UNITED STATES PATENT AND TRADEMARK OFFICE
`
`__________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`__________________________
`
`MYLAN PHARMACEUTICALS INC., DR. REDDY’S LABORATORIES, INC.,
`and DR. REDDY’S LABORATORIES, LTD.
`Petitioner,
`v.
`NOVO NORDISK A/S,
`Patent Owner.
`__________________________
`
`Case No. IPR2023-007241
`Patent No. 10,335,462
`__________________________
`
`DECLARATION OF ARTHUR Z. SCHWARTZBARD, M.D., F.A.C.C.
`
`
`1 IPR2024-00009 (Dr. Reddy’s Laboratories) has been joined with this proceeding.
`
`MPI EXHIBIT 1304 PAGE 1
`
`

`

`TABLE OF CONTENTS
`
`
`INTRODUCTION ......................................................................................... 15
`I.
`II. QUALIFICATIONS AND BACKGROUND ............................................... 15
`A.
`Education and Experience ................................................................... 15
`B.
`Basis of Opinions and Material Considered ........................................ 17
`C.
`Retention and Compensation .............................................................. 18
`III. SUMMARY OF OPINIONS ......................................................................... 18
`IV. PRIORITY DATE ......................................................................................... 23
`V.
`LEGAL PRINCIPLES ................................................................................... 24
`VI. OZEMPIC® .................................................................................................... 27
`VII. THE ’462 PATENT ....................................................................................... 31
`VIII. BACKGROUND ON TYPE 2 DIABETES AND CARDIOVASCULAR
`DISEASE ....................................................................................................... 32
`A.
`Type 2 Diabetes ................................................................................... 32
`B.
`Prevention and Treatment of T2D ....................................................... 35
`IX. CLINICAL PRACTICE BACKGROUND ................................................... 38
`A.
`The UK Prospective Diabetes Study ................................................... 38
`B.
`Treatment with Insulin ........................................................................ 41
`C.
`Treatment with Sulfonylureas ............................................................. 41
`D.
`Treatment with Metformin .................................................................. 42
`E.
`Treatment with Thiazolidinediones ..................................................... 43
`F.
`Treatment with DPP-4 Inhibitors ........................................................ 45
`G.
`Treatment with GLP-1 Receptor Agonists .......................................... 45
`1.
`GLP-1 Receptor Agonists Reduced HbA1c And Body Weight
` ................................................................................................... 46
`GLP-1 Receptor Agonists Were Believed To Be
`Cardioprotective ........................................................................ 48
`GLP-1 Receptor Agonist CVOTs Demonstrated Similar
`Cardiovascular Risk Reduction................................................. 63
`Treatment with SGLT-2 Inhibitors ..................................................... 64
`
`H.
`
`2.
`
`3.
`
`MPI EXHIBIT 1304 PAGE 2
`
`

`

`I.
`J.
`
`K.
`
`X.
`
`2.
`
`5.
`
`6.
`
`2.
`
`3.
`
`B.
`
`3.
`4.
`
`Treatment with GLP-1/GIP Receptor Agonists .................................. 66
`Lowering Blood Pressure and Treating High Cholesterol in Patients
`with T2D .............................................................................................. 67
`The 2008 FDA Guidance on Cardiovascular Outcome Trials in
`Diabetic Drugs ..................................................................................... 67
`PATENT OWNER HAS NOT SHOWN ANY SECONDARY
`CONSIDERATIONS ..................................................................................... 71
`A.
`Patent Owner Has Not Established Unexpected Results .................... 72
`1.
`The Prior Art Disclosed the Cardiovascular Benefits Associated
`with GLP-1 Receptor Agonists and Other Treatments For Type
`2 Diabetes .................................................................................. 72
`The Blaha Declaration Failed to Compare the Claimed Method
`to the Closest Prior Art ............................................................. 73
`The Blaha Declaration Failed to Address Nexus ...................... 75
`The Blaha Declaration Makes Improper Comparisons Between
`Separate Clinical Trials ............................................................. 78
`The Blaha Declaration Fails to Demonstrate that Any
`Differences Between Semaglutide and Liraglutide Were
`Differences in Kind, not Merely Degree .................................. 80
`The Blaha Declaration Makes Improper Comparisons to DPP-4
`Inhibitors, Which Were Not the Closest Prior Art ................... 83
`Patent Owner Has Not Shown Industry Praise and Acceptance ......... 85
`1.
`The Blaha Declaration Fails to Demonstrate that the Claimed
`Method Caused a “Paradigm Shift” in the Treatment of
`Cardiovascular Risk in Patients with T2D ................................ 85
`The Blaha Declaration Fails to Demonstrate Medical
`Association Guidelines Represent Praise for the Claimed
`Method ...................................................................................... 88
`The Blaha Declaration Fails to Demonstrate that
`“Cardiometabolic Medicine” is Industry Praise and Acceptance
` ................................................................................................... 96
`XI. RESERVATION OF RIGHTS ...................................................................... 97
`
`
`
`
`
`
`MPI EXHIBIT 1304 PAGE 3
`
`

`

`Abbreviation
`’462 patent
`(EX1001)
`2008 Guidance
`(EX1259)
`
`2018 Background
`(EX1260)
`
`Abdul-Ghani
`(EX2086)
`
`ACC 2018
`(EX2091)
`
`ACC-2020
`(EX2092)
`
`ADA-2010
`(EX1272)
`
`ADA-2022
`(EX2087)
`
`ADA-2024
`(EX1122)
`
`Arnett
`(EX1224)
`
`TABLE OF ABBREVIATIONS
`
`Description
`
`U.S. Patent No. 10,335,462
`FDA, Guidance for Industry, Diabetes Mellitus –
`Evaluating Cardiovascular Risk in New Antidiabetic
`Therapies to Treat Type 2 Diabetes (Dec. 2008)
`FDA Background Document, Endocrinologic and
`Metabolic Drugs Advisory Committee Meeting (Oct. 24-
`25, 2018)
`Abdul-Ghani, M., et al., Cardiovascular Disease and
`Type 2 Diabetes: Has the Dawn of a New Era Arrived?,
`Diabetes Care, 40:813-820 (2017).
`Das, S.R., et al., ACC Expert Consensus Decision
`Pathway on Novel Therapies for Cardiovascular Risk
`Reduction in Patients with Type 2 Diabetes and
`Atherosclerotic Cardiovascular Disease, J. Am. Coll.
`Cardiol., 72: 3200-3223 (2018)
`Das, S.R., et al., Expert Consensus Decision Pathway on
`Novel Therapies for Cardiovascular Risk Reduction in
`Patients with Type 2 Diabetes, J. Am. Coll. Cardiol., 76:
`1117-1145 (2020)
`American Diabetes Association, Standards of Medical
`Care in Diabetes - 2010, 33 DIABETES CARE S11 (2010)
`ADA Standards of Medical Care., Cardiovascular Disease
`and Risk Management: Standards of Medical Care in
`Diabetes, Diabetes Care 45(Suppl. 1):S144–S175 (2022)
`American Diabetes Association, Pharmacologic
`Approaches to Glycemic Treatment: Standards of Care in
`Diabetes-2023, 46 DIABETES CARE S140 (2023)
`Arnett, 2019 ACC/AHA Guideline on the Primary
`Prevention of Cardiovascular Disease, 140 CIRCULATION
`e596 (2019)
`
`MPI EXHIBIT 1304 PAGE 4
`
`

`

`Abbreviation
`
`Astrup
`(EX1251)
`
`Baggio
`(EX1228)
`
`Ban
`(EX1233)
`
`Bhansali
`(EX1137)
`
`Bose
`(EX1231)
`
`Braunwald’s
`(EX1257)
`
`Bucher
`(EX1255)
`Bydureon Label
`(Jan. 2012)
`(EX1020)
`
`Carbone
`(EX1250)
`
`Cecil
`(EX1129)
`
`CV
`
`Description
`Astrup, Safety, tolerability and sustained weight loss over
`2 years with the once-daily human GLP-1 analog,
`liraglutide, INTL. J. OBESITY, 36, 843-854 (2012)
`(published online Aug. 16, 2012).
`Baggio, Biology of Incretins: GLP-1 and GIP, 132
`GASTROENTEROLOGY 2131 (2007)
`Ban, Cardioprotective and Vasodilatory Actions of
`Glucagon-Like Peptide 1 Receptor Are Mediated
`Through Both Glucagon-Like Peptide 1 Receptor–
`Dependent and –Independent Pathways, 117
`CIRCULATION 2340 (2008)
`Bhansali et al., Historical Overview of Incretin Based
`Therapies, 58 SUPPL. TO JAPI 10 (2010)
`Bose, Glucagon-like Peptide 1 Can Directly Protect the
`Heart Against Ischemia/Reperfusion Injury, 54 DIABETES
`146 (2005)
`Diabetes and the Cardiovascular System, in
`BRAUNWALD’S HEART DISEASE, A TEXTBOOK OF
`CARDIOVASCULAR MEDICINE, Chapter 31 (12th ed. 2022)
`Bucher, The Results of Direct and Indirect Treatment
`Comparisons in Meta-Analysis of Randomized Controlled
`Trials, 50(6) J. CLIN. EPIDEMIOL. 683 (1997)
`Bydureon prescribing information (Jan. 2012)
`
`Carbone, The CANVAS Program: Implications of
`Canagliflozin on Reducing Cardiovascular Risk in
`Patients with Type 2 Diabetes Mellitus, 18 CARDIOVASC
`DIABETOL 64 (2019)
`CECIL TEXTBOOK OF MEDICINE, Chapters 233 (Obesity)
`and 242 (Diabetes Mellitus) (Goldman et al. eds., 22nd
`ed. 2004)
`Cardiovascular
`
`MPI EXHIBIT 1304 PAGE 5
`
`

`

`Abbreviation
`CVOT
`
`Chen
`(EX2478)
`
`Cosentino
`(EX2090)
`
`Davies
`(EX2093)
`
`DeBlock
`(EX1278)
`
`DeFronzo
`(EX1275)
`
`DM
`
`DPP
`(EX1274)
`
`Drab
`(EX1022)
`
`Eckel
`(EX2094)
`
`Emdin
`(EX1223)
`
`Description
`Cardiovascular outcome trial
`Chen, J., “Blockbuster Drug: What it is, How it works,”
`Investopedia,
`https://www.investopedia.com/terms/b/blockbuster-
`drug.asp, last updated Sept. 6, 2022
`Cosentino, F. et al., ESC Guidelines on diabetes, pre-
`diabetes, and cardiovascular diseases developed in
`collaboration with the EASD, Eur. Heart J., 41:255-323
`(2019)
`Davies, M.J, et al., Cardiovascular outcomes trials: a
`paradigm shift in the current management of type 2
`diabetes, Cardiovasc. Diabetol., 21:144 (2022)
`DeBlock, GLP-1 Receptor Agonists for Type 2 Diabetes,
`374 LANCET 4 (2009)
`DeFronzo, Pioglitazone: The Forgotten, Cost-Effective
`Cardioprotective Drug for Type 2 Diabetes, 16(2)
`DIABETES & VASCULAR DISEASE RESEARCH 133 (2019)
`Diabetes mellitus
`Diabetes Prevention Program (DPP),
`https://www.niddk.nih.gov/about-niddk/research-
`areas/diabetes/diabetes-prevention-program-dpp
`Drab, Incretin-Based Therapies for Type 2 Diabetes
`Mellitus: Current Status and Future Prospects, 30
`PHARMACOTHERAPY 609 (2010)
`Eckel, R.H. and Blaha, M.J., Cardiometabolic Medicine:
`A Call for a New Subspecialty Training Track in Internal
`Medicine, Am. J. Med., 132(7):788-790 (2019)
`Emdin, Blood Pressure Lowering in Type 2 Diabetes: A
`Systematic Review and Meta-Analysis, 313 J. AM. MED.
`ASSOC. 603 (2015)
`
`MPI EXHIBIT 1304 PAGE 6
`
`

`

`Abbreviation
`
`Evans
`(EX2095)
`
`EX1261
`
`FDA Guidance for
`Industry
`(EX1273)
`
`Fox
`(EX1218)
`
`Gerstein
`(EX1248)
`
`GLP
`
`Gore
`(EX1213)
`
`Grundy
`(EX1219)
`
`Gugliano
`(EX1220)
`
`Description
`Evans, L.M., et al., A population-adjusted indirect
`comparison of cardiovascular benefits of once-weekly
`subcutaneous semaglutide and dulaglutide in the
`treatment of patients with type 2 diabetes, with or
`without established cardiovascular disease, Endocrinol.
`Diab. Metab. 2021;4:e00259 (2021)
`Type 2 Diabetes Mellitus: Evaluating the Safety of New
`Drugs for Improving Glycemic Control, 85 Fed. Reg.
`13903 (Mar. 10, 2020)
`FDA, Guidance for Industry, Clinical Studies Section of
`Labeling for Human Prescription Drug and Biological
`Products — Content and Format (Jan. 2006)
`Fox, Update on Prevention of Cardiovascular Disease in
`Adults With Type 2 Diabetes Mellitus in Light of Recent
`Evidence, 132 CIRC. 691 (2015)
`Gerstein, Dulaglutide and Cardiovascular Outcomes in
`Type 2 Diabetes (REWIND): A Double-Blind,
`Randomised Placebo-Controlled Trial, 394 LANCET 121
`(2019)
`Glucagon-like peptide
`Gore, Diabetes Mellitus and Trends in Hospital Survival
`After Myocardial Infarction, 1994 to 2006, Data From
`the National Registry of Myocardial Infarction, 5 CIRC.
`CARDIOVASC. QUAL. OUTCOMES 791 (2012)
`Grundy, 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/
`ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the
`Management of Blood Cholesterol, 139 CIRC. e1082
`(2019)
`Gugliano, Benefit of Adding Ezetimibe to Statin Therapy
`on Cardiovascular Outcomes and Safety in Patients With
`Versus Without Diabetes Mellitus, 137 CIRCULATION
`1571 (2018)
`
`MPI EXHIBIT 1304 PAGE 7
`
`

`

`Abbreviation
`
`Harrison’s
`(EX1136)
`
`Hess
`(EX1216)
`HF
`
`Hirata
`(EX1232)
`
`Holman
`(EX1292)
`
`Holst
`(EX1028)
`
`Horton
`(EX1235)
`
`Invokana Label
`(EX1265)
`Jardiance Label
`(EX1264)
`Kernan
`(EX1227)
`
`King
`(EX1269)
`
`Knudsen 2010a
`(EX1033)
`
`Description
`HARRISON’S PRINCIPLES OF INTERNAL MEDICINE,
`Chapters 74 (Biology of Obesity), 75 (Evaluation and
`Management of Obesity), and 338 (Diabetes Mellitus)
`(Fauci et al. eds., 17th ed. 2008)
`Hess, Inflammation and Thrombosis in Diabetes, 105
`THROMB HAEMOST S43 (2011)
`Heart failure
`Hirata, Exendin-4 has an Anti-Hypertensive Effect in
`Salt-Sensitive Mice Model, 380 BIOCHEMICAL &
`BIOPHYSICAL RESEARCH COMMC’NS 44 (2009)
`Holman, 10-Year Follow-up of Intensive Glucose Control
`in Type 2 Diabetes, NEW ENGLAND. J. MED., 359:1577-89
`(2008)
`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)
`Horton, Weight Loss, Glycemic Control, and Changes in
`Cardiovascular Biomarkers in Patients With Type 2
`Diabetes Receiving Incretin Therapies or Insulin in a
`Large Cohort Database, 33 DIABETES CARE 1759 (2010)
`Invokana® prescribing information (July 2023)
`
`Jardiance® prescribing information (Sept. 2023)
`Kernan, Pioglitazone after Ischemic Stroke or Transient
`Ischemic Attack, 374 NEW ENG. J. MED. 1321 (2016)
`King, The UK Prospective Diabetes Study (UKPDS):
`Clinical and Therapeutic Implications for Type 2
`Diabetes, 48 BR. J. CLIN. PHARMACOL. 643 (1999)
`Knudsen, Liraglutide, a GLP-1 Analogue to Treat
`Diabetes, in ANALOGUE-BASED DRUG DISCOVERY II
`(Fischer & Ganellin eds. 2010)
`
`MPI EXHIBIT 1304 PAGE 8
`
`

`

`Abbreviation
`
`Knudsen 2010b
`(EX1066)
`
`Laiteerapong
`(EX1271)
`
`Lathief
`(EX1226)
`
`LEADER
`
`Lorenz
`(EX1139)
`
`Lovshin
`(EX1012)
`Lund
`(EX1035)
`MACE
`
`Madsbad
`(EX1052)
`
`Mannuci
`(EX1237)
`
`Description
`Knudsen, Liraglutide: The Therapeutic Promise from
`Animal Models, 64(suppl 167) INT’L J. CLINICAL
`PRACTICE 4 (2010)
`Laiteerapong, The Legacy Effect in Type 2 Diabetes:
`Impact of Early Glycemic Control on Future
`Complications (The Diabetes & Aging Study), 42
`DIABETES CARE 416 (2019)
`Lathief, Approach to Diabetes Management in Patients
`with CVD, 26 TRENDS IN CARDIOVASCULAR MED. 165
`(2016)
`Liraglutide Effect and Action in Diabetes: Evaluation of
`Cardiovascular Outcome Results (LEADER)
`Lorenz et al., Recent Progress and Future Options in the
`Development of GLP-1 Receptor Agonists for the
`Treatment of Diabesity, 23 BIOORGANIC & MED. CHEM.
`LETTERS 4011 (2013)
`Lovshin, Incretin-Based Therapies for Type 2 Diabetes
`Mellitus, 5 NATURE REV. ENDOCRINOLOGY 262 (2009)
`Lund, Emerging GLP-1 Receptor Agonists, 16 EXPERT
`OP. ON EMERGING DRUGS 607 (2011)
`Major adverse cardiovascular events
`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)
`Mannuci, Incretins and the Specific Mechanism of Action
`of Liraglutide, the First Applicable Human Glucagon-
`Like Peptide I Analog in the Treatment of Type 2
`Diabetes, 3 J. RECEPTOR, LIGAND & CHANNEL RSCH. 105
`(2013)
`
`MPI EXHIBIT 1304 PAGE 9
`
`

`

`Abbreviation
`
`Marso 2011
`(EX1242)
`
`Marso
`(EX1247)
`
`Marso-SUSTAIN 6
`(EX2101)
`
`Mells
`(EX1240)
`
`NCT657
`(EX1013)
`
`Nikolaidis
`(EX1230)
`
`Noyan-Ashraf
`(EX1234)
`
`Nyström
`(EX1229)
`
`Okerson
`(EX1236)
`
`Orasanu
`(EX1215)
`
`Description
`Marso, Cardiovascular Safety of Liraglutide Assessed in
`a Patient-Level Pooled Analysis of Phase 2–3 Liraglutide
`Clinical Development Studies, 8(3) DIABETES &
`VASCULAR DISEASE RESEARCH, 237 (2011)
`Marso, Liraglutide and Cardiovascular Outcomes in
`Type 2 Diabetes, 375 NEW ENGLAND J. MED. 311 (2016)
`Marso et al., Semaglutide and Cardiovascular Outcomes
`in Patients with Type 2 Diabetes, 375 N. ENGL. J. MED.
`1834 (2016)
`Mells, GLP-1 Analog, Liraglutide, Ameliorates Hepatic
`Steatosis and Cardiac Hypertrophy in C57BL/6J Mice
`Fed a Western Diet, 302 AM J PHYSIOL GASTROINTEST
`LIVER PHYSIOLG225 (2012)
`Clinical Trial No. NCT00696657
`Nikolaidis, Effects of Glucagon-Like Peptide-1 in
`Patients With Acute Myocardial Infarction and Left
`Ventricular Dysfunction After Successful Reperfusion,
`109 CIRCULATION 962 (2004)
`Noyan-Ashraf, GLP-1R Agonist Liraglutide Activates
`Cytoprotective Pathways and Improves Outcomes After
`Experimental Myocardial Infarction in Mice, 58
`DIABETES 975 (2009)
`Nyström, Effects of Glucagon-Like Peptide-1 on
`Endothelial Function in Type 2 Diabetes Patients with
`Stable Coronary Artery Disease, 287 AM J PHYSIOL
`ENDOCRINOL METAB. E1209 (2004)
`Okerson, Effects of Exenatide on Systolic Blood Pressure
`in Subjects With Type 2 Diabetes, 23 AM. J. HYPERTENS
`334 (2010)
`Orasanu, The Pathologic Continuum of Diabetic
`Vascular Disease, 53 J. AM. COL. CARDIOLOGY s35
`(2009)
`
`MPI EXHIBIT 1304 PAGE 10
`
`

`

`Abbreviation
`Ozempic Label
`(Sept. 2023)
`(EX2069)
`Parks
`(EX1254)
`
`Pignone
`(EX1225)
`
`POSA
`
`Ratner
`(EX1243)
`
`Ravassa
`(EX1252)
`
`Rawshani 2017
`(EX1212)
`
`Rawshani
`(EX1217)
`
`Reiger
`(EX1253)
`
`Sabatine 2015
`(EX1221)
`
`Sabatine 2017
`(EX1222)
`
`Description
`
`Ozempic® Prescribing Information (September 2023)
`
`Parks, Weighing Risks and Benefits of Liraglutide – the
`FDA’s Review of a New Antidiabetic Therapy, 362 NEW
`ENGLAND J. MED. 774 (2010)
`Pignone, Aspirin for Primary Prevention of
`Cardiovascular Events in People With Diabetes, 121
`CIRC. 2694 (2010)
`Person of ordinary skill in the art
`Ratner et al., Cardiovascular Safety of Exenatide BID: An
`Integrated Analysis From Controlled Clinical Trials in
`Participants with Type 2 Diabetes, 10 CARDIOVASCULAR
`DIABETOLOGY 22 (2011)
`Ravassa, GLP-1 and cardioprotection: from Bench to
`Bedside, Cardiovascular Research 94, 316-323 (2012)
`(published ahead of print on March 14, 2012).
`Rawshani, Mortality and Cardiovascular Disease in Type
`1 and Type 2 Diabetes, 376 NEW ENGLAND J. MED. 1407
`(2017).
`Rawshani, Risk Factors, Mortality, and Cardiovascular
`Outcomes in Patients with Type 2 Diabetes, 379 NEW
`ENGLAND J. MED. 633 (2018)
`Reiger, More Than 7 Years of Hindsight: Revisiting the
`FDA’s 2008 Guidance on Cardiovascular Outcomes
`Trials for Type 2 Diabetes Medications, 34(4) CLINICAL
`DIABETES J. 173 (2016)
`Sabatine, Efficacy and Safety of Evolocumab in Reducing
`Lipids and Cardiovascular Events, 372 NEW ENG. J.
`MED. 1500 (2015)
`Sabatine, Evolocumab and Clinical Outcomes in Patients
`with Cardiovascular Disease, 376 NEW ENG. J. MED.
`1713 (2017)
`
`MPI EXHIBIT 1304 PAGE 11
`
`

`

`Abbreviation
`
`Sesti
`(EX1239)
`
`Siversten
`(EX1244)
`
`Skrivanek
`(EX1113)
`
`Smilowitz
`(EX1246)
`
`SGLT
`
`Sokos
`(EX1245)
`
`Southwell
`(EX1256)
`
`Standl
`(EX1214)
`
`SUSTAIN-6
`
`T2D
`Trulicity® Label
`(11/2022)
`(EX1262)
`UKPDS
`
`Description
`Sesti, Glycemic Control Impact on Body Weight Potential
`to Reduce Cardiovascular Risk, Glucagon-like Peptide 1
`Agonists, 34 DIABETES CARE S272 (2011)
`Siversten, The Effect of Glucagon-Like Peptide 1 on
`Cardiovascular Risk, 9 NAT. REV. CARDIOL. 209 (2012)
`Skrivanek et al., Dose-Finding Results in an Adaptive,
`Seamless, Randomized Trial of Once-Weekly Dulaglutide
`Combined with Metformin in Type 2 Diabetes Patients
`(AWARD-5), 16 DIABETES OBESITY & METABOLISM 748
`(2014)
`Smilowitz, Glucagon-Like Peptide 1 Receptor Agonists
`for Diabetes Mellitus, A Role in Cardiovascular Disease,
`129 CIRCULATION 2305 (2014)
`Sodium-glucose co-transporter
`Sokos, Glucagon-Like Peptide-1 Infusion Improves Left
`Ventricular Ejection Fraction and Functional Status in
`Patients with Chronic Heart Failure, 12 J. CARD. FAIL.
`694 (2006)
`Southwell, Appropriate use of Prescription Medications
`for Diabetes and Weight Loss Helps to Ensure Patient
`Access and Safety, CIGNA HEALTHCARE NEWSROOM
`Standl, Heart Failure Considerations of
`Antihyperglycemic Medications for Type 2 Diabetes, 118
`CIRC. RES. 1830 (2016)
`Trial to Evaluate Cardiovascular and Other Long-term
`Outcomes with Semaglutide in Subjects with Type 2
`Diabetes (SUSTAIN-6)
`Type 2 diabetes
`
`Trulicity prescribing information (Nov. 2022)
`
`UK Prospective Diabetes Study
`
`MPI EXHIBIT 1304 PAGE 12
`
`

`

`Abbreviation
`
`UKPDS 33
`(EX1267)
`
`UKPDS 34
`(EX1270)
`
`UKPDS 38
`(EX1268)
`
`Ussher
`(EX1241)
`
`Varanasi
`(EX1238)
`
`Victoza® Label
`(7/2023)
`EX1263
`Vilsbøll
`(EX1040)
`
`Whelton
`(EX1266)
`
`White
`(EX1108)
`WO193
`(EX1060)
`
`Description
`UK Prospective Diabetes Study (UKPDS) Group,
`Intensive Blood-Glucose Control with Sulphonylureas or
`Insulin Compared with Convention Treatment and Risk of
`Complications in Patients with Type 2 Diabetes (UKPDS
`33), 352 LANCET 837 (1998)
`UK Prospective Diabetes Study (UKPDS) Group, Effect
`of Intensive Blood-Glucose Control with Metformin on
`Complications in Overweight Patients with Type 2
`Diabetes (UKPDS 34), 352 LANCET 854 (1998)
`UK Prospective Diabetes Study (UKPDS) Group, Tight
`Blood Pressure Control and Risk of Macrovascular and
`Microvascular Complications in Type 2 Diabetes:
`UKPDS 38, 317 BR. MED. J. 703 (1998)
`Ussher, Cardiovascular Biology of the Incretin System,
`33 ENDOCRINE REVIEWS 187 (2012)
`Varanasi, Clinical Use of Liraglutide in Type 2 Diabetes
`and its Effects on Cardiovascular Risk Factors, 18
`ENDOCRINE PRACTICE 140 (2012) (published online on
`August 19, 2011)
`
`Victoza prescribing information (July 2023)
`
`Vilsbøll, Glucagon-Like Peptide-1 and Diabetes
`Treatment, 21 INT’L DIABETES MONITOR 1 (2009)
`Whelton, 2017
`ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/
`ASPC/NMA/PCNA Guideline for the Prevention,
`Detection, Evaluation, and Management of High Blood
`Pressure in Adults, 138 CIRCULATION, e484 (2018)
`White, A Brief History of the Development of Diabetes
`Medications, 27 DIABETES SPECTRUM 82 (2014)
`WO 2011/058193
`
`MPI EXHIBIT 1304 PAGE 13
`
`

`

`Abbreviation
`
`Yu
`(EX1148)
`
`Zinman
`(EX1249)
`
`
`
`Description
`Yu et al., Antihypertensive Effect of Glucagon-Like
`Peptide 1 in Dahl Salt-Sensitive Rats, 21 J.
`HYPERTENSION 1125 (2003)
`Zinman, Empagliflozin, Cardiovascular Outcomes and
`Mortality in Type 2 Diabetes, 373 NEW ENGLAND J. MED.
`2117 (2015)
`
`
`MPI EXHIBIT 1304 PAGE 14
`
`

`

`I.
`
`I, Arthur Z. Schwartzbard, M.D., hereby declare as follows:
`INTRODUCTION
`I have been retained by Perkins Coie LLP, on behalf of Mylan
`1.
`
`Pharmaceuticals Inc. (“Mylan”), to provide my expert opinion regarding U.S. Patent
`
`No. 10,335,462 (“the ’462 patent”) (EX1001). Specifically, I have been asked to
`
`provide my opinions regarding certain objective indicia related to the cardiovascular
`
`benefits of GLP-1 receptor agonists and other drugs used to treat type 2 diabetes
`
`(“T2D”) in response to the declaration of Dr. Michael Blaha (EX2055).
`
`2.
`
`Unless otherwise indicated, I have personal knowledge of the facts and
`
`opinions set forth in this declaration. All statements herein made of my own
`
`knowledge are true, and all statements made based on information and belief are
`
`believed to be true. If called upon to do so, I would testify competently thereto.
`
`II. QUALIFICATIONS AND BACKGROUND
`A. Education and Experience
`I received my B.A. degree from Rutgers University, and I received my
`3.
`
`M.D. degree at the Sackler School of Medicine in 1990.
`
`4.
`
`I was an intern, resident, and chief resident in Internal Medicine at the
`
`Albert Einstein College of Medicine Hospital. After completing my cardiology
`
`fellowship at the New York University/Bellevue Hospitals in 1997, I became the
`
`Director of Non-Invasive Cardiology at the Manhattan campus of the New York
`
`MPI EXHIBIT 1304 PAGE 15
`
`

`

`Harbor Health Care System (“NYHHCS”), formerly known as the Manhattan VA
`
`Medical Center. In addition, I became an attending physician in Cardiology at NYU
`
`Medical Center and Bellevue Hospital Center.
`
`5.
`
`In January 2014, I moved from the noninvasive lab at the NYHHCS to
`
`devote myself to full-time clinical cardiology and research at NYU Medical Center.
`
`My CV is included as EX1305.
`
`6.
`
`For over 27 years, I have supervised the training of cardiology fellows
`
`in clinical and non-invasive cardiology at the VA Medical Center, Bellevue
`
`Hospital, and NYU Medical Center. I have directly supervised the clinical care of
`
`cardiology fellows and have lectured in the departments of medicine and cardiology
`
`on a full range of topics in clinical cardiology. I have been an attending physician in
`
`the coronary care units of NYU, Bellevue, and the VA Medical Center, and have
`
`been a consultant cardiologist in all three hospitals for many years. My clinical
`
`practice at NYU covers the full range of clinical cardiology. In addition, I have
`
`chaired an annual continuing medical education course in Preventive Cardiology at
`
`the NYU School of Medicine for 19 years, where I have lectured and listened to
`
`doctors of multiple specialties in topics related to cardiac risk assessment, preventive
`
`cardiology, diabetes, and cholesterol management. My research has spanned the full
`
`spectrum of non-invasive, clinical, and preventive cardiology,
`
`including
`
`hypertension, clinical lipidology, cholesterol management, and diabetes.
`
`MPI EXHIBIT 1304 PAGE 16
`
`

`

`7.
`
`I am an associate professor in the division of cardiology at the NYU
`
`School of Medicine, and I have been certified in both Internal Medicine and
`
`Cardiovascular Disease by the American Board of Internal Medicine. I am also a
`
`fellow of the American College of Cardiology.
`
`8. My current practice is in clinical and preventive cardiology at NYU
`
`Medical Center. I am the director of NYU’s preventive cardiology fellowship
`
`program, and I am also director of clinical lipid research at NYU Medical Center. I
`
`also attend on our consultative cardiology service where we see the full spectrum of
`
`cardiology patients and issues. In my outpatient practice, I am commonly referred
`
`patients both for primary prevention (those patients at risk for heart disease who
`
`have not yet experienced a cardiac event) and for secondary prevention (patients
`
`who already have established heart disease and are seeking to prevent a recurrent
`
`cardiac event). I also spend a significant amount of my time treating patients referred
`
`for lipid management or advanced hypertension treatment. My practice is limited to
`
`clinical cardiology and preventive cardiology.
`
`9.
`
`B.
`10.
`
`Publications I have authored are included in my attached CV.
`
`Basis of Opinions and Material Considered
`In reaching the conclusions described in this declaration, I have relied
`
`on the documents and materials cited in this Declaration and those identified in
`
`Appendix A. Each of these is a type of document that experts in my field would
`
`MPI EXHIBIT 1304 PAGE 17
`
`

`

`reasonably rely upon when forming their opinions. My opinions are also based on
`
`my education, training, knowledge, and personal and professional experience.
`
`C. Retention and Compensation
`I am being compensated for my time at a rate of $600 per hour for my
`11.
`
`consulting time and $700 per hour for deposition time. I will be reimbursed for any
`
`expenses that I incur during this work. My compensation is not contingent upon the
`
`substance of my opinions or the outcome of this proceeding.
`
`III. SUMMARY OF OPINIONS
`In 2012, before the priority date of the ’462 patent, clinicians treating
`12.
`
`patients with T2D had several options, including prescribing insulin, sulfonylureas,
`
`and metformin. Each of these drugs lowered blood glucose. The landmark UK
`
`Prospective Diabetes Study (“UKPDS”), which ran from 1977 until 1997, clinically
`
`demonstrated that lowering HbA1c from 7.9% to 7.0% resulted in microvascular2
`
`benefit and a trend towards macrovascular3 benefit, with long-term follow-up
`
`showing a macrovascular benefit. See, e.g., EX1272 (ADA-2010) at 9 (“Long-term
`
`follow-up of the DCCT and UK Prospective Diabetes Study (UKPDS) cohorts
`
`suggests that treatment to A1C targets below or around 7% in the years soon after
`
`
`2 Diabetic microvascular complications involve small blood vessels, such as
`capillaries, and include complications impacting the eyes, nerves, and kidneys.
`3 Diabetic macrovascular complications involve large blood vessels, and include
`complications such as stroke, heart attack, and amputation.
`
`MPI EXHIBIT 1304 PAGE 18
`
`

`

`the diagnosis of diabetes is associated with long-term reduction in risk of
`
`macrovascular disease.”); EX1270 (UKPDS34) at 7 (“Patients assigned intensive
`
`blood-glucose control with metformin had a 32% lower risk (P=0.0023) of
`
`developing any diabetes-related endpoint than those allocated conventional blood-
`
`glucose control (figures 5 and 6). These endpoints included macrovascular and
`
`microvascular complications and represented the effect of intensive policy with
`
`metformin on complication-free survival….For all macrovascular diseases together
`
`(myocardial infarction, sudden death, angina, stroke, and peripheral disease), the
`
`metformin group had a 30% (5-48, P=0.020) lower risk than the conventional
`
`treatment group….”); EX1292 (Holman) at 1 (in long term follow up in UKPDS,
`
`confirming insulin-sulfonylurea cohort demonstrated significant microvascular risk
`
`reduction (10% (P=0.0001), risk reduction for myocardial infarction (15%, P=0.01),
`
`and reduced death from any cause (13%, P=0.0007), and in the metformin cohort, a
`
`reduction in risk of myocardial infarction (33%, P=0.005) and death from any cause
`
`(27%, P=0.002). The cardiovascular disease reduction associated with these drugs
`
`was understood by POSAs, as reflected by medical association guidelines. See, e.g.,
`
`EX1272 (ADA-2010 at 10) (“In an epidemiologic analysis of the study cohort, a
`
`continuous association was observed such that for every percentage point lower
`
`median on-study A1C (e.g., 8–7%), there was a statistically significant 18%
`
`reduction in CVD events, again with no glycemic threshold. A recent report of 10
`
`MPI EXHIBIT 1304 PAGE 19
`
`

`

`years of follow-up of the UKPDS cohort described, for the participants originally
`
`randomized to intensive glycemic control compared with those randomized to
`
`conventional glycemic control, long-term reductions in MI (15% with sulfonylurea
`
`or
`
`insulin as
`
`initial pharmacotherapy, 33% with metformin as
`
`initial
`
`pharmacotherapy, both statistically significant) and in all-cause mortality (13 and
`
`27%, respectively, both statistically significant)”); EX1272 (ADA-2010) at 9
`
`(“Lowering A1C to below or around 7% has been shown to reduce microvascular
`
`and neuropathic complications of type 1 and type 2 diabetes.”). Moreover,
`
`management of the comorbid conditions associated with T2D was then and remains
`
`today a mainstay of clinical practice. Treating high blood pressure and dyslipidemia
`
`with separate therapeutic agents reduces cardiovascular risk in all patients, but the
`
`beneficial effects are more pronounced in diabetic patients. By 2012, medical
`
`practice in patients with T2D included managing blood glucose without causing
`
`hypoglycemia, treating high blood pressure, and lowering lipid levels to reduce
`
`cardiovascular risk in diabetic patients. EX1272 (ADA-2010) at 9, 19-23.
`
`13. GLP-1 receptor agonists and TZDs were known in the art by the priority
`
`date, including commercially available products like Victoza® (liraglutide)
`
`(approved in 2010) and Actos® (pioglitazone) (approved in 1999). FDA-approved
`
`and commercially available GLP-1 receptor agonists (i.e., dulaglutide and
`
`semaglutide) and SGLT-2 inhibitors (i.e., empagliflozin and dapagliflozin) have
`
`MPI EXHIBIT 1304 PAGE 20
`
`

`

`been welcome additions to the clinician’s armamentarium, which already included
`
`GLP-1 receptor agonists.
`
`14. By July 1, 2012,
`
`the cardiovascular effects demonstrated
`
`in
`
`cardiovascular outcome trials (“CVOT”) for GLP-1 receptor agonists had already
`
`been favorably suggested in the prior art based on basic science studies, studies with
`
`various preclinical models, and actual clinical experience. See Section IX.G.2. While
`
`CVOTs needed to be completed to provide further clinical evidence to confirm what
`
`the prior art had already taught, the POSA expected that GLP-1 receptor agonists
`
`would have cardiovascular benefits,
`
`including both microvascular and
`
`macrovascular benefits, before July 1, 2012. While Dr. Blaha suggests