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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.,
`Petitioner,
`v.
`
`NOVO NORDISK A/S,
`Patent Owner.
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`
`
`Case No. IPR2023-00723
`Patent No. 8,129,343
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`DECLARATION OF PETER FLATT, PH.D., IN SUPPORT OF PETITION
`FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,129,343
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`MPI EXHIBIT 1020 PAGE 1
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`

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`TABLE OF CONTENTS
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`
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`Page
`
`
`Introduction ..................................................................................... 10
`I.
`II. Qualifications and Background ........................................................... 10
`A.
`Education and Experience; Prior Testimony ................................ 10
`B.
`Legal Standards and Materials Reviewed .................................... 14
`C.
`Scope of Work ........................................................................ 17
`III. Person of Ordinary Skill in the Art ...................................................... 17
`IV. The ’343 Patent ................................................................................ 20
`V. Claim Construction ........................................................................... 23
`VI. Summary of Opinions ....................................................................... 23
`VII. Background on Diabetes, the Treatment of Diabetes, and GLP-1
`Analogues........................................................................................ 26
`A. Diabetes ................................................................................. 26
`B.
`The Treatment of Diabetes ........................................................ 27
`1.
`Insulin ........................................................................... 27
`2.
`Biguanides ..................................................................... 28
`3.
`Sulfonylureas ................................................................. 29
`4.
`Thiazolidinediones .......................................................... 29
`5.
`α-Glucosidase Inhibitors and Meglitinides.......................... 30
`6.
`DPP-4 and PDE3 Inhibitors.............................................. 30
`7.
`The Rise of GLP-1 Based Drugs ....................................... 31
`Peptides and GLP-1 Analogues.................................................. 35
`1.
`General Peptide Chemistry............................................... 35
`2.
`GLP-1 Peptides .............................................................. 38
`3.
`Designing GLP-1 Analogues ............................................ 42
`4.
`Liraglutide ..................................................................... 52
`5.
`Semaglutide ................................................................... 54
`
`C.
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`- 2 -
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`MPI EXHIBIT 1020 PAGE 2
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`

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`TABLE OF CONTENTS
`(continued)
`
`
`Page
`
`
`VIII. The Challenged Claims of the ’343 Patent Are Unpatentable As
`Obvious Under 35 U.S.C. § 103.......................................................... 57
`A.
`Scope and Content of the Prior Art ............................................. 57
`1.
`Bridon (Ex. 1014) ........................................................... 58
`2.
`Dong (Ex. 1013) ............................................................. 59
`3.
`Knudsen 2001 (Ex. 1011) ................................................ 61
`4.
`Knudsen 2004 (Ex. 1010) ................................................ 63
`5.
`Knudsen Patent (Ex. 1012)............................................... 66
`6.
`Additional Prior Art References and Knowledge ................. 69
`B. Ground 1: The Challenged Claims of the ’343 Patent Would
`Have Been Obvious Over Knudsen 2004 in View of the
`Knudsen Patent, Dong, and Bridon............................................. 78
`1.
`Claims 1 and 4 of the ’343 Patent...................................... 79
`2.
`Claims 2 and 5 of the ’343 Patent.................................... 120
`3.
`Claims 3 and 6 of the ’343 Patent.................................... 121
`C. Ground 2: The Challenged Claims of the ’343 Patent Would
`Have Been Obvious Over Knudsen 2001 in View of the
`Knudsen Patent, Dong, and Bridon........................................... 122
`1.
`Claims 1 and 4 of the ’343 Patent.................................... 122
`2.
`Claims 2 and 5 of the ’343 Patent.................................... 136
`3.
`Claims 3 and 6 of the ’343 Patent.................................... 137
`D. Ground 3: The Challenged Claims of the ’343 Patent Would
`Have Been Obvious in View of Common Drug Development
`Principles.............................................................................. 138
`IX. No Secondary Considerations Overcome Prima Facie Obviousness of
`the Claimed Subject Matter .............................................................. 142
`A.
`Semaglutide Did Not Produce Any Unexpected or Surprising
`Results ................................................................................. 143
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`MPI EXHIBIT 1020 PAGE 3
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`

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`TABLE OF CONTENTS
`(continued)
`
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`Page
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`
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`The Prior Art Did Not Teach Away From Semaglutide ............... 146
`B.
`There Was No Long-Felt But Unmet Need ................................ 146
`C.
`There Was No Industry Skepticism .......................................... 147
`D.
`Copying by Generic Drug Makers Is Irrelevant .......................... 147
`E.
`X. CONCLUSION .............................................................................. 148
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`MPI EXHIBIT 1020 PAGE 4
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`

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`
`
`TABLE OF ABBREVIATIONS
`
`Full Name of Cited Reference
`U.S. Patent No. 8,129,343
`U.S. Patent No. 5,512,549
`Adelhorst, Structure-Activity Studies of Glucagon-like
`Peptide-1*, 269(9) J. BIO. CHEM. 6275 (1994)
`Banting, The internal secretion of the pancreas, 7 J LAB
`CLIN MED. 251 (1922)
`Bayliss, The Mechanism of Pancreatic Secretion, 28(5) J.
`PHYSIOLOGY 325 (1902)
`Bell, Hamster Preproglucagon Contains the Sequence of
`Glucagon and Two Related Peptides, 302 NATURE 716
`(1983)
`U.S. Patent No. 6,514,500
`WO 91/11457
`Buse, Effects of Exenatide (Exendin-4) on Glycemic Control
`Over 30 Weeks in Sulfonylurea-Treated Patients with Type
`2 Diabetes, 27 DIABETES CARE 2628 (2004)
`Chang, The GLP-1 Derivative NN2211 Restores β-Cell
`Sensitivity to Glucose in Type 2 Diabetic Patients After a
`Single Dose, 52 DIABETES 1786 (2003)
`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. BIO. 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. BIO. CHEM. 10980 (1987)
`Cooper, Peptides as a Platform for Targeted Therapeutics
`for Cancer: Peptide – Drug Conjugates (PDCs), 50 CHEM.
`SOC. REV. 1480 (2021)
`
`Abbreviation
`’343 patent
`’549 patent
`Adelhorst
`
`Banting
`
`Bayliss
`
`Bell
`
`Bridon
`Buckley
`Buse
`
`Chang
`
`Cistola I
`
`Cistola II
`
`Cooper
`
`5
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`MPI EXHIBIT 1020 PAGE 5
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`

`

`
`
`
`
`TABLE OF ABBREVIATIONS
`(continued)
`
`Deacon, Dipeptidyl Peptidase IV Resistant Analogues of
`Glucagon-Like Peptide-1 which have Extended Metabolic
`Improved Biological Activity, 41
`Stability and
`DIABETOLOGIA 271 (1998)
`Degn, One Week’s Treatment with the Long-Acting
`Glucagon-Like Peptide 1 Derivative Liraglutide (NN2211)
`Markedly Improves 24-h Glycemia and α- and β-Cell
`Function and Reduces Endogenous Glucose Release in
`Patients with Type 2 Diabetes, 53 DIABETES 1187 (2004)
`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 Therapeutic Agents for the Treatment of
`Diabetes, 7 CURRENT PHARM. DESIGN 1399 (2001)
`Edwards, GLP-1: Target for a New Class of Antidiabetic
`Agents?, 97 J. R. SOC. MED. 270 (2004)
`Elbrønd, Pharmacokinetics, Pharmacodynamics, Safety,
`and Tolerability of a Single-Dose of NN2211, a Long-
`Acting Glucagon-Like Peptide 1 Derivative, in Healthy
`Male Subjects, 25 DIABETES CARE 1398 (2002)
`WO 03/002136
`Gault, Glucose-Dependent Insulinotropic Polypeptide
`Analogues and Their Therapeutic Potential for the
`Treatment of Obsity-Diabetes, 308 BIOCHEM. &
`BIOPHYSICAL RSCH. COMMC’NS 207 (2003)
`Göke, Glycosylation of
`the GLP-1 Receptor is a
`Prerequisite for Regular Receptor Function, 15(4)
`PEPTIDES 675 (1994)
`Harder, The Effect of Liraglutide, a Long-Acting Glucagon-
`Like Peptide 1 Derivative, on Glycemic Control, Body
`Composition, and 24-h Energy Expenditure in Patients with
`Type 2 Diabetes, 27 DIABETES CARE 1915 (2004)
`
`Deacon
`
`Degn
`
`Dong
`
`Drucker
`
`Edwards
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`Elbrond
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`Flink
`Gault
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`Göke
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`Harder
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`6
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`MPI EXHIBIT 1020 PAGE 6
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`

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`TABLE OF ABBREVIATIONS
`(continued)
`
`Holst, Truncated Glucagon-like Peptide I, an Insulin-
`Releasing Hormone from the Distal Gut, 211 (2) FEBS
`LETTERS 169 (1987)
`Holst, Implementation of GLP-1 Based Therapy of Type 2
`Diabetes Mellitus Using DPP-IV Inhibitors, in DIPEPTIDYL
`AMINOPEPTIDASES IN HEALTH AND DISEASE (Martin
`Hildebrandt et al. eds., 2003)
`Holst, The Incretin Approach for Diabetes Treatment
`Modulation of Islet Hormone Release by GLP-1 Agonism,
`53 (suppl. 3) DIABETES S197 (2004)
`Holst, Glucagon-Like Peptide 1 and Inhibitors of Dipeptidyl
`Peptidase IV in the Treatment of Type 2 Diabetes Mellitus,
`4 CURRENT OP. IN PHARM. 589 (2004)
`Holz, Glucagon-Like Peptide-1 Synthetic Analogs: New
`Therapeutic Agents for Use in the Treatment of Diabetes
`Mellitus, 10(22) CURR. MED. CHEM. 2471 (2003)
`Joy, Incretin Mimetics as Emerging Treatments for Type 2
`Diabetes, 39 ANN. PHARMACOTHER. 1108 (2005)
`Kenyon, 13C NMR Studies of the Binding of Medium-Chain
`Fatty Acids to Human Serum Albumin, 35 J. LIPID RSCH. 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)
`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)
`
`Holst
`
`Holst 2003
`
`Holst 2004
`
`Holst 2004b
`
`Holz
`
`Joy
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`Kenyon
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`Kim
`
`Knudsen 2000
`
`Knudsen 2001
`
`Knudsen 2004
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`7
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`MPI EXHIBIT 1020 PAGE 7
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`
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`TABLE OF ABBREVIATIONS
`(continued)
`
`U.S. Patent No. 6,268,343
`Korc, Update on Diabetes Mellitus, 20 DISEASE MARKERS
`161 (2004)
`Larsen, 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)
`LEHNINGER PRINCIPLES OF BIOCHEMISTRY (David L. Nelson
`et al. eds., 4th ed. 2005)
`Luna, Oral Agents in the Management of Type 2 Diabetes
`Mellitus, 63 AM. FAM PHYSICIAN 1747 (2001)
`MacDonald, The Multiple Actions of GLP-1 on the Process
`of Glucose-Stimulated Insulin Secretion, 51 (suppl. 3)
`DIABETES S434 (2002)
`Madsbad, Improved Glycemic Control with No Weight
`Increase in Patients with Type 2 Diabetes after Once-Daily
`Treatment with the Long-Acting Glucagon-Like Peptide 1
`Analog Liraglutide (NN2211), 27 DIABETES CARE 1335
`(2004)
`Markussen, Soluble, Fatty Acid Acylated Insulins Bind to
`Albumin and Show Protracted Action in Pigs, 39(3)
`DIABETOLOGIA 281 (1996)
`Mentlein, Dipeptidyl-Peptidase IV Hydrolyses Gastric
`Inhibitory Polypeptide, Glucagon-Like Peptide-1(7-
`36)Amide, Peptide Histidine Methionine and is Responsible
`for their Degradation in Human Serum, 214 EUR. J.
`BIOCHEM. 829 (1993)
`Mojsov, Insulinotropin: Glucagon-like Peptide I (7-37) Co-
`encoded in the Glucagon Gene is a Potent Simulator of
`Insulin Release in the Perfused Rat Pancreas, 79 J. CLIN.
`INVEST. 616 (1987)
`Nicholson, The Role of Albumin in Critical Illness, 85(4)
`BR. J. ANAESTHESIA 599 (2000)
`
`Knudsen Patent
`Korc
`
`Larsen
`
`Lehninger
`
`Luna
`
`MacDonald
`
`Madsbad
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`Markussen
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`Mentlein
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`Mojsov
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`Nicholson
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`MPI EXHIBIT 1020 PAGE 8
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`

`

`TABLE OF ABBREVIATIONS
`(continued)
`
`Ørskov, Biological Effects and Metabolic Rates of
`Glucagonlike Peptide-1 7–36 Amide and Glucagonlike
`Peptide-1 7–37 in Healthy Subjects are Indistinguishable,
`42 Diabetes 658 (1993)
`Ozempic prescribing information (Oct. 2022)
`PDR MEDICAL DICTIONARY 472-73 (1st ed. 1995)
`Peters, ALL ABOUT ALBUMIN BIOCHEMISTRY, GENETICS,
`AND MEDICAL APPLICATIONS (1996)
`Pyne, Cyclic Nucleotide Phosphodiesterases in Pancreatic
`Islets, 46 DIABETOLOGIA 1179 (2003)
`Rando, Functional Incorporation of Synthetic Glycolipids
`into Cells, 77(5) PROC. NATL. ACAD. SCI. USA 2510 (1980)
`Ribel, NN2211: A Long-Acting Glucagon-Like Peptide-1
`Derivative with Anti-Diabetic Effects in Glucose-Intolerant
`Pigs, 451 EUR. J. PHARMACOLOGY 217 (2002)
`WO 03/074005
`Sewald, PEPTIDES: CHEMISTRY AND BIOLOGY (2002)
`Victoza prescribing information (June 2022)
`
`Orskov
`
`Ozempic label
`PDR
`Peters
`
`Pyne
`
`Rando
`
`Ribel
`
`Sato
`Sewald
`Victoza label
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`
`
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`MPI EXHIBIT 1020 PAGE 9
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`
`
`I.
`
`INTRODUCTION
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`
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`1. My name is Peter R. Flatt, Ph.D. I have been retained by Mylan
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`Pharmaceuticals Inc. (“Mylan”). I understand that Mylan intends to petition for inter
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`partes review (“IPR”) of U.S. Patent No. 8,129,343 (“the ’343 patent”), Ex. 1002,
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`which is assigned to Novo Nordisk A/S (“Patent Owner”). As part of the petition, I
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`understand Mylan will request that the United States Patent and Trademark Office
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`(“USPTO”) cancel claims 1-6 of the ’343 patent (“the challenged claims”) as
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`unpatentable. I submit this expert declaration to address and support Mylan’s IPR
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`petition for the challenged claims of the ’343 patent.
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`II. QUALIFICATIONS AND BACKGROUND
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`A. Education and Experience; Prior Testimony
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`2.
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`I am currently a Professor of Biomedical Science, Director of the
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`Biomedical Sciences Research Institute, and Head of Diabetes Research Group at
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`Ulster University at Coleraine, Northern Ireland.
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`3.
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`I received a Bachelor of Science Degree in Biology and Chemistry from
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`Aston University in 1974. In 1977, I received a Ph.D. from Aston University where
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`my research was primarily related to insulin and glucagon, including studies on
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`obesity and diabetes. In 2018, I received a Doctor of Sciences from Ulster
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`University for pioneering research on gut hormones and peptide therapeutics for
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`diabetes.
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`4.
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`In 1978, after obtaining my Ph.D., I joined the University of Uppsala
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`
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`as a Postdoctoral Research Fellow in the Department of Medical Cell Biology.
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`5.
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`In 1980, I joined the University of Surrey where I was a lecturer and
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`senior lecturer in the Department of Biochemistry.
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`6.
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`In 1989, I joined Ulster University as a Professor of Biomedical
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`Sciences and Head of Diabetes Research Group in the School of Biomedical
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`Sciences. In 1992, I became the Director of the Biomedical Sciences Research
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`Centre. In 1994, I became the Head of the School of Biomedical Sciences. In 2012,
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`I became Course Director of BSc (Honours) Biomedical Science Degree Courses.
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`In 2017, I became the Director of Biomedical Sciences Research Institute, which
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`houses approximately 150 principal investigators and was rated in the top five UK
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`Units for research power in biomedical sciences in the nationwide REF assessment
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`in 2021.
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`7.
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`Throughout my career, my research has focused on peptides for use in
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`the treatment of diabetes and/or obesity, including naturally occurring peptides and
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`analogues of naturally occurring peptides. Specifically, my research has focused on
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`experimental diabetes research on gut hormones, peptide therapeutics, drug
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`discovery, cell therapy, beta-cell stimulus-secretion coupling and islet cell function.
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`8.
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`I have published numerous books, articles, abstracts, and the like,
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`related to experimental diabetes research on gut hormones, peptide therapeutics,
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`drug discovery, cell therapy, beta-cell stimulus-secretion coupling and islet cell
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`
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`function, including:
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`a. Four multi-author edited international research texts.
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`b. Six edited proceedings (i.e., colloquia, conferences, seminars, etc.).
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`c. 110 reviews and book chapters.
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`d. 570 original peer-reviewed scientific papers.
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`e. 29 patented inventions.
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`9. My publications have been cited more than 25,200 times and I have an
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`h-index of 75. I have presented approximately 100 research lectures at national or
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`international conferences in more than 20 countries around the world.
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`10.
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`I have received numerous awards throughout my career for my work in
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`the field of diabetes research, including:
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`a. Elected Fellow of the Institute of Biology (FIBiol now FBS)
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`b. Elected Fellow of the Royal Society of Chemistry (FRSC)
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`c. Recipient of Mary Jane Kugal Award of Juvenile Diabetes Federation
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`International
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`d. Recipient of Biochemistry Medal of Irish Section of the Biochemical
`
`Society
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`e. Elected Member of the Royal Irish Academy (MRIA) – Ireland’s
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`premier Learned Body for Sciences and Humanities
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`f. Awarded Ulster University Senior Distinguished Research Fellowship
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`g. Dorothy Hodgkin Award Lecturer of Diabetes UK
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`h. Niall O’Meara Lecturer of Irish Endocrine Society
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`i. Ernst-Friedrich Pfeiffer Memorial Lecture, European Association for
`
`the Study of Diabetes (AIDPIT)
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`j. Steno Rounds Medal, Steno Diabetes Centre, Denmark
`
`k. Elected Fellow of Higher Education Academy (FHEA)
`
`l. Listed in Expertsgate Objective Rankings of Medical Expertise 2022 as
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`No 2 Worldwide Expert for Experimental Diabetes and No 3 for Insulin
`
`Secretion
`
`11.
`
`In the previous four years, I have provided testimony in the following
`
`proceedings:
`
`Finland
`
`Sweden
`
`Portugal
`
`• Sitagliptin and metformin (Janumet, Revocation
`MSD’s SPC)
`• Court appearance: Merck & Co., Inc v. Teva
`Pharmaceuticals
`• Sitagliptin and metformin (Janumet Revocation
`MSD’s SPC)
`• Court appearance: MSD v KRKA d.d. Novo mesto
`• Sitagliptin and metformin (Janumet Revocation
`MSD’s SPC)
`• MSD v Pharmakern (2022)
`
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`
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`• MSD v Sandoz (2022)
`• MSD v Stada Arzneimittel AG and Ciclum Farma
`Unipessoal Lda (2023)
`
`12. My qualifications and publications are further described on my
`
`curriculum vitae, which can be found at Exhibit 1021.
`
`B. Legal Standards and Materials Reviewed
`
`13.
`
`In preparing and forming my opinions set forth in this declaration, I
`
`have been informed of the relevant legal principles. I have applied my understanding
`
`of those principles in forming my opinions. My understanding of those principles is
`
`summarized below.1
`
`14.
`
`I have been informed that Mylan bears the burden of proving
`
`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
`
`
`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
`
`unpatentability, 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, as explained to me by counsel, as a context for the opinions and conclusions I
`
`am providing in this declaration.
`
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`unpatentability is more probable than not. I have taken these principles into account
`
`
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`when forming my opinions.
`
`15.
`
`I understand that my opinions regarding unpatentability are from the
`
`viewpoint of a person having ordinary skill in the art (“POSA”), i.e. in the field of
`
`technology of the patent as of the priority date of the ’343 patent. I have also been
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`informed that claims should be given their plain and ordinary meaning in light of the
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`intrinsic evidence (i.e., the specification and the prosecution history) from the
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`perspective of a POSA.
`
`16.
`
`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.
`
`17.
`
`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
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`success in doing so. I further understand that absolute predictability of success is
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`not required for patent claims to be found obvious.
`
`18.
`
`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
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`technical grasp. If such an approach leads to the expected success, it is likely not
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`
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`the product of innovation but of ordinary skill and common sense. I understand that
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`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.
`
`19.
`
`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.
`
`20.
`
`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 when applicable this lead
`
`compound analysis involves a two-part 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.
`
`21. 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.
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`16
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`22. A list of the materials I considered, in addition to my experience,
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`
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`education, and training, in providing the opinions contained herein is attached as
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`Appendix A.
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`C.
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`23.
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`Scope of Work
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`I have been retained by Mylan as a technical expert to provide various
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`opinions regarding the ’343 patent. I am being compensated for my work in this
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`case at a rate of £500 (GBP) per hour plus expenses. My compensation is in no way
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`tied to the outcome of this case or to the content of this declaration. I do not have
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`any current or past affiliation with Patent Owner, any affiliates of Patent Owner
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`presently known to me, or the named inventors of the ’343 patent.
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`III. PERSON OF ORDINARY SKILL IN THE ART
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`24.
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`I understand my analysis is to be conducted from the perspective of a
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`POSA as of the priority date of the ’343 patent. I have also been informed by counsel
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`that in defining a POSA, the following factors may be considered: (1) the educational
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`level of the inventors; (2) the type of problems encountered in the art; (3) prior art
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`solutions to those problems; (4) rapidity with which innovations are made; and (5)
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`sophistication of the technology and educational level of active workers in the field.
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`Further, I understand a POSA is generally skilled in the relevant art (i.e., the subject
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`matter claimed and described in the patent).
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`25. A POSA would have understood the prior art references cited herein
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`
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`and would have the capability to draw inferences from them. It is understood that,
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`to the extent necessary, a POSA may collaborate with one or more other POSAs
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`and/or others with relevant knowledge for one or more aspects with which the others
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`may have expertise, experience, and/or knowledge. Additionally, a POSA could
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`have had a lower level of formal education than described in the following
`
`definitions if the person has a higher degree of experience.
`
`26.
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`In my opinion, the following definition of a POSA applies to the claims
`
`of the ’343 patent. The subject matter of the claims of the ’343 patent falls within
`
`the medicinal, chemical, and pharmacological arts and encompasses the skills,
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`education, and expertise of a team of individuals working together to develop and
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`formulate glucagon-like peptide 1 (“GLP-1”) analogues, as well as to use the GLP-
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`1 analogues to treat patients having type-2 diabetes or related conditions. Such a
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`team would have included individuals with an M.D., Pharm.D., or doctoral degree(s)
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`in chemistry, biochemistry, pharmaceutics, pharmaceutical sciences, chemical
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`engineering, biochemical engineering or related fields, with at least two years of
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`experience in developing therapeutic peptides or proteins, and experience with the
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`development, design, manufacture, formulation, or administration of therapeutic
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`peptides or proteins, and the literature concerning protein or peptide formulation and
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`design or diabetes treatments.
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`27. Alternatively, the POSA (1) would be a highly skilled scientist lacking
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`
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`an M.D., Pharm.D., or doctoral degree, but (2) (a) would have more than five years
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`of experience in the area of developing therapeutic proteins or peptides and/or (b)
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`would have experience with the development, design, manufacture, formulation, or
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`administration of therapeutic agents for diabetes, and the literature concerning
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`protein or peptide formulation and design or diabetes treatments. In either case, a
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`higher educational level could substitute for some amount of the requisite
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`experience.
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`28. Such a team also would have included persons with an appropriate level
`
`of skill in medicinal synthetic chemistry, including the synthesis and chemical
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`modification of peptides or proteins.
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`29. With respect to claims 2 and 5 of the ’343 patent, the team would have
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`included an individual with a Ph.D. in chemistry, biochemistry, pharmaceutics,
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`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 3 and 6 of the ’343 patent,
`
`the team would have included an individual with an M.D. and experience treating
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`patients having type-2 diabetes or related conditions.
`
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`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 ’343 patent. Within this
`
`definition, my background focuses on the chemical, biological, and biochemical
`
`aspects of the claims of the ’343 patent. This includes aspects of the claims related
`
`to the chemical structures of the claimed peptides, their biological and biochemical
`
`effects, and related issues.
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`IV. THE ’343 PATENT
`
`32.
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`I have read the ’343 patent, including its claims, which is titled
`
`“Acylated GLP-1 Compounds.”
`
`33.
`
`I understand that the ’343 patent has 6 issued claims, each of which is
`
`written in independent form.
`
`34. The ’343 patent lists Jesper Lau, Paw Bloch, and Thomas Kruse Hansen
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`as inventors.
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`35. The ’343 patent was filed on March 20, 2006, as U.S. Patent
`
`Application No. 11/908,834, which was a national-stage entry of
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`PCT/EP2006/060855. The ’343 patent claims priority to U.S. Provisional
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`Application No. 60/664,497, filed on March 23, 2005, as well as European
`
`application No. 05102171, filed March 18, 2005.
`
`36.
`
`I understand the earliest priority date to which the challenged claims of
`
`the ’343 patent are entitled is March 18, 2005, the filing date of European application
`
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`No. 05102171. Therefore, references that predate March 18, 2005, are prior art to
`
`
`
`the ’343 patent. To the extent Patent Owner later asserts and/or proves that the
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`challenged claims are entitled to an earlier priority or invention date, I reserve the
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`right to supplement this declaration.
`
`37. The ’343 patent has six independent claims. The first claim (as
`
`subsequently corrected) recites:
`
`1.
`
`A compound of the structure:
`
`where the amino acid sequence is that of SEQ ID No:7.
`
`38. The ’343 patent describes “SEQ ID No:7” as follows:
`
`
`
`
`
`21
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`Ex. 1002 (’343 patent) at 103.
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`
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`39. Claim 2 is an independent claim that recites a “pharmaceutical
`
`composition” that includes the same compound recited in claim 1 (depicted again in
`
`full) and “a pharmaceutically acceptable excipient.”
`
`40. Claim 3 is an independent claim that recites a “method for treating type
`
`2 diabetes in a subject” by administering “an effective amount” of a composition
`
`comprising the same compound depicted in claim 1 and an excipient.
`
`41. Claim 4, like claim 1, is directed to a compound, but this time is
`
`specified
`
`by
`
`its
`
`chemical
`
`name: N-ε26-[2-(2-[2-(2-[2-(2-[4-(17-
`
`Carboxyheptadecanoylamino)-4(S)-
`
`carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg
`
`34]GLP-1-(7-37)peptide.
`
`42. Claim 5, like claim 2, recites a “pharmaceutical composition” that
`
`includes the same compound recited in claim 4 (recited again in full by name) and
`
`“a pharmaceutically acceptable excipient.”
`
`43. Claim 6, like claim 3, recites a “method for treating type 2 diabetes in
`
`a subject” by administering “an effective amount” of a composition comprising the
`
`same compound recited in claim 4 and an excipient.
`
`44. The only apparent difference between the compounds of claims 1-3 and
`
`4-6 is that claims 4-6 specify the stereochemistry of the glutamic acid spacer attached
`
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`at Lys26:
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`
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`“N-ε26-[2-(2-[2-(2-[2-(2-[4-(17-Carboxyheptadecanoylamino)-4(S)-
`
`carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg
`
`34]GLP-1-(7-37)peptide.” Ex. 1002, claims 4-6 (emphasis added).
`
`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.
`
`In my opinion, the challenged claims of the ’343 patent would have
`
`been obvious over the combinations of prior art references set forth below,
`
`optionally and further in view of the knowledge of a POSA and the state of the art
`
`as of the priority date of the ’343 patent.
`
`23
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`48. As explained above, the challenged claims recite semaglutide (and
`
`
`
`claims 1-3 also include its stereoisomers)2, compositions containing semaglutide,
`
`and methods of treating type-2 diabetes using semaglutide compositions. Supra
`
`Section IV; infra Section VII.C.5. In my opinion, semaglutide would have been
`
`obvious in view of the prior art.
`
`49. Well before the priority date of the ’343 patent, other GLP-1(7-37)
`
`analogues had been identified and developed as therapeutic agents. Id. In my
`
`opinion, a POSA would have identified at least one specific prior art GLP-1(7-37)
`
`analogue, liraglutide, as worthy of further development. Specifically, liraglutide,
`
`Novo Nordisk’s first-generation GLP-1(7-37) analogue, would have been an
`
`obvious starting point for a POSA motivated t