IN THE UNITED STATES DISTRICT COURT
`
`FOR THE DISTRICT OF DELAWARE
`
`IN RE: OZEMPIC (SEMAGLUTIDE)
`PATENT LITIGATION
`NOVO NORDISK INC. AND NOVO
`NORDISK A/S,
`
`
`
`
`
`
`Plaintiffs/Counterclaim Defendants,
`
`No. 22-md-3038-CFC
`
`v.
`
`
`RIO BIOPHARMACEUTICALS INC., et
`al.,
`
`
`
`
`Defendants/Counterclaim Plaintiffs.
`
`C.A. No. 22-294-CFC
`
`NOVO NORDISK INC. and NOVO
`NORDISK A/S,
`
`
`
`
`
`Plaintiffs/Counterclaim Defendants,
`v.
`
`No. 22-cv-1040-CFC
`
`
`MYLAN PHARMACEUTICALS INC.,
`
`Defendant/Counterclaim Plaintiff.
`
`
`
`OPENING EXPERT REPORT OF WILLIAM J. JUSKO, PH.D.
`REGARDING INVALIDITY OF U.S. PATENT NO. 10,335,462
`
`
`
`
`
`
`
`
`
`Novo Nordisk Exhibit 2551
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
`
`

`

`TABLE OF CONTENTS
`
`
`Page
`
`
`I.
`
`QUALIFICATIONS AND BACKGROUND ................................................ 1
`A.
`EDUCATION AND EXPERIENCE ............................................................... 1
`B.
`PRIOR TESTIMONY ................................................................................. 5
`C.
`BASIS FOR OPINIONS AND MATERIALS CONSIDERED ............................. 6
`D.
`RETENTION AND COMPENSATION .......................................................... 6
`LEGAL STANDARDS .................................................................................. 7
`II.
`III. PERSON OF ORDINARY SKILL IN THE ART ......................................... 9
`IV. BRIEF SUMMARY OF OPINIONS ........................................................... 11
`V.
`THE ’462 PATENT ...................................................................................... 12
`A.
`THE SPECIFICATION AND CLAIMS OF THE ’462 PATENT ....................... 12
`B.
`THE PROSECUTION HISTORY OF THE ’462 PATENT .............................. 14
`VI. CLAIM CONSTRUCTION ......................................................................... 17
`VII. BACKGROUND .......................................................................................... 18
`A.
`PHARMACOKINETICS AND PHARMACODYNAMICS ................................ 18
`B. DRUG DEVELOPMENT – CLINICAL TRIAL DESIGN ............................... 21
`C.
`PHARMACOKINETICS AND PHARMACODYNAMICS RELATED TO
`GLP-1 AND SEMAGLUTIDE .................................................................. 27
`1.
`GLP-1 ....................................................................................... 28
`2.
`GLP-1 derivatives .................................................................... 29
`SEMAGLUTIDE CLINICAL TRIALS ......................................................... 36
`D.
`VIII. SCOPE AND CONTENT OF THE PRIOR ART ........................................ 41
`A. WO ’421 ............................................................................................. 42
`B.
`LOVSHIN 2009 ..................................................................................... 45
`C. WO ’537 ............................................................................................. 47
`D.
`SEMAGLUTIDE CLINICAL TRIALS ......................................................... 49
`1.
`NCT00696657 .......................................................................... 49
`2.
`NCT00851773 .......................................................................... 51
`
`
`
`
`
`-i-
`
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`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
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`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`Public Availability of ClinicalTrials.gov ................................. 54
`3.
`KNUDSEN 2004 .................................................................................... 60
`E.
`LUND ................................................................................................... 61
`F.
`SEINO .................................................................................................. 65
`G.
`H. VICTOZA LABEL .................................................................................. 67
`I.
`SHARGEL ............................................................................................. 69
`J.
`TAMIMI ................................................................................................ 70
`K.
`FDA EXPOSURE RESPONSE 2003 ........................................................ 72
`L.
`ICH 1994 ............................................................................................ 74
`M. KNUDSEN 2010B ................................................................................. 77
`N.
`BHANSALI ............................................................................................ 77
`O. MADSBAD 2011 ................................................................................... 82
`P.
`’833 PATENT ....................................................................................... 84
`Q. ADDITIONAL PRIOR ART AND REFERENCES .......................................... 85
`INVALIDITY OF THE ’462 PATENT ....................................................... 86
`A.
`CLAIMS 1 AND 3 OF THE ’462 PATENT ARE ANTICIPATED BY WO
`’421, LOVSHIN 2009, OR NCT00696657 ............................................. 86
`1. WO ’421 Anticipated Claims 1 and 3 of the ’462 Patent ........ 86
`2.
`Lovshin 2009 Anticipated Claims 1 and 3 of the ’462
`Patent ........................................................................................ 92
`NCT00696657 Anticipated Claims 1 and 3 of the ’462
`Patent ........................................................................................ 97
`CLAIMS 1, 3-5, AND 7 OF THE ’462 PATENT WOULD HAVE BEEN
`OBVIOUS ........................................................................................... 101
`1.
`Claims 1, 3-5, and 7 of the ’462 Patent Would Have Been
`Obvious Over WO ’421, NCT00696657, WO ’537
`and/or Lovshin 2009, Optionally in View of One or More
`of the ’833 Patent and Madsbad 2011 ................................... 101
`
`B.
`
`3.
`
`-ii-
`
`
`
`
`
`IX.
`
`
`
`
`
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`Novo Nordisk Exhibit 2551
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00003
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`2.
`
`Claims 1, 3-5, and 7 of the ’462 Patent Would Have Been
`Obvious Over WO ’421 Alone or in View of the ’833
`Patent ...................................................................................... 120
`Claims 1, 3-5, and 7 of the ’462 Patent Would Have Been
`Obvious Over WO ’537 in View of Lovshin 2009 ................ 132
`CONCLUSION ........................................................................................... 145
`
`3.
`
`-iii-
`
`
`
`
`
`X.
`
`
`
`
`
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`IPR2023-00724
`Page 00004
`
`

`

`
`
`
`
`
`
`TABLE OF ABBREVIATIONS
`
`Full Name of Cited Reference
`U.S. Patent App. Pub. No. 2011/0166321
`U.S. Patent No. 10,335,462 (NN-OZEM-000000071-95)
`Prosecution History for U.S. Patent No. 10,335,462 (NN-
`OZEM-000003820-4446)
`U.S. Patent App. Pub. No. 2004/0102486
`U.S. Patent No. 5,512,549
`U.S. Patent No. 8,114,833 (SEMA(JDG)_0000447-68)
`Bell, Hamster Preproglucagon Contains the Sequence of
`Glucagon and Two Related Peptides, 302 NATURE 716
`(1983)
`Bhansali, Historical Overview of Incretin Based
`Therapies, 58 J. ASSOC. OF PHYSICIANS OF INDIA 10 (2010)
`(SEMA(JDG)_0000014-18)
`Blonde, Comparison of Liraglutide Versus Other Incretin-
`Related Anti-Hyperglycaemic Agents, 14 (suppl. 2)
`DIABETES, OBESITY & METABOLISM 20 (2012)
`ClinicalTrials.gov Background, CLINICALTRIALS.GOV,
`https://clinicaltrials.gov/ct2/about-site/background (last
`visited Mar. 15, 2024)
`Drab, Incretin-Based Therapies for Type 2 Diabetes
`Mellitus: Current Status and Future Prospects, 30
`PHARMACOTHERAPY 609 (2010)
`FDA Guidance for Industry, Exposure-Response
`Relationships - Study Design, Data, Analysis, and
`Regulatory Applications (Apr. 2003)
`Garber, Efficacy of Metformin in Type II Diabetes: Results
`of a Double-Blind, Placebo-Controlled, Dose-Response
`Trial, 102 AM. J. MED. 491 (1997)
`
`Abbreviation
`’321 publication
`’462 patent
`’462 patent prosecution
`history
`’486 publication
`’549 patent
`’833 patent
`Bell
`
`Bhansali
`
`Blonde
`
`ClinicalTrials.gov
`Background
`
`Drab
`
`FDA Exposure Response
`2003
`
`Garber
`
`
`
`
`
`-iv-
`
`
`
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`IPR2023-00724
`Page 00005
`
`

`

`
`
`
`
`
`
`TABLE OF ABBREVIATIONS
`(continued)
`
`Full Name of Cited Reference
`Award: ClinicalTrials.gov,
`https://ash.harvard.edu/news/clinicaltrials.gov (last visited
`Mar. 15, 2024)
`Holst, Truncated Glucagon-like Peptide I, an Insulin-
`Releasing Hormone from the Distal Gut, 211 (2) FEBS
`LETTERS 169 (1987)
`International Conference on Harmonisation; Dose-
`Response Information to Support Drug Registration;
`Guideline; Availability, 59 Fed. Reg. 55972 (Nov. 9, 1994)
`EMA, ICH Topic S 7 A Safety Pharmacology Studies for
`Human Pharmaceuticals (June 2001)
`Kirillova, Results and Outcome Reporting in
`ClinicalTrials.gov, What Makes it Happen?, 7(6) PLOS
`ONE 1 (2012)
`Knudsen, Glucagon-like Peptide-1: The Basis of a New
`Class of Treatment for Type 2 Diabetes, 47 J. MED.
`CHEMISTRY 4128 (2004)
`Knudsen, Liraglutide: The Therapeutic Promise from
`Animal Models, 64(suppl 167) INT J CLIN PRACT 4 (2010)
`Landersdorfer, Pharmacokinetic/Pharmacodynamic
`Modelling in Diabetes Mellitus, 47(7) CLIN
`PHARMACOKINET 417 (2008)
`Landersdorfer, Mechanism-Based Population
`Pharmacokinetic Modelling in Diabetes: Vildagliptin as a
`Tight Binding Inhibitor and Substrate of Dipeptidyl
`Peptidase IV, 73 Br J Clin Pharmacol 391 (2011)
`Landersdorfer, Mechanism-Based Population Modelling of
`the Effects of Vildagliptin on GLP-1, Glucose and Insulin
`in Patients with Type 2 Diabetes, 73 BR J CLIN
`PHARMACOL 373 (2011)
`Lovshin, Incretin-Based Therapies for Type 2 Diabetes
`Mellitus, 5 NATURE REVIEWS ENDOCRINOLOGY 262 (2009)
`(SEMA(JDG)_0002250-58)
`
`- v -
`
`Abbreviation
`Harvard Award
`
`Holst
`
`ICH 1994
`
`ICH 2001
`
`Kirillova
`
`Knudsen 2004
`
`Knudsen 2010b
`
`Landersdorfer 2008
`
`Landersdorfer 2011a
`
`Landersdorfer 2011b
`
`Lovshin 2009
`
`Novo Nordisk Exhibit 2551
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00006
`
`

`

`
`
`
`
`
`
`TABLE OF ABBREVIATIONS
`(continued)
`
`Full Name of Cited Reference
`Lund, Emerging GLP-1Receptor Agonists, 16 EXPERT
`OPINION ON EMERGING DRUGS 607 (2011)
`Madsbad, An Overview of Once-Weekly Glucagon-Like
`Peptide-1 Receptor Agonists - Available Efficacy and
`Safety Data and Perspectives for the Future, 13 DIABETES,
`OBESITY & METABOLISM 394 (2011)
`(SEMA(JDG)_0002439-52)
`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)
`Møller, Mechanism-Based Population Modelling for
`Assessment of L-Cell Function Based on Total GLP-1
`Response Following an Oral Glucose Tolerance Test, 38 J.
`PHARMACOKINET PHARMACODYN 713 (2011)
`Monami, Effects of Glucagon-Like Peptide-1 Receptor
`Agonists on Body Weight: A Meta-Analysis, 2012
`EXPERIMENTAL DIABETES RSCH. 1 (2012)
`Murphy, Review of the Safety and Efficacy of Exenatide
`Once Weekly for the Treatment of Type 2 Diabetes
`Mellitus, 46 ANN PHARMACOTHER 812 (2012)
`Clinical Trial No. NCT00696657 (Internet Archive)
`Clinical Trial No. NCT00851773 (Internet Archive)
`Rohatagi, Model-Based Development of a PPARγ Agonist,
`Rivoglitazone, to Aid Dose Selection and Optimize Clinical
`Trial Designs, 48 J. CLIN. PHARM. 1420 (2008)
`Seino, Dose-Dependent Improvement in Glycemia with
`Once-Daily Liraglutide without Hypoglycemia or Weight
`Gain: A Double-Blind, Randomized, Controlled Trial in
`Japanese Patients with Type 2 Diabetes, 81 DIABETES
`RSCH. & CLINICAL PRACTICE 161 (2008)
`Shargel, APPLIED BIOPHARMACEUTICS &
`PHARMACOKINETICS (5th ed. 2005)
`
`Abbreviation
`Lund
`
`Madsbad 2011
`
`Mojsov
`
`Moller
`
`Monami
`
`Murphy
`
`NCT00696657
`NCT00851773
`Rohatagi
`
`Seino
`
`Shargel
`
`- vi -
`
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`

`

`
`
`
`
`
`
`TABLE OF ABBREVIATIONS
`(continued)
`
`Full Name of Cited Reference
`Tamimi, Drug Development: From Concept to Marketing!,
`113 NEPHRON CLIN PRACT C125 (2009)
`Tasneem, The Database for Aggregate Analysis of
`ClinicalTrials.gov (AACT) and Subsequent Regrouping by
`Clinical Specialty, 7(3) PLOS ONE 1(2012)
`Victoza, PHYSICIANS’ DESK REFERENCE (65th ed. 2010)
`International Patent App. Pub. No. WO 2011/058193
`International Patent App. Pub. No. WO 2011/073328
`International Patent App. Pub. No. WO 2011/138421
`(SEMA(JDG)_0002087-158)
`International Patent App. Pub. No. WO 91/11457
`International Patent App. Pub. No. WO 2006/097537
`(SEMA(JDG)_0002453-528)
`Yun, Pharmacokinetic and Pharmacodynamic Modelling
`of the Effects of Glimepiride on Insulin Secretion and
`Glucose Lowering in Healthy Humans, 31 J. CLIN. PHARM.
`& THER. 469 (2006)
`Zarin, The ClinicalTrials.gov Results Database—Update
`and Key Issues, 364 NEW ENGL. J. MED. 852 (2011)
`
`Abbreviation
`Tamimi
`
`Tasneem
`
`Victoza label
`WO ’193
`WO ’328
`WO ’421
`
`WO ’457
`WO ’537
`
`Yun
`
`Zarin
`
`- vii -
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`

`

`
`
`
`1. My name is William J. Jusko, Ph.D. I have been retained by Mylan
`
`Pharmaceuticals Inc., Dr. Reddy’s Laboratories, Ltd. and Dr. Reddy’s Laboratories,
`
`Inc., Rio Biopharmaceuticals Inc. and EMS S/A; Sun Pharmaceutical Industries Ltd.
`
`and Sun Pharmaceutical Industries, Inc.; and Zydus Worldwide DMCC, Zydus
`
`Pharmaceuticals (USA) Inc., and Zydus Lifesciences Limited (collectively, the
`
`“defendants”). I understand that Novo Nordisk Inc. and Novo Nordisk A/S
`
`(collectively, “Novo Nordisk” or “Plaintiffs”) have asserted that the defendants
`
`infringe claims 1, 3-5, and 7 of U.S. Patent No. 10,335,462 (“’462 patent”). I have
`
`been asked to express my opinions regarding the validity of certain asserted claims
`
`of the ’462 patent.
`
`I.
`
`QUALIFICATIONS AND BACKGROUND
`
`A. EDUCATION AND EXPERIENCE
`
`2.
`
`I am a Professor of Pharmaceutical Sciences at the University of
`
`Buffalo School of Pharmacy and Pharmaceutical Sciences. My specialty and
`
`research
`
`focus
`
`broadly
`
`include Pharmacokinetics, Pharmacodynamics,
`
`Pharmacogenomics, and Pharmacometrics.
`
`3. My research interests also include theoretical, basic, and clinical
`
`aspects of
`
`the pharmacokinetics
`
`and pharmacodynamics of various
`
`immunosuppressive agents including corticosteroids, as well as drugs used to treat
`
`diabetes, inflammation, and cancer.
`
`
`
`
`
`-1-
`
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`

`

`
`
`
`
`
`
`4.
`
`I have characterized the effects of diverse drugs in cells, tissues,
`
`animals,
`
`and
`
`human
`
`subjects
`
`and
`
`have
`
`evolved
`
`advanced
`
`pharmacokinetic/pharmacodynamic (“PK/PD”) models for rapidly acting as well as
`
`cascade-type processes. I also have developed mechanism-based pharmacokinetic,
`
`pharmacodynamic, and disease progression models and computational methods
`
`describing the action of various drugs and utilized mathematical models of drug
`
`action to determine optimal dosage regimens for diverse drugs.
`
`5.
`
`I have worked as a consultant for the Food and Drug Administration
`
`(FDA) Clinical Pharmacology Advisory Committee, the National Institutes of
`
`Health (NIH) Pharmacology Study Section, the Council for International Exchange
`
`of Scholars, and for many pharmaceutical companies.
`
`6.
`
`From 2001 to 2016, I served as chair of the University of Buffalo
`
`Department of Pharmaceutical Sciences. More than 100 students and fellows have
`
`completed research training under my guidance.
`
`7.
`
`I have published more than 670 research articles and serve on the
`
`editorial boards of numerous academic journals, including formerly being the editor-
`
`in-chief for the Journal of Pharmacokinetics and Pharmacodynamics.
`
`8.
`
`I received a Bachelor of Pharmacy in 1965 from State University of
`
`New York at Buffalo. I remained at State University of New York (SUNY) at
`
`Buffalo where I completed my Ph.D. in Pharmaceutical Sciences in 1969.
`
`
`
`- 2 -
`
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`

`

`
`
`
`
`
`
`9.
`
`I began my academic career in 1969 as an Assistant Professor of
`
`Pharmacology at the Boston University School of Medicine, where I remained for
`
`years.
`
`10.
`
`I have been a faculty member at the University of Buffalo since 1972.
`
`From 1972 to 1974, I was an Assistant Professor of Pharmaceutics at the University
`
`of Buffalo.
`
`11.
`
`I remained at the University of Buffalo from 1974 to present, where I
`
`transitioned through several roles including as the Director of the Doctor of
`
`Pharmacy Program, Vice-Chairman of the Department of Pharmacy, Professor of
`
`Pharmaceutical Sciences, Chair of Pharmaceutical Sciences, and Director of the
`
`Center of Excellence in Pharmacokinetics and Pharmacodynamics. I am now
`
`currently a SUNY Distinguished Professor in Pharmaceutical Sciences.
`
`12. My expertise has been recognized by my peers. I received the 2020
`
`Distinguished Pharmaceutical Scientist Award from the American Association of
`
`Pharmaceutical Sciences (“AAPS”). The Distinguished Pharmaceutical Scientist
`
`Award is the AAPS’s most esteemed honor and is a lifetime achievement that
`
`recognizes an individual who has made substantial contributions to the research and
`
`advancement of pharmaceutical sciences.
`
`13.
`
`I received the 2019 Lewis B. Sheiner Lecturer Award from the
`
`International Society of Pharmacometrics (“ISoP”); the 2018 Oscar B. Hunter
`
`
`
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`
`
`
`
`Career Award in Therapeutics from the American Society for Clinical Pharmacology
`
`and Therapeutics; a coveted MERIT (Method to Extend Research in Time) Award
`
`from the NIH; and several other awards.
`
`14.
`
`I have appreciable experience in studying the pharmaceutical and
`
`pharmacological properties of drugs used to treat diabetes. My curriculum vitae
`
`(“CV”) lists at least 31 such publications with 21 involving the study of antidiabetic
`
`drugs or the diabetes disease conditions in animal models (diabetic rats) and 10
`
`pertaining to the study of antidiabetic drugs in healthy or diabetic humans. Part of
`
`this work was supported by the Pfizer Company when I directed my Department’s
`
`participation in the UB/Pfizer Strategic Alliance in PK/PD with millions of dollars
`
`of support from the company.
`
`15.
`
`I am also an inventor on a patent application assigned to SmithKline
`
`Beecham Corporation in which I assisted in the development of their antidiabetic
`
`drug, Avandia (rosiglitazone) and helped to describe the Exposure/Response
`
`(PK/PD) relationships between plasma drug concentrations, lowering of glucose,
`
`and lowering of glycated hemoglobin (HbA1c) concentrations in blood in type 2
`
`diabetic patients. See ’486 publication. This drug was approved by the FDA as the
`
`first-in-class known as “insulin sensitizers” that help the uptake of glucose by
`
`transporters into tissues. I later helped the Daiichi Sankyo Company in developing
`
`
`
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`

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`
`
`
`
`rivoglitazone, a drug in the same class with similar effects. See Rohatagi. We
`
`generated Exposure/Response relationships for a range of doses in these studies.
`
`16.
`
`I have particularly relevant experiences pertaining to glucagon-like
`
`peptide-1 (“GLP-1”)-related mechanisms in diabetes, some of which I discuss in
`
`more detail below. I also have considerable experience in designing studies
`
`(including dosing studies) and assessing pharmacokinetic and pharmacodynamic
`
`data from phase I, II, and III clinical trials. This includes clinical trials for the
`
`antidiabetic drugs rosiglitazone, rivoglitazone, pramlintide, vildagliptin, inhaled
`
`insulin and others.
`
`17.
`
`I am currently a consultant for ReveraGen BioPharma, Inc. advising on
`
`dosing in their clinical trials and performing data analyses for their steroid
`
`vamorolone in treating adolescent males with Duchenne muscular dystrophy.
`
`18. A copy of my CV, attached as Exhibit A, provides a more
`
`comprehensive review of my work and describes my qualifications in greater detail,
`
`including a list of all publications that I authored during my career.
`
`B.
`
`PRIOR TESTIMONY
`
`19.
`
`In the past four years, I have testified in the following proceedings:
`
`
`
`
`
`Kellington v. Bayer, 5:14-CV-00002 (W.D. VA), 2:14-CV-00036-
`WMA;
`
`Hospira Inc. v. Genentech, Inc., IPR2017-00805 (PTAB);
`
`
`
`
`- 5 -
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`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`KVK-Tech, Inc. v. Shire PLC, IPR2018-00290, IPR2018-00293
`(PTAB);
`
`Novartis AG v. Apotex Inc., Civil Action No. 15-6934 (SRC)(CLW);
`
`Tris Pharma, Inc. v. Teva Pharmaceuticals USA, Inc., 2-20-cv-05212
`(D.N.J.);
`
`Novartis Pharmaceuticals Corp. v. Dr. Reddy’s Labs. Inc., C.A. No.
`21-1106 (D. Del.);
`
`Mylan Pharmaceuticals Inc. v. Novo Nordisk A/S, IPR2023-00724
`(P.T.A.B.).
`
`
`C. BASIS FOR OPINIONS AND MATERIALS CONSIDERED
`
`20. A list of the materials I considered, in addition to my experience,
`
`education, and training, to provide the opinions contained in this report is attached
`
`as Exhibit B.
`
`D. RETENTION AND COMPENSATION
`
`21.
`
`I have been retained by counsel for the defendants as a technical expert
`
`to provide certain of my opinions regarding the ’462 patent. I receive $800 per hour
`
`for this work. No part of my compensation is dependent upon my opinions given or
`
`the outcome of this proceeding. I have no affiliations with Novo Nordisk Inc. or
`
`Novo Nordisk A/S, or any affiliates presently known to me, or the named inventor
`
`on the ’462 patent.
`
`
`
`- 6 -
`
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`

`

`
`
`
`II. LEGAL STANDARDS
`
`
`
`22.
`
`In preparing and forming my opinions set forth in this report, I have
`
`been informed by counsel of the relevant legal principles. I applied my
`
`understanding of those principles in forming my opinions. My understanding of
`
`those principles is summarized below.1 I took these principles into account when
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`forming my opinions in this proceeding.
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`23.
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`I understand that my opinions regarding invalidity are presented from
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`the viewpoint of a person of ordinary skill in the art (“POSA” or “skilled artisan”)
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`in the field of technology of the patent as of the patent’s priority date. In this report,
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`my opinions are premised on the perspective of a POSA at the time of the earliest
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`claimed priority date listed on the face of the ’462 patent, July 1, 2012. See ’462
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`patent at cover page. To the extent that Novo Nordisk later asserts that the asserted
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`1 In performing my analysis and reaching my opinions and conclusions, I have been
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`informed of and have been advised to apply various legal principles relating to
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`invalidity, which I set forth herein. In setting forth these legal standards, it is not my
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`intention to testify about the law. I only provide my understanding of the law, as
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`explained to me by counsel, as a context for the opinions and conclusions I am
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`providing.
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`- 7 -
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`Novo Nordisk Exhibit 2551
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00015
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`claims are entitled to an earlier priority or invention date, I reserve the right to
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`supplement this report.
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`24.
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`I have been informed that the defendants bear the burden of proving
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`invalidity by clear and convincing evidence. I have been told that this means the
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`Court, considering the evidence, must have an abiding conviction that it is highly
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`probable that the asserted claims are invalid.
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`25.
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`I understand that for a patent claim to be invalid as anticipated, a prior
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`art reference must disclose each element of the claim expressly and/or inherently as
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`arranged in the claim.
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`26. Counsel has informed me that the concept of patent obviousness
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`involves four factual inquiries: (1) the scope and content of the prior art; (2) the
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`differences between the claimed invention and the prior art; (3) the level of ordinary
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`skill in the art; and (4) secondary considerations of non-obviousness.
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`27.
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`It is my understanding from counsel that when there is some recognized
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`reason to solve a problem, and there are a finite number of identified, predictable
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`and known solutions, a person of ordinary skill in the art has good reason to pursue
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`the known options within his or her technical grasp. If such an approach leads to the
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`expected success, it is likely not the product of innovation but of ordinary skill and
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`common sense. It is my understanding that any need or problem known in the field
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`of endeavor at the time of invention or addressed by the patent can provide a reason
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`- 8 -
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`Novo Nordisk Exhibit 2551
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00016
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`

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`for combining prior art elements to arrive at the claimed subject matter. I understand
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`that only a reasonable expectation of success is necessary to show obviousness.
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`III. PERSON OF ORDINARY SKILL IN THE ART
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`28.
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`In my opinion, the following definition of a person of ordinary skill in
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`the art (“POSA” or “skilled artisan”) applies to the claims of the ’462 patent. If the
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`Court adopts, or the parties agree to, a different definition of a POSA I reserve the
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`right to amend and/or supplement my opinions on invalidity.
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`29. A POSA here would have had (1) an M.D., a Pharm. D., or a Ph.D. in
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`pharmacy, chemical engineering, bioengineering, chemistry, or related discipline;
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`(2) at least two years of experience in protein or peptide therapeutic development
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`and/or manufacturing or diabetes treatments; and/or (3) experience with the
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`development, design, manufacture, formulation, or administration of therapeutic
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`agents, and the literature concerning protein or peptide formulation and design, or
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`diabetes treatments.
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`30. Alternatively, the POSA would be (1) a highly skilled scientist lacking
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`an M.D., Pharm. D., or Ph.D., but would have (2) more than five years of experience
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`in the area of protein or peptide therapeutic development and/or manufacturing or
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`diabetes treatments; and/or (3) experience with the development, design,
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`manufacture, formulation, or administration of therapeutic agents for diabetes, and
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`- 9 -
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`Novo Nordisk Exhibit 2551
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00017
`
`

`

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`the literature concerning protein or peptide formulation and design, or diabetes
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`treatments.
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`31. A POSA would have understood the prior art references referred to
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`herein and would have the capability to draw inferences. It is understood that, to the
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`extent necessary, a POSA may collaborate with one or more other POSAs for one or
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`more aspects with which the other POSA may have expertise, experience, and/or
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`knowledge. Additionally, a POSA could have had a lower level of formal education
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`than what I describe here if the person has a higher degree of experience.
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`32.
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`I understand that Novo Nordisk proposed that a person of ordinary skill
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`in the art would have, among other possible qualifications, an M.D., Ph.D. or
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`equivalent degree in Pharmacology, Pharmaceutics, Biopharmaceutics, or a related
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`field, and 3-5 years of experience conducting clinical research in the field of diabetes
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`treatments, including the design of dosing regimens and dosage forms for type 2
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`diabetes treatments, or 3-5 years of research or industry experience relating to
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`developing pharmaceutical formulations.
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`33. As shown by my qualifications provided in my CV and as explained in
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`this report, I met the qualifications of a POSA for purposes of the ’462 patent
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`regardless of which party’s definition is adopted.
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`34. Regardless of which party’s definition is adopted for a POSA, my
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`opinions would not change.
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`- 10 -
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`Novo Nordisk Exhibit 2551
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00018
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`

`

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`IV. BRIEF SUMMARY OF OPINIONS
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`35.
`
`In my opinion, WO ’421 anticipates claims 1 and 3 of the ’462 patent.
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`36.
`
`In my opinion, Lovshin 2009 anticipates claims 1 and 3 of the ’462
`
`patent.
`
`37.
`
`In my opinion, NCT00696657 anticipates claims 1 and 3 of the ’462
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`patent.
`
`38.
`
`In my opinion, claims 1, 3-5, and 7 of the ’462 patent would have been
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`obvious over WO ’421, NCT00696657, WO ’537 and/or Lovshin 2009, optionally
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`in view of one or more of the ’833 patent and Madsbad 2011.
`
`39.
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`In my opinion, claims 1, 3-5, and 7 of the ’462 patent would have been
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`obvious over WO ’421 alone or in view of the ’833 patent.
`
`40.
`
`In my opinion, claims 1, 3-5, and 7 of the ’462 patent would have been
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`obvious over WO ’537 in view of Lovshin 2009.
`
`41.
`
`I understand that the defendants’ expert Dr. Paul Dalby is submitting
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`an expert report with his opinions about why claims 4, 5, and 7 of the ’462 patent,
`
`directed to formulation-related elements, are obvious over the prior art. I defer to Dr.
`
`Dalby’s opinion regarding obviousness with respect to claims 4, 5, and 7 of the ’462
`
`patent.
`
`42.
`
`I understand that experts retained by Novo Nordisk may provide
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`opinions regarding alleged secondary considerations of nonobviousness of the
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`
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`- 11 -
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`Novo Nordisk Exhibit 2551
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00019
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`

`

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`
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`asserted ’462 patent claims. I reserve the right to address any secondary
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`considerations that Novo Nordisk’s experts may provide.
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`V. THE ’462 PATENT
`
`A. THE SPECIFICATION AND CLAIMS OF THE ’462 PATENT
`
`43.
`
`I have read the ’462 patent, titled “Use of Long-Acting GLP-1
`
`Peptides,” and reviewed the relevant portions of the prosecution history of the ’462
`
`patent. The ’462 patent issued from U.S. Patent Application No. 15/656,042 (“’042
`
`Application”), filed July 21, 2017, which is a continuation of U.S. Application No.
`
`14/409,493, filed as PCT/EP2013/063004, filed June 21, 2013, and claims priority
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`to Provisional Application No. 61/708,162, filed October 1, 2012, and Provisional
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`Application No. 61/694,837, filed August 30, 2012, and European patent 12174535,
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`filed July 1, 2012, and European patent 12186781, filed October 1, 2012. ’462 patent
`
`at cover page. The ’462 patent lists Christine Bjoern Jensen as the sole inventor and
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`Novo Nordisk A/S as the Assignee. Id.
`
`44. The ’462 patent has one independent claim and nine dependent claims.
`
`45.
`
`Independent claim 1 recites “[a]method for treating type 2 diabetes,
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`comprising administering semaglutide once weekly in an amount of 1.0 mg to a
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`subject in need thereof.”
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`46. Claim 2 recites, “[t]he method according to claim 1, wherein the
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`semaglutide is administered by parenteral administration.”
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`- 12 -
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`Novo Nordisk Exhibit 2551
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00020
`
`

`

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`
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`47. Claim 3 recites, “[t]he method according to claim 2, wherein the
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`solution2 is administered by subcutaneous injection.”
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`48. Claim 4 recites, “[t]he method according to claim 1, wherein the
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`semaglutide is administered in the form of an isotonic aqueous solution comprising
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`phosphate buffer at a pH in the range of 7.0-9.0.”
`
`49. Claim 5 recites, “[t]he method according to claim 4, wherein the
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`solution further comprises propylene glycol and phenol.”
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`50. Claim 6 recites, “[t]he method according to claim 4, wherein the pH is
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`7.4.”
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`51. Claim 7 recites, “[t]he method according to claim 6, wherein the
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`solution further comprises propylene glycol and phenol.”
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`52. Claim 8 recites, “[t]he method according to claim 4, wherein the
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`phosphate buffer is a sodium dihydrogen phosphate buffer.”
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`53. Claim 9 recites, “[t]he method according to claim 1, wherein the
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`semaglutide is administered by subcutaneous injection in the form of an isotonic
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`aqueous solution comprising at a sodium dihydrogen phosphate buffer at a pH in the
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`
`2 I note that although claim 3 recites, “[t]he method according to claim 2 [which
`depends from claim 1], wherein the solution is administered by subcutaneous
`injection,” neither claim 2 nor claim 1 recites “a solution.”
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`
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`- 13 -
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`Novo Nordisk Exhibit 2551
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00021
`
`

`

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`range of 7.0-9.0, and wherein the solution further comprises propylene glycol and
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`phenol.”
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`54. Claim 10 recites, “[t]he method according to claim 9, wherein the pH
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`is 7.4.”
`
`B