`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`MYLAN PHARMACEUTICALS INC.,
`WOCKHARDT BIO AG,
`TEVA PHARMACEUTICALS USA, INC.,
`AUROBINDO PHARMA U.S.A., INC.,
`SUN PHARMACEUTICAL INDUSTRIES, LTD.,
`SUN PHARMA GLOBAL FZE and
`AMNEAL PHARMACEUTICALS LLC
`Petitioners,
`
`v.
`
`ASTRAZENECA AB,
`Patent Owner.
`
`
`Case: IPR2015-013401
`U.S. Patent No. RE44,186
`
`
`PATENT OWNER ASTRAZENECA AB’S EXHIBIT LIST
`(as of December 12, 2016)
`
`
`
`
`
`
`
`
`1 Petitioner Wockhardt from IPR2016-01029, Petitioner Teva from IPR2016-
`01122, Petitioner Aurobindo from IPR2016-01117, and Petitioners Sun/Amneal
`from IPR2016-01104 have been added as Petitioners to this proceeding.
`
`
`
`
`
`
`
`Exhibit
`
`Description
`
`Exhibit 2001 Doreen M. Ashworth et al., 4-
`Cyanothiazolidides as Very Potent, Stable
`Inhibitors of Dipeptidyl Peptidase IV, 6
`BIOORG. & MED. CHEM. LETT. 2745 (1996)
`
`Exhibit 2002 David R. Magnin et al., Synthesis of Novel
`Potent Dipeptidyl Peptidase IV Inhibitors with
`Enhanced Chemical Stability: Interplay
`Between the N-Terminal Amino Acid Alkyl
`Side Chain and the Cyclopropyl Group of α-
`Aminoacyl-L-cis-4,5- methanoprolinenitrile-
`Based Inhibitors, 47 J. MED. CHEM. 2587
`(2004)
`
`Exhibit 2003
`
`Jeffrey A. Robl & Lawrence G. Hamann, The
`Discovery of the Dipeptidyl Peptidase-4
`(DPP4) Inhibitor Onglyza™: From Concept
`to Market, in ACCOUNTS IN DRUG DISCOVERY:
`CASE STUDIES IN MEDICINAL CHEMISTRY (Joel
`C. Barrish et al. eds., 2011)
`
`Exhibit 2004 AstraZeneca Annual Report and Form 20-F
`Information 2014, available at
`www.astrazeneca.com/annualreport2014
`
`Exhibit 2005
`
`Jens J. Holst & Carolyn F. Deacon, Inhibition
`of the Activity of Dipeptidyl-Peptidase IV as a
`Treatment for Type 2 Diabetes, 47 DIABETES
`1663 (1998)
`
`Exhibit 2006 Kathleen Aertgeerts et al., Crystal Structure of
`Human Dipeptidyl Peptidase IV in Complex
`with a Decapeptide Reveals Details on
`Substrate Specificity and Tetrahedral
`intermediate Formation, 13 PROTEIN SCI. 412
`(2004)
`
`Status
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Exhibit 2007 K. Augustyns et al., The Unique Properties of
`Dipeptidyl- Peptidase IV (DPP IV / CD26)
`
`Served and
`Filed
`
`3
`
`
`
`
`
`Exhibit
`
`Description
`and the Therapeutic Potential of DPP IV
`Inhibitors, 6 CURR. MED. CHEM. 311 (1999)
`
`Exhibit 2008 George R. Flentke et al., Inhibition of
`Dipeptidyl Aminopeptidase IV (DP-IV) by
`Xaa-boroProdipeptides and Use of These
`Inhibitors to Examine the Role of DP-IV in T-
`cell Function, 88 PROC. NAT’L ACAD. SCI.
`1556 (1991)
`
`Exhibit 2009 Robert P. Pauly et al., Improved Glucose
`Tolerance in Rats Treated With the Dipeptidyl
`Peptidase IV (CD26) Inhibitor Ile-
`Thiazolidide, 48 METAB. 385 (1999)
`
`Exhibit 2010 Hans-U Demuth et al., Abstract, Single Dose
`Treatment of Diabetic Patients by the DP IV
`Inhibitor P32/98, 49 DIABETES 413-P (2000)
`
`Exhibit 2011 U.S. Patent No. 5,939,560
`
`Exhibit 2012 Paul Rothenberg et al., Abstract, Treatment
`with a DPP-IV Inhibitor, NVP-DPP728,
`Increases Prandial Intact GLP-1 Levels and
`Reduced Glucose Exposure in Humans, 49
`DIABETES 160-OR (2000)
`
`Exhibit 2013 U.S. Patent No. 6,166,063
`
`Exhibit 2014 Ligaya M. Simpkins et al., Potent Non-Nitrile
`Dipeptidic Dipeptidyl Peptidase IV Inhibitors,
`17 BIOORG. & MED. CHEM. LETT. 6476
`(2007)
`
`Exhibit 2015
`
`János Fischer et al., Pioneer and Analogue
`Drugs, in ANALOGUE-BASED DRUG
`DISCOVERY III 3 (János Fischer et al. eds.,
`
`Status
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`4
`
`
`
`
`
`Exhibit
`
`Description
`
`Status
`
`2013)
`
`Exhibit 2016 Thomas E. Hughes et al., NVP-DPP728: (1-
`[[[2-[(5- Cyanopyridin-2-yl)amino
`]ethyl]amino ]acetyl]-2-cyano-(S)-
`pyrrolidine ), a Slow-Binding Inhibitor of
`Dipeptidyl Peptidase IV, 38 BIOCHEM. 11597
`(1999)
`
`Exhibit 2017 Coralie Nguyen et al., Specific and
`Irreversible Cyclopeptide Inhibitors of
`Dipeptidyl Peptidase IV Activity of the T-Cell
`Activation Antigen CD26, 41 J. MED. CHEM.
`2100 (1998)
`
`Exhibit 2018 Aiying Wang et al., Potency, Selectivity and
`Prolonged Binding of Saxagliptin to DPP4:
`Maintenance of DPP4 Inhibition by
`Saxagliptin In Vitro and Ex Vivo When
`Compared to a Rapidly- Dissociating DPP4
`Inhibitor, 12 BMC PHARM. 1 (2012)
`
`Exhibit 2019 Defendants Joint Initial Invalidity Contentions
`Regarding U.S. Patent No. RE44,186
`
`Exhibit 2020 M.A. Nauck et al., Effects of Subcutaneous
`Glucagon-Like Peptide 1(GLP-1 [7–36
`Amide]) in Patients with NIDDM, 39
`DIABETOLOGIA 1546 (1996)
`
`Exhibit 2021 Nancy L. Thompson et al., A Fischer Rat
`Substrain Deficient in Dipeptidyl Peptidase IV
`Activity Makes Normal Steady-State RNA
`Levels and an Altered Protein: Use as a Liver-
`Cell Transplantation Model, 273 J. BIOCHEM.
`497 (1991)
`
`Exhibit 2022
`
`Int’l Pub. No. WO 95/15309
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`5
`
`
`
`
`
`Exhibit
`
`Description
`
`Exhibit 2023 U.S. Patent No. 6,011,155
`
`
`Exhibit 2024
`
`Von R. Hiltmann et al., 2-Acylaminopyridin-
`Derivate mit morphinagonistischer und -
`antagonistischer Wirksamkeit, 24 ARZNEIM.
`FORSCH. 584 (1974)
`
`Exhibit 2025 U.S. Patent No. 4,591,598
`
`Exhibit 2026 German Patent Pub. No. 25 21 895 A1
`
`Exhibit 2027 U.S. Patent No. 3,325,478
`
`Exhibit 2028 Stephen Hanessian et al., Probing the
`Importance of Spacial and Conformational
`Domains in Captopril Analogs for Angiotensin
`Converting Enzyme Activity, 8 BIOORG. &
`MED. CHEM. LETT. 2123 (1998)
`
`Exhibit 2029 Koert Gerzon et al., The Adamantyl Group in
`Medicinal Agents I. Hypoglycemic N-
`Arylsulfonyl-N’adamantylureas, 6 J. MED.
`CHEM. 760 (1963)
`
`Exhibit 2030 F. R. Rubio et al., Urinary Metabolites of
`Rimantadine in Humans, 16 DRUG METAB. &
`DISPOSITION 773 (1988)
`
`Exhibit 2031 Gunter Fischer et al., The Conformation
`Around the Peptide Bond Between the P1-
`And P2-Positions Is Important for Catalytic
`Activity of Some Proline-Specific Proteases,
`742 BBA 452 (1983)
`
`Status
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Exhibit 2032 U.S. Patent No. 4,954,158
`
`Served and
`
`6
`
`
`
`
`
`Exhibit
`
`Description
`
`Exhibit 2033 Masahiro Yoshioka et al., Role of Rat
`Intestinal Brush-Border Membrane
`Angiotensin-Converting Enzyme in Dietary
`Protein Digestion, 253 AM. J. PHYSIOL. G781
`(1987)
`
`Exhibit 2034 German Patent Pub. No. 3324263 A1
`
`Exhibit 2035 Stephen Hanessian et al., The Stereocontrolled
`Synthesis of Enantiopure α-Methano
`Heterocycles and Constrained Amino Acid
`Analogs, 37 TETRAHEDRON LETT. 8967 (1996)
`
`Exhibit 2036 CAplus Records for German Patent Pub. No.
`3324263 A1
`
`Exhibit 2037 Roberto Pellicciari et al., Synthesis of All Four
`Diastereoisomers of 4-
`(Carboxymethyl)proline, a Conformationally
`Constrained Analogue of 2-Aminoadipic Acid,
`1 J. CHEM. SOC. 1251 (1995)
`
`Exhibit 2038 Viacheslav V. Tverezovsky et al., Synthesis of
`(2S, 3R, 4S)-3,4- Methanoproline and
`Analogues by Cyclopropylidene Insertion, 53
`TETRAHEDRON 14773 (1997)
`
`Exhibit 2039 Frank L. Switzer et al., Synthesis of (4)-2,3-
`Methanoproline: A Novel Inhibitor of
`Ethylene Biosynthesis, 45 TETRAHEDRON
`6091 (1989)
`
`Status
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Exhibit 2040 Alain Hercouet et al., First Asymmetric
`Synthesis of (-)-(2S, 3R)-Methanoproline, 7
`TETRAHEDRON: ASYMMETRY 1267 (1996)
`
`Served and
`Filed
`
`7
`
`
`
`
`
`Exhibit
`
`Description
`
`Exhibit 2041 Raymond A. Pederson et al., Improved
`Glucose Tolerance in Zucker Fatty Rats by
`Oral Administration of the Dipeptidyl
`Peptidase IV Inhibitor Isoleucine
`Thiazolidide, 47 DIABETES 1253 (1998)
`
`Exhibit 2042
`
`Jingrong Li et al., Aminoacylpyrrolidine-2-
`nitriles: Potent and Stable Inhibitors of
`Dipeptidyi-Peptidase IV (CD 26), 323 ARCH.
`BIOCHEM. & BIOPHYSICS 148 (1995)
`
`Exhibit 2043 Stephen Hanessian et al., The Synthesis of 4,5-
`Methano Congeners of α-Kainic and α-allo-
`Kainic Acids as Probes for Glutamate
`Receptors 37 TETRAHEDERON LETT. 8971
`(1996)
`
`Exhibit 2044 Koppel et al., The Metabolism of
`Tromantadine 12 BIOMED. MASS. SPECTROM.
`497 (1985)
`
`Exhibit 2045 Su et al., Characterization of the In Vitro and
`In Vivo Metabolism and Disposition and
`Cytochrome P450 Inhibition/Induction Profile
`of Saxagliptin in Human 40 DRUG METAB.
`AND DISPOSITION 1345 (2012)
`
`Exhibit 2046 He et al., Absorption, Metabolism, and
`Excretion of [14C]Vildagliptin, a Novel
`Dipeptidyl Peptidase 4 Inhibitor, in Humans
`37 DRUG METAB. AND DISPOSITION 536
`(2009)
`Exhibit 2047 Onglyza® Prescribing Info., revised Aug. 2015
`
`Exhibit 2048 Kombiglyze™ XR Prescribing Info., revised
`Aug. 2015
`
`Status
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`8
`
`
`
`
`
`Exhibit
`
`Exhibit 2049
`
`Description
`Januvia® Prescribing Info., revised Mar. 2015
`
`Exhibit 2050 Galvus® Prescribing Info.
`
`Exhibit 2051 Evidentiary Declaration of ANN E. WEBER,
`PH.D.
`
`Exhibit 2052 CV for ANN E. WEBER, PHD.
`
`Exhibit 2053 Declaration of John Kozikowski
`
`Exhibit 2054 Table of Contents for ANALOGUE-BASED
`DRUG DISCOVERY III 3 (János Fischer et al.
`eds., 2013) (Exhibit 2015)
`
`Exhibit 2055 Transcript of Telephone Conference Call of
`June 17, 2016
`
`Exhibit 2056 Declaration of ANN E. WEBER, PH.D.
`
`Exhibit 2057 Declaration of M. JAMES LENHARD, M.D.
`
`Exhibit 2058 CV for M. JAMES LENHARD, M.D.
`
`Exhibit 2059 Redacted Declaration of CHRISTINE S.
`MEYER, PH.D.
`
`Exhibit 2059A Declaration of CHRISTINE S. MEYER,
`PH.D. (PROTECTIVE ORDER MATERIAL)
`
`Exhibit 2060 CV for CHRISTINE S. MEYER, PH.D.
`
`Exhibit 2061
`
`John E. Gerich, Physiology of Glucose
`
`Status
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served only
`
`Served only
`
`Served only
`
`Served only
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed – Not
`Public
`
`Served and
`Filed
`
`Served and
`
`9
`
`
`
`
`
`Exhibit
`
`Description
`Homeostasis, 2 DIABETES, OBESITY & METAB.
`345 (2000)
`
`Status
`Filed
`
`Exhibit 2062 CENTERS FOR DISEASE CONTROL AND
`PREVENTION, NATIONAL DIABETES STATISTICS
`REPORT 2014)
`
`Exhibit 2063 Ralph A. DeFronzo, Pharmacologic Therapy
`for Type 2 Diabetes Mellitus, 131 ANNALS
`INTERNAL MED. 281 (1999)
`
`Exhibit 2064 Barbara A. Ramlo-Halsted and Steven V.
`Edelman, The Natural History of Type 2
`Diabetes: Implications for Clinical Practice,
`26 DIABETES 771 (1999)
`
`Exhibit 2065 American Diabetes Association, Standards of
`Medical Care in Diabetes – 2016, 39
`DIABETES CARE S1 (Jan. 2016)
`
`Exhibit 2066 Darwin L. Brown and David Brillon, New
`Directions in Type 2 Diabetes Mellitus: An
`Update of Current Oral Antidiabetic Therapy,
`91 J. NAT. MED. ASSOC’N 389 (1999)
`
`Exhibit 2067 Richard A. Harrigan et al., Oral Agents for the
`Treatment of Type 2 Diabetes Mellitus:
`Pharmacology, Toxicity, and Treatment, 38
`ANNALS EMERGENCY MED. 68 (2001)
`
`Exhibit 2068 Martin Hildebrandt et al., A Guardian Angel:
`The Involvement of Dipeptidyl Peptidase IV in
`Psychoneuroendocrine Function, Nutrition
`and Immune Defence, 99 CLINICAL SCI. 93
`(2000)
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Exhibit 2069 Daniel J. Drucker, Perspectives in Diabetes:
`Glucagon-Like Peptides, 47 DIABETES 159
`(1998)
`
`Served and
`Filed
`
`10
`
`
`
`
`
`Exhibit
`
`Exhibit 2070
`
`Description
`
`Ingrid De Meester et al., CD26, Let It Cut or
`Cut It Down, 20 IMMUNOLOGY TODAY 367
`(1999)
`
`Exhibit 2071 Hanne B. Rasmussen et al., Crystal Structure
`of Human Dipeptidyl Peptidase IV/CD26 in
`Complex with a Substrate Analog, 10 NAT.
`STRUCT. BIOL. 19 (2003)
`
`Exhibit 2072 William J. Metzler et al., Involvement of DPP-
`IV Catalytic Residues in Enzyme-Saxagliptin
`Complex Formation, 17 PROTEIN SCI. 240
`(2008)
`
`Exhibit 2073 Aberra Fura et al., Pharmacokinetics of the
`Dipeptidyl Peptidase 4 Inhibitor Saxagliptin
`In Rats, Dogs, and Monkeys and Clinical
`Projections, 37 DRUG METABOLISM AND
`DISPOSITION 1164 (2009)
`
`Exhibit 2074 Reserved
`
`Exhibit 2075 H. U. Demuth et al., Dipeptidylpeptidase IV -
`Inactivation with N-Peptidyl-O-Aroyl
`Hydroxylamines, 2 J. ENZYME INHIB. 129
`(1988)
`
`Exhibit 2076 U.S. Patent No. 4,935,493
`
`Exhibit 2077 Tradjenta® Prescribing Info., revised Aug.
`2015
`
`Exhibit 2078 Ekkehard Schön et al., Dipeptidyl Peptidase
`IV in the Immune System, 372 BIOL. CHEM.
`HOPPE-SEYLER 305 (1991)
`Exhibit 2079 Nesina® Prescribing Info., revised Aug. 2015
`
`Status
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`11
`
`
`
`
`
`Exhibit
`
`Description
`
`Exhibit 2080 Annex I, Summary of Product Characteristics
`for Galvus® 50 mg Tablets
`Exhibit 2081 New Galvus® Clinical Data Reinforces
`Efficacy Profile; Safety Update Provided To
`Regulatory Agencies, NOVARTIS MEDIA
`RELEASES (Nov. 6, 2007)
`
`Exhibit 2082 Yutaka Takeuchi, Safety, Tolerability,
`Pharmacokinetics and Pharmacodynamics of
`E3024, a Novel and Selective Dipeptidyl
`Peptidase-IV Inhibitor, in Healthy Japanese
`Male Subjects: Rash Development in Men and
`Its Possible Mechanism, 4 PHARM. & PHARM.
`663 (2013)
`
`Exhibit 2083 William G. Gutheil & William W.
`Bachovchin, Separation of L-Pro-DL-boroPro
`into its Component Diastereomers and Kinetic
`Analysis of Their Inhibition of Dipeptidyl
`Peptidase IV. A New Method for the Analysis
`of Slow, Tight-Binding Interaction, 32
`BIOCHEM. 8723 (1993)
`
`Exhibit 2084 PJ Guillausseau, Influence of Oral
`Antidiabetic Drugs Compliance on Metabolic
`Control in Type 2 Diabetes. A Survey in
`General Practice, 29 DIABETES METAB. 79
`(2003)
`
`Exhibit 2085
`
`Joyce A. Cramer, A Systematic Review of
`Adherence with Medications for Diabetes, 27
`DIABETES CARE 1218 2004)
`
`Exhibit 2086 Adisinsight.springer.com/drugs
`
`Exhibit 2087 Excerpts from BURGER’S MEDICINAL
`CHEMISTRY AND DRUG DISCOVERY (Manfred
`
`Status
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`12
`
`
`
`
`
`Exhibit
`
`Description
`E. Wolff ed., John Wiley & Sons 1995)
`
`Exhibit 2088 C. E. Powell & I. H. Slater, Blocking of
`Inhibitory Adrenergic Receptors by a
`Dichloro Analog of Isoproterenol, 122 J.
`PHARMACOL. EXP. THER. 480 (1958)
`
`Exhibit 2089 C. G. Wermuth et al., Glossary of Terms Used
`in Medicinal Chemistry, 70 PURE & APPL.
`CHEM. 1129 (1998)
`
`Exhibit 2090 George W. Muller et al., A Concise Two-Step
`Synthesis Of Thalidomide, 3 ORG. PROCESS
`RES. DEV. 139 (1999)
`
`Exhibit 2091
`
`Israel Schechter & Arieh Berger, On the Size
`of the Active Site in Proteases. I. Papain, 27
`BIOCHEM. & BIOPHYS. RESEARCH COMMC’NS
`157 (1967)
`
`Exhibit 2092 Excerpts from DONALD VOET & JUDITH G.
`VOET, BIOCHEMISTRY (John Wiley & Sons, 2d
`ed. 1995)
`
`Exhibit 2093 Nigel M. Hooper, Proteases: A Primer, 38
`ESSAYS IN BIOCHEM. 1 (2002)
`
`Exhibit 2094 Neil D. Rawlings & Alan J. Barrett,
`Evolutionary Families of Peptidases, 290
`BIOCHEM. J. 205 (1993)
`
`Exhibit 2095 Bogdan Boduszek et al., Dipeptide
`Phosphonates as Inhibitors of Dipeptidyl
`Peptidase IV, 37 J. MED. CHEM. 3969 (1994)
`
`Exhibit 2096 Rolf Mentlein et al., Dipeptidyl-Peptidase IV
`Hydrolyses Gastric Inhibitory Polypeptide,
`Glucagon-Like Peptide-1(7-36)Amide,
`Peptide Histidine Methionine and Is
`Responsible for Their Degradation in Human
`
`13
`
`Status
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`
`
`
`
`Exhibit
`
`Description
`Serum, 214 EUR. J. BIOCHEM. 829 (1993)
`
`Exhibit 2097 Daniel M. Kemp, Chapter 1: Type 2 Diabetes:
`Disease Overview, in NEW THERAPEUTIC
`STRATEGIES FOR TYPE 2 DIABETES: SMALL
`MOLECULE APPROACHES (Robert M. Jones ed.,
`2012)
`
`Exhibit 2098 Ann E. Weber, Dipeptidyl Peptidase IV
`Inhibitors for the Treatment of Diabetes, 47 J.
`MED. CHEM. 4135 (2004)
`
`Exhibit 2099 WO Patent App. Pub. No. 95/29691
`
`Exhibit 2100 Pfizer Inc., v. Mylan Pharm. Inc., 71 F. Supp.
`3d 458 (D. Del. 2014), aff’d 628 Fed. Appx.
`764 (Fed. Cir. 2016)
`
`Exhibit 2101 AstraZeneca Annual Report and Form 20-F
`Information 2007, available at
`http://www.astrazeneca-
`annualreports.com/2007/AZ_Annual_Report
`_2007_EN.pdf
`
`Exhibit 2102 AstraZeneca Annual Report and Form 20-F
`Information 2008, available at
`http://www.astrazeneca-
`annualreports.com/2008/
`AZ_Annual_Report_2008_EN.pdf
`
`Exhibit 2103 AstraZeneca Annual Report and Form 20-F
`Information 2009, available at
`http://www.astrazeneca-
`annualreports.com/2009/
`AZ_Annual_Report_2009_EN.pdf
`
`Status
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Exhibit 2104 AstraZeneca Annual Report and Form 20-F
`Information 2010, available at
`http://www.astrazeneca-
`
`Served and
`Filed
`
`14
`
`
`
`
`
`Exhibit
`
`Description
`annualreports.com/2010/
`AZ_Annual_Report_2010_EN.pdf
`
`Exhibit 2105 AstraZeneca Annual Report and Form 20-F
`Information 2011, available at
`http://www.astrazeneca-
`annualreports.com/2011/
`AZ_Annual_Report_2011_EN.pdf
`
`Exhibit 2106 AstraZeneca Annual Report and Form 20-F
`Information 2012, available at
`http://www.astrazeneca-
`annualreports.com/2012/
`AZ_Annual_Report_2012_EN.pdf
`
`Exhibit 2107 AstraZeneca Annual Report and Form 20-F
`Information 2013, available at
`http://www.astrazeneca-
`annualreports.com/2013/_assets/pdfs/
`AstraZeneca_Annual_Report_2013.pdf
`
`Exhibit 2108 AstraZeneca Annual Report and Form 20-F
`Information 2015, available at
`http://www.astrazeneca-
`annualreports.com/2015/assets/pdf/
`AZ_Annual_Report_2015.pdf
`
`Exhibit 2109 Bristol-Myers Squibb Annual Report 2007,
`available from http://investor.bms.com/
`investors/financial-information/annual-
`reports/default.aspx
`
`Exhibit 2110 Bristol-Myers Squibb Annual Report 2008,
`available from http://investor.bms.com/
`investors/financial-information/annual-
`reports/default.aspx
`
`Status
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Exhibit 2111 Bristol-Myers Squibb Annual Report 2009,
`available from http://investor.bms.com/
`
`Served and
`Filed
`
`15
`
`
`
`
`
`Exhibit
`
`Description
`investors/financial-information/annual-
`reports/default.aspx
`
`Exhibit 2112 Bristol-Myers Squibb Annual Report 2010,
`available from http://investor.bms.com/
`investors/financial-information/annual-
`reports/default.aspx
`
`Exhibit 2113 Bristol-Myers Squibb Annual Report 2011,
`available from http://investor.bms.com/
`investors/financial-information/annual-
`reports/default.aspx
`
`Exhibit 2114 Bristol-Myers Squibb Annual Report 2012,
`available from http://investor.bms.com/
`investors/financial-information/annual-
`reports/default.aspx
`
`Exhibit 2115 Bristol-Myers Squibb Annual Report 2013,
`available from http://investor.bms.com/
`investors/financial-information/annual-
`reports/default.aspx
`
`Exhibit 2116 Bristol-Myers Squibb Annual Report 2014,
`available from http://investor.bms.com/
`investors/financial-information/annual-
`reports/default.aspx
`
`Exhibit 2117
`
`IMS Health National Prescription Audit
`(NPA) Data, January 2009 to October 2015
`(PROTECTIVE ORDER MATERIAL)
`
`Exhibit 2118
`
`IMS Health National Sales Perspective (NSP)
`Data, January 2009 to October 2015
`(PROTECTIVE ORDER MATERIAL)
`
`Exhibit 2119
`
`IMS Integrated Promotional Services (IPS)
`Data, January 2009 to September 2015
`(PROTECTIVE ORDER MATERIAL)
`
`Status
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed – Not
`Public
`
`Served and
`Filed – Not
`Public
`
`Served and
`Filed – Not
`Public
`
`16
`
`
`
`
`
`Exhibit
`
`Description
`
`Exhibit 2120 FDA Approved Drug Products Database,
`available at https://www.accessdata.
`fda.gov/scripts/cder/drugsatfda, last accessed
`February 21, 2016. (“FDA Approved Drug
`Products Database”)
`
`Exhibit 2121
`
`Exhibit 2122
`
`Exhibit 2123
`
`“Bristol-Myers Squibb and AstraZeneca
`Announce Worldwide Collaboration to
`Develop and Commercialize Diabetes
`Compounds,” Press Release dated January 11,
`2007, available from
`http://news.bms.com/press-release/bristol-
`myers-squibb-and-astrazeneca-announce-
`worldwide-collaboration-develop-and-comm,
`last accessed February 6, 2016
`
`“AstraZeneca Completes Acquisition of
`Bristol-Myers Squibb Share of Global
`Diabetes Alliance,” February 3, 2014 Press
`Release, available at http://www.astrazeneca-
`us.com/media/press-
`releases/Article/20140203-astrazeneca-
`completes-acquisition-of-diabetes-alliance,
`last accessed February 7, 2016
`
`“Merck Provides Update on Combination
`Medicine JUVISYNC (sitagliptin and
`simvastatin) Tablets,” Merck Press Release,
`September 23, 2013, available at
`http://www.mercknewsroom.com/
`news/company-statements/merck-provides-
`update-combination-medicine-juvisync-
`sitagliptin-and-simvasta, last accessed
`February 13, 2016
`
`Status
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Exhibit 2124 FDA Orange Book: Approved Drug Products
`with Therapeutic Equivalence Evaluations,
`available at http://www.accessdata.fda.gov/
`
`Served and
`Filed
`
`17
`
`
`
`
`
`Exhibit
`
`Description
`scripts/cder/ob, last accessed February 21,
`2016
`
`Exhibit 2125 U.S. Patent No. 7,951,400
`
`Exhibit 2126 U.S. Patent No. 8,628,799
`
`Exhibit 2127
`
`Exhibit 2128
`
`Exhibit 2129
`
`Exhibit 2130
`
`Exhibit 2131
`
`Exhibit 2132
`
`“Onglyza.com,” available at
`https://www.onglyza.com/treatment-for-type-
`2-diabetes.html, last accessed July 29, 2016
`
`“ONGLYZA® (saxagliptin),” available at
`https://www.onglyza-hcp.com/, last accessed
`July 29, 2016
`
`“Onglyza® Patient Brochure,” available from
`https://www.onglyza-hcp.com/
`content/dam/physician-services/us/164-hcp-
`onglyza-com/assets/pdf/ONGLYZA_
`Consumer_Brochure.pdf, last accessed July
`29, 2016
`
`“Januvia.com – Money Saving Offers &
`Coupons,” available at http://www.
`januvia.com/sitagliptin/januvia/consumer/
`special_offers/index.xhtml, last accessed July
`29, 2016
`
`“Tradjenta.com – Savings Card,” available at
`https://www.tradjenta.com/savings-card, last
`accessed July 29, 2016
`
`“Nesina.com – Takeda Diabetes Advantage
`Program,” available at https://www
`.nesina.com/nesina/diabetes-savings-program,
`last accessed July 29, 2016
`
`Status
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Exhibit 2133
`
`“KombiglyzeXR.com,” available at
`
`Served and
`
`18
`
`
`
`
`
`Exhibit
`
`Description
`https://www.kombiglyzexr.com, last accessed
`July 29, 2016.
`
`Status
`Filed
`
`Exhibit 2134
`
`Exhibit 2135
`
`Exhibit 2136
`
`Exhibit 2137
`
`“KOMBIGLYZE XR (saxagliptin and
`metformin HCl extended release),” available
`at https://www.kombiglyzexr-hcp.com, last
`accessed July 29, 2016
`
`“Kombiglyze™ XR Patient Brochure,”
`available from https://www.kombiglyzexr-hcp
`.com/content/dam/physician-services/us/159-
`hcp-kombigylyzexr-com/assets/pdf/
`KXR_Consumer_Brochure.pdf, last accessed
`July 29, 2016
`
`IMS Institute for Healthcare Informatics,
`“HSRN Data Brief: National Prescription
`Audit,” IMS Health, available at
`https://www.imshealth.com/files/web/
`IMSH%20Institute/NPA_Data_Brief-.pdf, last
`accessed July 29, 2016
`
`IMS Institute for Healthcare Informatics,
`“HSRN Data Brief: National Sales
`Perspective,” IMS Health, available at
`https://www.imshealth.com/files/
`web/IMSH%20Institute/NSP_Data_Brief-
`.pdf, last accessed July 29, 2016
`
`Exhibit 2138 Guha, R., et al., “The economics of
`commercial success in pharmaceutical patent
`litigation,” Landslide, Vol. 1, No. 5 (2009)
`
`Exhibit 2139 Robinson, W.T., et al., “First-mover
`advantages from pioneering new markets: A
`survey of empirical evidence.” Review of
`Industrial Organization, Vol. 9, No. 1 (1994),
`pp.1-23
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`19
`
`
`
`
`
`Exhibit
`
`Description
`
`Exhibit 2140 Berndt, et al. “Information, marketing, and
`pricing in the US antiulcer drug market,” The
`American Economic Review, Vol. 85, No. 2
`(1995), pp.100-105
`
`Exhibit 2141 Rickwood, S. and Gauntlett, C., “Global
`Report 2012: The Diabetes Olympics,”
`Medical Marketing and Media, August 2012,
`available at http://media.mmm-
`online.com/documents/38/
`diabetes_olympics_9328.pdf, last accessed
`July 29, 2016
`
`Exhibit 2142 Merck & Co., Inc. 2015 Annual Report on
`Form 10-K, available from
`http://investors.merck.com/investors/financial-
`reports/annual-reports-and-proxy-
`statements/default.aspx
`
`Exhibit 2143 Eli Lilly and Company 2015 Annual Report
`and Proxy Statement, available from
`https://investor.lilly.com/annuals.cfm
`
`Exhibit 2144
`
`“Bristol-Myers Squibb CEO Discusses Q3
`2013 Results - Earnings Call Transcript,”
`Seeking Alpha Transcripts, October 23, 2013,
`available at
`http://seekingalpha.com/article/1764422-
`bristol-myers-squibb-ceo-discusses-q3-2013-
`results-earnings-call-transcript?part=single,
`last accessed July 29, 2016
`
`Status
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Exhibit 2145 Berndt, E.R., “The US pharmaceutical
`industry: why major growth in times of cost
`containment?” Health Affairs, Vol. 20, No. 2
`(2001)
`
`Served and
`Filed
`
`Exhibit 2146 Grabowski, H., et al., “Does generic entry
`always increase consumer welfare?” Food and
`
`Served and
`Filed
`
`20
`
`
`
`
`
`Exhibit
`
`Description
`Drug Law Journal, Vol. 67, No. 3 (2012), pp.
`373-3915
`
`Status
`
`Exhibit 2147 Bagwell, K., “Economic Analysis of
`Advertising,” in M. Armstrong and R. Porter,
`(Eds.) Handbook of Industrial Organization
`Volume 3, Elsevier, 2007, pp. 1701-1844
`
`Exhibit 2148
`
`“IMS Integrated Promotional Services,”
`available at http://imsservicecatalog.com/
`moreinfo.php?id2=4417, last accessed March
`2, 2016; IMS Integrated Promotional Services
`Data
`
`Exhibit 2149 Hans-Ulrich Demuth & Jochen Heins,
`Catalytic Mechanism of Dipeptidyl Peptidase
`IV in Dipeptidyl Peptidase IV (CD26) in
`Metabolism and the Immune Response, in
`DIPEPTIDYL PEPTIDASE IV (CD26) IN
`METABOLISM AND THE IMMUNE RESPONSE
`(Bernhard Fleischer ed., 1995)
`
`Exhibit 2150 Roger J. Snow & William W. Bachovchin,
`Boronic Acid Inhibitors of Dipeptidyl
`Peptidase IV: A New Class of
`Immunosuppressive Agents, 3 ADV. MED.
`CHEM. 149 (1995)
`
`Exhibit 2151 KJL Augustyns et al., Pyrrolidides: Synthesis
`and Structure-Activity Relationship as
`Inhibitors of Dipeptidyl Peptidase IV, 32 EUR.
`J. MED. CHEM. 301 (1997)
`
`Exhibit 2152 Sumiko Tanaka et al., Anti-Arthritic Effects of
`the Novel Dipeptidyl Peptidase IV Inhibitors
`TMC-2A And TSL-225, 40
`IMMUNOPHARMACOLOGY 21 (1998)
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Exhibit 2153 WO Patent App. Pub. No. 99/61431
`
`Served and
`
`21
`
`
`
`
`
`Exhibit
`
`Description
`
`Exhibit 2154 WO Patent App. Pub. No. 99/46272
`
`Exhibit 2155 WO Patent App. Pub. No. 99/62914
`
`Exhibit 2156 U.S. Patent No. 6,172,081
`
`Exhibit 2157 U.S. Patent No. 6,107,317
`
`Exhibit 2158 U.S. Patent No. 6,110,949
`
`Exhibit 2159
`
`J. J. Nemunaitis et al., A Phase 1 Trial of PT-
`100 in Patients Receiving Myelosuppressive
`Chemotherapy, 22 J. CLIN. ONCOL. 2572
`(2004)
`
`Exhibit 2160 K. Glund et al., Abstract, Single Dose-
`Escalation Study to Investigate the Safety and
`Tolerability of the DP IV Inhibitor P32/98 in
`Healthy Volunteers, 108 EXP. CLIN.
`ENDOCRONOL. DIABETES pFr105 (2000)
`
`Exhibit 2161 Nancy A. Thornberry & Ann E. Weber,
`Discovery of JANUVIA™ (Sitagliptin), a
`Selective Dipeptidyl Peptidase IV Inhibitor for
`the Treatment of Type 2 Diabetes, 7 CURR.
`TOP. IN MED. CHEM. 557 (2007)
`
`Status
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Exhibit 2162 Paul E. Wiedeman, DPPIV Inhibition:
`Promising Therapy for the Treatment of Type
`2 Diabetes, 45 PROGRESS IN MED. CHEM. 63
`(2007)
`
`Served and
`Filed
`
`Exhibit 2163
`
`Jack P. Uetrech, New Concepts in
`
`Served and
`
`22
`
`
`
`
`
`Exhibit
`
`Description
`Immunology Relevant to Idiosyncratic Drug
`Reactions: The “Danger Hypothesis” and
`Innate Immune System, 12 CHEM. RES.
`TOXICOL. 387 (1999)
`
`Exhibit 2164 Craig Lammert et. al., Relationship Between
`Daily Dose and Oral Medications and
`Idiosyncratic Drug-Induced Liver Injury:
`Search for Signals, 47 HEPATOLOGY 2003
`(2008)
`
`Exhibit 2165 Torsten Hoffmann & Hans-Ulrich Demuth,
`Therapeutic Strategies Exploiting DP IV
`Inhibition, Target Disease: Type 2 Diabetes,
`in ECTOPEPTIDASES (Jürgen Langner &
`Siegfried Ansorge eds., 2002)
`
`Exhibit 2166 Catherine A. Abbott et al., Cloning,
`Expression and Chromosomal Localization of
`a Novel Human Dipeptidyl Peptidase (DPP)
`IV Homolog, DPP8, 267 EUR. J. BIOCHEM.
`6140 (2000)
`
`Exhibit 2167 Robert Underwood et al., Sequence,
`Purification, and Cloning of an Intracellular
`Serine Protease, Quiescent Cell Proline
`Dipeptidase, 274 J. BIOL. CHEM. 34053 (1999)
`
`Exhibit 2168 B. Balkan et al., Inhibition of Dipeptidyl
`Peptidase IV with NVP-DPP728 Increases
`Plasma GLP-1(7-36 Amide) Concentrations
`and Improves Oral Glucose Tolerance in
`Obese Zucker Rats, 42 DIABETOLOGIA 1324
`(1999)
`
`Exhibit 2169 DPP-IV Targets (Dec. 1, 1998)
`
`Status
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Exhibit 2170 Ronald E. White et al., Regioselectivity in the
`
`Served and
`
`23
`
`
`
`
`
`Exhibit
`
`Description
`Cytochromes P-450: Control by Protein
`Constraints and by Chemical Reactivities, 228
`ARCHIVES OF BIOCHEM. & BIOPHYS. 493
`(1984)
`
`Status
`Filed
`
`Exhibit 2171 David J. Augeri et al., Discovery and
`Preclinical Profile of Saxagliptin (BMS-
`477118): A Highly Potent, Long-Acting,
`Orally Active Dipeptidyl Peptidase IV
`Inhibitor for the Treatment of Type 2
`Diabetes, 48 J. Med. Chem. 5025 (2005)
`
`Exhibit 2172 DP4 Chemistry Significant Events (Jan. 5,
`1999)
`
`Exhibit 2173 Declaration of JEFFREY ROBL, PH.D.
`
`Exhibit 2174 Deposition Transcript of DAVID P.
`ROTELLA, PH.D. (May 26, 2016)
`
`Exhibit 2175 DP4 Chemistry Significant Events (Mar. 30,
`2000)
`
`Exhibit 2176 Mika Nabeno et al., A Comparative Study of
`the Binding Modes of Recently Launched
`Dipeptidyl Peptidase IV Inhibitors in the
`Active Site, 434 BIOCHEM. & BIOPHYS.
`RESEARCH COMMC’NS 191 (2013)
`
`Exhibit 2177 Design and Development of the Selective
`DPP-4 Inhibitor Sitagliptin
`
`Exhibit 2178 DP4 Chemistry Significant Events (Oct. 30,
`2000)
`
`Exhibit 2179 Christina Olsen & Nicolai Wagtmann,
`Identification and Characterization of Human
`DPP9, a Novel Homologue of Dipeptidyl
`Peptidase IV, 299 GENE 185 (2002)
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`24
`
`
`
`
`
`Exhibit
`
`Description
`
`Exhibit 2180 Shintaro Nakayama et al., A Zone of
`Classification System for Risk Assessment of
`Idiosyncratic Drug Toxicity Using Daily Dose
`and Covalent Binding, 37 DRUG METAB. &
`DISPOSITION 1970 (2009)
`
`Exhibit 2181 Yamanouchi Pharm. Co. v. Danbury
`Pharmacal, Inc., 21 F. Supp. 2d 366
`(S.D.N.Y. 1998), aff’d sub nom. Yamanouchi
`Pharm. Co. v. Danbury Pharmacal, Inc., 231
`F.3d 1339 (Fed. Cir. 2000)
`
`Exhibit 2182 DP4 Chemistry Significant Events (Jan. 5,
`2000)
`
`Exhibit 2183 DP4 Chemistry Significant Events (Apr. 26,
`1999)
`
`Exhibit 2184 DP4 Chemistry Significant Events (Aug. 11,
`1999)
`
`Exhibit 2185 DP4 Chemistry Significant Events (Oct. 1,
`1999)
`
`Exhibit 2186 DP4 Chemistry Significant Events (Nov. 4,
`1999)
`
`Exhibit 2187 DP4 Future Program (Dec. 16, 1999)
`
`Exhibit 2188 Monthly Summary, DP4 Inhibitors
`
`Exhibit 2189 Monthly Summary, DP4 Inhibitors
`
`Exhibit 2190 Excerpts from David Betebenner, Notebook
`No. 47583 (Feb. 26, 2001)
`
`Exhibit 2191
`
`In re Cyclobenzaprine Hydrochloride
`
`Status
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Served and
`Filed
`
`Se