`
`IN THE UNITED STATES DISTRICT COURT
`
`FOR THE DISTRICT OF DELAWARE
`
`No. 22-md-3038-CFC
`
`No. 22-cv-294-CFC
`CONSOLIDATED
`ANDA CASE
`
`No. 22-cv-1040-CFC
`ANDA CASE
`
`IN RE: OZEMPIC (SEMAGLUTIDE)
`PATENT LITIGATION
`
`
`
`NOVO NORDISK INC. and NOVO
`NORDISK A/S,
`
`Plaintiffs/Counterclaim
`Defendants,
`
`v.
`
`
`RIO BIOPHARMACEUTICALS INC. et al.,
`
`Defendants/Counterclaim
`Plaintiffs.
`
`
`
`NOVO NORDISK INC. and NOVO
`NORDISK A/S,
`
`Plaintiffs/Counterclaim
`Defendants,
`
`v.
`
`
`MYLAN PHARMACEUTICALS INC.,
`
`Defendant/Counterclaim
`Plaintiff.
`
`
`
`Opening Expert Report of Dr. John Bantle
`Regarding Invalidity of U.S. Patent No. 10,335,462
`
`
`
`Novo Nordisk Exhibit 2024
`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; Prior Testimony .............................. 1
`B.
`Basis for Opinions and Materials Considered ............................. 4
`C. Retention and Compensation .................................................... 4
`Summary of Opinions ........................................................................ 4
`II.
`III. Legal Standards ................................................................................. 7
`IV. Person of Ordinary Skill in the Art ...................................................... 9
`V.
`The ’462 Patent and Its Asserted Claims ........................................... 11
`VI. Claim Construction .......................................................................... 19
`VII. Background on Diabetes and the use of GLP-1 Derivatives for the
`Treatment of Diabetes ...................................................................... 20
`A. Diabetes Generally ................................................................. 20
`B. Diabetes Treatment ................................................................. 22
`C. The Use of GLP-1 Derivatives to Treat Diabetes ...................... 25
`D. Use of Liraglutide to Treat Diabetes ........................................ 27
`E.
`Extended-Use GLP-1 Receptor Agonists ................................. 32
`VIII. Scope and Content of the Prior Art ................................................... 41
`A. Lovshin .................................................................................. 43
`B. Madsbad ................................................................................ 45
`C. U.S. Patent No. 8,114,833 ....................................................... 47
`D. WO 2006/097537 ................................................................... 54
`E. WO 2011/138421 ................................................................... 60
`F. NCT00696657 Semaglutide Clinical Trial Record .................... 64
`1.
`Clinical Trial No. NCT00696657 ................................... 64
`2.
`ClinicalTrials.gov is a Part of the POSA’s Knowledge ..... 66
`G. Other Technical Background Forming the POSA’s
`Knowledge ............................................................................. 73
`
`ii
`
`Novo Nordisk Exhibit 2024
`Dr. Reddy's Lab'ys, Inc. v. Novo Nordisk A/S
`IPR2024-00009
`Page 00002
`
`

`

`
`
`IX.
`
`TABLE OF CONTENTS
`(continued)
`
`Page
`
`Clinical Trial No. NCT00851773 ................................... 73
`1.
`Bhansali ........................................................................ 79
`2.
`3. Drucker 2003 ................................................................. 84
`4. Holst 2004 ..................................................................... 85
`5. Knudsen 2001 ............................................................... 89
`6. Knudsen 2004 ............................................................... 93
`7. Knudsen patent (U.S. Patent No. 6,268,343) ................... 98
`8.
`Lund ............................................................................ 103
`9. U.S. Patent Application Pub. No. US2007/0010424 ...... 103
`10. Victoza label ................................................................. 108
`11. WO 03/002136 ............................................................ 111
`12. Additional prior art and references ................................ 116
`Invalidity of the Asserted Claims of the ’462 Patent .......................... 117
`A. Each of WO ’421, NCT00696657, and Lovshin anticipated
`claims 1 and 3 ........................................................................ 117
`1. WO ’421 ...................................................................... 118
`2. NCT00696657 .............................................................. 126
`3.
`Lovshin ........................................................................ 133
`B. All Asserted Claims of the ’462 Patent Would Have Been
`Obvious Over the Prior Art .................................................... 141
`1.
`Claims 1, 3, 4, 5, and 7 of the ’462 patent would have
`been obvious over WO ’421, NCT00696657, WO ’537
`and/or Lovshin, optionally in view of one or more of
`the ’833 Patent and Madsbad ........................................ 142
`Claims 1, 3, 4, 5, and 7 of the ’462 patent would have
`been obvious over WO ’421 alone or in view of the
`’833 patent ................................................................... 168
`Claims 1, 3, 4, 5, and 7 of the ’462 patent would have
`been obvious over WO ’537 in view of Lovshin ............. 181
`
`3.
`
`2.
`
`iii
`
`Novo Nordisk Exhibit 2024
`Dr. Reddy's Lab'ys, Inc. v. Novo Nordisk A/S
`IPR2024-00009
`Page 00003
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`
`
`C. All Claims of the ’462 Patent Are Invalid for Lack of
`Written Description if They Would not have been Obvious ..... 194
`X. Reservation of Rights ...................................................................... 202
`
`iv
`
`Novo Nordisk Exhibit 2024
`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 Application Pub. No. US2011/0166321
`U.S. Patent Application Pub. No. US2007/0010424
`U.S. Patent No. 10,335,462
`NN-OZEM-000000071-95
`U.S. Patent No. 10,335,462 file history
`NN-OZEM-000003820-4446
`U.S. Patent No. 5,512,549
`U.S. Patent No. 8,114,833
`SEMA(JDG)_0000447-468
`Banting, The Internal Secretion of the Pancreas, 7 J. LAB.
`CLINICAL MED. 251 (1922)
`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
`Highlights of Prescribing Information: Bydureon, Rev.
`1/2012
`https://www.accessdata.fda.gov/drugsatfda_docs/label/20
`12/
`022200Orig1s000lbledt.pdf (last accessed Feb. 26, 2024)
`Highlights of Prescribing Information: Byetta, Rev.
`10/2009
`https://www.accessdata.fda.gov/drugsatfda_docs/label/20
`09/
`021773s9s11s18s22s25lbl.pdf (last accessed Feb. 26, 2024)
`ClinicalTrials.gov Background, CLINICALTRIALS.GOV,
`https://clinicaltrials.gov/about-site/about-ctg (last visited
`Mar. 15, 2024)
`
`Abbreviation
`’321 publication
`’424 publication
`’462 patent
`
`’462 file history
`
`’549 patent
`’833 patent
`
`Banting
`
`Bell
`
`Bhansali
`
`Bydureon label
`
`Byetta label
`
`ClinicalTrials.g
`ov Background
`
`5
`
`Novo Nordisk Exhibit 2024
`Dr. Reddy's Lab'ys, Inc. v. Novo Nordisk A/S
`IPR2024-00009
`Page 00005
`
`

`

`
`
`
`
`TABLE OF ABBREVIATIONS
`(continued)
`
`Full Name of Cited Reference
`Drab, Incretin-Based Therapies for Type 2 Diabetes Mellitus:
`Current Status and Future Prospects, 30 PHARMACOTHERAPY
`609 (2010)
`Drucker, Enhancing Incretin Action for the Treatment of Type 2
`Diabetes, 26 DIABETES CARE 2929 (2003)
`Drucker, The Incretin System: Glucagon-Like Peptide-1 Receptor
`Agonists and Dipeptidyl Peptidase-4 Inhibitors in Type 2
`Diabetes, 368 LANCET 1696 (2006)
`Drucker, The Biology Of Incretin Hormones, 3 CELL
`METABOLISM 153 (2006)
`Glaesner, Engineering and Characterization of the Long-Acting
`Glucagon-Like Peptide-1 Analogue LY2189265, an Fc Fusion
`Protein, 26 DIABETES/METABOLISM RSCH. & REV. 287
`(2010)
`HARRISON’S PRINCIPLES OF INTERNAL MED., Chapter 338
`(Fauci et al. eds. 17th ed. 2008)
`Award: ClinicalTrials.gov,
`https://ash.harvard.edu/news/clinicaltrialsgov (last visited
`Mar. 15, 2024)
`Holst, Truncated Glucagon-like Peptide I, an Insulin-Releasing
`Hormone from the Distal Gut, 211 FEBS LETTERS 169 (1987)
`Holst, Glucagon-Like Peptide 1 and Inhibitors of Dipeptidyl
`Peptidase IV in the Treatment of Type 2 Diabetes Mellitus, 4
`CURRENT OP. IN PHARMACOLOGY 589 (2004)
`Jimenez-Solem, Dulaglutide, a Long-Acting GLP-1 Analog
`Fused with an Fc Antibody Fragment for the Potential Treatment
`of Type 2 Diabetes, 12 CURRENT OP. IN MOLECULAR
`THERAPEUTICS 790 (2010)
`Kim, Effects of Once-Weekly Dosing of a Long-Acting Release
`Formulation of Exenatide on Glucose Control and Body Weight in
`Subjects with Type 2 Diabetes, 30 DIABETES CARE 1487 (2007)
`SEMA(JDG)_0002583-2589
`
`Abbreviation
`Drab
`
`Drucker 2003
`
`Drucker 2006a
`
`Drucker 2006b
`
`Glaesner
`
`Harrison’s
`
`Harvard Award
`
`Holst 1987
`
`Holst 2004
`
`Jimenez-Solem
`
`Kim
`
`6
`
`Novo Nordisk Exhibit 2024
`Dr. Reddy's Lab'ys, Inc. v. Novo Nordisk A/S
`IPR2024-00009
`Page 00006
`
`

`

`
`
`
`
`TABLE OF ABBREVIATIONS
`(continued)
`
`Full Name of Cited Reference
`Knudsen, GLP-1 Derivatives as Novel Compounds for the
`Treatment of Type 2 Diabetes: Selection of NN2211 for Clinical
`Development, 26 DRUGS OF THE FUTURE 677 (2001)
`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, a GLP-1 Analogue to Treat Diabetes in
`ANALOGUE-BASED DRUG DISCOVERY II (Fischer &
`Ganellin eds. 2010)
`Knudsen, Liraglutide: The Therapeutic Promise from Animal
`Models, 64 INT’L J. CLINICAL PRACTICE 4 (2010)
`U.S. Patent No. 6,268,343
`SEMA(JDG)_0000487-624
`Lovshin, Incretin-Based Therapies for Type 2 Diabetes Mellitus,
`5 NATURE REV. ENDOCRINOLOGY 262 (2009)
`SEMA(JDG)_0002250-58
`Lund, Emerging GLP-1 Receptor Agonists, 16 EXPERT OP. 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
`Marre, GLP-1 Receptor Agonists Today, 93 DIABETES RSCH. &
`CLINICAL PRAC. 317 (2011)
`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)
`Monami, Effects of Glucagon-Like Peptide-1 Receptor Agonists
`on Body Weight: A Meta-Analysis, 2012 EXPERIMENTAL
`DIABETES RSCH. 1 (2012)
`
`Abbreviation
`Knudsen 2001
`
`Knudsen 2004
`
`Knudsen 2010a
`
`Knudsen 2010b
`
`Knudsen patent
`
`Lovshin
`
`Lund
`
`Madsbad
`
`Marre
`
`Mojsov
`
`Monami
`
`7
`
`Novo Nordisk Exhibit 2024
`Dr. Reddy's Lab'ys, Inc. v. Novo Nordisk A/S
`IPR2024-00009
`Page 00007
`
`

`

`
`
`
`
`TABLE OF ABBREVIATIONS
`(continued)
`
`Full Name of Cited Reference
`NCT00167115, CLINICALTRIALS.GOV,
`https://www.clinicaltrials.gov/ct2/show/NCT00167115
`(last visited Mar. 15, 2024)
`NCT01933490, CLINICALTRIALS.GOV,
`https://www.clinicaltrials.gov/ct2/show/NCT01933490
`(last visited Mar. 15, 2024)
`Clinical Trial No. NCT00696657
`Clinical Trial No. NCT00851773
`Nielsen, Pharmacology of Exenatide (Synthetic Exendin-4): A
`Potential Therapeutic for Improved Glycemic Control of Type 2
`Diabetes, 117 REGUL. PEPTIDES 77 (2004)
`Novo Nordisk Pipeline – Semaglutide (2010-2011)
`http://novonordisk.com:80/science/pipeline
`/rd_pipeline.asp?showid=7 (Internet Archive captures)
`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)
`Tamimi, Drug Development: From Concept to Marketing!, 113
`NEPHRON CLINICAL PRACTICE 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. 2011)
`Vilsbøll, Glucagon-Like Peptide-1 and Diabetes Treatment, 21
`INTERNATIONAL DIABETES MONITOR 1 (2009)
`Int’l Patent Application Pub. No. WO 03/002136
`SEMA(JDG)_0000373-422
`Int’l Patent Application Pub. No. WO 2011/058193
`Int’l Patent Application Pub. No. WO 2011/073328
`
`Abbreviation
`NCT00167115
`
`NCT01933490
`
`NCT00696657
`NCT00851773
`Nielsen
`
`Novo Pipeline
`
`Seino
`
`Tamimi
`
`Tasneem
`
`Victoza label
`Vilsbøll
`
`WO ’136
`
`WO ’193
`WO ’328
`
`8
`
`Novo Nordisk Exhibit 2024
`Dr. Reddy's Lab'ys, Inc. v. Novo Nordisk A/S
`IPR2024-00009
`Page 00008
`
`

`

`TABLE OF ABBREVIATIONS
`(continued)
`
`Full Name of Cited Reference
`Int’l Patent Application Pub. No. WO 2011/138421
`SEMA(JDG)_0002087-2158
`Int’l Patent Application Publication No. WO 91/11457
`Int’l Patent Application Pub. No. WO 2006/097537
`SEMA(JDG)_0002453-2528
`Zarin, The ClinicalTrials.gov Results Database—Update and
`Key Issues, 364 NEW ENGL. J. MED. 852 (2011)
`
`Abbreviation
`WO ’421
`
`WO ’457
`WO ’537
`
`Zarin
`
`
`
`
`
`
`
`9
`
`Novo Nordisk Exhibit 2024
`Dr. Reddy's Lab'ys, Inc. v. Novo Nordisk A/S
`IPR2024-00009
`Page 00009
`
`

`

`
`
`
`1. My name is John P. Bantle, M.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, “defendants”), to provide my expert opinions
`
`regarding the invalidity of the asserted claims of U.S. Patent No. 10,335,462
`
`(“’462 patent”), which I understand to be claims 1, 3, 4, 5, and 7.
`
`I. QUALIFICATIONS AND BACKGROUND
`A. Education and Experience; Prior Testimony
`2.
`I am a medical endocrinologist and Professor Emeritus of Medicine
`
`in the Division of Endocrinology and Diabetes, Department of Medicine, at the
`
`University of Minnesota. I have substantial experience in clinical research,
`
`treatment of patients, and academic publications in the field of the treatment of
`
`diabetes and related conditions.
`
`3.
`
`I earned a Bachelor of Science degree in 1970 from the University
`
`of Minnesota and a Doctor of Medicine degree in 1972 from the University of
`
`Minnesota Medical School. I completed an
`
`internship at Cleveland
`
`Metropolitan General Hospital in 1973; residencies in internal medicine at the
`
`Mayo Clinic in Rochester, Minnesota, and Dunedin Public Hospital in
`
`1
`
`Novo Nordisk Exhibit 2024
`Dr. Reddy's Lab'ys, Inc. v. Novo Nordisk A/S
`IPR2024-00009
`Page 00010
`
`

`

`
`
`any documents the parties have exchanged. Additionally, I may rely on visual
`
`aids and/or demonstrative exhibits that I prepare or have prepared on my behalf
`
`based upon my opinions.
`
`I declare that all statements made herein of my knowledge are true, and
`
`that all statements made on information and belief are believed to be true, and
`
`that these statements were made with the knowledge that willful false statements
`
`and the like so made are punishable by fine or imprisonment, or both, under
`
`Section 1001 of Title 18 of the United States Code.
`
`Dated:
`
`
`
`
`
`
`
`By:
`
`
`
`Dr. John Bantle
`
`203
`
`Novo Nordisk Exhibit 2024
`Dr. Reddy's Lab'ys, Inc. v. Novo Nordisk A/S
`IPR2024-00009
`Page 00011
`
`