ANTITHROMBOTIC/ANTICOAGULANT DRUGS: TECHNOLOGIES AND GLOBAL MARKETS

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1 ANTITHROMBOTIC/ANTICOAGULANT DRUGS: TECHNOLOGIES AND GLOBAL MARKETS PHM119B September 2016 Anuj Pathak Project Analyst ISBN: BCC Research 49 Walnut Park, Building 2 Wellesley, MA USA (toll-free within the USA), or (+1) information@bccresearch.com

2 TABLE OF CONTENTS CHAPTER 1 INTRODUCTION 2 STUDY GOALS AND OBJECTIVES 2 REASONS FOR DOING THIS STUDY 2 SCOPE OF THE STUDY 2 METHODOLOGY AND INFORMATION SOURCES 3 ANALYST'S CREDENTIALS 3 RELATED BCC RESEARCH REPORTS 3 BCC RESEARCH WEBSITE 4 DISCLAIMER 4 CHAPTER 2 EXECUTIVE SUMMARY 6 EXECUTIVE SUMMARY 6 SUMMARY TABLE GLOBAL MARKET FOR ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY REGION, THROUGH 2021 ($ SUMMARY FIGURE GLOBAL MARKET FOR ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY REGION, ($ 7 7 CHAPTER 3 INDUSTRY OVERVIEW 10 MAJOR DEVELOPMENTS 10 COAGULATION FACTORS TARGETED TO REDUCE CVD 10 DEVELOPMENT OF ANTIDOTES FOR THROMBIN INHIBITORS 10 Andexanet Alfa 10 Praxbind (Idarucizumab) 11 TABLE 1 PRAXBIND (IDARUCIZUMAB) DRUG LABEL 12 SALES PERFORMANCE OF MAJOR DRUGS PROJECTED THROUGH XARELTO (RIVAROXABAN) 12 ELIQUIS (APIXABAN) 12 PRADAXA (DABIGATRAN ETEXILATE MESYLATE) 13 LOVENOX (ENOXAPARIN) 13 PLAVIX (CLOPIDOGREL) 13 TABLE 2 GLOBAL MARKET FOR ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY TYPE, THROUGH 2020 ($ PATENT ANALYSIS 14 PATENT BY ASSIGNEE 14 FIGURE 1 COMPANY SHARES OF PATENTS ON ANTITHROMBOTICS AND ANTICOAGULANTS, JAN TO APRIL 2016 FIGURE 2 COMPANY SHARES OF PATENTS ON ANTICOAGULANTS, JAN TO APRIL 2016 EPIDEMIC OF CARDIOVASCULAR DISEASE 17 TABLE 3 EPIDEMIC OF CARDIOVASCULAR DISEASES 18 RISK FACTORS AND PREVENTION OF CVD 20 CLASSIFICATION OF CARDIOVASCULAR DISEASES 20 CORONARY HEART DISEASE 20 Prevalence of CHD in the U.S. 21 TABLE 4 CORONARY HEART DISEASE PROFILE 21 TABLE 5 DISTRIBUTION OF HEART DISEASE BY RACE/ETHNICITY,

3 ACUTE MYOCARDIAL INFARCTION 23 TABLE 6 ACUTE MYOCARDIAL INFARCTION DISEASE PROFILE 24 THE CIRCULATORY SYSTEM 25 BLOOD VESSEL STRUCTURE 25 BLOOD FLOW 26 CONDITIONS 27 THROMBUS 27 EMBOLUS 28 ALTERATIONS IN VENOUS FLOW 29 DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM 29 TABLE 7 VIRCHOW S TRIAD: THREE MAIN FACTORS IN PREDISPOSITION TO PULMONARY EMBOLISM HEMOSTASIS (THE CLOTTING PROCESS) 31 DISEASES ASSOCIATED WITH THROMBOEMBOLISM 32 ACUTE CORONARY SYNDROME 32 ISCHEMIC HEART DISEASE 32 Etiology 33 Mechanisms of Coronary Atherosclerosis 33 Pathophysiology of Ischemia 34 ANGINA PECTORIS 35 CHRONIC ISCHEMIC CARDIOMYOPATHY 35 SUDDEN CARDIAC DEATH 35 ATRIAL FIBRILLATION 36 Causes 36 CEREBROVASCULAR DISEASE 37 STENT THROMBOSIS 38 DEMOGRAPHICS 39 TABLE 8 GLOBAL POPULATION BY SELECTED REGION, ( 39 TABLE 9 GLOBAL POPULATION GROWTH BY SELECTED REGION, (AVERAGE PERCENTAGE GROWTH PER YEAR) FIGURE 3 GLOBAL POPULATION GROWTH BY SELECTED REGION, (AVERAGE PERCENTAGE GROWTH) CV, VTE, AF AND STROKE DEMOGRAPHICS 42 Venous Thromboembolism 42 Venous Thromboembolism and Lifestyle 43 Venous Thromboembolism and Air Travel CHAPTER 4 ANTICOAGULANTS 47 OVERVIEW 47 PRODUCTS 48 LOW MOLECULAR WEIGHT HEPARIN 48 Lovenox 48 TABLE 10 LOVENOX DRUG LABEL 49 Fragmin 50 TABLE 11 FRAGMIN DRUG LABEL 50 Innohep 52 TABLE 12 INNOHEP DRUG LABEL 52 Orgaran 53

4 TABLE 13 ORGARAN DRUG LABEL 54 Normiflo 55 TABLE 14 NORMIFLO DRUG LABEL 56 Embolex 56 TABLE 15 EMBOLEX DRUG LABEL 57 Fraxiparine 57 TABLE 16 FRAXIPARINE DRUG LABEL 58 Ariven/Arteven 58 TABLE 17 ARIVEN/ARTEVEN DRUG LABEL 59 ORAL ANTICOAGULANTS (VITAMIN K ANTAGONISTS) 59 GLOBAL MARKET FORECAST 60 TABLE 18 GLOBAL MARKET FOR ANTICOAGULANT DRUGS BY REGION, THROUGH 2021 ($ FIGURE 4 GLOBAL MARKET FOR ANTICOAGULANT DRUGS BY REGION, ($ MARKET BY GEOGRAPHIC REGION 62 TABLE 19 GLOBAL MARKET SHARES OF ANTICOAGULANT DRUGS BY REGION, 2015 FIGURE 5 GLOBAL MARKET SHARES OF ANTICOAGULANT DRUGS BY REGION, 2015 TABLE 20 GLOBAL MARKET SHARES OF ANTICOAGULANT DRUGS BY REGION, 2021 FIGURE 6 GLOBAL MARKET SHARES OF ANTICOAGULANT DRUGS BY REGION, 2021 MARKET BY DRUG TYPE 64 TABLE 21 GLOBAL MARKET FOR ANTICOAGULANT DRUGS BY TYPE, THROUGH 2021 ($ TABLE 22 GLOBAL MARKET FOR LOW MOLECULAR WEIGHT HEPARIN BY REGION, THROUGH 2021 ($ TABLE 23 GLOBAL MARKET FOR ORAL ANTICOAGULANTS (VITAMIN K ANTAGONISTS) BY REGION, THROUGH 2021 ($ FIGURE 7 GLOBAL MARKET FOR ORAL ANTICOAGULANTS (VITAMIN K ANTAGONISTS) BY REGION, ($ TABLE 24 GLOBAL MARKET SHARES OF ANTICOAGULANT DRUGS BY TYPE, FIGURE 8 GLOBAL MARKET SHARES OF ANTICOAGULANT DRUGS BY TYPE, TABLE 25 GLOBAL MARKET SHARES OF ANTICOAGULANT DRUGS BY TYPE, FIGURE 9 GLOBAL MARKET SHARES OF ANTICOAGULANT DRUGS BY TYPE, COMPETITIVE ANALYSIS 68 TABLE 26 GLOBAL MARKET SHARES OF ANTICOAGULANT DRUGS BY COMPANY, COMPETITIVE ANALYSIS, 2014 ($ MILLIONS/%) FIGURE 10 GLOBAL MARKET SHARES OF ANTICOAGULANT DRUGS BY COMPANY, COMPETITIVE ANALYSIS, CHAPTER 5 ANTIPLATELETS 71 OVERVIEW 71 PRODUCTS 71 ORAL ANTIPLATELETS 71 Plavix 71 TABLE 27 PLAVIX DRUG LABEL 71 Pletal 72

5 TABLE 28 PLETAL DRUG LABEL 73 Effient 74 TABLE 29 EFFIENT DRUG LABEL 74 Ticlid 75 Brilinta 75 TABLE 30 BRILINTA DRUG LABEL 75 IV ANTIPLATELETS 76 Integrilin 76 TABLE 31 INTEGRILIN DRUG LABEL 77 Aggrastat 78 TABLE 32 AGGRASTAT DRUG LABEL 78 ReoPro 79 TABLE 33 REOPRO DRUG LABEL 80 GLOBAL MARKET FORECAST 80 TABLE 34 GLOBAL MARKET FOR ANTIPLATELET DRUGS BY REGION, THROUGH 2021 ($ FIGURE 11 GLOBAL MARKET FOR ANTIPLATELET DRUGS BY REGION, ($ MARKET BY GEOGRAPHIC REGION 82 TABLE 35 GLOBAL MARKET SHARES OF ANTIPLATELET DRUGS BY REGION, 2015 FIGURE 12 GLOBAL MARKET SHARES OF ANTIPLATELET DRUGS BY REGION, 2015 TABLE 36 GLOBAL MARKET SHARES OF ANTIPLATELET DRUGS BY REGION, 2021 FIGURE 13 GLOBAL MARKET SHARES OF ANTIPLATELET DRUGS BY REGION, 2021 MARKET BY DRUG TYPE 84 TABLE 37 GLOBAL MARKET FOR ANTIPLATELET DRUGS BY TYPE, THROUGH 2021 ($ FIGURE 14 GLOBAL MARKET FOR ANTIPLATELET DRUGS BY TYPE, ($ TABLE 38 GLOBAL MARKET FOR ORAL ANTIPLATELET DRUGS BY REGION, THROUGH 2021 ($ TABLE 39 GLOBAL MARKET FOR IV ANTIPLATELET DRUGS BY REGION, THROUGH 2021 ($ TABLE 40 GLOBAL MARKET SHARES OF ANTIPLATELET DRUGS BY TYPE, FIGURE 15 GLOBAL MARKET SHARES OF ANTIPLATELET DRUGS BY TYPE, TABLE 41 GLOBAL MARKET SHARES OF ANTIPLATELET DRUGS BY TYPE, FIGURE 16 GLOBAL MARKET SHARES OF ANTIPLATELET DRUGS BY TYPE, COMPETITIVE ANALYSIS 88 TABLE 42 GLOBAL MARKET FOR ANTIPLATELET DRUGS BY COMPANY, COMPETITIVE ANALYSIS, 2014 ($ MILLIONS/%) FIGURE 17 GLOBAL MARKET FOR ANTIPLATELET DRUGS BY COMPANY, COMPETITIVE ANALYSIS, CHAPTER 6 THROMBIN INHIBITORS 91 OVERVIEW 91 PRODUCTS 91 DIRECT THROMBIN INHIBITORS 91

6 Argatroban 91 Angiomax 91 Iprivask 91 Pradaxa 92 THROMBOLYTIC AGENTS 92 Thrombolytic Enzymes 92 Tissue Plasminogen Activators 93 Activase 93 Retavase 93 TNKase 93 ATryn 93 DIRECT FACTOR XA INHIBITORS 93 Xarelto 93 Betrixaban 94 Savaysa (Edoxaban) 94 Eliquis 94 GLOBAL THROMBIN INHIBITOR MARKET FORECAST 95 TABLE 43 GLOBAL MARKET FOR THROMBIN INHIBITORS BY REGION, THROUGH 2021 ($ FIGURE 18 GLOBAL MARKET FOR THROMBIN INHIBITORS BY REGION, ($ REGIONAL MARKET SHARES OF THROMBIN INHIBITORS 96 TABLE 44 GLOBAL MARKET SHARES OF SALES OF THROMBIN INHIBITORS BY REGION, 2015 FIGURE 19 GLOBAL MARKET SHARES OF SALES OF THROMBIN INHIBITORS BY REGION, 2015 TABLE 45 GLOBAL MARKET SHARES OF SALES OF THROMBIN INHIBITORS BY REGION, 2021 FIGURE 20 GLOBAL MARKET SHARES OF SALES OF THROMBIN INHIBITORS BY REGION, 2021 MARKET BY DRUG TYPE 98 TABLE 46 GLOBAL MARKET FOR THROMBIN INHIBITORS BY TYPE, THROUGH 2021 ($ FIGURE 21 GLOBAL MARKET FOR THROMBIN INHIBITORS BY TYPE, ($ TABLE 47 GLOBAL MARKET SHARES OF THROMBIN INHIBITORS BY TYPE, FIGURE 22 GLOBAL MARKET SHARES OF THROMBIN INHIBITORS BY TYPE, TABLE 48 GLOBAL MARKET SHARES OF SALES OF THROMBIN INHIBITORS BY TYPE, 2021 FIGURE 23 GLOBAL MARKET SHARES OF SALES OF THROMBIN INHIBITORS BY TYPE, 2021 TABLE 49 GLOBAL MARKET FOR THROMBIN INHIBITOR DRUGS BY COMPANY, 2014 ($ MILLIONS/%) FIGURE 24 GLOBAL MARKET SHARES OF THROMBIN INHIBITOR DRUGS BY COMPANY, 2014 RESEARCH AND DEVELOPMENT 102 GLOBAL ANTICOAGULANT/ANTITHROMBOTIC MARKET FORECAST 104 TABLE 50 GLOBAL MARKET FOR ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY TYPE, THROUGH 2021 ($

7 FIGURE 25 GLOBAL MARKET FOR ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY TYPE, ($ TABLE 51 GLOBAL MARKET SHARES OF ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY TYPE, 2015 FIGURE 26 GLOBAL MARKET SHARES OF ANTITHROMBIN/ANTICOAGULANT DRUGS BY TYPE, 2015 TABLE 52 GLOBAL MARKET SHARES OF ANTITHROMBIN/ANTICOAGULANT DRUGS BY TYPE, 2021 FIGURE 27 GLOBAL MARKET SHARES OF ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY TYPE, 2021 MARKET BY GEOGRAPHIC REGION 107 TABLE 53 GLOBAL MARKET FOR ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY REGION, THROUGH 2021 ($ FIGURE 28 GLOBAL MARKET FOR ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY REGION, ($ TABLE 54 GLOBAL MARKET SHARES OF ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY REGION, 2015 FIGURE 29 GLOBAL MARKET SHARES OF ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY REGION, 2015 TABLE 55 GLOBAL MARKET SHARES OF ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY REGION, 2021 FIGURE 30 GLOBAL MARKET SHARES OF ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY REGION, 2021 COMPETITIVE ANALYSIS 110 TABLE 56 GLOBAL MARKET FOR ANTITHROMBIN/ANTICOAGULANT DRUGS BY COMPANY, COMPETITIVE ANALYSIS, 2014 ($ MILLIONS/%) FIGURE 31 GLOBAL MARKET FOR ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY COMPANY, COMPETITIVE ANALYSIS, CHAPTER 7 COMPANY PROFILES 113 ABBOTT LABORATORIES 113 HISTORY 113 RECENT DEVELOPMENTS 114 PRODUCTS 114 LOCATIONS 114 CORPORATE MANAGEMENT 114 ARMETHEON INC. 114 HISTORY 114 PRODUCTS 115 RECENT DEVELOPMENTS 115 CORPORATE MANAGEMENT 115 ASTRAZENECA 115 HISTORY 115 PRODUCTS 115 RECENT DEVELOPMENTS 116 LOCATIONS 116 CORPORATE MANAGEMENT 116 BAXTER INTERNATIONAL 116 HISTORY 116 PRODUCTS 117

8 RECENT DEVELOPMENTS 117 LOCATIONS 117 CORPORATE MANAGEMENT 117 BAYER AG 117 HISTORY 117 PRODUCTS 118 RECENT DEVELOPMENTS 118 LOCATIONS 118 CORPORATE MANAGEMENT 118 BIOVASCULAR INC. 119 HISTORY 119 PRODUCTS 119 LOCATIONS 119 CORPORATE MANAGEMENT 119 BOEHRINGER INGELHEIM GMBH 119 HISTORY 120 PRODUCTS 120 RECENT DEVELOPMENTS 120 LOCATIONS 120 CORPORATE MANAGEMENT 120 BRISTOL-MYERS SQUIBB CO. 121 HISTORY 121 PRODUCTS 121 RECENT DEVELOPMENTS 121 LOCATIONS 121 CORPORATE MANAGEMENT 122 CSL BEHRING 122 HISTORY 122 PRODUCTS 122 RECENT DEVELOPMENTS 122 LOCATIONS 123 CORPORATE MANAGEMENT 123 DAIICHI SANKYO CO. LTD. 123 HISTORY 123 PRODUCTS 123 RECENT DEVELOPMENTS 124 LOCATIONS 124 CORPORATE MANAGEMENT 124 ELI LILLY 124 HISTORY 124 PRODUCTS 125 LOCATIONS 125 CORPORATE MANAGEMENT 125 EMISPHERE TECHNOLOGIES 125 HISTORY 126 PRODUCTS 126 CORPORATE MANAGEMENT 126

9 F. HOFFMANN-LA ROCHE AG 126 HISTORY 126 PRODUCTS 127 RECENT DEVELOPMENTS 127 LOCATIONS 127 CORPORATE MANAGEMENT 127 GENENTECH 127 HISTORY 128 PRODUCTS 128 LOCATIONS 128 CORPORATE MANAGEMENT 128 GLAXOSMITHKLINE 128 HISTORY 129 PRODUCTS 129 LOCATIONS 129 CORPORATE MANAGEMENT 129 JOHNSON & JOHNSON 129 HISTORY 130 PRODUCTS 130 RECENT DEVELOPMENTS 130 LOCATIONS 130 CORPORATE MANAGEMENT 130 LIGAND PHARMACEUTICALS INC. 130 HISTORY 131 PRODUCTS 131 LOCATIONS 131 CORPORATE MANAGEMENT 131 THE MEDICINES CO. 131 HISTORY 131 PRODUCTS 132 RECENT DEVELOPMENTS 132 CORPORATE MANAGEMENT 132 MERCK 132 HISTORY 132 PRODUCTS 133 LOCATIONS 133 CORPORATE MANAGEMENT 133 MERRION PHARMACEUTICALS LTD. 133 HISTORY 133 PRODUCTS 134 LOCATIONS 134 CORPORATE MANAGEMENT 134 MICROBIX BIOSYSTEMS INC. 134 HISTORY 134 PRODUCTS 134 LOCATIONS 135 CORPORATE MANAGEMENT 135

10 NOVARTIS 135 HISTORY 135 PRODUCTS 135 RECENT DEVELOPMENTS: 136 LOCATIONS 136 CORPORATE MANAGEMENT 136 ONO PHARMACEUTICAL CO. LTD. 136 HISTORY 136 PRODUCTS 137 LOCATIONS 137 CORPORATE MANAGEMENT 137 OTSUKA PHARMACEUTICAL CO. LTD. 137 HISTORY 137 PRODUCTS 138 RECENT DEVELOPMENTS 138 LOCATIONS 138 CORPORATE MANAGEMENT 138 PFIZER INC. 139 HISTORY 139 PRODUCTS 139 RECENT DEVELOPMENTS: 140 CORPORATE MANAGEMENT 140 PORTOLA PHARMACEUTICALS 140 HISTORY 140 PRODUCTS 140 RECENT DEVELOPMENTS 140 LOCATION 141 CORPORATE MANAGEMENT 141 REVO BIOLOGICS INC. 141 HISTORY 141 PRODUCTS 141 LOCATIONS 142 CORPORATE MANAGEMENT 142 SANOFI 142 HISTORY 142 PRODUCTS 142 LOCATIONS 144 CORPORATE MANAGEMENT 144 SANTA CRUZ BIOTECHNOLOGY INC. 144 HISTORY 144 PRODUCTS 144 LOCATIONS 144 CORPORATE MANAGEMENT 144 SERVIER LABORATORIES 145 HISTORY 145 LOCATIONS 145 CORPORATE MANAGEMENT 145

11 SHIRE PHARMACEUTICALS 145 HISTORY 145 PRODUCTS 146 LOCATIONS 146 CORPORATE MANAGEMENT 146 SUN PHARMACEUTICALS 146 HISTORY 146 PRODUCTS 147 RECENT DEVELOPMENTS 147 LOCATIONS 148 CORPORATE MANAGEMENT 148 TEVA PHARMACEUTICALS LTD. 148 HISTORY 148 PRODUCTS 148 RECENT DEVELOPMENTS 149 LOCATIONS 149 CORPORATE MANAGEMENT 149 CHAPTER 8 APPENDIX A: LIST OF PATENTS 151 TABLE 57 LIST OF PATENTS ON ANTITHROMBOTICS AND ANTICOAGULANTS, 2011-APRIL CHAPTER 9 APPENDIX B: DIRECTORY OF COMPANIES COVERED IN THIS REPORT 160

12 LIST OF TABLES TABLE HEADING SUMMARY TABLE GLOBAL MARKET FOR ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY REGION, THROUGH 2021 ($ TABLE 1 PRAXBIND (IDARUCIZUMAB) DRUG LABEL 12 TABLE 2 GLOBAL MARKET FOR ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY TYPE, THROUGH 2020 ($ TABLE 3 EPIDEMIC OF CARDIOVASCULAR DISEASES 18 TABLE 4 CORONARY HEART DISEASE PROFILE 21 TABLE 5 DISTRIBUTION OF HEART DISEASE BY RACE/ETHNICITY, TABLE 6 ACUTE MYOCARDIAL INFARCTION DISEASE PROFILE 24 TABLE 7 VIRCHOW S TRIAD: THREE MAIN FACTORS IN PREDISPOSITION TO PULMONARY EMBOLISM TABLE 8 GLOBAL POPULATION BY SELECTED REGION, ( 39 TABLE 9 GLOBAL POPULATION GROWTH BY SELECTED REGION, (AVERAGE PERCENTAGE GROWTH PER YEAR) TABLE 10 LOVENOX DRUG LABEL 49 TABLE 11 FRAGMIN DRUG LABEL 50 TABLE 12 INNOHEP DRUG LABEL 52 TABLE 13 ORGARAN DRUG LABEL 54 TABLE 14 NORMIFLO DRUG LABEL 56 TABLE 15 EMBOLEX DRUG LABEL 57 TABLE 16 FRAXIPARINE DRUG LABEL 58 TABLE 17 ARIVEN/ARTEVEN DRUG LABEL 59 TABLE 18 GLOBAL MARKET FOR ANTICOAGULANT DRUGS BY REGION, THROUGH 2021 ($ TABLE 19 GLOBAL MARKET SHARES OF ANTICOAGULANT DRUGS BY REGION, 2015 TABLE 20 GLOBAL MARKET SHARES OF ANTICOAGULANT DRUGS BY REGION, 2021 TABLE 21 GLOBAL MARKET FOR ANTICOAGULANT DRUGS BY TYPE, THROUGH 2021 ($ TABLE 22 GLOBAL MARKET FOR LOW MOLECULAR WEIGHT HEPARIN BY REGION, THROUGH 2021 ($ TABLE 23 GLOBAL MARKET FOR ORAL ANTICOAGULANTS (VITAMIN K ANTAGONISTS) BY REGION, THROUGH 2021 ($ TABLE 24 GLOBAL MARKET SHARES OF ANTICOAGULANT DRUGS BY TYPE, TABLE 25 GLOBAL MARKET SHARES OF ANTICOAGULANT DRUGS BY TYPE, TABLE 26 GLOBAL MARKET SHARES OF ANTICOAGULANT DRUGS BY COMPANY, COMPETITIVE ANALYSIS, 2014 ($ MILLIONS/%) TABLE 27 PLAVIX DRUG LABEL 71 TABLE 28 PLETAL DRUG LABEL 73 TABLE 29 EFFIENT DRUG LABEL 74 TABLE 30 BRILINTA DRUG LABEL 75 TABLE 31 INTEGRILIN DRUG LABEL 77 TABLE 32 AGGRASTAT DRUG LABEL 78 TABLE 33 REOPRO DRUG LABEL 80 TABLE 34 GLOBAL MARKET FOR ANTIPLATELET DRUGS BY REGION, THROUGH 2021 ($ TABLE 35 GLOBAL MARKET SHARES OF ANTIPLATELET DRUGS BY REGION, TABLE 36 GLOBAL MARKET SHARES OF ANTIPLATELET DRUGS BY REGION,

13 TABLE HEADING TABLE 37 GLOBAL MARKET FOR ANTIPLATELET DRUGS BY TYPE, THROUGH 2021 ($ TABLE 38 GLOBAL MARKET FOR ORAL ANTIPLATELET DRUGS BY REGION, THROUGH 2021 ($ TABLE 39 GLOBAL MARKET FOR IV ANTIPLATELET DRUGS BY REGION, THROUGH 2021 ($ TABLE 40 GLOBAL MARKET SHARES OF ANTIPLATELET DRUGS BY TYPE, TABLE 41 GLOBAL MARKET SHARES OF ANTIPLATELET DRUGS BY TYPE, TABLE 42 GLOBAL MARKET FOR ANTIPLATELET DRUGS BY COMPANY, COMPETITIVE ANALYSIS, 2014 ($ MILLIONS/%) TABLE 43 GLOBAL MARKET FOR THROMBIN INHIBITORS BY REGION, THROUGH 2021 ($ TABLE 44 GLOBAL MARKET SHARES OF SALES OF THROMBIN INHIBITORS BY REGION, 2015 TABLE 45 GLOBAL MARKET SHARES OF SALES OF THROMBIN INHIBITORS BY REGION, 2021 TABLE 46 GLOBAL MARKET FOR THROMBIN INHIBITORS BY TYPE, THROUGH 2021 ($ TABLE 47 GLOBAL MARKET SHARES OF THROMBIN INHIBITORS BY TYPE, TABLE 48 GLOBAL MARKET SHARES OF SALES OF THROMBIN INHIBITORS BY TYPE, 2021 TABLE 49 GLOBAL MARKET FOR THROMBIN INHIBITOR DRUGS BY COMPANY, 2014 ($ MILLIONS/%) TABLE 50 GLOBAL MARKET FOR ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY TYPE, THROUGH 2021 ($ TABLE 51 GLOBAL MARKET SHARES OF ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY TYPE, 2015 TABLE 52 GLOBAL MARKET SHARES OF ANTITHROMBIN/ANTICOAGULANT DRUGS BY TYPE, 2021 TABLE 53 GLOBAL MARKET FOR ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY REGION, THROUGH 2021 ($ TABLE 54 GLOBAL MARKET SHARES OF ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY REGION, 2015 TABLE 55 GLOBAL MARKET SHARES OF ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY REGION, 2021 TABLE 56 GLOBAL MARKET FOR ANTITHROMBIN/ANTICOAGULANT DRUGS BY COMPANY, COMPETITIVE ANALYSIS, 2014 ($ MILLIONS/%) TABLE 57 LIST OF PATENTS ON ANTITHROMBOTICS AND ANTICOAGULANTS, 2011-APRIL

14 LIST OF FIGURES FIGURE TITLE SUMMARY FIGURE GLOBAL MARKET FOR ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY REGION, ($ FIGURE 1 COMPANY SHARES OF PATENTS ON ANTITHROMBOTICS AND ANTICOAGULANTS, JAN TO APRIL 2016 FIGURE 2 COMPANY SHARES OF PATENTS ON ANTICOAGULANTS, JAN TO APRIL 2016 FIGURE 3 GLOBAL POPULATION GROWTH BY SELECTED REGION, (AVERAGE PERCENTAGE GROWTH) FIGURE 4 GLOBAL MARKET FOR ANTICOAGULANT DRUGS BY REGION, ($ FIGURE 5 GLOBAL MARKET SHARES OF ANTICOAGULANT DRUGS BY REGION, 2015 FIGURE 6 GLOBAL MARKET SHARES OF ANTICOAGULANT DRUGS BY REGION, 2021 FIGURE 7 GLOBAL MARKET FOR ORAL ANTICOAGULANTS (VITAMIN K ANTAGONISTS) BY REGION, ($ FIGURE 8 GLOBAL MARKET SHARES OF ANTICOAGULANT DRUGS BY TYPE, FIGURE 9 GLOBAL MARKET SHARES OF ANTICOAGULANT DRUGS BY TYPE, FIGURE 10 GLOBAL MARKET SHARES OF ANTICOAGULANT DRUGS BY COMPANY, COMPETITIVE ANALYSIS, 2014 FIGURE 11 GLOBAL MARKET FOR ANTIPLATELET DRUGS BY REGION, ($ FIGURE 12 GLOBAL MARKET SHARES OF ANTIPLATELET DRUGS BY REGION, FIGURE 13 GLOBAL MARKET SHARES OF ANTIPLATELET DRUGS BY REGION, FIGURE 14 GLOBAL MARKET FOR ANTIPLATELET DRUGS BY TYPE, ($ FIGURE 15 GLOBAL MARKET SHARES OF ANTIPLATELET DRUGS BY TYPE, FIGURE 16 GLOBAL MARKET SHARES OF ANTIPLATELET DRUGS BY TYPE, FIGURE 17 GLOBAL MARKET FOR ANTIPLATELET DRUGS BY COMPANY, COMPETITIVE ANALYSIS, 2014 FIGURE 18 GLOBAL MARKET FOR THROMBIN INHIBITORS BY REGION, ($ FIGURE 19 GLOBAL MARKET SHARES OF SALES OF THROMBIN INHIBITORS BY REGION, 2015 FIGURE 20 GLOBAL MARKET SHARES OF SALES OF THROMBIN INHIBITORS BY REGION, 2021 FIGURE 21 GLOBAL MARKET FOR THROMBIN INHIBITORS BY TYPE, ($ FIGURE 22 GLOBAL MARKET SHARES OF THROMBIN INHIBITORS BY TYPE, FIGURE 23 GLOBAL MARKET SHARES OF SALES OF THROMBIN INHIBITORS BY TYPE, 2021 FIGURE 24 GLOBAL MARKET SHARES OF THROMBIN INHIBITOR DRUGS BY COMPANY, 2014 FIGURE 25 GLOBAL MARKET FOR ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY TYPE, ($ FIGURE 26 GLOBAL MARKET SHARES OF ANTITHROMBIN/ANTICOAGULANT DRUGS BY TYPE, 2015 FIGURE 27 GLOBAL MARKET SHARES OF ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY TYPE, 2021 FIGURE 28 GLOBAL MARKET FOR ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY REGION, ($

15 FIGURE TITLE FIGURE 29 GLOBAL MARKET SHARES OF ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY REGION, 2015 FIGURE 30 GLOBAL MARKET SHARES OF ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY REGION, 2021 FIGURE 31 GLOBAL MARKET FOR ANTITHROMBOTIC/ANTICOAGULANT DRUGS BY COMPANY, COMPETITIVE ANALYSIS,

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