DNA VACCINES: TECHNOLOGIES AND GLOBAL MARKETS

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DNA VACCINES: TECHNOLOGIES AND GLOBAL MARKETS BIO067B July 2014 Jon Evans Project Analyst ISBN: 1-56965-883-8 BCC Research 49 Walnut Park, Building 2 Wellesley, MA 02481 USA 866-285-7215 (toll-free within the USA), or (+1) 781-489-7301 www.bccresearch.com information@bccresearch.com

TABLE OF CONTENTS CHAPTER 1 INTRODUCTION 2 STUDY GOALS AND OBJECTIVES 2 REASONS FOR DOING THE STUDY 2 INTENDED AUDIENCE 3 SCOPE OF REPORT 3 TABLE A SCOPE OF REPORT 3 METHODOLOGY 4 INFORMATION SOURCES 4 RELATED BCC RESEARCH REPORTS 4 ANALYST CREDENTIALS 4 BCC RESEARCH WEBSITE 4 DISCLAIMER 5 CHAPTER 2 SUMMARY 7 SUMMARY TABLE GLOBAL VALUE OF DNA VACCINE MARKET BY APPLICATION, SUMMARY FIGURE GLOBAL VALUE OF DNA VACCINE MARKET BY APPLICATION, 2013-2019 ($ MILLIONS) 7 7 CHAPTER 3 OVERVIEW 11 INTRODUCTION 11 DNA VACCINE TECHNOLOGIES COVERED IN THIS REPORT 11 TABLE 1 SCOPE OF THIS REPORT 11 GLOBAL MARKET FOR DNA VACCINES 12 TABLE 2 GLOBAL VALUE OF DNA VACCINE MARKET BY APPLICATION, THROUGH 2019 ($ MILLIONS) TABLE 3 GLOBAL VALUE OF HUMAN DNA VACCINE MARKET BY INDICATION, FORCES DRIVING DNA VACCINE MARKET GROWTH 13 TABLE 4 DNA VACCINE INDUSTRY GROWTH DRIVING FORCES 13 LIFE CYCLE STATUS OF DNA VACCINE TECHNOLOGIES 14 TABLE 5 LIFE CYCLE STAGE OF VACCINE TYPES 14 COMMERCIAL STATUS OF DNA VACCINE TECHNOLOGIES 14 TABLE 6 COMMERCIAL STATUS OF DNA VACCINES 14 DNA VACCINE INDUSTRY 15 TABLE 7 DNA VACCINE INDUSTRY STRUCTURE 15 12 12 CHAPTER 4 DNA VACCINE TECHNOLOGIES 18 HISTORY 18 TABLE 8 DNA VACCINE HISTORY 19 THE HUMAN IMMUNE SYSTEM 20 TABLE 9 COMPONENTS OF THE IMMUNE SYSTEM 20 VACCINES 22 VACCINE EVOLUTION 22 FIGURE 1 EVOLUTION OF VACCINE TECHNOLOGIES 22 VACCINE TYPES 23

TABLE 10 VACCINE TYPES 23 Technology Life Cycle Stage of Vaccine Types 24 TABLE 11 TECHNOLOGY LIFE CYCLE STAGE OF VACCINE TYPES 24 DNA VACCINES 25 INTRODUCTION 25 FIGURE 2 MECHANISM OF ACTION OF A DNA VACCINE 25 CHANGING VACCINE PARADIGM 26 TABLE 12 CHANGING VACCINE PARADIGM 26 TABLE 13 ADVANTAGES AND DISADVANTAGES OF DNA VACCINES 27 FIGURE 3 SAFETY AND EFFICACY PROFILE OF DNA VERSUS VIRAL-VECTOR VACCINES FUNCTION AND SCOPE OF DNA VACCINES 29 FIGURE 4 DNA VACCINE FUNCTION AND MARKET SCOPE 29 TABLE 14 EMERGING COMPETITIVE LANDSCAPE FOR DNA VACCINES 31 CANCER DNA VACCINES 31 TABLE 15 CANCER VACCINE TYPES 32 DNA VACCINE TECHNOLOGY VALUE CHAIN 33 FIGURE 5 DNA VACCINE TECHNOLOGY VALUE CHAIN 33 TABLE 16 TECHNOLOGY DRIVERS FOR DNA VACCINE VALUE CHAIN 34 Antigen Discovery 35 Plasmid Design 35 TABLE 17 PLASMID DESIGN OBJECTIVES 35 TABLE 18 WAYS TO OPTIMIZE MAMMALIAN GENE EXPRESSION IN PLASMID DNA 36 Plasmid Manufacture 37 FIGURE 6 CONVENTIONAL AND PLASMID DNA VACCINE PRODUCTION PROCESS 38 TABLE 19 DNA PLASMID QUALITY COMPARISON 38 Delivery Technologies 39 TABLE 20 COMPARISON OF DNA DELIVERY TECHNOLOGIES 39 Uncomplexed pdna 39 Electroporation 40 FIGURE 7 EP PROCESS SCHEMATIC 41 Liposomes 41 Gold Particles 42 Nanoparticles 42 Bacterial Ghosts 43 Bacteriophages 43 Viruses 43 TABLE 21 IN VIVO VIRAL VECTOR TECHNOLOGIES COMPARED 44 Targeting Technologies 45 FIGURE 8 STRATEGIES FOR TARGETING DENDRITIC CELLS 46 Adjuvant Technologies 46 TABLE 22 DNA VACCINE ADJUVANT TECHNOLOGIES 46 DNA VACCINE TECHNOLOGY NEEDS 47 TABLE 23 TECHNOLOGY NEEDS FOR DNA VACCINES 48 29 CHAPTER 5 DNA VACCINE APPLICATIONS 51 RESEARCH TOOL APPLICATIONS 51 CLINICAL APPLICATIONS 51

OVERVIEW TO DNA VACCINE CLINICAL TRIALS PROCESS 51 TABLE 24 DNA VACCINE DEVELOPMENT FLOW SHEET 52 TABLE 25 DNA VACCINE PRECLINICAL DEVELOPMENT STEPS 53 FIGURE 9 FUTURE VACCINE CLINICAL TRIALS OVERVIEW 53 DNA VACCINE CLINICAL TRIALS SUMMARY 55 TABLE 26 DNA VACCINES CLINICAL TRIALS SUMMARY BY STARTING YEAR, AS OF APRIL 2014 TABLE 27 DNA VACCINE CLINICAL PHASE I TRIALS SUMMARY, AS OF APRIL 2014 56 TABLE 28 DNA VACCINE CLINICAL PHASE I/II TRIALS SUMMARY, AS OF APRIL 2014 59 TABLE 29 DNA VACCINE CLINICAL PHASE II TRIALS SUMMARY, AS OF APRIL 2014 60 TABLE 30 DNA VACCINE CLINICAL PHASE II/III TRIALS SUMMARY, AS OF APRIL 2014 61 TABLE 31 DNA VACCINE CLINICAL PHASE III TRIALS SUMMARY, AS OF APRIL 2014 62 TABLE 32 DNA VACCINE CLINICAL PHASE IV TRIALS SUMMARY, AS OF APRIL 2014 64 CANCER DNA VACCINE CLINICAL TRIALS 65 TABLE 33 DNA VACCINE CANCER CLINICAL TRIALS SUMMARY, AS OF APRIL 2014 65 Melanoma 67 INFECTIOUS DISEASE DNA VACCINES 68 TABLE 34 INFECTIOUS DISEASES DNA VACCINES CLINICAL TRIALS, AS OF APRIL 2014 HSV 73 HPV 73 Influenza 74 HBV 75 Japanese Encephalitis 76 CMV 76 HIV 77 ALLERGY AND AUTOIMMUNE DISEASE 78 TABLE 35 INFECTIOUS DISEASES DNA VACCINES CLINICAL TRIALS, AS OF APRIL 2014 BIODEFENSE DNA VACCINES 78 ANIMAL HEALTH DNA VACCINES 79 55 68 78 CHAPTER 6 DNA VACCINE INDUSTRY 82 VACCINE INDUSTRY STRUCTURAL SHIFTS 82 TABLE 36 VACCINE INDUSTRY STRUCTURAL SHIFTS 82 INDUSTRY STRUCTURE 83 TABLE 37 VACCINE INDUSTRY STRUCTURE: TRADITIONAL VERSUS EMERGING 83 FIGURE 10 MARKETING OF APPROVED VACCINES IN THE UNITED STATES, 2014 (%) 84 TABLE 38 COMPARISON OF VACCINES AND PHARMACEUTICALS BUSINESSES 85 DNA VACCINE INDUSTRY COMPETITORS 87 TABLE 39 DNA VACCINE INDUSTRY COMPETITOR POSITION 87 DNA VACCINE COMMERCIAL VALUE CHAIN 88 FIGURE 11 DNA VACCINE COMMERCIAL VALUE CHAIN 89 DNA VACCINE COMPETITOR STRATEGIC POSITIONING 89 TABLE 40 LARGE PHARMA VACCINE COMPANY STRATEGIC FOCUS 89 TABLE 41 INTEGRATED BIOTECHNOLOGY COMPANY STRATEGIC FOCUS 90 TABLE 42 INTEGRATED BIOTECHNOLOGY COMPANY STRATEGIC MARKET FOCUS 91 TABLE 43 SPECIALIZED BIOTECHNOLOGY COMPANY STRATEGIC FOCUS 93

RESEARCH & DEVELOPMENT FOCUS 94 TABLE 44 ASTELLAS PHARMA INC. OPEN CLINICAL TRIALS, AS OF APRIL 2014 94 TABLE 45 BAVARIAN NORDIC OPEN CLINICAL TRIALS, AS OF APRIL 2014 94 TABLE 46 BEIJING CENTER FOR DISEASE CONTROL AND PREVENTION; MUNICIPAL SCIENCE & TECHNOLOGY COMMISSION OPEN CLINICAL TRIALS, AS OF APRIL 2014 TABLE 47 CITY OF HOPE MEDICAL CENTER, NATIONAL CANCER INSTITUTE (NCI) OPEN CLINICAL TRIALS, AS OF APRIL 2014 TABLE 48 DYNAVAX TECHNOLOGIES CORPORATION OPEN CLINICAL TRIALS, AS OF APRIL 2014 TABLE 49 GLAXOSMITHKLINE OPEN CLINICAL TRIALS, AS OF APRIL 2014 96 TABLE 50 IMPERIAL COLLEGE LONDON OPEN CLINICAL TRIALS, AS OF APRIL 2014 96 TABLE 51 MERCK SHARP & DOHME OPEN CLINICAL TRIALS, AS OF APRIL 2014 97 TABLE 52 NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES (NIAID) OPEN CLINICAL TRIALS, AS OF APRIL 2014 TABLE 53 NATIONAL TAIWAN UNIVERSITY HOSPITAL OPEN CLINICAL TRIALS, AS OF APRIL 2014 TABLE 54 SANOFI OPEN CLINICAL TRIALS, AS OF APRIL 2014 98 TABLE 55 SIDNEY KIMMEL COMPREHENSIVE CANCER CENTER OPEN CLINICAL TRIALS, AS OF APRIL 2014 TABLE 56 U.S. ARMY MEDICAL RESEARCH OPEN CLINICAL TRIALS, AS OF APRIL 2014 TABLE 57 UNIVERSITY OF COLORADO OPEN CLINICAL TRIALS, AS OF APRIL 2014 99 TABLE 58 UNIVERSITY OF OXFORD OPEN CLINICAL TRIALS, AS OF APRIL 2014 100 TABLE 59 UNIVERSITY OF WISCONSIN OPEN CLINICAL TRIALS, AS OF APRIL 2014 100 INDUSTRY ACQUISITIONS AND STRATEGIC ALLIANCES 100 TABLE 60 INDUSTRY ACQUISITIONS AND MERGERS, 2006-2014 100 TABLE 61 DNA VACCINE STRATEGIC ALLIANCES 102 95 95 95 97 98 98 99 CHAPTER 7 DNA VACCINE MARKETS 105 GROWTH DRIVING FORCES 105 TABLE 62 DNA VACCINE INDUSTRY GROWTH DRIVING FORCES 105 MARKET FORECASTS 106 OVERVIEW 106 TABLE 63 GLOBAL VALUE OF PHARMACEUTICAL MARKET BY TYPE, THROUGH 2019 ($ MILLIONS) DNA VACCINE MARKETS BY END USE 107 TABLE 64 GLOBAL VALUE OF DNA VACCINES BY END USE, THROUGH 2019 ($ MILLIONS) DNA VACCINE RESEARCH TOOLS MARKETS 108 TABLE 65 GLOBAL VALUE OF DNA VACCINES RESEARCH TOOLS MARKET BY APPLICATION, DNA VACCINE CLINICAL MARKETS 108 TABLE 66 GLOBAL VALUE OF CLINICAL DNA VACCINES MARKET BY APPLICATION, Strategic Positioning 109 FIGURE 12 DNA VACCINE STRATEGIC MARKET GRID 109 Allergies 110 TABLE 67 DNA VACCINE ALLERGY MARKET OPPORTUNITIES 110 Cancer Therapeutics 110 TABLE 68 CAUSE OF DEATH, WORLDWIDE, 2004 AND 2030 (% OF ALL DEATHS) 111 106 107 108 109

Infectious Diseases 111 DNA CANCER VACCINES MARKET 111 TABLE 69 GLOBAL VALUE OF CANCER CLINICAL DNA VACCINES BY INDICATION, TABLE 70 DNA VACCINE CANCER MARKET OPPORTUNITIES 112 Melanoma 114 Solid Tumors (Including Ovarian, Breast and Small-Cell Lung Cancer) 114 Pancreatic Cancer 114 INFECTIOUS DISEASE DNA VACCINE MARKETS 114 TABLE 71 GLOBAL VALUE OF INFECTIOUS DISEASE CLINICAL DNA VACCINES MARKET BY INDICATION, CMV 115 HBV 116 HPV 116 HCV 117 HIV 117 ANIMAL HEALTH DNA VACCINE MARKETS 118 TABLE 72 GLOBAL VALUE OF ANIMAL HEALTH CLINICAL DNA VACCINES MARKET, BY INDICATION, Canine Melanoma 119 Equine West Nile Virus 119 Leishmaniasis 119 Feline Leukemia Virus 120 Fish Vaccine Adjuvants 120 BIODEFENSE DNA VACCINE MARKETS 120 TABLE 73 GLOBAL VALUE OF BIODEFENSE CLINICAL DNA VACCINES MARKET, BY END USE, DNA VACCINE MARKETS BY DELIVERY TECHNOLOGY 123 TABLE 74 GLOBAL VALUE OF CLINICAL DNA VACCINES MARKET BY DELIVERY TECHNOLOGY, DNA VACCINE MARKET BY FORMAT AND FUNCTION 124 TABLE 75 GLOBAL VALUE OF CLINICAL DNA VACCINES MARKET BY VACCINE FORMAT, TABLE 76 GLOBAL VALUE OF CLINICAL DNA VACCINES MARKET BY FUNCTION, DNA VACCINES MARKET BY GEOGRAPHICAL REGION 125 TABLE 77 GLOBAL VALUE OF DNA VACCINES MARKET, BY GEOGRAPHICAL REGION, 112 115 118 121 124 125 125 126 CHAPTER 8 COMPANY PROFILES 128 ADIMMUNE 128 ADVANCED BIOSCIENCE LABORATORIES INC. 128 ALDEVRON LLC 129 ALTEA THERAPEUTICS 129 ALTHEA TECHNOLOGIES INC. 130 ANGES MG INC. 130 AVAX TECHNOLOGIES 131 BAVARIAN NORDIC A/S 131 BIGDNA, LTD. 132

BIOJECT MEDICAL TECHNOLOGIES INC. 133 BTX HARVARD APPARATUS 134 CHANGCHUN BAIKE PHARMACEUTICAL CO. LTD. 134 CHRONTECH PHARMA 134 COBRA BIOMANUFACTURING PLC 135 CRUCELL 136 CYTRX CORP. 137 DENDREON CORP. 137 DYNAVAX TECHNOLOGIES 138 EUROVACC FOUNDATION, THE 138 FIT BIOTECH OYJ PLC 139 GENEART AG 140 GENETIC IMMUNITY 141 GENEXINE 142 GENOMIDEA INC. 143 GENOVAC GMBH 144 GENVEC INC. 145 GEOVAX LABS 145 GLAXOSMITHKLINE 146 GREENPAK BIOTECH LTD. 148 HENDERSON MORLEY PLC 148 ICHOR MEDICAL SYSTEMS INC. 149 IGXBIO INC. 150 IMMUNOMIC THERAPEUTICS INC. 150 IMMUNOVACCINE INC. 151 IN CELL ART 152 INDIAN IMMUNOLOGICALS 153 INOVIO 154 INVIVOGEN 156 JUVARIS BIOTHERAPEUTICS INC. 156 LENTIGEN CORP. 157 MANNKIND CORP. 157 MERCK 158 TABLE 78 MERCK VACCINE PRODUCTS 159 MERIAL LTD. 159 MOGAM BIOTECHNOLOGY RESEARCH INSTITUTE 160 MOLOGEN AG 160 MULTIMERIC BIOTHERAPEUTICS INC. 161 NATURE TECHNOLOGY CORP. 162 NIH VACCINE RESEARCH CENTER 162 NOVARTIS 163 OXFORD BIOMEDICA PLC 164 PFIZER 164 PLASMIDFACTORY GMBH & CO. 165 PROFECTUS BIOSCIENCES INC. 166 QED BIOSCIENCE INC. 167 SANOFI-AVENTIS 168

STATENS SERUM INSTITUT 169 SUPRATEK PHARMA 170 TOLERION INC. 170 VALNEVA SE 171 VAXGEN INC. 171 VAXIION THERAPEUTICS INC. 172 VAXONCO INC. 173 VGX PHARMACEUTICALS LLC 173 VGXI INC. 174 VICAL INC. 174 VIROMED CO. LTD. 175 XENETIC BIOSCIENCE INC. 176 TABLE 79 COMPANIES WITH ACTIVE DNA VACCINE CLINICAL TRIALS 176

LIST OF TABLES TABLE HEADING TABLE A SCOPE OF REPORT 3 SUMMARY TABLE GLOBAL VALUE OF DNA VACCINE MARKET BY APPLICATION, TABLE 1 SCOPE OF THIS REPORT 11 TABLE 2 GLOBAL VALUE OF DNA VACCINE MARKET BY APPLICATION, THROUGH 2019 ($ MILLIONS) TABLE 3 GLOBAL VALUE OF HUMAN DNA VACCINE MARKET BY INDICATION, TABLE 4 DNA VACCINE INDUSTRY GROWTH DRIVING FORCES 13 TABLE 5 LIFE CYCLE STAGE OF VACCINE TYPES 14 TABLE 6 COMMERCIAL STATUS OF DNA VACCINES 14 TABLE 7 DNA VACCINE INDUSTRY STRUCTURE 15 TABLE 8 DNA VACCINE HISTORY 19 TABLE 9 COMPONENTS OF THE IMMUNE SYSTEM 20 TABLE 10 VACCINE TYPES 23 TABLE 11 TECHNOLOGY LIFE CYCLE STAGE OF VACCINE TYPES 24 TABLE 12 CHANGING VACCINE PARADIGM 26 TABLE 13 ADVANTAGES AND DISADVANTAGES OF DNA VACCINES 27 TABLE 14 EMERGING COMPETITIVE LANDSCAPE FOR DNA VACCINES 31 TABLE 15 CANCER VACCINE TYPES 32 TABLE 16 TECHNOLOGY DRIVERS FOR DNA VACCINE VALUE CHAIN 34 TABLE 17 PLASMID DESIGN OBJECTIVES 35 TABLE 18 WAYS TO OPTIMIZE MAMMALIAN GENE EXPRESSION IN PLASMID DNA 36 TABLE 19 DNA PLASMID QUALITY COMPARISON 38 TABLE 20 COMPARISON OF DNA DELIVERY TECHNOLOGIES 39 TABLE 21 IN VIVO VIRAL VECTOR TECHNOLOGIES COMPARED 44 TABLE 22 DNA VACCINE ADJUVANT TECHNOLOGIES 46 TABLE 23 TECHNOLOGY NEEDS FOR DNA VACCINES 48 TABLE 24 DNA VACCINE DEVELOPMENT FLOW SHEET 52 TABLE 25 DNA VACCINE PRECLINICAL DEVELOPMENT STEPS 53 TABLE 26 DNA VACCINES CLINICAL TRIALS SUMMARY BY STARTING YEAR, AS OF APRIL 2014 TABLE 27 DNA VACCINE CLINICAL PHASE I TRIALS SUMMARY, AS OF APRIL 2014 56 TABLE 28 DNA VACCINE CLINICAL PHASE I/II TRIALS SUMMARY, AS OF APRIL 2014 59 TABLE 29 DNA VACCINE CLINICAL PHASE II TRIALS SUMMARY, AS OF APRIL 2014 60 TABLE 30 DNA VACCINE CLINICAL PHASE II/III TRIALS SUMMARY, AS OF APRIL 2014 61 TABLE 31 DNA VACCINE CLINICAL PHASE III TRIALS SUMMARY, AS OF APRIL 2014 62 TABLE 32 DNA VACCINE CLINICAL PHASE IV TRIALS SUMMARY, AS OF APRIL 2014 64 TABLE 33 DNA VACCINE CANCER CLINICAL TRIALS SUMMARY, AS OF APRIL 2014 65 TABLE 34 INFECTIOUS DISEASES DNA VACCINES CLINICAL TRIALS, AS OF APRIL 2014 TABLE 35 INFECTIOUS DISEASES DNA VACCINES CLINICAL TRIALS, AS OF APRIL 2014 TABLE 36 VACCINE INDUSTRY STRUCTURAL SHIFTS 82 TABLE 37 VACCINE INDUSTRY STRUCTURE: TRADITIONAL VERSUS EMERGING 83 TABLE 38 COMPARISON OF VACCINES AND PHARMACEUTICALS BUSINESSES 85 TABLE 39 DNA VACCINE INDUSTRY COMPETITOR POSITION 87 TABLE 40 LARGE PHARMA VACCINE COMPANY STRATEGIC FOCUS 89 7 12 12 55 68 78

TABLE HEADING TABLE 41 INTEGRATED BIOTECHNOLOGY COMPANY STRATEGIC FOCUS 90 TABLE 42 INTEGRATED BIOTECHNOLOGY COMPANY STRATEGIC MARKET FOCUS 91 TABLE 43 SPECIALIZED BIOTECHNOLOGY COMPANY STRATEGIC FOCUS 93 TABLE 44 ASTELLAS PHARMA INC. OPEN CLINICAL TRIALS, AS OF APRIL 2014 94 TABLE 45 BAVARIAN NORDIC OPEN CLINICAL TRIALS, AS OF APRIL 2014 94 TABLE 46 BEIJING CENTER FOR DISEASE CONTROL AND PREVENTION; MUNICIPAL SCIENCE & TECHNOLOGY COMMISSION OPEN CLINICAL TRIALS, AS OF APRIL 2014 TABLE 47 CITY OF HOPE MEDICAL CENTER, NATIONAL CANCER INSTITUTE (NCI) OPEN CLINICAL TRIALS, AS OF APRIL 2014 TABLE 48 DYNAVAX TECHNOLOGIES CORPORATION OPEN CLINICAL TRIALS, AS OF APRIL 2014 TABLE 49 GLAXOSMITHKLINE OPEN CLINICAL TRIALS, AS OF APRIL 2014 96 TABLE 50 IMPERIAL COLLEGE LONDON OPEN CLINICAL TRIALS, AS OF APRIL 2014 96 TABLE 51 MERCK SHARP & DOHME OPEN CLINICAL TRIALS, AS OF APRIL 2014 97 TABLE 52 NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES (NIAID) OPEN CLINICAL TRIALS, AS OF APRIL 2014 TABLE 53 NATIONAL TAIWAN UNIVERSITY HOSPITAL OPEN CLINICAL TRIALS, AS OF APRIL 2014 TABLE 54 SANOFI OPEN CLINICAL TRIALS, AS OF APRIL 2014 98 TABLE 55 SIDNEY KIMMEL COMPREHENSIVE CANCER CENTER OPEN CLINICAL TRIALS, AS OF APRIL 2014 TABLE 56 U.S. ARMY MEDICAL RESEARCH OPEN CLINICAL TRIALS, AS OF APRIL 2014 99 TABLE 57 UNIVERSITY OF COLORADO OPEN CLINICAL TRIALS, AS OF APRIL 2014 99 TABLE 58 UNIVERSITY OF OXFORD OPEN CLINICAL TRIALS, AS OF APRIL 2014 100 TABLE 59 UNIVERSITY OF WISCONSIN OPEN CLINICAL TRIALS, AS OF APRIL 2014 100 TABLE 60 INDUSTRY ACQUISITIONS AND MERGERS, 2006-2014 100 TABLE 61 DNA VACCINE STRATEGIC ALLIANCES 102 TABLE 62 DNA VACCINE INDUSTRY GROWTH DRIVING FORCES 105 TABLE 63 GLOBAL VALUE OF PHARMACEUTICAL MARKET BY TYPE, THROUGH 2019 ($ MILLIONS) TABLE 64 GLOBAL VALUE OF DNA VACCINES BY END USE, THROUGH 2019 ($ MILLIONS) TABLE 65 GLOBAL VALUE OF DNA VACCINES RESEARCH TOOLS MARKET BY APPLICATION, TABLE 66 GLOBAL VALUE OF CLINICAL DNA VACCINES MARKET BY APPLICATION, TABLE 67 DNA VACCINE ALLERGY MARKET OPPORTUNITIES 110 TABLE 68 CAUSE OF DEATH, WORLDWIDE, 2004 AND 2030 (% OF ALL DEATHS) 111 TABLE 69 GLOBAL VALUE OF CANCER CLINICAL DNA VACCINES BY INDICATION, TABLE 70 DNA VACCINE CANCER MARKET OPPORTUNITIES 112 TABLE 71 GLOBAL VALUE OF INFECTIOUS DISEASE CLINICAL DNA VACCINES MARKET BY INDICATION, TABLE 72 GLOBAL VALUE OF ANIMAL HEALTH CLINICAL DNA VACCINES MARKET, BY INDICATION, TABLE 73 GLOBAL VALUE OF BIODEFENSE CLINICAL DNA VACCINES MARKET, BY END USE, TABLE 74 GLOBAL VALUE OF CLINICAL DNA VACCINES MARKET BY DELIVERY TECHNOLOGY, 95 95 95 97 98 98 106 107 108 109 112 115 118 121 124

TABLE HEADING TABLE 75 GLOBAL VALUE OF CLINICAL DNA VACCINES MARKET BY VACCINE FORMAT, TABLE 76 GLOBAL VALUE OF CLINICAL DNA VACCINES MARKET BY FUNCTION, TABLE 77 GLOBAL VALUE OF DNA VACCINES MARKET, BY GEOGRAPHICAL REGION, TABLE 78 MERCK VACCINE PRODUCTS 159 TABLE 79 COMPANIES WITH ACTIVE DNA VACCINE CLINICAL TRIALS 176 125 125 126

LIST OF FIGURES FIGURE TITLE SUMMARY FIGURE GLOBAL VALUE OF DNA VACCINE MARKET BY APPLICATION, 2013-2019 ($ MILLIONS) FIGURE 1 EVOLUTION OF VACCINE TECHNOLOGIES 22 FIGURE 2 MECHANISM OF ACTION OF A DNA VACCINE 25 FIGURE 3 SAFETY AND EFFICACY PROFILE OF DNA VERSUS VIRAL-VECTOR VACCINES 29 FIGURE 4 DNA VACCINE FUNCTION AND MARKET SCOPE 29 FIGURE 5 DNA VACCINE TECHNOLOGY VALUE CHAIN 33 FIGURE 6 CONVENTIONAL AND PLASMID DNA VACCINE PRODUCTION PROCESS 38 FIGURE 7 EP PROCESS SCHEMATIC 41 FIGURE 8 STRATEGIES FOR TARGETING DENDRITIC CELLS 46 FIGURE 9 FUTURE VACCINE CLINICAL TRIALS OVERVIEW 53 FIGURE 10 MARKETING OF APPROVED VACCINES IN THE UNITED STATES, 2014 (%) 84 FIGURE 11 DNA VACCINE COMMERCIAL VALUE CHAIN 89 FIGURE 12 DNA VACCINE STRATEGIC MARKET GRID 109 7