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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`MYLAN PHARMACEUTICALS INC.,
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`Petitioner,
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`v.
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`NOVO NORDISK A/S,
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`Patent Owner.
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`Case No. IPR2023-00722
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`Patent No. 8,536,122
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`DECLARATION OF DR. CHRISTOPHER J. SOARES, PH.D.,
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,536,122
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`MPI EXHIBIT 1022 PAGE 1
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`

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`TABLE OF CONTENTS
`
`
`Page
`
`
`I.
`II.
`
`B.
`
`INTRODUCTION ............................................................................................................. 7
`QUALIFICATIONS AND BACKGROUND ................................................................... 7
`A.
`Education and Experience; Prior Testimony ......................................................... 7
`B.
`Legal Standards and Materials Reviewed ............................................................ 10
`C.
`Scope of Work ..................................................................................................... 13
`PERSON OF ORDINARY SKILL IN THE ART ........................................................... 14
`III.
`THE ’122 PATENT ......................................................................................................... 16
`IV.
`CLAIM CONSTRUCTION ............................................................................................. 21
`V.
`SUMMARY OF OPINIONS ........................................................................................... 21
`VI.
`VII. BACKGROUND ON DRUG SYNTHESIS .................................................................... 25
`A.
`Drug-Structure Optimization ............................................................................... 25
`B.
`Peptide Synthesis ................................................................................................. 28
`VIII. SCOPE AND CONTENT OF THE PRIOR ART ........................................................... 38
`IX.
`THE POSA WOULD HAVE BEEN MOTIVATED TO USE A DI-AEEA
`SPACER AND C18 FATTY DIACID WITH A REASONABLE EXPECTATION
`OF SUCCESS .................................................................................................................. 49
`A.
`The POSA would have been motivated to modify liraglutide by adding a
`di-AEEA spacer to the existing glutamic acid linker with a reasonable
`expectation of success. ......................................................................................... 51
`The POSA would have been motivated to modify liraglutide by acylating
`a C18 fatty diacid onto the di-AEEA spacer via a glutamic acid linker with
`a reasonable expectation of success. .................................................................... 70
`A POSA WOULD HAVE ARRIVED AT THE CLAIMED INVENTION
`THROUGH ROUTINE EXPERIMENTATION OF KNOWN VARIABLES ............... 81
`CONCLUSION ................................................................................................................ 87
`
`X.
`
`XI.
`
`
`
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`-2-
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`MPI EXHIBIT 1022 PAGE 2
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`

`

`
`
`TABLE OF ABBREVIATIONS
`
`
`
`Full Name of Cited Reference
`U.S. Patent No. 8,536,122
`Accardo, Physicochemical Properties of Mixed Micellar
`Aggregates Containing CCK Peptides and Gd Complexes
`Designed as Tumor Specific Contrast Agents in MRI, 126
`J. AM. CHEM. SOC. 3097 (2004)
`Adelhorst, Structure-Activity Studies of Glucagon-like
`Peptide-1*, 269(9) J. BIO. CHEM. 6275 (1994)
`Albericio, Orthogonal Protecting Groups for N(alpha)-
`amino and C-terminal carboxyl functions in Solid-Phase
`Peptide Synthesis, 55(2) BIOPOLYMERS 123 (2000)
`Amblard, Fundamentals of Modern Peptide Synthesis, in
`PEPTIDE SYNTHESIS AND APPLICATIONS 3 (John Howl ed.,
`2005)
`Autio, Mini-PEG Spacering of VAP-1-Targeting 68Ga-
`DOTAVAP-P1 Peptide
`Improves PET
`Imaging of
`Inflammation, 1 EJNMMI RSCH. 1 (2011)
`Baggio, A Recombinant Human Glucagon-Like Peptide
`(GLP)-1–Albumin Protein (Albugon) Mimics Peptidergic
`Activation of GLP-1 Receptor–Dependent Pathways
`Coupled with Satiety, Gastrointestinal Motility, and
`Glucose Homeostasis, 53(9) DIABETES 2492 (2004)
`Bhattacharya, Crystallographic Analysis Reveals Common
`Modes of Binding of Medium and Long-Chain Fatty Acids
`to Human Serum Albumin, 303 J. MOL. BIOL. 721 (2000)
`U.S. Patent No. 6,514,500
`Cistola, Carbon 13 NMR Studies of Saturated Fatty Acids
`Bound to Bovine Serum Albumin. I. The filling of
`Individual Fatty Acid Binding Sites, 262(23) J BIOL CHEM.
`10971 (1987)
`Cistola, Carbon 13 NMR Studies of Saturated Fatty Acids
`Bound
`to Bovine Serum Albumin. II. Electrostatic
`Interactions in Individual Fatty Acid Binding Sites,
`262(23) J BIOL CHEM. 10980 (1987)
`
`
`
`
`
`-3-
`
`
`
`Abbreviation
`’122 patent
`Accardo
`
`Adelhorst
`
`Albericio
`
`Amblard
`
`Autio
`
`Baggio
`
`Bhattacharya
`
`Bridon
`Cistola I
`
`Cistola II
`
`MPI EXHIBIT 1022 PAGE 3
`
`

`

`
`
`TABLE OF ABBREVIATIONS
`(continued)
`
`
`Full Name of Cited Reference
`Clodfelter, Effects of Non-Covalent Self-Association on the
`Subcutaneous Absorption of a Therapeutic Peptide, 15(2)
`PHARM. RSCH. 254 (1998)
`Nulf, DNA Assembly using Bis-Peptide Nucleic Acids
`(bisPNAs), 30(13) NUCLEIC ACIDS RES.2782 (2002)
`Dong, Glucagon-Like Peptide-1 Analogs with Significantly
`Improved in vivo Activity, in PEPTIDES: THE WAVE OF THE
`FUTURE (Michal Lebl et al. eds., 2001)
`Drucker, Development of Glucagon-Like Peptide-1-Based
`Pharmaceuticals as Therapeutic Agents for the Treatment
`of Diabetes, 7 CURRENT PHARM. DESIGN 1399 (2001)
`Drucker, Discovery, Characterization, and Clinical
`Development of the Glucagon-Like Peptides, 127(12) J.
`CLIN. INVEST. 4217 (2017)
`U.S. Patent No. 5,359,030
`U.S. Patent No. 7,576,050
`Veronese, Introduction and Overview of Peptide and
`Protein Pegylation, 54 ADVANCED DRUG DELIVERY
`REVIEWS 453 (2002)
`Holst, The Incretin Approach for Diabetes Treatment
`Modulation of Islet Hormone Release by GLP-1 Agonism,
`53 (suppl. 3) DIABETES S197 (2004)
`Holz, Glucagon-Like Peptide-1 Synthetic Analogs: New
`Therapeutic Agents for Use in Treatment of Diabetes
`Mellitus, 10 CURRENT MED. CHEM. 2471 (2003)
`Kenyon, 13C NMR Studies of the Binding of Medium-
`Chain Fatty Acids to Human Serum Albumin, 35(3) J LIPID
`RES. 458 (1994)
`Kim, Development and Characterization of a Glucagon-
`Like Peptide 1-Albumin Conjugate: The Ability to Activate
`the Glucagon-Like Peptide 1 Receptor In Vivo, 52(3)
`DIABETES 751 (2003)
`
`
`
`- 4 -
`
`Abbreviation
`Clodfelter
`
`Corey 2002
`
`Dong
`
`Drucker 2001
`
`Drucker 2017
`
`Ekwuribe
`Greig
`Veronese
`
`Holst 2004
`
`Holz
`
`Kenyon
`
`Kim
`
`MPI EXHIBIT 1022 PAGE 4
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`

`

`
`
`TABLE OF ABBREVIATIONS
`(continued)
`
`
`Full Name of Cited Reference
`Kiso, Amide Formation, Deprotection, and Disulfide
`Formation in Peptide Synthesis, in PEPTIDES: SYNTHESIS,
`STRUCTURES, AND APPLICATIONS 39 (Bernd Gutte ed.,
`1995)
`U.S. Patent No. 6,268,343
`Knudsen, Potent Derivatives of Glucagon-Like Peptide-1
`with Pharmacokinetic Properties Suitable for Once Daily
`Administration, 43(9) J MED CHEM. 1664 (2000)
`Knudsen, 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
`(2001)
`Knudsen, Glucagon-Like Peptide-1: The Basis of a New
`Class of Treatment for Type 2 Diabetes, 47(17) J MED
`CHEM. 4128 (2004)
`Kurtzhals, Albumin Binding of Insulins Acylated with Fatty
`Acids: Characterization of the Ligand-Protein Interaction
`and Correlation between Binding Affinity and Timing of
`the Insulin Effect in vivo, 312 BIOCHEM J. 725 (1995)
`LEHNINGER PRINCIPLES OF BIOCHEMISTRY (David L.
`Nelson et al. eds., 4th ed. 2005)
`Luu, Automated Multiple Peptide Synthesis: Improvements
`in Obtaining Quality Peptides, 47 INT’L J. PEPTIDE
`PROTEIN RSCH 91 (1996)
`Markussen, Soluble, Fatty Acid Acylated Insulins Bind to
`Albumin and Show Protracted Action in Pigs, 39(3)
`DIABETOLOGIA 281 (1996)
`Meinenhofer, Peptide Synthesis: A Review of the Solid-
`Phase Method, in HORMONAL PROTEINS AND PEPTIDES
`(Choh Hao Li ed., 1973)
`Ozempic prescribing information (Oct. 2022)
`
`Abbreviation
`Kiso
`
`Knudsen Patent
`Knudsen 2000
`
`Knudsen 2001
`
`Knudsen 2004
`
`Kurtzhals
`
`Lehninger
`
`Luu 1996
`
`Markussen
`
`Meienhofer
`
`Ozempic Label
`
`
`
`- 5 -
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`MPI EXHIBIT 1022 PAGE 5
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`

`

`
`
`TABLE OF ABBREVIATIONS
`(continued)
`
`
`Full Name of Cited Reference
`Pasut, Protein, Peptide and Non-Peptide Drug PEGylation
`for Therapeutic Application, 14 EXPERT OPINION ON
`THERAPEUTIC PATENTS 859 (2004)
`Peters, ALL ABOUT ALBUMIN BIOCHEMISTRY, GENETICS,
`AND MEDICAL APPLICATIONS (1996)
`Rando, Functional Incorporation of Synthetic Glycolipids
`into Cells, 77(5) PROC. NATL. ACAD. SCI. USA 2510
`(1980)
`Roberts, Chemistry for Peptide and Protein PEGylation,
`54(4) ADV DRUG DELIV. REV. 459 (2002)
`WO 03/74005
`Schmidt, Fatty Acylation of Proteins, 988 BIOCHIMICA ET
`BIOPHYSICA ACTA 411 (1989)
`Sewald, PEPTIDES: CHEMISTRY AND BIOLOGY (2002)
`Tonsgard,
`Binding
`of
`Straight-Chain
`Saturated
`Dicarboxylic Acids to Albumin, 82 J. CLIN. INVEST. 1567
`(1988)
`
`
`Abbreviation
`Pasut
`
`Peters
`
`Rando 1980
`
`Roberts
`
`Sato
`Schmidt 1989
`
`Sewald
`Tonsgard 1988
`
`
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`MPI EXHIBIT 1022 PAGE 6
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`
`
`I.
`
`INTRODUCTION
`
`1. My name is Christopher J. Soares, Ph.D. I have been retained by
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`Mylan Pharmaceuticals Inc. (“Mylan”). I understand that Mylan intends to petition
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`for inter partes review (“IPR”) of U.S. Patent No. 8,536,122 (“the ’122 patent”),
`
`Ex. 1001, which is assigned to Novo Nordisk A/S (“Patent Owner”). As part of the
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`petition, I understand Mylan will request that the United States Patent and
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`Trademark Office (“USPTO”) cancel claims 1-2, 4-11, 13, and 15 of the ’122
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`patent (“the challenged claims”) as unpatentable. I submit this expert declaration to
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`address and support Mylan’s IPR petition for the challenged claims of the ’122
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`patent.
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`II. QUALIFICATIONS AND BACKGROUND
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`A. Education and Experience; Prior Testimony
`
`2.
`
`I am currently the Founder/CEO of AcheRx, a peptide therapeutics
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`company investigating diseases linked to the perception and transmission of
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`neuropathic pain.
`
`3.
`
`I received a Bachelor of Science in Chemistry from the University of
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`Bombay, India in 1980, a Master of Science in Chemistry from Hampton
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`University in 1984, and a Ph.D. from the University of California, Davis in 1989,
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`where my research focused on the total synthesis of natural products using a novel
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`chemical rearrangement.
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`-7-
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`MPI EXHIBIT 1022 PAGE 7
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`4.
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`Since receiving my Ph.D., I have gained extensive experience as a
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`peptide medicinal chemist, with additional expertise in drug discovery and
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`development related to peptide therapeutics. In 1989, I started my career in peptide
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`and protein design as a postdoctoral fellow at The Scripps Research Institute,
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`where I remained until 1992.
`
`5.
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`From 1992 to 1998, I worked at Amylin Pharmaceuticals, Inc., a
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`biotechnology company focused on discovering new medicines for metabolic
`
`disorders including diabetes and obesity, first as a Senior Research Associate,
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`Process Chemistry, then as a Staff Scientist, Research Chemistry, and finally as a
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`Senior Staff Scientist, Research Chemistry.
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`6.
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`After working as a Research Scientist in medicinal chemistry at
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`CombiChem Inc. (later DuPont Pharmaceuticals Inc.) from 1998 to 2002, I
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`returned to Amylin, where I worked until 2010, beginning as a Scientific
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`Investigator, Research Chemistry, then as a Senior Scientific Investigator,
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`Research Chemistry, and finally as an Associate Director, Research. While at
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`Amylin, I incorporated my knowledge of peptide structure and protein design into
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`drug discovery and development. As a co-program leader for various peptide-based
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`drug discovery efforts I successfully nominated three candidates for clinical
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`development. Of these candidates two were in the calcitonin family of hormones
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`that include amylin and calcitonin gene-related peptide (“CGRP”) and the third
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`MPI EXHIBIT 1022 PAGE 8
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`was a glucagon-like peptide 1 (“GLP-1”) agonist developed as a chemically
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`
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`superior analogue of the approved drug Byetta. One other drug molecule I
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`designed was a dual amylin and GLP-1 agonist that resulted in the initiation of a
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`program to develop hybrid peptide hormones. I also lead a discovery program to
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`identify oral and long-acting analogues and formulations of GLP-1 agonists
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`towards the end of my association with Amylin Pharmaceuticals Inc. I successfully
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`coordinated the projects, collaborated with various research and development
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`groups (e.g., in vitro and in vivo assay development, bioanalytical assay
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`development, regulatory strategy, budgets, staffing), and produced publications
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`and patents from each project.
`
`7.
`
`From 2010-2013 I served as a consulting R&D director at Avryll
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`Therapeutics Inc., developing liposome formulations of a therapeutic for cartilage
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`repair. In 2013, I founded AcheRx, LLC, a company focusing on the design and
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`development of peptide therapeutics for neuropathic pain and migraine. While at
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`AcheRx, I have been involved with the discovery of a novel series of peptide
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`CGRP antagonists, for which I have received multiple compound and method-of-
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`use patents. I have also designed a novel dual CGRP-amylin peptide agonist as a
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`potential new weight-loss therapeutic for which I have an issued patent.
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`Additionally, I have been awarded a Small Business Innovative Research (SBIR)
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`grant from the NIH/NINDS for developing a slow-release formulation of a CGRP
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`
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`MPI EXHIBIT 1022 PAGE 9
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`antagonist. The lead peptide has been chosen by the NIH Preclinical Screening
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`
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`Platform for Pain (PSPP) program as a potential compound to develop as a non-
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`addictive pain therapeutic.
`
`8.
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`Throughout my career, I have produced numerous peer-reviewed
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`publications related to peptide design and therapeutics. I have also been named as
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`the sole or co-inventor on several issued patents related to my work.
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`9.
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`I am a member of the American Association of Pharmaceutical
`
`Sciences (AAPS), the American Peptide Society (APS) and the European Peptide
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`Society (EPS). At the national meeting of the AAPS in 2007, I gave a presentation
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`on the discovery and development of a novel peptide therapeutic for metabolic
`
`diseases at the ‘Peptide Leads to the Drugs of Tomorrow’ section. The lead peptide
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`in this program was licensed to a large pharmaceutical company after Phase II
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`clinical studies.
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`10.
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`In the previous four years, I have not provided testimony in any
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`proceedings.
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`11. My qualifications are further described on my curriculum vitae, at
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`Exhibit 1023.
`
`B.
`
`Legal Standards and Materials Reviewed
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`12.
`
`In preparing and forming my opinions set forth in this declaration, I
`
`have been informed of the relevant legal principles. I have applied my
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`MPI EXHIBIT 1022 PAGE 10
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`understanding of those principles in forming my opinions. My understanding of
`
`
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`those principles is summarized below.1
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`13.
`
`I have been informed that Mylan bears the burden of proving
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`unpatentability by a preponderance of the evidence. Counsel has informed me that
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`this “preponderance of the evidence” standard means Mylan must show that
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`unpatentability is more probable than not. I have taken these principles into
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`account when forming my opinions.
`
`14.
`
`I understand that my opinions regarding unpatentability are from the
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`viewpoint of a person having ordinary skill (“POSA”) in the field of technology of
`
`the patent as of the priority date of the ’122 patent. I have also been informed that
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`claims should be given their plain and ordinary meaning in light of the intrinsic
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`evidence (i.e., the specification and the prosecution history) from the perspective
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`of a POSA.
`
`
`1 In performing my analysis and reaching my opinions and conclusions, I have
`
`been informed of and been advised to apply various legal principles relating to un-
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`patentability, which I set forth herein. In setting forth these legal standards, it is not
`
`my intention to testify about the law. I only provide my understanding of the law,
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`as explained to me by counsel, as a context for the opinions and conclusions I am
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`providing in this declaration.
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`- 11 -
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`MPI EXHIBIT 1022 PAGE 11
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`15.
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`I also understand that the concept of patent obviousness involves four
`
`factual inquiries: (1) the scope and content of the prior art; (2) the differences
`
`between the claimed invention and the prior art; (3) the level of ordinary skill in
`
`the art; and (4) secondary considerations of non-obviousness.
`
`16.
`
`I was informed that claims of a patent may be found obvious if, in
`
`view of the prior art, a POSA would have been motivated to combine the teachings
`
`of the prior art to arrive at the claimed subject matter with a reasonable expectation
`
`of success in doing so. I further understand that absolute predictability of success is
`
`not required for patent claims to be found obvious.
`
`17.
`
`I understand that when there is some recognized reason to solve a
`
`problem, and there are a finite number of identified, predictable and known
`
`solutions, a POSA has good reason to pursue the known options within their
`
`technical grasp. If such an approach leads to the expected success, it is likely not
`
`the product of innovation but of ordinary skill and common sense. I understand
`
`that any need or problem known in the field of endeavor at the time of invention or
`
`addressed by the patent can provide a reason for combining prior art elements to
`
`arrive at the claimed subject matter.
`
`18.
`
`I was also informed that the claims of a patent may be found obvious
`
`if, in view of the prior art, the claimed subject matter involves combinations of
`
`known elements that would have been obvious to try.
`
`
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`MPI EXHIBIT 1022 PAGE 12
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`19.
`
`I also understand from counsel that claims of a patent directed to
`
`chemical compounds may, in some instances, require what’s referred to as a lead
`
`compound obviousness analysis. I was informed that this lead compound analysis
`
`involves a two-part obviousness test. First, Mylan must show that a POSA would
`
`have selected a prior art compound, or compounds, as a “lead compound” (i.e., a
`
`compound that would be a natural choice for further development efforts). I
`
`understand a POSA could identify multiple compounds as “lead compounds” so
`
`long as a POSA would have had a reason to select each proposed lead compound.
`
`20. Second, Mylan must show that a POSA would have been motivated to
`
`modify the lead compound(s) to arrive at the claimed compound. I understand the
`
`motivation to modify a lead compound can come from any number of sources and
`
`does not need to be explicitly disclosed in the prior art.
`
`21. A list of the materials I considered, in addition to my experience,
`
`education, and training, in providing the opinions contained herein is attached as
`
`Appendix A.
`
`C.
`
`Scope of Work
`
`22.
`
`I have been retained by Mylan as a technical expert to provide various
`
`opinions regarding the ’122 patent. I am being compensated for my work in this
`
`case at a rate of $900 per hour plus expenses. My compensation is in no way tied
`
`to the outcome of this case or to the content of this declaration. I do not have any
`
`
`
`- 13 -
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`MPI EXHIBIT 1022 PAGE 13
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`current or past affiliation with Patent Owner, any affiliates of Patent Owner
`
`
`
`presently known to me, or the named inventors of the ’122 patent.
`
`III. PERSON OF ORDINARY SKILL IN THE ART
`
`23.
`
`I understand my analysis is to be conducted from the perspective of a
`
`POSA as of the priority date of the ’122 patent. I have also been informed by
`
`counsel that in defining a POSA, the following factors may be considered: (1) the
`
`educational level of the inventors; (2) the type of problems encountered in the art;
`
`(3) prior art solutions to those problems; (4) rapidity with which innovations are
`
`made; and (5) sophistication of the technology and educational level of active
`
`workers in the field. Further, I understand a POSA is generally skilled in the
`
`relevant art (i.e., the subject matter claimed and described in the patent).
`
`24. A POSA would have understood the prior art references cited herein
`
`and would have the capability to draw inferences from them. It is understood that,
`
`to the extent necessary, a POSA may collaborate with one or more other POSAs
`
`and/or others with relevant knowledge for one or more aspects with which the
`
`others may have expertise, experience, and/or knowledge. Additionally, a POSA
`
`could have had a lower level of formal education than described in the following
`
`definitions if the person has a higher degree of experience.
`
`
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`MPI EXHIBIT 1022 PAGE 14
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`
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`25.
`
`I understand that Dr. Flatt has provided an opinion, with which I
`
`agree, that the following definition of a POSA should apply with respect to the
`
`challenged claims of the ’122 patent.
`
`26. The subject matter of the claims of the ’122 patent 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 analogues, as well as to use the GLP-1 analogues to treat patients
`
`having type-2 diabetes or related conditions. Such a team would have included
`
`individuals with 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.
`
`27. Alternatively, the POSA (1) would be a highly skilled scientist
`
`lacking an M.D., Pharm.D., or doctoral degree, but (2) (a) would have more than
`
`five years of experience in the area of developing therapeutic proteins or peptides
`
`and/or (b) would have experience with the development, design, manufacture,
`
`formulation, or administration of therapeutic agents for diabetes, and the literature
`
`
`
`- 15 -
`
`MPI EXHIBIT 1022 PAGE 15
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`concerning protein or peptide formulation and design or diabetes treatments. In
`
`
`
`either case, a higher educational level could substitute for some amount of the
`
`requisite experience.
`
`28. Such a team also would have included persons with an appropriate
`
`level of skill in medicinal synthetic chemistry, including the synthesis and
`
`chemical modification of peptides or proteins.
`
`29. With respect to claim 13 of the ’122 patent, the team would have
`
`included an individual with a Ph.D. in chemistry, biochemistry, pharmaceutics,
`
`pharmaceutical sciences, chemical engineering, biochemical engineering or related
`
`fields, with at least two years of experience in the formulation of therapeutic
`
`peptides or proteins.
`
`30. With respect to the subject matter of claim 15 of the ’122 patent, the
`
`team would have included an individual with an M.D. and experience treating
`
`patients having type-2 diabetes or related conditions.
`
`31. As explained above, and as is evident from my CV, I met the
`
`qualifications of a POSA as of the priority date of the ’122 patent.
`
`IV. THE ’122 PATENT
`
`32.
`
`I have read the ’122 patent, including its claims, which is titled
`
`“Acylated GLP-1 Compounds.” I understand that the ’122 patent has 16 issued
`
`claims, of which only claim 1 is an independent claim. The ’122 patent lists Jesper
`
`
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`MPI EXHIBIT 1022 PAGE 16
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`

`

`
`Lau, Florencio Zaragoza Doerwald, Paw Bloch, and Thomas Kruse Hansen as
`
`
`
`inventors.
`
`33. The ’122 patent was filed on March 5, 2012, as U.S. Patent
`
`Application No. 13/412,283, a continuation of application No. 11/908,834, filed as
`
`application No. PCT/EP2006/060855 on March 20, 2006, and now U.S. Patent
`
`No. 8,129,343. The ’122 patent also claims priority to U.S. Provisional Application
`
`No. 60/664,497, filed on March 23, 2005, as well as European application
`
`No. 05102171, filed March 18, 2005.
`
`34.
`
`I understand the earliest priority date to which the challenged claims
`
`of the ’122 patent are entitled is March 18, 2005, the filing date of European
`
`application No. 05102171. Therefore, I understand that references that predate
`
`March 18, 2005, are prior art to the ’122 patent. To the extent Patent Owner later
`
`asserts and/or proves that the challenged claims are entitled to an earlier priority or
`
`invention date, I reserve the right to supplement this declaration.
`
`35. The ’122 patent has one independent claim, which recites:
`
`1. A compound of formula II (SEQ ID No. 3):
`
`
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`MPI EXHIBIT 1022 PAGE 17
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`

`

`
`
`
`
`
`
`
`
`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;
`
`- 18 -
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`MPI EXHIBIT 1022 PAGE 18
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`

`

`
`
`
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`Xaa30 is Ala, Glu, or Arg2; 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 [various spacers]
`
`where B is an acidic group selected from
`
`
`
`36. Claim 2 depends from independent claim 1 and recites a narrower set
`
`of possible amino acids than is recited in claim 1 (designated by “Xaa”).
`
`37. Claim 4 depends from independent claim 1 and recites that the “GLP-
`
`1 analog comprises Aib8 or Gly8 in position 8 of the GLP-1(7-37) sequence.”
`
`Claim 5 depends from claim 4 and specifies that the amino acid at position 8 is Aib
`
`(i.e., aminoisobutyric acid).
`
`38. Claims 6 and 7 depend from independent claim 1 and specify that the
`
`GLP-1 analogue comprises no more than six (claim 6) or three (claim 7) “amino
`
`
`2 I understand that while claim 1 originally recited “Xaa33 is Ala, Glu, or Arg,” a
`
`certificate of correction was issued by the USPTO on April 4, 2015, to revise this
`
`claim term to read “Xaa30 is Ala, Glu, or Arg.”
`
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`MPI EXHIBIT 1022 PAGE 19
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`

`

`
`acid residues which have been exchanged, added or deleted as compared to GLP-
`
`
`
`1(7-37).”
`
`39. Claim 8 depends from independent claim 1 and recites that the “GLP-
`
`1 analog comprises only one lysine residue.”
`
`40. Claim 9 depends from independent claim 1 and recites that the GLP-1
`
`analogue “according to claim 1 ... is Aib8, Arg34-GLP-1(7-37) or Aib8,22, Arg34-
`
`GLP-1(7-37).”
`
`41. Claim 10 depends from independent claim 1 and further specifies that
`
`“U is a spacer selected from” the following:
`
`42. Claim 11 depends from claim 10 and requires “B,” as recited in
`
`
`
`independent claim 1, to be:
`
`
`
`
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`MPI EXHIBIT 1022 PAGE 20
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`

`

`
`
`
`
`43. Claim 13 depends from independent claim 1 and recites “[a]
`
`pharmaceutical composition comprising a compound according to claim 1, and a
`
`pharmaceutically acceptable excipient.”
`
`44. Claim 15 depends from independent claim 1 and recites “[a] method
`
`for treating hyperglycemia and/or type 2 diabetes in a subject, said method
`
`comprising administering to a subject in need of such treatment an effective
`
`amount of a GLP-1 analog according to claim 1.”
`
`V. CLAIM CONSTRUCTION
`
`45.
`
`I have been informed that claim terms should be given their plain and
`
`ordinary meaning in light of the intrinsic evidence (i.e., the specification and the
`
`prosecution history) from the perspective of a POSA. I also understand that while
`
`extrinsic evidence (e.g., scientific publications) may be considered when
`
`interpreting the meaning of claim terms in some circumstances, it is generally
`
`given less weight than intrinsic evidence.
`
`46. There are no terms relevant to my opinions that require construction
`
`beyond the plain and ordinary meaning.
`
`VI. SUMMARY OF OPINIONS
`
`47.
`
`I understand that additional experts are offering opinions on behalf of
`
`Mylan regarding obviousness of the challenged claims of the ’122 patent. In
`
`particular, I understand that Dr. Peter Flatt, Ph.D., and Dr. John Bantle, M.D., have
`
`
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`MPI EXHIBIT 1022 PAGE 21
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`

`
`explained that as of the priority date, the POSA would have been motivated to
`
`
`
`pursue an improved GLP-1 analogue that required less frequent administration,
`
`which would have been preferred by patients and likely improved compliance with
`
`treatment regimens.3 To this end, I understand that Dr. Flatt has opined that the
`
`POSA would have been motivated to select liraglutide as a lead compound for
`
`further development, and that, given the goal of less frequent administration, a
`
`POSA would have found it obvious to modify liraglutide to make semaglutide (a
`
`GLP-1 analogue encompassed by all challenged claims of the ’122 patent).
`
`Specifically, I understand that Dr. Flatt opines that the POSA would have been
`
`motivated to modify liraglutide, with a reasonable expectation of successfully
`
`improving its half-life while retaining at least the same antidiabetic properties, by
`
`(1) substituting aminoisobutyric acid (“Aib”) for alanine (“Ala”) at position 8 of
`
`the peptide chain; (2) adding a spacer with two [2-(2-amino)ethoxy)]ethoxy acetic
`
`acid (“AEEA”) units between the existing glutamyl spacer-fatty acid substituent
`
`and the lysine (“Lys”) at position 26 (“Lys26”) of the peptide chain; and
`
`(3) acylating the peptide with a C18 fatty diacid rather than the C16 monocarboxylic
`
`acid used in liraglutide.
`
`
`3 I understand that Dr. Paul Dalby, Ph.D., is also offering expert opinions on behalf
`
`of Mylan, particularly as to formulation issues pertinent to the challenged claims.
`
`
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`
`
`48. For purposes of this declaration, I assume the POSA’s motivation to
`
`select liraglutide as a lead compound. I further explain from the perspective of a
`
`medicinal chemist why it is also my opinion that a POSA would have been
`
`motivated to add a di-AEEA spacer between Lys26 and the glutamyl-fatty acid
`
`substituent of liraglutide to further improve the compound’s half-life and
`
`hydrophilicity/solubility with a reasonable expectation of success. It is also my
`
`opinion that the POSA would have been motivated to modify liraglutide by using a
`
`C18 fatty diacid in place of the C16 fatty monoacid used in liraglutide with a
`
`reasonable expectation of success.
`
`49. First, as to the addition of a di-AEEA spacer, as I explain in Section
`
`IX.A, this would have been an obvious application of routine principles known for
`
`decades in the prior art. Indeed, the art taught the successful use of polyethylene
`
`glycol (“PEG”)-based molecules as spacer groups between fatty acids and peptides
`
`to increase the peptide’s half-life by improving albumin binding. And studies from
`
`as early as 1980 reported the benefits of using the PEG-based AEEA moiety
`
`specifically. AEEA spacers were also expressly used in GLP-1 analogues to
`
`increase peptide half-life with successful results, including the use of two AEEA
`
`molecules together (i.e., a “di-AEEA” spacer), as used later in semaglutide, in
`
`prior-art embodiments. The POSA would have thus had ample motivation to use
`
`one or more PEG-based molecules, and specifically the AEEA moiety, as a spacer
`
`
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`

`

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`to increase the length of the linkage between Lys26 and the existing glutamic acid
`
`
`
`linker used in liraglutide. A POSA would have understood that the increased length
`
`imparted by a di-AEEA spacer would enhance albumin binding by virtue of the
`
`space it creates between the peptide and albumin, ensuring the two would not
`
`interfere with one another. And the POSA would have had a reasonable
`
`expectation that it could implement such a spacer (indeed, the chemistry itself was
`
`routine) to improve the half-life or hydrophilicity/solubility of t