`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`v.
`
`NOVO NORDISK A/S,
`Patent Owner.
`
`
`
`
`
`
`
`
`Case No. IPR2023-00722
`Patent No. 8,536,122
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`DECLARATION OF PETER FLATT, PH.D., IN SUPPORT OF PETITION
`FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,536,122
`
`
`
`
`
`
`
`
`
`
`MPI EXHIBIT 1020 PAGE 1
`
`
`
`TABLE OF CONTENTS
`
`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 ’122 Patent ................................................................................ 20
`V. Claim Construction ........................................................................... 25
`VI. Summary of Opinions ....................................................................... 25
`VII. Background on Diabetes, the Treatment of Diabetes, and GLP-1
`Analogues........................................................................................ 28
`A. Diabetes ................................................................................. 28
`B.
`The Treatment of Diabetes ........................................................ 28
`1.
`Insulin ........................................................................... 29
`2.
`Biguanides ..................................................................... 29
`3.
`Sulfonylureas ................................................................. 30
`4.
`Thiazolidinediones .......................................................... 31
`5.
`α-Glucosidase Inhibitors and Meglitinides.......................... 31
`6.
`DPP-4 and PDE3 Inhibitors.............................................. 32
`7.
`The Rise of GLP-1 Based Drugs ....................................... 33
`Peptides and GLP-1 Analogues.................................................. 37
`1.
`General Peptide Chemistry............................................... 37
`2.
`GLP-1 Peptides .............................................................. 39
`3.
`Designing GLP-1 Analogues ............................................ 43
`4.
`Liraglutide ..................................................................... 53
`5.
`Semaglutide ................................................................... 55
`VIII. The Challenged Claims of the ’122 Patent Are Unpatentable As
`Obvious Under 35 U.S.C. § 103.......................................................... 63
`
`C.
`
`2
`
`MPI EXHIBIT 1020 PAGE 2
`
`
`
`TABLE OF CONTENTS
`(continued)
`
`Page
`
`
`
`A.
`
`Scope and Content of the Prior Art ............................................. 63
`1.
`Bridon (Ex. 1014) ........................................................... 64
`2.
`Dong (Ex. 1013) ............................................................. 65
`3.
`Knudsen 2001 (Ex. 1011) ................................................ 66
`4.
`Knudsen 2004 (Ex. 1010) ................................................ 69
`5.
`Knudsen Patent (Ex. 1012)............................................... 71
`6.
`Additional Prior Art References and Knowledge ................. 75
`B. Ground 1: The Challenged Claims of the ’122 Patent Would
`Have Been Obvious Over Knudsen 2004 in View of the
`Knudsen Patent, Dong, and Bridon............................................. 84
`1.
`Claims 1-2 and 4-11 of the ’122 Patent .............................. 84
`2.
`Claim 13 of the ’122 Patent ............................................ 126
`3.
`Claim 15 of the ’122 Patent ............................................ 127
`C. Ground 2: The Challenged Claims of the ’122 Patent Would
`Have Been Obvious Over Knudsen 2001 in View of the
`Knudsen Patent, Dong, and Bridon........................................... 128
`1.
`Claims 1-2 and 4-11 of the ’122 Patent ............................ 129
`2.
`Claim 13 of the ’122 Patent ............................................ 142
`3.
`Claim 15 of the ’122 Patent ............................................ 143
`D. Ground 3: The Challenged Claims of the ’122 Patent Would
`Have Been Obvious in View of Common Drug Development
`Principles.............................................................................. 144
`IX. No Secondary Considerations Overcome Prima Facie Obviousness of
`the Claimed Subject Matter .............................................................. 148
`A.
`Semaglutide Did Not Produce Any Unexpected or Surprising
`Results ................................................................................. 149
`The Prior Art Did Not Teach Away From Semaglutide ............... 152
`There Was No Long-Felt But Unmet Need ................................ 153
`There Was No Industry Skepticism .......................................... 153
`
`B.
`C.
`D.
`
`3
`
`MPI EXHIBIT 1020 PAGE 3
`
`
`
`TABLE OF CONTENTS
`(continued)
`
`Page
`
`
`
`Copying by Generic Drug Makers Is Irrelevant .......................... 154
`E.
`X. CONCLUSION .............................................................................. 154
`
`4
`
`MPI EXHIBIT 1020 PAGE 4
`
`
`
`
`
`TABLE OF ABBREVIATIONS
`
`Full Name of Cited Reference
`U.S. Patent No. 8,536,122
`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
`’122 patent
`’549 patent
`Adelhorst
`
`Banting
`
`Bayliss
`
`Bell
`
`Bridon
`Buckley
`Buse
`
`Chang
`
`Cistola I
`
`Cistola II
`
`Cooper
`
`5
`
`MPI EXHIBIT 1020 PAGE 5
`
`
`
`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
`
`Elbrond
`
`Flink
`Gault
`
`Göke
`
`Harder
`
`6
`
`MPI EXHIBIT 1020 PAGE 6
`
`
`
`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
`
`Kenyon
`
`Kim
`
`Knudsen 2000
`
`Knudsen 2001
`
`Knudsen 2004
`
`7
`
`MPI EXHIBIT 1020 PAGE 7
`
`
`
`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
`
`Markussen
`
`Mentlein
`
`Mojsov
`
`Nicholson
`
`8
`
`MPI EXHIBIT 1020 PAGE 8
`
`
`
`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
`
`
`
`
`
`
`
`9
`
`MPI EXHIBIT 1020 PAGE 9
`
`
`
`
`
`I.
`
`INTRODUCTION
`
`1. My name is Peter R. Flatt, Ph.D. I have been retained by Mylan
`
`Pharmaceuticals Inc. (“Mylan”). I understand that Mylan intends to petition for inter
`
`partes review (“IPR”) of U.S. Patent No. 8,536,122 (“’122 patent”), Ex. 1001, which
`
`is assigned to Novo Nordisk A/S (“Patent Owner”). As part of the petition, I
`
`understand Mylan will request that the United States Patent and Trademark Office
`
`(“USPTO”) cancel claims 1-2, 4-11, 13, and 15 of the ’122 patent (“the challenged
`
`claims”) as unpatentable. I submit this expert declaration to address and support
`
`Mylan’s IPR petition for the challenged claims of the ’122 patent.
`
`II. QUALIFICATIONS AND BACKGROUND
`
`A. Education and Experience; Prior Testimony
`
`2.
`
`I am currently a Professor of Biomedical Science, Director of the
`
`Biomedical Sciences Research Institute, and Head of Diabetes Research Group at
`
`Ulster University at Coleraine, Northern Ireland.
`
`3.
`
`I received a Bachelor of Science Degree in Biology and Chemistry from
`
`Aston University in 1974. In 1977, I received a Ph.D. from Aston University where
`
`my research was primarily related to insulin and glucagon, including studies on
`
`obesity and diabetes. In 2018, I received a Doctor of Sciences from Ulster
`
`University for pioneering research on gut hormones and peptide therapeutics for
`
`diabetes.
`
`10
`
`MPI EXHIBIT 1020 PAGE 10
`
`
`
`
`
`
`
`4.
`
`In 1978, after obtaining my Ph.D., I joined the University of Uppsala
`
`
`
`as a Postdoctoral Research Fellow in the Department of Medical Cell Biology.
`
`5.
`
`In 1980, I joined the University of Surrey where I was a lecturer and
`
`senior lecturer in the Department of Biochemistry.
`
`6.
`
`In 1989, I joined Ulster University as a Professor of Biomedical
`
`Sciences and Head of Diabetes Research Group in the School of Biomedical
`
`Sciences. In 1992, I became the Director of the Biomedical Sciences Research
`
`Centre. In 1994, I became the Head of the School of Biomedical Sciences. In 2012,
`
`I became Course Director of BSc (Honours) Biomedical Science Degree Courses.
`
`In 2017, I became the Director of Biomedical Sciences Research Institute, which
`
`houses approximately 150 principal investigators and was rated in the top five UK
`
`Units for research power in biomedical sciences in the nationwide REF assessment
`
`in 2021.
`
`7.
`
`Throughout my career, my research has focused on peptides for use in
`
`the treatment of diabetes and/or obesity, including naturally occurring peptides and
`
`analogues of naturally occurring peptides. Specifically, my research has focused on
`
`experimental diabetes research on gut hormones, peptide therapeutics, drug
`
`discovery, cell therapy, beta-cell stimulus-secretion coupling and islet cell function.
`
`8.
`
`I have published numerous books, articles, abstracts, and the like,
`
`related to experimental diabetes research on gut hormones, peptide therapeutics,
`
`11
`
`MPI EXHIBIT 1020 PAGE 11
`
`
`
`
`
`
`drug discovery, cell therapy, beta-cell stimulus-secretion coupling and islet cell
`
`
`
`function, including:
`
`a. Four multi-author edited international research texts.
`
`b. Six edited proceedings (i.e., colloquia, conferences, seminars, etc.).
`
`c. 110 reviews and book chapters.
`
`d. 570 original peer-reviewed scientific papers.
`
`e. 29 patented inventions.
`
`9. My publications have been cited more than 25,200 times and I have an
`
`h-index of 75. I have presented approximately 100 research lectures at national or
`
`international conferences in more than 20 countries around the world.
`
`10.
`
`I have received numerous awards throughout my career for my work in
`
`the field of diabetes research, including:
`
`a. Elected Fellow of the Institute of Biology (FIBiol now FBS)
`
`b. Elected Fellow of the Royal Society of Chemistry (FRSC)
`
`c. Recipient of Mary Jane Kugal Award of Juvenile Diabetes Federation
`
`International
`
`d. Recipient of Biochemistry Medal of Irish Section of the Biochemical
`
`Society
`
`e. Elected Member of the Royal Irish Academy (MRIA) – Ireland’s
`
`premier Learned Body for Sciences and Humanities
`
`12
`
`MPI EXHIBIT 1020 PAGE 12
`
`
`
`
`
`
`
`
`
`f. Awarded Ulster University Senior Distinguished Research Fellowship
`
`g. Dorothy Hodgkin Award Lecturer of Diabetes UK
`
`h. Niall O’Meara Lecturer of Irish Endocrine Society
`
`i. Ernst-Friedrich Pfeiffer Memorial Lecture, European Association for
`
`the Study of Diabetes (AIDPIT)
`
`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
`
`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)
`
`13
`
`MPI EXHIBIT 1020 PAGE 13
`
`
`
`
`
`
`
`
`
`• 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
`
`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 unpatent-
`
`ability, 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.
`
`14
`
`MPI EXHIBIT 1020 PAGE 14
`
`
`
`
`
`
`unpatentability is more probable than not. I have taken these principles into account
`
`
`
`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 ’122 patent. I have also been
`
`informed that claims 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.
`
`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
`
`success in doing so. I further understand that absolute predictability of success is
`
`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
`
`15
`
`MPI EXHIBIT 1020 PAGE 15
`
`
`
`
`
`
`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.
`
`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.
`
`16
`
`MPI EXHIBIT 1020 PAGE 16
`
`
`
`
`
`
`
`22. 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.
`
`23.
`
`Scope of Work
`
`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 £500 (GBP) 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 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
`
`24.
`
`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).
`
`17
`
`MPI EXHIBIT 1020 PAGE 17
`
`
`
`
`
`
`
`25. 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.
`
`26.
`
`In my opinion, the following definition of a POSA applies to the claims
`
`of the ’122 patent. 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 glucagon-like peptide 1 (“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.
`
`18
`
`MPI EXHIBIT 1020 PAGE 18
`
`
`
`
`
`
`
`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 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.
`
`19
`
`MPI EXHIBIT 1020 PAGE 19
`
`
`
`
`
`
`
`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. Within this
`
`definition, my background focuses on the chemical, biological, and biochemical
`
`aspects of the claims of the ’122 patent. This includes aspects of the claims related
`
`to the chemical structures of the claimed peptides, their biological and biochemical
`
`effects, and related issues.
`
`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 clai m. The ’122 patent lists Jesper
`
`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, filed 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
`
`20
`
`MPI EXHIBIT 1020 PAGE 20
`
`
`
`
`
`
`No. 05102171. Therefore, 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):
`
`
`
`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;
`
`21
`
`MPI EXHIBIT 1020 PAGE 21
`
`
`
`
`
`
`
`
`
`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; 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
`
`
`
`
`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.”
`
`22
`
`MPI EXHIBIT 1020 PAGE 22
`
`
`
`
`
`
`
`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., α-
`
`aminoisobutyric acid).
`
`38. Claims 6 and 7 depend from independent claim 1 and specify that the
`
`GLP-1 analogue has no more than six (claim 6) or three (claim 7) “amino 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).”
`
`23
`
`MPI EXHIBIT 1020 PAGE 23
`
`
`
`
`
`
`
`41. Claim 10 depends from independent claim 1 and requires the spacer to
`
`
`
`be selected from:
`
`
`42. Claim 11 depends from claim 10 and requires “B,” as recited in
`
`independent claim 1, to be:
`
`
`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.”
`
`24
`
`MPI EXHIBIT 1020 PAGE 24
`
`
`
`
`
`
`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 ter