`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`________________________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________________
`BPI LABS, LLC,
`PETITIONER,
`v.
`ELI LILLY AND COMPANY
`PATENT OWNER.
`________________________________
`Case IPR2025-01346
`Patent 9,474,780
`________________________________
`PETITION FOR INTER PARTES REVIEW OF USPN 9,474,780
`UNDER 35 U.S.C. §§ 311 ET SEQ. AND
`37 C.F.R. § 42.100 ET SEQ.
`
`
`
`
`
`
`
`
` i
`TABLE OF CONTENTS
`
`I. INTRODUCTION ........................................................................................... 1
`II. OVERVIEW OF THE ARGUMENT ............................................................. 1
`III. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8(a)(1) .......................... 4
`A. Real Party-In-Interest Under 37 C.F.R. § 42.8(b)(1) ............................ 4
`B. Related Matters Under 37 C.F.R. § 42.8(b)(2) ..................................... 5
`C. Lead and Back-Up Counsel Under 37 C.F.R. § 42.8(b)(3) .................. 5
`D. Service Information Under 37 C.F.R. § 42.8(b)(4) ............................... 6
`E. Payment of Fees Under 37 C.F.R. § 42.15............................................ 7
`F. Certification of Word Count Under 37 C.F.R. § 42.24(d) .................... 7
`IV. GROUNDS FOR STANDING UNDER 37 C.F.R. § 42.104(a) ..................... 7
`V. IDENTIFICATION OF GROUNDS FOR WHICH REVIEW IS
`REQUESTED UNDER 37 C.F.R. § 42.104(b)(1) .......................................... 7
`VI. HOW THE CHALLENGED CLAIMS ARE TO BE CONSTRUED
`UNDER 37 C.F.R. § 42.104(b)(3) .................................................................. 8
`VII. OVERVIEW OF THE ’780 PATENT ............................................................ 8
`VIII. BACKGROUND OF TECHNOLOGY ........................................................ 10
`A. General Knowledge Regarding Peptide Chemistry ............................ 10
`B. Rational Design of GLP-1/GIP Co-Agonists ...................................... 24
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` ii
`IX. PRIOR ART QUALIFIES UNDER 35 USC §§102 and 103 ....................... 27
`X. HOW THE CLAIMS ARE UNPATENTABLE UNDER 37 C.F.R.
`§ 42.104(b)(4) ................................................................................................ 28
`A. Level of Skill in the Art ....................................................................... 28
`B. Alsina-Fernandez in view of DiMarchi and Lau renders obvious
`claims 1-2, 4-7, 9-10, and 12-18 ......................................................... 28
`XI. SECONDARY CONSIDERATIONS ........................................................... 74
`XII. CONCLUSION .............................................................................................. 77
`
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` iii
`LIST OF EXHIBITS1
`
`Exhibit
`No Description
`1001 U.S. Patent No. 9,474,780.
`1002 Declaration of Virginia Cornish, PH.D. in support of IPR2025-01024.
`1003 Intentionally left blank.
`1004 Prosecution History (Excerpts) of U.S. Patent No. 9,474,780.
`1005 WO 2016/111971 Search Report.
`1006 WO 2016/111971 Written Opinion.
`1007 WO 2011/119657 A1 Publication (Alsina-Fernandez).
`1008 WO 2013/164483 A1 Publication (Just).
`1009 WO 2006/097537 A2 Publication (Lau)
`1010 WO 2014/202727 A1 Publication.
`1011 Fields G. B. Introduction to peptide synthesis. Current protocols in protein
`science, Chapter 18, 2002; 18.1.1–18.1.9.
`1012 US 2015/0299281 A1 Publication.
`1013
`SAXENDA (liraglutide) injection drug label (Dec. 2014) (“SAXENDA”)
`available at
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206321Or
`ig1s000lbl.pdf.
`1014 Nelson, D. L., et al., Chapters 4-5, 7, Lehninger Principles of Biochemistry, 3rd
`ed. (eds. Ryan, M., et al., Worth Publishers) 2000.
`1015
`Segaloff, D. L., et al., Chapter 9: Internalization of Peptide Hormones and
`Hormone Receptors, Hormones and their Actions, Part I, (eds. Cooke, B. A., et
`al., Elsevier) 1988, 133-149.
`1016
`Zhang Y., Baranov P.V., Atkins J.F., Gladyshev V.N. Pyrrolysine and
`selenocysteine use dissimilar decoding strategies. J Biol Chem. 2005 May
`27;280(21):20740-51.
`1017 WO 2010/011439 A1 Publication (DiMarchi).
`
`1 For ease of reference Petitioner uses the same exhibit numbering scheme as used
`in IPR2025-01024 for the same exhibits.
`
`
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`
` iv
`Exhibit
`No Description
`1018 Merrifield R. B. Solid phase peptide synthesis. I. The synthesis of a tetrapeptide.
`J. Am. Chem. Soc. 1963; 85:2149–2154.
`1019 Sawyer, W. H., Manning, M. Synthetic analogs of oxytocin and the vasopressins.
`Annu Rev. Pharm. 1973.
`1020 Keen, H. et al. Human insulin produced by recombinant DNA technology: safety
`and hypoglycaemic potency in healthy men. Lancet 1980; 2, 398–401.
`1021
`Karten M.J., Rivier J.E. Gonadotropin-releasing hormone analog design.
`Structure-function studies toward the development of agonists and antagonists:
`rationale and perspective. Endocr Rev. 1986 Feb;7(1):44-66.
`1022
`Garay R.P., El-Gewely R., Armstrong J.K, Garratty G., Richette P. Antibodies
`against polyethylene glycol in healthy subjects and in patients treated with PEG-
`conjugated agents. Expert Opin Drug Deliv. 2012 Nov;9(11):1319-23.
`1023 Knudsen L.B. Liraglutide: the therapeutic promise from animal models. Int J Clin
`Pract Suppl. 2010 Oct;(167):4-11.
`1024 Ward B.P., et al. Peptide lipidation stabilizes structure to enhance biological
`function. Mol Metab. 2013 Sep 5;2(4):468-79.
`1025 Zhang L., Bulaj G. Converting peptides into drug leads by lipidation. Curr Med
`Chem. 2012;19(11):1602-18.
`1026
`Krauson A.J., He J., Wimley A.W., Hoffmann A.R., Wimley W.C. Synthetic
`molecular evolution of pore-forming peptides by iterative combinatorial library
`screening. ACS Chem Biol. 2013 Apr 19;8(4):823-31.
`1027 Lam K.S., et al. A new type of synthetic peptide library for identifying ligand-
`binding activity. Nature. 1991 Nov 7;354(6348):82-4.
`1028
`Liu T., Qian Z., Xiao Q., Pei D. High-throughput screening of one-bead-one-
`compound libraries: identification of cyclic peptidyl inhibitors against
`calcineurin/NFAT interaction. ACS Comb Sci. 2011 Sep 12;13(5):537-46.
`1029 Tautermann C.S. GPCR structures in drug design, emerging opportunities with
`new structures. Bioorg Med Chem Lett. 2014 Sep 1;24(17):4073-9.
`1030 Donnelly D. The structure and function of the glucagon-like peptide-1 receptor
`and its ligands. Br J Pharmacol. 2012 May;166(1):27-41.
`1031
`Rajagopal, S., Rajagopal, K., & Lefkowitz, R. J. Teaching old receptors new
`tricks: biasing seven-transmembrane receptors. Nature Reviews. Drug Discovery,
`2010;9(5), 373–386.
`1032
`Yu Z, Jin T. New insights into the role of cAMP in the production and function of
`the incretin hormone glucagon-like peptide-1 (GLP-1). Cell Signal. 2010
`Jan;22(1):1-8.
`
`
`
`
`
`
`
`
` v
`Exhibit
`No Description
`1033 Roed S.N., et al. Functional consequences of glucagon-like peptide-1 receptor
`cross-talk and trafficking. J Biol Chem. 2015 Jan 9;290(2):1233-43.
`1034
`Jorgensen R., Norklit Roed S., Heding A., Elling C. E. Beta-arrestin-2 as a
`competitor for GRK2 interaction with the GLP-1 receptor upon receptor
`activation. Pharmacology. 2011;88, 174–18.
`1035
`Jorgensen R., Kubale V., Vrecl M., Schwartz T.W., Elling C.E. Oxyntomodulin
`differentially affects glucagon-like peptide-1 receptor beta-arrestin recruitment
`and signaling through Galpha(s). J Pharmacol Exp Ther. 2007 Jul;322(1):148-54.
`1036
`Sonoda N, et al. Beta-Arrestin-1 mediates glucagon-like peptide-1 signaling to
`insulin secretion in cultured pancreatic beta cells. Proc Natl Acad Sci U S A. 2008
`May 6;105(18):6614-9.
`1037 Siu F.Y., et al. Structure of the human glucagon class B G-protein-coupled
`receptor. Nature. 2013 Jul 25;499(7459):444-9.
`1038 Hoare S.R. Mechanisms of peptide and nonpeptide ligand binding to Class B G-
`protein-coupled receptors. Drug Discov Today. 2005 Mar 15;10(6):417-27.
`1039 Hoare S. R. Allosteric modulators of class B G-protein-coupled receptors. Current
`Neuropharmacology. 2007;5(3), 168–179.
`1040 Seino Y., Fukushima M., Yabe D. GIP and GLP-1, the two incretin hormones:
`Similarities and differences. J Diabetes Investig. 2010 Apr 22;1(1-2):8-23.
`1041 Brown J.C., Mutt V., Pederson R.A. Further purification of a polypeptide
`demonstrating enterogastrone activity. J Physiol 1970; 209: 57–64.
`1042 Inagaki, N., et al. Gastric inhibitory polypeptide: Structure and chromosomal
`localization of the human gene. Mol Endocrinol 1989; 3: 1014–1021.
`1043 Dupre J., et al. Stimulation of insulin secretion by gastric inhibitory polypeptide in
`man. J Clin Endocrinol Metab 1973; 37: 826–828.
`1044
`Adrian T.E., Bloom S.R., Hermansen K., et al. Pancreatic polypeptide, glucagon
`and insulin secretion from the isolated perfused canine pancreas. Diabetologia
`1978; 14: 413–417.
`1045
`Lund P.K., Goodman R.H., Dee P.C., Habener J.F. Pancreatic preproglucagon
`cDNA contains two glucagon-related coding sequences arranged in tandem. Proc
`Natl Acad Sci U S A. 1982 Jan;79(2):345-9.
`1046
`Hui H., Farilla L., Merkel P., Perfetti R. The short half-life of glucagon-like
`peptide-1 in plasma does not reflect its long-lasting beneficial effects. Eur J
`Endocrinol. 2002 Jun;146(6):863-9.
`1047 Singh A. K. Dipeptidyl peptidase-4 inhibitors: Novel mechanism of actions.
`Indian journal of endocrinology and metabolism, 2014;]8(6), 753–759.
`
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`
`
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`
` vi
`Exhibit
`No Description
`1048
`Kieffer T.J., McIntosh C.H.S., Pederson R.A. Degradation of glucose‐ dependent
`insulinotropic polypeptide (GIP) and truncated glucagon-like peptide‐1 (tGLP‐1)
`in vitro and in vivo by dipeptidyl peptidase IV (DDP IV). Endocrinology 1995;
`136: 3585–36596.
`1049 Montrose-Rafizadeh C., et al. High potency antagonists of the pancreatic
`glucagon-like peptide-1 receptor. J Biol Chem. 1997;272:21201–21206.
`1050 VICTOZA (liraglutide) injection drug label (Jan. 2010) (“VICTOZA”) available
`at https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022341lbl .pdf.
`1051 Bode B. Liraglutide: a review of the first once-daily GLP-1 receptor agonist. Am J
`Manag Care. 2011 Mar;17(2 Suppl):S59-70.
`1052
`Neumiller J.J., Campbell R.K. Liraglutide: a once-daily incretin mimetic for the
`treatment of type 2 diabetes mellitus. Ann Pharmacother. 2009 Sep;43(9):1433-
`44.
`1053
`BYDUREON (exenatide) injection drug label (Jan. 2012) (“BYDUREON”)
`available at
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022200Or
`ig1s000lbledt.pdf.
`1054 BYETTA (exenatide) injection drug label (Apr. 2005) (“BYETTA”) available at
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021773lbl .pdf.
`1055
`TRULICITY (dulaglutide) injection drug label (Sept. 2014) (“TRULICITY”)
`available at
`https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/125469Ori
`g1s000Lbl.pdf.
`1056
`ADLYXIN (lixisenatide) injection drug label (Jul. 2016) (“ADLYXIN”) available
`at https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208471Or
`ig1s000lbl.pdf.
`1057
`OZEMPIC (Semaglutide) injection drug label (Dec. 2017) (“OZEMPIC”)
`available at
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209637lbl .pdf.
`1058
`Monami M., Dicembrini I., Marchionni N., Rotella C.M., Mannucci E. Effects of
`glucagon-like peptide-1 receptor agonists on body weight: a meta-analysis. Exp
`Diabetes Res. 2012;2012:672658.
`1059 Day J.W., et al. A new glucagon and GLP-1 co-agonist eliminates obesity in
`rodents. Nat Chem Biol. 2009 Oct;5(10):749-57.
`1060 Pocai A., et al. Glucagon-like peptide 1/glucagon receptor dual agonism reverses
`obesity in mice. Diabetes. 2009 Oct;58(10):2258-66.
`
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`
` vii
`Exhibit
`No Description
`1061 Finan B., Ma T., et al. Unimolecular dual incretins maximize metabolic benefits
`in rodents, monkeys, and humans. Sci Transl Med. 2013 Oct 30;5(209):209ra151.
`1062 Stenkamp R.E., et al. Crystal structure of rhodopsin: A G protein-coupled
`receptor. 3 ChemBioChem. 2002 963-67.
`1063 Rasmussen S.G., et al. Crystal structure of the human beta2 adrenergic G-protein-
`coupled receptor. Nature. 2007 Nov 15;450(7168):383-7.
`1064
`Stevens R. C., et al. The GPCR Network: a large-scale collaboration to determine
`human GPCR structure and function. Nat Rev Drug Discovery, 2013;12(1), 25–
`34.
`1065 Berman, H. M., et al. The Protein Data Bank. Nuc Acids Res, 2000; 28(1), 235–
`242.
`1066
`Xiao Q, Giguere J, Parisien M, Jeng W, St-Pierre SA, Brubaker PL, Wheeler MB.
`Biological activities of glucagon-like peptide-1 analogues in vitro and in vivo.
`Biochemistry. 2001 Mar 6;40(9):2860-9.
`1067 Adelhorst K., Hedegaard B.B., Knudsen L.B., Kirk O. Structure-activity studies of
`glucagon-like peptide-1. J Biol Chem. 1994;269:6275–6278.
`1068
`Manandhar B., Ahn J.M. Glucagon-like peptide-1 (GLP-1) analogs: recent
`advances, new possibilities, and therapeutic implications. J Med Chem. 2015 Feb
`12;58(3):1020-37.
`1069
`Thum A., Hupe-Sodmann K., et al. Endoproteolysis by isolated membrane
`peptidases reveal metabolic stability of glucagon-like peptide-1 analogs, exendins-
`3 and -4. Exp Clin Endocrinol Diabetes. 2002 May;110(3):113-8.
`1070
`Fineman M. S., et al., Clinical relevance of anti-exenatide antibodies: safety,
`efficacy and cross-reactivity with long-term treatment. Diabetes Obes Metab.
`2012 Jun;14(6):546-54.
`1071
`Buse J. B., et al., Liraglutide Treatment Is Associated with a Low Frequency and
`Magnitude of Antibody Formation with No Apparent Impact on Glycemic
`Response or Increased Frequency of Adverse Events: Results from the Liraglutide
`Effect and Action in Diabetes (LEAD) Trials, The Journal of Clinical
`Endocrinology & Metabolism, Volume 96, Issue 6, 1 June 2011, Pages 1695–
`1702.
`1072
`Doyle M.E., et al. The importance of the nine-amino acid C-terminal sequence of
`exendin-4 for binding to the GLP-1 receptor and for biological activity. Regul
`Pept. 2003 Jul 15;114(2-3):153-8.
`1073 Simonsen L., Holst J.J., Madsen, K., Deacon C.F. The C-terminal extension of
`exendin-4 provides additional metabolic stability when added to GLP-1, while
`
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` viii
`Exhibit
`No Description
`there is minimal effect of truncating exendin-4 in anaesthetized pigs. Regulatory
`Peptides. 2013 Feb 10;181:17-21.
`1074
`Tatarkiewicz, K., et al., A novel long-acting glucose-dependent insulinotropic
`peptide analogue: enhanced efficacy in normal and diabetic rodents. Diabetes,
`obesity & metabolism, 2014 (1), 75–85.
`1075 WO 2015/067715 A2 Publication.
`1076
`Lorenz M., Evers A., Wagner M. Recent progress and future options in the
`development of GLP-1 receptor agonists for the treatment of diabesity. Bioorganic
`& Med. Chem. Letters 23, 2013, 4011-4018.
`1077 Intentionally left blank.
`1078 Karp, G., Chapter 2.5, Cell and Molecular Biology: Concepts and Experiments,
`7th ed. (John Wiley & Sons) 2013, pp. 42-54.
`1079
`Madsen K., et al., Structure-Activity and Protraction Relationship of Long-Acting
`Glucagon-like Peptide-1 Derivatives: Importance of Fatty Acid Length, Polarity,
`and Bulkiness. J. Med. Chem. 2007, 50, 6126-6132.
`1080 IPR2025-01024 Petition.
`1081 Intentionally left blank.
`1082 Runge et al., Crystal Structure of the Ligand-bound Glucagon-like Peptide-1
`Receptor Extracellular Domain; J Biological Chem (2008), 283:11340-11347.
`1083
`Torekov et al., Obesity- an indication for GLP-1 treatment? Obesity
`pathophysiology and GLP-1 treatment potential, Obesity Reviews 2011, 12:8, pp.
`593-601.
`1084 Declaration of Dr. Zhaohui Sunny Zhou, PH.D. in support of IPR2025-01346
`1085 Curriculum Vitae of Dr. Zhaohui Sunny Zhou, Ph.D.
`
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`
` 1
`I. INTRODUCTION
`BPI Labs, LLC (“Petitioner”) requests inter partes Review pursuant to 35
`U.S.C. §§ 311 et seq. and 37 C.F.R. §§ 42.100 et seq., of claims 1-2, 4-7, 9-10, 12-
`18 (the “Challenged Claims”) of U.S. Patent No. 9,474,780 (“the ’780 Patent”). See
`EX1001.
`The ’780 Patent is also being challenged in IPR2025-01024 filed by a different
`petitioner, Empower Clinic Services LLC (“Empower IPR”). See EX1080 and
`EX1081. The ground of rejection in the instant Petition is different than the ground
`raised in the Empower IPR. Petitioner here relies on the teachings of WO
`2010/011439 to DiMarchi. (“DiMarchi”), which is not cited in the Empower IPR.
`DiMarchi’s teachings are highly relevant to the claims of the ’780 Patent as
`DiMarchi teaches ways to increase the efficacy of co-GIP/GLP-1 agonists while
`reducing immunogenicity.
`As set out in this Petition, the Challenged Claims are unpatentable as obvious
`over the combination of WO 2011/119657 to Alsina-Fernandez (“Alsina-
`Fernandez”) in view of DiMarchi and WO 2006/097537 to Lau, et al. (“Lau”).
`Therefore, the Board should institute this IPR.
`II. OVERVIEW OF THE ARGUMENT
`The ’780 Patent purports to have invented dual incretin peptide mimetic
`compounds that activate receptors for both human glucose-dependent insulinotropic
`
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` 2
`polypeptide (“GIP”) and glucagon-like peptide-1 (“GLP-1”). EX1001 at 1:3-8.
`However, the ’780 Patent admits that peptides with dual agonist GIP/GLP-1 activity
`were known in the art, and cites to Alsina-Fernandez as one such example. EX1001
`at 1:55-57. 2 The ’780 Patent merely applies well-known peptide design and
`modification strategies taught by DiMarchi and Lau to the peptide disclosed in
`Alsina-Fernandez.
`As evidenced by the declaration of Dr. Zhaohui Sunny Zhou, Ph.D, (“Dr.
`Zhou”)3, a person of ordinary skill in the art (“POSA”) at the time of the invention
`was motivated to develop GLP-1/GIP co-agonist compounds for the treatment of
`diabetes mellitus, as well as weight loss, since the dosing of GLP-1 agonist
`compounds alone was limited by the nausea and vomiting preventing these single
`agonist compounds from reaching their full efficacy for glycemic control and weight
`loss. EX1081 at ¶113. The prior art relied on in this petition (Alsina-Fernandez,
`DiMarchi, and Lau) provided guidance to a POSA on how to develop and improve
`
`2 Alsina-Fernandez is assigned to Patent Owner and has two inventors in common
`with the ’780 Patent (Alsina-Fernandez and Bokvist). Compare EX1001 with
`EX1007.
`3 Dr. Zhou is an expert with over thirty years of experience in the areas of
`polypeptides and proteins, including extensive work on peptide drugs including GIP
`and GLP-1 receptor agonists. EX1084 at ¶1.
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` 3
`GLP-1/GIP co-agonist compounds in the form of well-known structural
`substitutions and modifications that represented rational design strategies. Id.
`Particularly in view of a POSA’s background knowledge in this well studied
`field, a POSA would have been motivated to (1) solve/mitigate the issues associated
`with nausea and vomiting caused by selective GLP-1 agonist compounds; (2)
`minimize any potential immunogenicity associated with regular administration of
`the GLP-1/GIP co-agonist compounds; and (3) provide for a longer half-life and
`duration of effect, allowing for less frequent injections of the medication (e.g.,
`weekly vs daily). Id.
`The illustration below provides the straightforward modifications a POSA
`would make to the Alsina-Fernandez GLP-1/GIP co-agonist peptide provided in his
`Example 2 based on the teachings of DiMarchi and Lau to arrive at a compound
`within the scope of the claims of the ’780 Patent.
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` 4
`
`As explained herein, a POSA would have been motivated to combine Alsina-
`Fernandez, DiMarchi, and Lau to implement these structural changes illustrated
`above and would have a reasonable expectation of success in doing so.
`III. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8(a)(1)
`Petitioner satisfies each requirement for Inter Partes Review of the ’780
`Patent pursuant to 37 C.F.R. § 42.8(a)(1).
`A. Real Party-In-Interest Under 37 C.F.R. § 42.8(b)(1)
`The Petitioner and real-party-in-interest is BPI Labs, LLC with a physical
`address at 12393 Belcher Rd S., Suite 450, Largo, FL 33773-3097. An additional
`real-party-in-interest is Belcher Pharmaceuticals, LLC.
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` 5
`B. Related Matters Under 37 C.F.R. § 42.8(b)(2)
`The ’780 Patent is being challenged in IPR2025-01024 in petition filed by
`Empower Clinic Services, LLC. The petitioner of the instant IPR, BPI Labs, LLC is
`neither a real-party in interest nor a privy with respect to IPR2025-01024 and the
`parties involved. See Applications in Internet Time, LLC v. RPX Corporation, 897
`F.3d 1336 (Fed. Cir. 2018).
`To the best of Petitioner’s knowledge, the ’780 Patent is not involved in any
`other proceedings including district court litigation.
`C. Lead and Back-Up Counsel Under 37 C.F.R. § 42.8(b)(3)
`Petitioner is represented by the following counsel:
`
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` 6
`Lead Counsel Backup Counsel4
`
`James P. Murphy
`Reg. No. 55,474
`Polsinelli PC
`1000 Louisiana Street
`Suite 6400
`Houston, Texas 77002
`Tel: (713) 374-1631
`jpmurphy@polsinelli.com
`
`
`
`
`Corey Casey
`Reg. No. 66,950
`Polsinelli PC
`900 West 48th Place
`Suite 900
`Kansas City, Missouri 64112
`Tel: (816) 572-4439
`ccasey@polsinelli.com
`
`
`
`
`Pursuant to 37 C.F.R. § 42.10(b), Powers of Attorney have been filed with
`this Petition.
`D. Service Information Under 37 C.F.R. § 42.8(b)(4)
`Physical mailing service information for lead and back-up counsel is as
`follows:
`James Murphy
`Polsinelli PC
`1000 Louisiana Street
`Suite 6400
`Houston, Texas 77002
`Petitioner also consents to service by e-mail at the above e-mail addresses provided
`for lead and backup counsel.
`
`4 Petitioner intends to seek pro hac vice admission for Mr. Chad Landmon also with
`Polsinelli PC as an additional back-up counsel at the appropriate time.
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` 7
`E. Payment of Fees Under 37 C.F.R. § 42.15
` All required fees have been paid with the filing of this Petition. Petitioner
`further authorizes the U.S. Patent & Trademark Office to charge Deposit Account
`No. 50-1662 for any fees, including the fee set forth in 37 C.F.R. § 42.15(a) for this
`Petition.
`F. Certification of Word Count Under 37 C.F.R. § 42.24(d)
` Petitioner certifies that the word count in this Petition, including all footnotes
`and annotations, is 13,993 words as counted by the word-processing program
`(Microsoft Word for Office 365) used to generate this Petition, where such word
`count excludes the table of contents, mandatory notices, certificate of service, list of
`exhibits, and this certificate of word count. This Petition is in compliance with the
`14,000 word limit set forth in 37 C.F.R. § 42.24(a)(1)(i).
`IV. GROUNDS FOR STANDING UNDER 37 C.F.R. § 42.104(a)
`Petitioner certifies that the ’780 Patent is available for inter partes review.
`Petitioner is not barred or estopped from requesting an inter partes review of the
`’780 Patent claims on the grounds identified in this Petition. 37 C.F.R. § 42.104(a).
`V. IDENTIFICATION OF GROUNDS FOR WHICH REVIEW IS
`REQUESTED UNDER 37 C.F.R. § 42.104(b)(1)
`Petitioner asserts that claims 1-2, 4-7, 9-10, 12-18 are rendered obvious under
`35 U.S.C. §103 by Alsina-Fernandez in view of DiMarchi and Lau.
`
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` 8
`VI. HOW THE CHALLENGED CLAIMS ARE TO BE CONSTRUED
`UNDER 37 C.F.R. § 42.104(b)(3)
`Petitioner does not believe that any term requires construction to resolve the
`invalidity grounds presented in this Petition as the prior art renders the Challenged
`Claims unpatentable under any reasonable interpretation.
`VII. OVERVIEW OF THE ’780 PATENT
`The ’780 Patent is generally directed to “dual incretin peptide mimetic
`compounds that agonize receptors for both human and glucose-dependent
`insulinotropic polypeptide (GIP) and Glucagon-like peptide-1 (GLP-1), and may be
`useful for treating type 2 diabetes mellitus (T2D).” Id. at 1:1-8. GIP and GLP-1 are
`natural incretins secreted from the gut following a meal to enhance insulin secretion,
`nutrient disposal, and sensation of satiety. Id. at 1:20-36.
`The ’780 Patent acknowledges that use of these incretins individually was
`known but asserts that dosing of GLP-1 analogues was limited by adverse effects,
`such as nausea and vomiting, often preventing dosing from reaching full efficacy.
`Id. at 1:36-40 and 2:13-22. The ’780 Patent also acknowledges it was known that
`native GIP and GLP-1 are inactivated rapidly by the ubiquitous DPP-IV protease,
`making them useful only for short-term metabolic control. Id. at 1:41-44.
`The ’780 Patent admits that GIP analogues with dual GIP/GLP-1 activity were
`known in the art and that known structural modifications of these compounds have
`specific effects on properties and functions of these compounds. Id. at 1:55-57. For
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`example, the use of fatty acid side chains as albumin binding motifs extend the half-
`life of these compounds. Id. at 2:4-11; see also EX1008, at 49:3-50:2 (“it is thought
`that the lipophilic substituent binds albumin in the blood stream, thus shielding the
`compounds employed in the context of the invention from enzymatic degradation
`which can enhance the half-life of the compounds”) and 50:24-31.
`Despite the admitted disclosure of existing co-agonists of GIP and GLP-1, the
`’780 Patent asserts that a need still existed for a “balanced” co-agonism of GIP and
`GLP-1 receptors that could provide weight loss, have stability against deactivation
`by DPP-IV, and support once-weekly dosing. Id. at 1:45-54 and 2:28-41.
`The ’780 Patent presents “an embodiment” in the form of “a compound of
`Formula I,” illustrated below:
`
`wherein X1 is Aib; X2 is Aib; K at position 20 is chemically
`modified through conjugation to the epsilon-amino group
`of the K side-chain with ([2-(2-Amino-ethoxy)-ethoxy]-
`acetyl)2-(γGlu)a-CO—(CH2)b—CO2H wherein a is 1 to 2
`and b is 10 to 20; X3 is Phe or 1-Nal; and the C-terminal
`amino acid is optionally amidated as a C-terminal primary
`amide (SEQ ID NO: 11), or a pharmaceutically acceptable
`salt thereof.
`Id. at 2:53-65. When X1 is Aib, X2 is Aib, and X3 is Phe (F), the compound of
`Formula I has the following base structure, which is consistent with SEQ ID Nos. 3
`and 11 provided in the ’780 Patent:
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`VIII. BACKGROUND OF TECHNOLOGY5
`A. General Knowledge Regarding Peptide Chemistry
`Peptides are short strings of at least two amino acids linked by covalent
`peptide bonds (i.e., amide bonds). EX1084 at ¶59; EX1011 at 18.1.1. Both natural
`and engineered peptides can trigger a signaling pathway by interacting with the
`receptor for that signaling pathway. EX1014 at 118-119, 203, Fig. 5-5. Some
`signaling peptide ligands act as peptide hormones. See EX1015.
`Proteinogenic Amino Acids
`Proteins in the body are naturally formed using 20 common amino acids as
`building blocks. EX1084 at ¶60. Figure 2.26 below shows the chemical structures
`of these amino acids, as reproduced in the prior art.
`
`5 Cited references not named in a ground of rejection are cited for the purpose of
`showing the state of the art and the background knowledge of a POSA. Randall Mfg.
`v. Rea, 733 F.3d 1355, 1362-63 (Fed. Cir. 2013).
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` EX1078 at 52.
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`As shown above, the portion of each structure shown in black represents
`“the backbone,” which is common to all amino acids. EX1084 at ¶61. The portion
`of the structures provided in red indicate the side chains, which are the primary
`source of differentiation among the different amino acids. Id.
`These amino acid residues were regularly described using a three-letter code
`or a one-letter code, as illustrated in this chart:
`Full 3-Letter 1-Letter Full 3-Letter 1-Letter
`Glycine Gly G Phenylalanine Phe F
`Alanine Ala A Tyrosine Tyr Y
`Valine Val V Tryptophan Trp W
`Leucine Leu L Lysine Lys K
`Methionine Met M Arginine Arg R
`Isoleucine Ile I Histidine His H
`Serine Ser S Asparagine Asn N
`Threonine Thr T Glutamine Gln Q
`Cysteine Cys C Aspartate Asp D
`Proline Pro P Glutamate Glu E
`EX1084 at ¶62; EX1014 at 118, Table 5-1. The side chains of the amino acids can
`alter the chemical characteristics of different amino acids, sometimes impacting the
`function of the amino acid, and, consequently, the peptides containing these amino
`acids. EX1084 at ¶63.
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`Synthetic Analogues of Peptides as Drugs
`Peptide synthesis was described as early as 1901 and was continually
`improved upon up to the time of the invention. EX1084 at ¶¶64-66. By late 2014,
`modification of peptides for the purpose of improving pharmacokinetics and
`pharmacodynamics was routine. EX1084 at ¶67. Skilled artisans routinely modified
`peptides to stabilize them against proteolysis and degradation. Id. One approach
`involved PEGylation (the process whereby polyethylene glycol (PEG) is covalently
`attached to another molecule). Id. However, this approach was known to result in
`undesirable immunogenicity. Id. Specifically, in 2012, Garay reported that, in
`contrast to the common thinking that PEG is non-immunogenic and non-antigenic,
`up to 25% of healthy blood donors (i.e., no indication of being previously treated
`with a PEGylated drug), and up to 89% of patients treated with a PEGylated drug
`have anti-PEG antibodies that can elicit responses to PEGylated drugs or
`compounds. Id.; EX1022 at Abstract, 1320. The response elicited by these PEG
`antibodies can result in decreased therapeutic efficacy and reduced tolerance to
`PEGylated drug compounds. Id.; EX1022 at Abstract, 1320. Consequently, a POSA
`approached PEGylation strategies with caution (particularly for chronic and repeated
`dosing), and would have been focused on other peptide development strategies. Id.
`A more desirable approach involved conjugation of the peptide to a lipophilic
`moiety. EX1084 at ¶68. Knudsen et al. reported that the addition of fatty acid chains
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`to the Lys20 residue of liraglutide, a GLP-1 receptor agonist peptide, promotes
`reversible binding of the peptide to albumin in the blood, decreasing degradation by
`DPP-IV and protracting circulation and therapeutic effect. Id.; EX1023 at 5. Ward
`et al. disclosed that “site-specific lipidation alone could generate balanced, high
`potency co-agonism in glucagon-based peptides.” Id.; EX1024 at 475. Further,
`Zhang et al. explained that lipidation is commonly employed to improve metabolic
`stability, membrane permeability, and bioavailability of peptide drugs. Id.; EX1025
`at Abstract. Therefore, a POSA viewed conjugation with lipophilic moieties (e.g.,
`fatty acid chains) to be a more desirable peptide synthesis strategy, as it avoided the
`unwanted immunogenicity reported to be present with PEGylation, while at the same
`time imparting advantageous properties on the peptide, including decreased
`degradation by DPP-IV and prolonging circulation and therapeutic effect of the
`peptide (thereby extending the half-life and allowing for less frequent administration
`of the peptide). Id.
`Incretin GPCR Ligands – GIP and GLP-1
`GIP and GLP-1 are both incretins that exist naturally in the body to activate
`the GIP and GLP-1 receptors. EX1084 at ¶¶69-70. In 1987, Mosjov and others
`discovered that the 37-residue GLP-1 peptide was actually a pro-peptide that was
`activated by cleavage of the first six N-terminal residues, leaving a conserved
`histidine as the N-terminal residue of the active forms of GLP-1(7-37) and GLP-1(7-
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`36). EX1084 at ¶¶71-72; EX1025 at Abstract. These two N-terminally truncated
`products (GLP-1(7-37) and GLP-1(7-36) amide) are the active species in vivo, are
`equipotent to one another, are the major physiological incretin in humans, and are
`commonly referred to as the endogenous form of GLP-1. EX1084 at ¶72; EX1030
`at 27. Accordingly, amino acid residue numbering for endogenous GLP-1 often is
`performed using the convention of positions (1-30) or (1-31)—referring to the
`positions of the active peptide—rather than positions (7-36)/(7-37) of the pro-
`peptide. Id. In addition to increasing insulin secretion and expression, endogenous
`GLP-1 inhibits pancreatic beta-cell apoptosis, promotes beta-cell neogenesis,
`reduces glucagon secretion, delays gastric emptying, promotes satiety, and increases
`peripheral glucose disposal, thus playing a central role in controlling postprandial
`blood sugar levels. EX1084 at ¶72; EX1030 at 27-28.
`Due to its impact on blood glucose, GLP-1 was considered a potential
`therapeutic for the treatment of diabetes, but there were two primary limitations on
`the use of exogenous GLP-1 for the treatment of diabetes and other disease states:
`(1) a very short half-life (only a few minutes); and (2) rapid degradation, with
`functional loss by DPP-IV-catalyzed cleavage of the two N-terminal residues (1-2)
`of the active form (residues 7-8 of the pro-peptide). EX1084 at ¶73; EX1030 at 28;
`EX1046 at Abstract. Though some forms of endogenous peptide cleavage activate
`GLP-1 (i.e., cleaving N-terminal residues 1-6 of the pro-peptide), other forms
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`essentially deactivate i