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 2025
`Dr. Reddy's Lab'ys, Inc. v. Novo Nordisk A/S
`IPR2024-00009
`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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`Novo Nordisk Exhibit 2025
`Dr. Reddy's Lab'ys, Inc. v. Novo Nordisk A/S
`IPR2024-00009
`Page 00002
`
`

`

`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.
`
`
`
`
`
`
`Novo Nordisk Exhibit 2025
`Dr. Reddy's Lab'ys, Inc. v. Novo Nordisk A/S
`IPR2024-00009
`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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`Novo Nordisk Exhibit 2025
`Dr. Reddy's Lab'ys, Inc. v. Novo Nordisk A/S
`IPR2024-00009
`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-
`
`
`
`Novo Nordisk Exhibit 2025
`Dr. Reddy's Lab'ys, Inc. v. Novo Nordisk A/S
`IPR2024-00009
`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 2025
`Dr. Reddy's Lab'ys, Inc. v. Novo Nordisk A/S
`IPR2024-00009
`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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`Novo Nordisk Exhibit 2025
`Dr. Reddy's Lab'ys, Inc. v. Novo Nordisk A/S
`IPR2024-00009
`Page 00007
`
`

`

`
`
`
`
`
`
`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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`Novo Nordisk Exhibit 2025
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`IPR2024-00009
`Page 00008
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`
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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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`Novo Nordisk Exhibit 2025
`Dr. Reddy's Lab'ys, Inc. v. Novo Nordisk A/S
`IPR2024-00009
`Page 00009
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`362.Moreover, at trial I may rely upon documents and/or other materials
`
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`produced in this litigation, publicly available documents, and/or any documents the
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`parties have exchanged, such as discovery responses. Additionally, I may rely on
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`visual aids and/or demonstrative exhibits that I prepare or have been prepared on my
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`
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`behalf based upon my opinions.
`
`
`
`
`
`Dated: 3/19/2024
`
`By:� � WilliamJ. Jus�
`
`
`
`- 146 -
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`Novo Nordisk Exhibit 2025
`Dr. Reddy's Lab'ys, Inc. v. Novo Nordisk A/S
`IPR2024-00009
`Page 00010
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