resp. 1,7–8; Pet. 2, 6, 67.
`Challenged claim 1 is reproduced below.
`
`7
`
`
`
`IPR2023-00722
`Patent 8,536,122 B2
`1. A compound of formula II (SEQ ID No. 3):
`
`
`
`wherein
`Xaa7 is L-histidine, D-histidine, desamino-histidine,
`2-amino-histidine, β-hydroxy-histidine, homohistidine,
`Nα-acetyl-histidine, a-fluoromethyl-histidine,
`a-methyl-histidine, 3-pyridylalanine, 2-pyridylalanine, or
`4-pyridylalanine;
`Xaa8 is Gly, Val, Leu, Ile, Lys, Aib, (1-aminocyclopropyl)
`carboxylic acid, (1-aminocyclobutyl) carboxylic acid,
`(1-aminocyclopentyl) carboxylic acid, (1-aminocyclohexyl)
`carboxylic acid, (1-aminocycloheptyl) carboxylic acid, or
`(1-aminocyclooctyl) carboxylic acid;
`Xaa16 is Val or Leu;
`Xaa18 is Ser, Lys, or Arg;
`Xaa19 is Tyr or Gln;
`Xaa20 is Leu or Met;
`Xaa22 is Gly, Glu, or Aib;
`Xaa23 is Gln, Glu, Lys, or Arg;
`Xaa25 is Ala or Val;
`Xaa27 is Glu or Leu;
`
`8
`
`
`
`IPR2023-00722
`Patent 8,536,122 B2
`Xaa33 is Ala, Glu, or Arg;
`Xaa33 is Val or Lys;
`Xaa34 is Lys, Glu, Asn, or Arg;
`Xaa35 is Gly or Aib;
`Xaa36 is Arg, Gly, Lys, or is absent;
`Xaa37 is Gly, Ala, Glu, Pro, Lys, or is absent;
`Xaa38 is Lys, Ser, amide, or is absent; and
`where U is a spacer selected from
`
`
`
`
`
`
`
`
`
`
`
`9
`
`
`
`IPR2023-00722
`Patent 8,536,122 B2
`
`
`
`and
`
`
`
`
`
`where n is 12, 13, 14, 15, 16, 17, or 18,
`l is 12, 13, 14, 15, 16, 17, or 18,
`m is 0, 1, 2, 3, 4, 5, or 6,
`s is 0, 1, 2, or 3,
`p is 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 is an acidic group selected from
`and
`
`
`
`
`
`
`Ex. 1001, 1:2–124:43; Certificate of Correction 1.
`With respect to the challenged dependent claims, claims 2, and 4–11
`recite compounds within the genus of claim 1. See id. at 124:44–126:41.
`Claim 13 recites a pharmaceutical compound comprising a compound of
`claim 1. Id. at 131:16–18. Claim 15 recites a method of treating
`hyperglycemia and/or type 2 diabetes by administering a GLP-1 analog
`according to claim 1. Id. at 131:22–132:17.
`
`10
`
`
`
`IPR2023-00722
`Patent 8,536,122 B2
`F. Asserted Grounds of Unpatentability
`Petitioner asserts that claims 1, 2, 4–11, 13, and 15 would have been
`unpatentable on the following grounds:
`Claim(s)
`Reference(s)/Basis
`Challenged 35 U.S.C. §
`Knudsen 2004, 9
`1, 2, 4–11,
`103
`Knudsen Patent, Dong,10
`13, 15
`Bridon 11
`Knudsen 2001, 12
`1, 2, 4–11,
`Knudsen Patent, Dong, Bridon
`13, 15
`Knudsen 2004, Knudsen 2001,
`1, 2, 4–11,
`Knudsen Patent, Dong, Bridon
`13, 15
`Petitioner further relies, inter alia, on the Declarations of Peter Flatt,
`
`Ph.D. (Ex. 1020), Christopher J. Soares, Ph.D. (Ex. 1022), Paul Dalby,
`
`103
`
`103
`
`Ground
`1
`
`2
`
`313
`
`
`9 L. B. Knudsen, Glucagon-like Peptide-1: The Basis of a New Class of
`Treatment for Type 2 Diabetes, 47 J. MED. CHEM. 4128–4134 (2004). (Ex.
`1010).
`10 J. Z. Dong et al., Glucagon-Like Peptide-I Analogs 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).
`11 D.P. Bridon et al., US 6,514,500 B1, issued Feb. 4, 2003. (“Bridon”)
`(Ex. 1014).
`12 L. B. Knudsen et al., GLP-1 derivatives as novel compounds for the
`treatment of type 2 diabetes: selection of NN2211 for clinical development,
`26(7) DRUGS OF THE FUTURE 677–685 (2001). (Ex. 1011).
`13 Petitioner casts Ground 3 as directed to “[o]bviousness over the prior art
`and common drug development principles.” Pet. 5. Insofar as Petitioner’s
`review of the “Scope and Content of the Prior Art,” addresses only Knudsen
`2004, Knudsen 2001, Knudsen Patent, Dong, and Bridon, we infer that
`Ground 3 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 same prior art
`as Grounds 1 and 2.”).
`
`11
`
`
`
`IPR2023-00722
`Patent 8,536,122 B2
`Ph.D. (Ex. 1024), and John Bantle, M.D. (Ex. 1026). Patent Owner’s
`Preliminary Response does not identify the testimony of subject matter
`declarant(s).
`
`II. ANALYSIS
`
`A. Legal Standards
`“In an [inter partes review], the petitioner has the burden from the
`onset to show with particularity why the patent it challenges is
`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 inter partes
`review petitions to identify “with particularity . . . the evidence that supports
`the grounds for the challenge to each claim”)). This burden of persuasion
`never shifts to Patent Owner. See Dynamic Drinkware, LLC v. Nat’l
`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 and the prior art are such that the claimed
`invention as a whole would have been obvious before the effective filing
`date of the claimed invention to a person having ordinary skill in the art to
`which the claimed invention pertains. See KSR Int’l Co. v. Teleflex Inc., 550
`U.S. 398, 406 (2007). The question of obviousness is resolved on the basis
`of underlying factual determinations including: (1) the scope and content of
`the prior art; (2) any differences between the claimed subject matter and the
`prior art; (3) the level of ordinary skill in the art; and (4) objective evidence
`of nonobviousness, if any. Graham v. John Deere Co., 383 U.S. 1, 17–18
`(1966).
`
`12
`
`
`
`IPR2023-00722
`Patent 8,536,122 B2
`In analyzing the obviousness of a combination of prior art elements, it
`can be important to identify a reason that would have prompted one of skill
`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 of a challenged claim is not necessary to establish
`obviousness. Id. Rather, “any need or problem known in the field of
`endeavor at the time of invention and addressed by the patent can provide a
`reason for combining the elements in the manner claimed.” Id. 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 the teachings of the prior art
`references to achieve the claimed invention, and that the skilled artisan
`would have had a reasonable expectation of success in doing so.” In 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
`whether a new chemical compound is prima facie obvious over particular
`prior art. The fact finder first determines whether a chemist of ordinary skill
`would have selected one or more prior art compounds as lead compounds, or
`starting points, for further development efforts. (Otsuka Pharm. Co. v.
`Sandoz Inc., 678 F.3d 1280, 1291 (Fed. Cir. 2012). The Court defines a lead
`compound as “a compound in 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
`development efforts.” Altana Pharma AG v. Teva Pharm. USA, Inc., 566
`F.3d 999, 1008 (Fed. Cir. 2009). The second step involves determining
`
`13
`
`
`
`IPR2023-00722
`Patent 8,536,122 B2
`“whether the prior art would have supplied one of ordinary skill in the art
`with a reason or motivation to modify a lead compound to 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 encountered in the art, the prior art solutions to those problems, the
`rapidity with which innovations are made, the sophistication of the
`technology, and the educational level of active workers in 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 of individuals working together to develop and formulate GLP-1
`analogs to 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
`
`an M.D., Pharm.D., or doctoral degree(s) in chemistry,
`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
`
`
`
`IPR2023-00722
`Patent 8,536,122 B2
`Id. at 7–8 (citing Ex. 1020 ¶ 26; Ex. 1022 ¶ 26; Ex. 1024 ¶ 20; Ex. 1026
`¶ 24). 14 Patent Owner does not offer a different level of ordinary skill in the
`art. See generally Prelim. Resp.
`On the current record, and for the purposes of this decision, we accept
`Petitioner’s proposed definition, as it appears consistent with the level of
`skill in the art reflected in the prior art of record and the disclosure of the
`’122 Patent. See Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001)
`(“the prior art itself [may] reflect[] an appropriate level” as evidence of the
`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
`We interpret a claim “using the same claim construction standard that
`would be used to construe the claim in a civil action under 35 U.S.C.
`282(b).” 37 C.F.R. § 42.100(b) (2020). Under this standard, we construe the
`claim “in accordance with the ordinary and customary meaning of such
`claim as understood by one of ordinary skill in the art and the prosecution
`history pertaining to the patent.” Id. Moreover, “the specification ‘is always
`highly relevant to the claim construction analysis. Usually it is dispositive; it
`is the single best guide to the meaning of a disputed term.’” In 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
`
`
`14 We need not consider Petitioner’s similar, but alternative, definitions. See
`id. at 8–9.
`
`15
`
`
`
`IPR2023-00722
`Patent 8,536,122 B2
`decision. See Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co. 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 of Asserted References
`Petitioner’s Grounds are based on a combinations of Knudsen 2004
`and/or Knudsen 2001 with Knudsen Patent, Dong, and Bridon, which we
`briefly address below.
`Knudsen 2004 (Ex. 1010)
`1.
`Knudsen 2004 provides an overview of GLP-1 based compounds in
`development. Ex. 1010. By way of background, Knudsen 2004 discloses that
`“GLP-1 was discovered in 1984 and found to be an important incretin. It is a
`product of the preproglucagon gene and is released from the L-cells in the
`intestine upon food intake and potently releases insulin from the β-cells in
`the pancreas.” Id. 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).” Id. Knudsen 2004 explains that
`“[t]he numbering of GLP-1 starts with 7 because it was originally believed
`that GLP-1(1-37) was the active hormone.” The current numbering system
`began when it was discovered that the active hormone is formed upon
`removal of the first 6 N-terminal amino acids. Id. The naturally-occurring
`“hormone is degraded rapidly by the enzyme dipeptidyl peptidase IV (DDP-
`IV) and cleared by the kidneys resulting in a half-life of less than 2 min after
`iv administration and a clearance higher than that of the normal cardiac
`output.” Id.
`
`16
`
`
`
`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-IV and rapid clearance,” the challenge
`in making GLP-1 receptor peptide-therapeutics “is to make a stable
`compound with a long half-life.” Id. at 1429, 4130. In this respect, Knudsen
`2004 discloses that there are two subclasses of GLP-1 analogs in clinical
`development as 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 shows a 53% structural
`homology to GLP-1. Id. at 4129. 15 Knudsen 2004 notes that exendin-4 is
`more resistant to proteolytic degradation than GLP-1, but that certain
`modifications designed to further increase its stability “may . . . be at the
`expense of an immune reaction to the peptide.” Id. at 4130.
`With respect to GLP-1, Knudsen 2004 illustrates the structure-activity
`relationships of GLP-1(7–37) in Figure 3, reproduced below.
`
`
`15 We presume without deciding that exendin-4 derivatives, such as
`exenatide, are GLP-1 analogs within the meaning of the ’122 patent.
`
`17
`
`
`
`IPR2023-00722
`Patent 8,536,122 B2
`
`
`
`Figure 3 is a color-coded representation of GLP-1 amino acids 7–37.
`Ex. 1010, 4130. According to Knudsen 2004, “it has been proposed that the
`N-terminal part of the peptide is responsible for the high-affinity binding to
`the core of the receptor, whereas the C-terminal is more responsible for the
`selectivity by interacting with the large N-terminal of the receptor.” Id. With
`respect to the individual amino acids shown in Figure 3, Knudson 2004
`discloses that Ala8, colored blue, may be modified for DPP-IV stability,
`whereas amino acids Ser18, Gln23, Lys26, Glu27, Lys34, and Arg36, colored
`green, may be derivatized with a long fatty acid. Id.
`Knudsen 2004 lists seven known GLP-1 analogs, but states that most
`of these compounds “are in the discovery phase or in small-scale ½ 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 phase 2 clinical trials with liraglutide, (γ-L-
`glutamyl(N-α-hexadecanoyl))-Lys26,Arg34-GLP-1(7–37) (NN2211). Id. at
`
`18
`
`
`
`IPR2023-00722
`Patent 8,536,122 B2
`4130. 16 Referencing “[s]everal preclinical and clinical studies,” Knudsen
`2004 states that “Liraglutide is equipotent to GLP-1 and has a half-life that is
`more than 10-fold larger that of exendin-4, 8 h vs 26 min after iv
`administration,[] respectively.” Id. “Liraglutide is part of a 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 binding sites, resulting in a pharmacokinetic
`profile with slow absorption and a long half-life.” Id. Liraglutide in
`particular is acylated at Lysine 26 with ((γ-L-glutamoyl(N-ε-hexadecanoyl)).
`Id. Knudsen explains that acylation at different sites on GLP-1 may improve
`half-life while retaining potency or, alternatively, destroy potency. See id.
`With respect to the latter, Knudsen 2004 cautions that “[a] potency-
`destroying SAR[17] has . . . been generated in which acylation in the N-
`terminus position 8 leads to a compound about 20 times less potent than
`GLP-1,” whereas, “[a]cylation with two fatty acids on both naturally present
`lysines in positions 26 and 34 destroys potency.” Id.
`
`2. Knudsen 2001 (Ex. 1011)
`Knudsen 2001 explains that GLP-1’s mode of action suggests it would
`provide “the ideal treatment of type 2 diabetes.” Ex. 1011, 679. However,
`GLP-1 is “metabolized rapidly by DPP-IV” and “cleared very rapidly from
`the kidneys.” Id. To address the short physiological half-life, Knudsen 2001
`discloses GLP-1 derivatives for treating type 2 diabetes, specifically
`
`
`16 By way of context, liraglutide is now the active ingredient in Saxenda and
`Victoza commercial products. See Exs. 3002, 3003.
`17 “SAR” refers to Structure-Activity-Relationship. See Ex. 1020 ¶ 80.
`
`19
`
`
`
`IPR2023-00722
`Patent 8,536,122 B2
`NN2211, later named liraglutide. See id. at 677, 680 (Table 1, compound 5).
`According to Knudsen 2001,
` [f]atty acid derivatization has been used successfully to
`protract the action of insulin 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 optimal for once-daily administration. Fatty acids or fatty
`diacids, optionally extended with a “spacer” between the
`epsilon-amino group of the lysine side chain and the carboxyl
`group of the fatty acid, were used. Acylation with simple fatty
`acids increases the net negative charge of the resulting molecule
`with one (by blocking the epsilon-amino group of the lysine),
`whereas peptides acylated with a L-glutamoyl-spacer or with
`diacids provides a further increase of the negative charge. The
`addition of a negative charge to the acylated molecule is
`expected to improve solubility 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 with a
`fatty acid equal to or longer than 12 carbon atoms were considerabl[y]
`protracted compared to native GLP-1, which had a half-life after s.c.
`administration of only 1.2 h.” Id. Focusing on a set of examples derivatized
`with a γ-Glu-C16 monoacid, Knudsen 2001 notes that “[m]any different
`positions in the C-terminal part of GLP-1 could be derivatized with quite
`long fatty acids, visualized with compounds 3-9 (EC50 30-121 pM) without
`affecting the potency.” Id. at 680 (referencing compound numbers and
`potency data from Table 1). Focusing on a series of compounds derivatized
`on lysine 26, however, Knudsen further notes that, “[w]ithin the γ-Glu
`spacer monoacid series (5, 16-18), derivatization with a C18 acid (16, 194
`pM ) led to a significant loss of activity compared to C16 (5, 68 pM), C14
`
`20
`
`
`
`IPR2023-00722
`Patent 8,536,122 B2
`(17, 22 pm) and C12 (18, 27 pm). Id. 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) was seen.” Id.
`Of the twenty-two compounds listed in Table 1, Knudsen 2001
`identifies compounds 4, 5, 7, 8, 18, 20 and 21 as “very potent,” with
`compounds 5, 7, and 8, showing “dramatic differences in plasma half-lives”
`as compared to naturally-occurring GLP-1. Id. at 679–680 (Table II).
`Knudsen 2001 explains that, although “[a] number of compounds were both
`very potent and had plasma half-lives above 10 h, making them suitable as
`drugs for the treatment of type 2 diabetes using once-daily administration,”
`only liraglutide (compound 5) was selected for clinical development. Id. at
`681–682. According to Knudsen 2001, liraglutide showed “equal potency to
`GLP-1” in in vitro testing, and its “mechanism of protraction involves
`binding to albumin, metabolic stability towards DPP-IV and slow release
`from the injection site.” Id. Knudsen 2001 further describes the specific
`attributes of liraglutide and the reasons for choosing it as the best compound
`for clinical development. Id. Knudsen 2001 reports, for example, that
`acylation of lysine 26 with a γ-L-Glu spacer “gave the most potent” and
`“metabolically stable compound” with a half-life of 20 hours. Id. Although
`“[a]mino acid substitutions in position 8 can give better metabolic stability
`against DPP-IV,” that was not needed for liraglutide because “quite a
`substantial protection against DPP-IV was obtained by acylation alone, and
`since any amino acid substitution poses a risk of immunogenicity.” Id.
`Knudsen 2001, concludes:
`[liraglutide] is a metabolically stable compound with potency
`equal to GLP-1. It has been characterized to act as a GLP-1
`
`21
`
`
`
`IPR2023-00722
`Patent 8,536,122 B2
`compound in several animal models, including the ability to
`lower body weight. [liraglutide] is currently the only GLP-1
`compound in clinical development that 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
`clinical trials will reveal the potential of [liraglutide] as a
`promising new treatment for type 2 diabetes.
`Id. at 682.
`
`3. Knudsen Patent (Ex. 1012)
`Knudsen Patent is 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. Id. at
`code (57).
`Knudsen Patent describes various modifications to naturally occurring
`GLP-1. See Ex. 1012, 8:13–23. Knudsen Patent states, For example, “[t]he
`GLP-1 derivatives of the present invention preferably have only one or two
`Lys wherein the ε-amino group of one or both Lys is substituted with a
`lipophilic substituent.” Id. at 12:24–26. The lipophilic substituent may be
`attached via a spacer, wherein suitable spacers are α, ω-amino acids, such as
`“succinic acid, Lys, Glu or Asp, or a dipeptide such as Gly-Lys.” Id. at
`17:55–60. “Other preferred spacers are Nε-(γ-L-glutamyl[)], Nε-(β-L-
`asparagyl), Nε-glycyl, and N-(α-(γ-aminobutanoyl)[)].” Id. at 18:11–13.
`“The lipophilic substituents preferably comprises 4–40 carbon atoms . . .
`T
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
