CELL-BASED ASSAYS: TECHNOLOGIES AND GLOBAL MARKETS

CELL-BASED ASSAYS: TECHNOLOGIES AND GLOBAL MARKETS BIO080B April 2014 Usha Nagavarapu Project Analyst ISBN: 1-56965-794-7 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

BIO080B - Cell-based Assays: Technologies and Global Markets ABOUT BCC RESEARCH BCC Research publishes market research reports that make organizations worldwide more profitable with intelligence that drives smart business decisions. These reports cover today's major industrial and technology sectors, including emerging markets. For more than 40 years we've helped customers identify new market opportunities with accurate and reliable data and insight, including market sizing, forecasting, industry overviews, and identification of significant trends and key competitors. We partner with analysts who are experts in specific areas of industry and technology, providing unbiased measurements and assessments of global markets. Our clients include the top companies in industries around the world as well as universities, business schools, start-ups, consulting firms and investment companies. BCC Research is a unit of Eli Research LLC. Visit our website at www.bccresearch.com. Contact us: (+1) 781-489-7301 (U.S. Eastern time), or email information@bccresearch.com. CONDITIONS OF PURCHASE The purchase of the bound or electronic copy of this report constitutes a contractual agreement between BCC Research and the purchaser. When purchased under a single-user license, this report is intended for use solely by the person who made the purchase. When purchased under a multiple-user license, this report is intended for access by the maximum number of users specified by the license. For information, email information@bccresearch.com or telephone (+1) 781-489-7301 (U.S. Eastern time). The report and its contents are not to be made available to other persons, autonomous divisions, foreign subsidiaries of the same company, or other companies, unless specified by contract and/or license. It is here stipulated that terms in an authorized contract or license will supercede any other conditions cited in any other location. Reproduction of any material in this report is strictly forbidden without written permission of the publisher; email editor@bccresearch.com. REPORT SUBSCRIPTIONS BCC Research offers cost-effective Report Subscription services that provide organizations with access to reports in selected industry categories, including our back catalog of reports and newly published reports. CUSTOM ANALYSES BCC Research provides custom research studies tailored to our clients needs in areas related to the subject research material but perhaps not covered in detail in this report. Please contact BCC Research to discuss such services: email information@bccresearch.com or telephone (+1) 781-489-7301 (U.S. Eastern time). Copyright BCC Research, Wellesley MA USA, Website: www.bccresearch.com

BIO080B - Cell-based Assays: Technologies and Global Markets DISCLAIMER This publication provides informative material of a professional nature. It does not constitute managerial, legal or accounting advice, nor should it serve as a corporate policy guide, laboratory manual or an endorsement of any product. This information is intended to be as accurate as possible at the time of publication, but BCC Research LLC assumes no responsibility for any losses or damages that might result because of reliance on this material. Copyright 2014 by BCC Research, Wellesley, MA 02481 USA Reproduction of any material in this report is strictly forbidden without express permission of the Publisher; email editor@bccresearch.com. To receive a complete catalog of BCC Research studies, please visit our Web site at www.bccresearch.com/product-catalog. Copyright BCC Research, Wellesley MA USA, Website: www.bccresearch.com

TABLE OF CONTENTS CHAPTER 1 INTRODUCTION... 2 STUDY GOALS AND OBJECTIVES... 2 REASONS FOR DOING THE STUDY... 2 SCOPE AND FORMAT... 2 INTENDED AUDIENCE... 3 METHODOLOGY... 3 ANALYST CREDENTIALS... 3 RELATED BCC RESEARCH REPORTS... 3 BCC RESEARCH WEBSITE... 3 DISCLAIMER... 4 CHAPTER 2 SUMMARY... 6 SUMMARY TABLE GLOBAL MARKET FOR CELL-BASED ASSAYS, THROUGH 2018 ($... 7 SUMMARY FIGURE GLOBAL MARKET FOR CELL-BASED ASSAYS, 2012-2018 ($... 7 CHAPTER 3 OVERVIEW... 9 INTRODUCTION... 9 DRUG DISCOVERY... 9 FIGURE 1 DRUG DISCOVERY PROCESS AND STEPS... 9 TABLE 1 CELL-BASED ASSAYS AND USES... 10 HIGH-CONTENT SCREENING INSTRUMENTATION AND SOFTWARE... 10 DATA ANALYSIS... 11 OVERVIEW: CELL-BASED ASSAYS... 12 TOOLS FOR DRUG DISCOVERY... 14 HIGH-CONTENT SCREENING... 17 History of High-Content Screening... 19 CELL-BASED SCREENING... 20 Types of Cell-Based Assays... 21 TABLE 2 TYPES OF CELL-BASED ASSAYS... 21 Proliferation Assays... 21 WST Reagents... 22 Fluorescence-Based Assays... 22 Apoptosis Assays... 22 TABLE 3 APOPTOTIC MARKERS... 23 Caspase Assays... 23 DNA Fragmentation Assays... 24 Annexin V and Cell Permeability Assays... 24

Mitochondrial Assays... 24 Activation Assays... 25 Assays to Measure Gene Expression... 25 Proof of Concept for Cell-Based Assays... 26 TABLE 4 PROOF OF CONCEPT FOR CELL-BASED ASSAYS... 26 Cell-Based Assays and Technology Trends... 26 Why Cell-Based Approaches?... 27 In Vitro Homogeneous Assays... 27 Cell-Based Reporter Assays... 28 Cell-Based Assays and Future Growth... 28 TABLE 5 GLOBAL MARKET AND FORECAST FOR CELL-BASED... 29 ASSAYS, THROUGH 2018 ($ FIGURE 2 GLOBAL MARKET AND FORECAST FOR CELL-BASED... 29 ASSAYS, 2012-2018 ($ Cell-Based Assays for GPCRs... 29 Immortalized Cells... 30 Why Immortalized Cells?... 31 Future... 32 Primary Cells... 32 Stem Cells and Cell-Based Assays... 34 Embryonic Stem Cells and Cell-Based Assays... 35 New Developments: 3D Cell-Based Models... 36 CHAPTER 4 ASSAYS FOR DRUG DISCOVERY... 38 CELL-BASED APPROACHES FOR ADME/TOX SCREENING... 38 MARKET OPPORTUNITY... 40 ADME AND TOXICITY SCREENING... 41 Cytochrome P450... 42 TABLE 6 BIOLOGICAL ASSAY SYSTEMS FOR THE EVALUATION OF... 42 CYTOCHROME P450 ENZYME ISOFORMS TABLE 7 HEPATOCYTE ASSAY SYSTEMS... 44 TABLE 8 ADME ASSAYS... 45 TABLE 9 COMMON TOXICITY ASSAYS... 45 Optical Oxygen Sensors... 45 Characterized Cell Lines for Cell-Based ADME and Toxicity Screening... 45 TABLE 10 TRADITIONAL METHODS OF ADME/TOX TESTING... 46 TABLE 11 CONVENTIONAL IN VITRO ADME/TOX SCREENING METHODS... 46 Predictive ADME/Tox Screening... 47 MULTIPLEXED CELL-BASED ASSAYS... 48 Compound Effects on Cells... 48

CELL-BASED BIOLOGICAL ASSAYS... 50 General Bioassay Guidance... 50 HIGH-THROUGHPUT IMAGING-BASED PLATFORM FOR CELL-BASED ASSAYS... 51 CELL ASSAYS IN TODAY'S DRUG DISCOVERY PROCESS... 52 LABEL-FREE CELLULAR ASSAYS: THE RELEVANT FUTURE OF DRUG... 55 DISCOVERY Label-Free Assays and Applications... 56 Benefits of Label-Free Assays... 56 TABLE 12 LABEL-FREE ASSAYS AND APPLICATIONS... 57 Advantages... 57 Major Challenges for Adoption of Label-Free Technology... 59 CONCLUSIONS... 60 CHAPTER 5 CELL BASED ASSAYS: CURRENT TECHNOLOGIES... 62 FACTORS IN CELL-BASED ASSAY DEVELOPMENT... TABLE 13 FACTORS FOR CELL-BASED ASSAY DEVELOPMENT... REPORTER GENE TECHNOLOGY... TABLE 14 DIFFERENT APPROACHES TO CELL-BASED SYSTEMS FOR DRUG... SCREENING CELL-BASED ASSAYS FOR STUDYING PROTEIN-PROTEIN INTERACTIONS... 62 63 64 67 67 CELL-BASED PROTEIN-FRAGMENT COMPLEMENTATION ASSAYS... 68 MEASURING CALCIUM SIGNALING... 69 CELL-BASED LABEL-FREE APPROACHES... 69 AUTOMATION AND MINIATURIZATION... 70 CELL PATTERNING... 71 CELL-BASED ASSAYS AND PHYSIOLOGICAL RELEVANCE... 72 CELL-BASED ASSAYS AND MULTIPLEXING... DEVELOPING REPORTER ASSAYS... REPORTER ASSAYS AND MULTIPLEXING... ULTRAHIGH-THROUGHPUT SCREENING... 72 72 73 74 DEVELOPMENT OF PATHHUNTER ASSAY... 75 HIGH-CONTENT SCREENING TECHNOLOGY... TABLE 15 CURRENT CONFOCAL HCS PLATFORMS... TABLE 16 WIDEFIELD HCS PLATFORMS... IMAGING CELLS FOR CELL-BASED ASSAYS... MICROSCOPIC VISUALIZATION OF CELLS... QUANTUM DOTS... LABEL-FREE IMAGING... INVESTIGATIONAL NEW DRUG (IND) STUDIES IN DRUG DEVELOPMENT... TABLE 17 STUDIES FOR FILING AN IND... TABLE 18 STUDIES FOR CLINICAL FILINGS... ROLE OF ADME IN DRUG DESIGN... PRODRUG STRATEGIES... 76 77 77 77 78 79 79 81 81 82 82 84 MOLECULAR MODELING... 85 SUMMARY... 85 LIMITATIONS OF THE USE OF CELL-BASED ASSAYS IN THE PROCESS OF RISK... 85 ASSESSMENT BOTTLENECKS IN CELL-BASED SCREENING... 87

METHODS TO IMPROVE THROUGHPUT IN CELL-BASED ASSAYS... NEW TECHNOLOGIES... DATACHIP... BIND TECHNOLOGY... SIMUGEN... MINIATURIZATION OF BIOLOGICAL ASSAYS... MICROFLUIDIC CELL-CULTURE SYSTEMS FOR DRUG RESEARCH... CONCLUSION... 88 89 89 90 90 90 91 92 CHAPTER 6 COMMERCIALIZATION OF CELL-BASED ASSAYS... 94 ROLE OF CELL-BASED ASSAYS... 94 DRUG DISCOVERY AND CELL-BASED ASSAYS... 94 OPPORTUNITIES FOR MARKET ADOPTION... TABLE 19 BIOLOGICAL APPLICATIONS FOR HCA... MEASURING CELL PROLIFERATION... COMPANIES OFFERING CELL PROLIFERATION ASSAYS... 94 96 97 97 Roche Applied Science... 97 BioVision... 97 Promega... 98 EMD Millipore... 98 MOVE TOWARD THERAPIES WITH STEM AND IMMUNE CELLS... 99 CELL-BASED SCREENING ASSAYS... 99 COMPANIES... 99 Euroscreen... 100 Arena Pharmaceuticals... 100 GPCR... 101 ORPHAN RECEPTORS... 101 SUMMARY... 103 CHAPTER 7 GLOBAL CELL-BASED ASSAY AND INSTRUMENTATION... 105 MARKET CURRENT MARKET OVERVIEW... 105 ROLE OF CELL-BASED ASSAYS... 105 CELL-BASED ASSAY MARKET... MARKET DYNAMICS... CELL-BASED ASSAYS AND PRECLINICAL DEVELOPMENT... HIGH-THROUGHPUT SCREENING... 106 107 108 108 TABLE 20 GLOBAL HTS MARKET, THROUGH 2018 ($... 109 Advantages of HTS Assays... 109 Major Drivers... 109 TABLE 21 HTS TECHNOLOGIES: KEY COMPANIES... 110 DRUG DISCOVERY TECHNOLOGY MARKET... TABLE 22 GLOBAL MARKET FOR DRUG DISCOVERY TECHNOLOGIES,... THROUGH 2018 ($ FIGURE 3 GLOBAL MARKET FOR DRUG DISCOVERY TECHNOLOGIES... 2012-2018 ($ CELL-BASED ASSAYS: MARKET DRIVERS... CELLULAR BIOLOGY... 111 111 111 112 112

RNA and DNA Reagents Market... 113 TABLE 23 GLOBAL MARKET FOR REAGENTS AND TOOLS USED IN DNA... 113 AND RNA RESEARCH, THROUGH 2018 ($ FIGURE 4 GLOBAL MARKET FOR REAGENTS AND TOOLS USED IN DNA... 113 AND RNA RESEARCH, 2012-2018 ($ Life Science Tools Market... 114 TABLE 24 GLOBAL MARKET FOR LIFE SCIENCE TOOLS, THROUGH... 114 2018 ($ FIGURE 5 GLOBAL MARKET FOR LIFE SCIENCE TOOLS, 2012-2018 ($... 114 Cell Biology Reagents... 114 TABLE 25 GLOBAL MARKET FOR CELL BIOLOGY REAGENTS AND... 115 TOOLS, THROUGH 2018 ($ FIGURE 6 GLOBAL MARKET FOR CELL BIOLOGY REAGENTS AND... 115 TOOLS, 2012-2018 ($ Reagent Development... 115 CELL CULTURE MARKET... 115 TABLE 26 GLOBAL MARKET FOR CELL CULTURE TOOLS, THROUGH 2018... 116 ($ FIGURE 7 GLOBAL MARKET FOR CELL CULTURE TOOLS, 2012-2018 ($... 116 Cell Culture Reagent Market... 116 TABLE 27 GLOBAL MARKET FOR CELL CULTURE REAGENTS,... 117 THROUGH 2018 ($ FIGURE 8 GLOBAL MARKET FOR CELL CULTURE REAGENTS,... 117 2012-2018 ($ TABLE 28 U.S. MARKET FOR CELL CULTURE REAGENTS, THROUGH... 118 2018 ($ FIGURE 9 U.S. MARKET FOR CELL CULTURE REAGENTS, 2012-2018 ($... 118 Three-Dimensional Cell Culture Market... 118 TABLE 29 GLOBAL MARKET FOR 3D CELL CULTURE REAGENTS,... 118 THROUGH 2018 ($ FIGURE 10 GLOBAL MARKET FOR 3D CELL CULTURE REAGENTS,... 119 2012-2018 ($ CELL-BASED ASSAYS MARKET GROWTH... 119 CELL-BASED ASSAYS: KEY GROWTH FACTORS... 119 TABLE 30 CELL-BASED ASSAY COMPANIES... 119 TABLE 31 GLOBAL MARKET FOR CELL-BASED ASSAYS, THROUGH 2018... 121

($ FIGURE 11 GLOBAL MARKET FOR CELL-BASED ASSAYS, 2012-2018 ($... 121 MARKET DEMAND... 121 TABLE 32 LIMITATIONS OF CELL-BASED ASSAYS... 122 CELL-BASED ASSAYS: BASIC RESEARCH... 122 TABLE 33 GLOBAL MARKET FOR CELL-BASED ASSAYS USED IN BASIC... 124 RESEARCH, THROUGH 2018 ($ FIGURE 12 GLOBAL MARKET FOR CELL-BASED ASSAYS USED IN BASIC... 124 RESEARCH, 2012-2018 ($ STEM CELLS AND TOXICITY TESTING... 124 Market Drivers... 125 ADME AND TOXICOLOGY MARKET... 125 CYPROTEX... 126 IN VITRO PREDICTIVE TOXICOLOGY... 127 TABLE 34 GLOBAL MARKET FOR IN VITRO TOXICITY TESTS, THROUGH... 127 2017 ($ FIGURE 13 GLOBAL MARKET FOR IN VITRO TOXICITY TESTS, 2012-2017... 127 ($ ADME-TOXICOLOGY TESTING MARKET... 127 SPECIALIZED CELL-BASED ASSAYS... 128 TABLE 35 GLOBAL MARKET FOR SPECIALIZED CELL-BASED ASSAYS... 128 USED IN DRUG DISCOVERY, THROUGH 2018 ($ FIGURE 14 GLOBAL MARKET FOR SPECIALIZED CELL-BASED ASSAYS... 129 USED IN DRUG DISCOVERY, 2012-2018 ($ TABLE 36 IN VITRO PREDICTIVE TOXICOLOGY ASSAYS... 129 ADME: TOOLS AND TECHNOLOGIES... 130 ADME STUDIES FOR FDA SUBMISSIONS... 130 MARKET PLAYERS... 131 TABLE 37 GLOBAL MARKET FOR ADME ASSAYS, THROUGH 2018 ($... 132 FIGURE 15 GLOBAL MARKET FOR ADME ASSAYS, 2012-2018 ($... 132 CELL-BASED ASSAYS FOR DRUG DISCOVERY: GLOBAL MARKET... TABLE 38 GLOBAL MARKET FOR CELL-BASED ASSAYS USED IN DRUG... DISCOVERY BY SEGMENT, THROUGH 2018 ($ FIGURE 16 GLOBAL MARKET FOR CELL-BASED ASSAYS USED IN DRUG... DISCOVERY BY SEGMENT, 2012-2018 ($ CELL-BASED ASSAYS: KEY HISTORICAL FACTS... 133 133 133 133 TABLE 39 KEY COMPANIES... 134 CELL MIGRATION ASSAYS... 135 HIGH-CONTENT SCREENING MARKET... 136 TABLE 40 GLOBAL MARKET FOR HIGH-CONTENT SCREENING ASSAYS AND... 137 INSTRUMENTATION, THROUGH 2018 ($

FIGURE 17 GLOBAL MARKET FOR HIGH-CONTENT SCREENING ASSAYS... AND INSTRUMENTATION, 2012-2018 ($ TABLE 41 HCS MARKET: MAJOR COMPANIES... HCS MARKET DRIVERS... COMPANIES... 137 139 140 140 Thermo Fisher Scientific... 140 Molecular Devices... 141 TABLE 42 MOLECULAR DEVICES: PRODUCTS... 141 Instruments for High-Content Screening... 141 TABLE 43 HCS SYSTEM PLATFORMS... 142 HIGH-CONTENT SCREENING KITS... 143 Companies... 144 EMD Millipore... 144 TABLE 44 MILLIPORE PRODUCTS: APPLICATIONS... 144 HIGH-CONTENT SCREENING INSTRUMENTATION MARKET... TABLE 45 GLOBAL MARKET FOR HIGH-CONTENT SCREENING... INSTRUMENTS, THROUGH 2018 ($ FIGURE 18 GLOBAL MARKET FOR HIGH-CONTENT SCREENING... INSTRUMENTS, 2012-2018 ($ FLOW CYTOMETERS... 144 145 146 146 TABLE 46 KEY COMPANIES... 147 LABEL-FREE DETECTION MARKET... MICROPLATE INSTRUMENTATION AND SUPPLIES... CHALLENGES WITH CELL-BASED ASSAYS... FUTURE OF CELL-BASED ASSAYS... IN VITRO INFLAMMATION MODELS... 3D CULTURE... NEW DEVELOPMENTS... 147 148 148 149 150 150 151 Multiplex Assays for GPCR Signaling... 152 CELL-BASED ASSAYS FOR RESEARCH PURPOSES... 152 G PROTEIN-COUPLED RECEPTORS... 153 GPCR Drugs... 153 TABLE 47 GPCR-TARGETING KEY DRUGS... 154 TABLE 48 KEY COMPANIES WITH GPCR PRODUCTS... 154 Companies and Technologies... 155 Multispan... 155 DiscoveRx... 155 Omeros... 155 TABLE 49 OMEROS: GPCRS AND INDICATIONS... 156 Patent Position... 157 AB Vector... 158 Cisbio... 159 PerkinElmer... 159 Codex Biosolutions... 159

ChanTest... 160 Corning Life Sciences... 160 GPCRs: A Potent Class of Drug Targets... 160 TABLE 50 ASSAY METHODS TO STUDY GPCRS (%)... 161 TABLE 51 GPCR PRIMARY SCREENING ASSAYS... 161 TABLE 52 GLOBAL MARKET FOR GPCR SCREENING AND PROFILING,... 162 2010 ($ KEY FACTS... CELL-BASED ASSAYS: SCREENING ION CHANNELS... LABEL-FREE DETECTION... COMPANIES... 162 163 164 165 Life Technologies (Invitrogen Corp.)... 165 TABLE 53 LIFE TECHNOLOGIES PRODUCTS... 165 TABLE 54 INVITROGEN'S CELL-BASED TECHNOLOGIES... 167 CellSensor Assays... 167 LanthaScreen Assays... 167 TABLE 55 COMPARISON OF YEARS ENDED DEC. 31, 2011 AND... 168 2010 ($ MILLIONS/%) Molecular Devices... 168 Roche Applied Science... 169 Thermo Fisher Scientific... 169 TABLE 56 THERMO FISHER SCIENTIFIC S ANALYTICAL... 169 TECHNOLOGIES SEGMENT REVENUE, 2012 AND 2013 ($ CONCLUSION... 169 CHAPTER 8 GLOBAL REGIONAL MARKETS... 172 GLOBAL MARKET FOR CELL-BASED ASSAYS... 172 CELL-BASED ASSAYS IN THE LEADING EMERGING MARKETS... 173 China... 173 Summary... 173 TABLE 57 GLOBAL MARKET FOR CELL-BASED ASSAYS BY REGION,... 174 THROUGH 2018 ($ FIGURE 19 GLOBAL MARKET FOR CELL-BASED ASSAYS BY REGION,... 174 2012-2018 ($ Emerging Economies... 175 U.S. MARKET... 175 TABLE 58 U.S. MARKET FOR CELL-BASED ASSAYS, THROUGH 2018 ($... 176 FIGURE 20 U.S. MARKET FOR CELL-BASED ASSAYS, 2012-2018 ($... 176

Market Overview... 176 TABLE 59 KEY GROWTH DRIVERS OF THE MARKET FOR CELL-BASED... 177 ASSAYS What are Cell-Based Assays and Why the Hype?... 177 EUROPEAN MARKET... 178 TABLE 60 EUROPEAN CELL-BASED ASSAY MARKET, THROUGH 2018 ($... 178 FIGURE 21 EUROPEAN CELL-BASED ASSAY MARKET, 2012-2018 ($... 179 DRUG DISCOVERY IN THE EMERGING ECONOMIES... 179 DRUG DISCOVERY IN INDIA AND CHINA... 180 China... 180 TABLE 61 CHINA S DRUG DISCOVERY OUTSOURCING MARKET,... 181 THROUGH 2018 ($ FIGURE 22 CHINA DRUG DISCOVERY OUTSOURCING MARKET,... 181 2012-2018 ($ Challenges... 181 India... 181 TABLE 62 INDIAN DRUG DISCOVERY MARKET, 2009 AND 2010 ($... 182 FIGURE 23 INDIAN DRUG DISCOVERY MARKET, 2009-2010 ($... 182 ADVANCES IN CELL-BASED ASSAYS... 183 CONTRACT RESEARCH ORGANIZATIONS AND CELL-BASED ASSAYS... 184 OUTLOOK... 185 CHAPTER 9 KEY COMPANIES... 187 ACEA BIOSCIENCES... 187 BD BIOSCIENCES... 187 BECKMAN COULTER... 188 CELLULAR DYNAMICS INTERNATIONAL... 188 CALIPER LIFE SCIENCES... 189 CELSIS IVT... 190 CISBIO BIOASSAYS... 190 DISCOVERX CORP.... 190 EMD MILLIPORE... 191 ENZO LIFE SCIENCES... 191 EVOTEC AG... 191 GE HEALTHCARE... 192 HEMOGENIX... 192 LIFE TECHNOLOGIES... 192 LONZA... 193 MOLECULAR DEVICES (DANAHER)... 194

ONCOIMMUNIN... 194 ORIGENE TECHNOLOGIES... 194 PERKINELMER... 195 PROMEGA CORP.... 195 ROCHE... 195 STEMCELLS INC.... 196 THERMO FISHER SCIENTIFIC... 196 TTP LABTECH... 197 VIVO BIOSCIENCES... 197 VITRO BIOPHARMA... 198 CHAPTER 10 LEGAL ASPECTS OF CELL-BASED ASSAYS... 200 INTELLECTUAL PROPERTY LANDSCAPE OF CELL-BASED ASSAYS... 200 LATEST NEWS, ALLIANCES AND MERGERS... 202 Thermo Fisher Scientific to Sell Cell Culture Business... 202 3D Cell Culture Start-up... 203 Vivo Biosciences, ACEA Biosciences and Roche to Develop New... 203 xcelligence System Assays for Stem Cell and Cancer Research DiscoveRx Corp. Acquires KINOMEscan... 203 Promega and Celsis In Vitro Technologies Introduced More Reliable... 204 Solutions for ADME/Tox Testing in Primary Hepatocytes Vitro Expands HemoGenix Alliance to Include Cell-Based Testing for... 204 Liver Toxicity Platypus Licenses Cell Exclusion Zone Technology to Cell Biolabs... 205 Ion Channel and GPCR Screening Services and Products... 205 LABEL-FREE TECHNOLOGIES... 205 PerkinElmer Launches the EnSpire Multimode Plate Reader... 206 SUMMARY AND OUTLOOK... 206 CHAPTER 11 BIBLIOGRAPHY... 209

LIST OF TABLES SUMMARY TABLE GLOBAL MARKET FOR CELL-BASED ASSAYS, THROUGH 2018 ($... 7 TABLE 1 CELL-BASED ASSAYS AND USES... 10 TABLE 2 TYPES OF CELL-BASED ASSAYS... 21 TABLE 3 APOPTOTIC MARKERS... 23 TABLE 4 PROOF OF CONCEPT FOR CELL-BASED ASSAYS... 26 TABLE 5 GLOBAL MARKET AND FORECAST FOR CELL-BASED ASSAYS,... 29 THROUGH 2018 ($ TABLE 6 BIOLOGICAL ASSAY SYSTEMS FOR THE EVALUATION OF... 42 CYTOCHROME P450 ENZYME ISOFORMS TABLE 7 HEPATOCYTE ASSAY SYSTEMS... 44 TABLE 8 ADME ASSAYS... 45 TABLE 9 COMMON TOXICITY ASSAYS... 45 TABLE 10 TRADITIONAL METHODS OF ADME/TOX TESTING... 46 TABLE 11 CONVENTIONAL IN VITRO ADME/TOX SCREENING METHODS... 46 TABLE 12 LABEL-FREE ASSAYS AND APPLICATIONS... 57 TABLE 13 FACTORS FOR CELL-BASED ASSAY DEVELOPMENT... 63 TABLE 14 DIFFERENT APPROACHES TO CELL-BASED SYSTEMS FOR DRUG... 67 SCREENING TABLE 15 CURRENT CONFOCAL HCS PLATFORMS... 77 TABLE 16 WIDEFIELD HCS PLATFORMS... 77 TABLE 17 STUDIES FOR FILING AN IND... 81 TABLE 18 STUDIES FOR CLINICAL FILINGS... 82 TABLE 19 BIOLOGICAL APPLICATIONS FOR HCA... 96 TABLE 20 GLOBAL HTS MARKET, THROUGH 2018 ($... 109 TABLE 21 HTS TECHNOLOGIES: KEY COMPANIES... 110 TABLE 22 GLOBAL MARKET FOR DRUG DISCOVERY TECHNOLOGIES,... 111 THROUGH 2018 ($ TABLE 23 GLOBAL MARKET FOR REAGENTS AND TOOLS USED IN DNA AND... 113 RNA RESEARCH, THROUGH 2018 ($ TABLE 24 GLOBAL MARKET FOR LIFE SCIENCE TOOLS, THROUGH 2018 ($... 114 TABLE 25 GLOBAL MARKET FOR CELL BIOLOGY REAGENTS AND TOOLS,... 115 THROUGH 2018 ($ TABLE 26 GLOBAL MARKET FOR CELL CULTURE TOOLS, THROUGH 2018 ($... 116 TABLE 27 GLOBAL MARKET FOR CELL CULTURE REAGENTS, THROUGH 2018... 117 ($

TABLE 28 U.S. MARKET FOR CELL CULTURE REAGENTS, THROUGH 2018 ($... 118 TABLE 29 GLOBAL MARKET FOR 3D CELL CULTURE REAGENTS, THROUGH... 118 2018 ($ TABLE 30 CELL-BASED ASSAY COMPANIES... 119 TABLE 31 GLOBAL MARKET FOR CELL-BASED ASSAYS, THROUGH 2018 ($... 121 TABLE 32 LIMITATIONS OF CELL-BASED ASSAYS... 122 TABLE 33 GLOBAL MARKET FOR CELL-BASED ASSAYS USED IN BASIC... 124 RESEARCH, THROUGH 2018 ($ TABLE 34 GLOBAL MARKET FOR IN VITRO TOXICITY TESTS, THROUGH 2017 ($... 127 TABLE 35 GLOBAL MARKET FOR SPECIALIZED CELL-BASED ASSAYS USED IN... 128 DRUG DISCOVERY, THROUGH 2018 ($ TABLE 36 IN VITRO PREDICTIVE TOXICOLOGY ASSAYS... 129 TABLE 37 GLOBAL MARKET FOR ADME ASSAYS, THROUGH 2018 ($... 132 TABLE 38 GLOBAL MARKET FOR CELL-BASED ASSAYS USED IN DRUG... 133 DISCOVERY BY SEGMENT, THROUGH 2018 ($ TABLE 39 KEY COMPANIES... 134 TABLE 40 GLOBAL MARKET FOR HIGH-CONTENT SCREENING ASSAYS AND... 137 INSTRUMENTATION, THROUGH 2018 ($ TABLE 41 HCS MARKET: MAJOR COMPANIES... 139 TABLE 42 MOLECULAR DEVICES: PRODUCTS... 141 TABLE 43 HCS SYSTEM PLATFORMS... 142 TABLE 44 MILLIPORE PRODUCTS: APPLICATIONS... 144 TABLE 45 GLOBAL MARKET FOR HIGH-CONTENT SCREENING INSTRUMENTS,... 145 THROUGH 2018 ($ TABLE 46 KEY COMPANIES... 147 TABLE 47 GPCR-TARGETING KEY DRUGS... 154 TABLE 48 KEY COMPANIES WITH GPCR PRODUCTS TABLE 49 OMEROS: GPCRS AND INDICATIONS... 154... 156 TABLE 50 ASSAY METHODS TO STUDY GPCRS (%)... 161 TABLE 51 GPCR PRIMARY SCREENING ASSAYS... 161 TABLE 52 GLOBAL MARKET FOR GPCR SCREENING AND PROFILING, 2010 ($... 162 TABLE 53 LIFE TECHNOLOGIES PRODUCTS... 165 TABLE 54 INVITROGEN'S CELL-BASED TECHNOLOGIES... 167 TABLE 55 COMPARISON OF YEARS ENDED DEC. 31, 2011 AND 2010 ($... 168 MILLIONS/%) TABLE 56 THERMO FISHER SCIENTIFIC S ANALYTICAL TECHNOLOGIES... 169 SEGMENT REVENUE, 2012 AND 2013 ($ TABLE 57 GLOBAL MARKET FOR CELL-BASED ASSAYS BY REGION, THROUGH... 174 2018 ($ TABLE 58 U.S. MARKET FOR CELL-BASED ASSAYS, THROUGH 2018 ($... 176

TABLE 59 KEY GROWTH DRIVERS OF THE MARKET FOR CELL-BASED ASSAYS... 177 TABLE 60 EUROPEAN CELL-BASED ASSAY MARKET, THROUGH 2018 ($... 178 TABLE 61 CHINA S DRUG DISCOVERY OUTSOURCING MARKET, THROUGH... 181 2018 ($ TABLE 62 INDIAN DRUG DISCOVERY MARKET, 2009 AND 2010 ($... 182

LIST OF FIGURES SUMMARY FIGURE GLOBAL MARKET FOR CELL-BASED ASSAYS, 2012-2018 ($... 7 FIGURE 1 DRUG DISCOVERY PROCESS AND STEPS... 9 FIGURE 2 GLOBAL MARKET AND FORECAST FOR CELL-BASED ASSAYS,... 29 2012-2018 ($ FIGURE 3 GLOBAL MARKET FOR DRUG DISCOVERY TECHNOLOGIES... 111 2012-2018 ($ FIGURE 4 GLOBAL MARKET FOR REAGENTS AND TOOLS USED IN DNA AND... 113 RNA RESEARCH, 2012-2018 ($ FIGURE 5 GLOBAL MARKET FOR LIFE SCIENCE TOOLS, 2012-2018 ($... 114 FIGURE 6 GLOBAL MARKET FOR CELL BIOLOGY REAGENTS AND TOOLS,... 115 2012-2018 ($ FIGURE 7 GLOBAL MARKET FOR CELL CULTURE TOOLS, 2012-2018 ($... 116 FIGURE 8 GLOBAL MARKET FOR CELL CULTURE REAGENTS, 2012-2018 ($... 117 FIGURE 9 U.S. MARKET FOR CELL CULTURE REAGENTS, 2012-2018 ($... 118 FIGURE 10 GLOBAL MARKET FOR 3D CELL CULTURE REAGENTS, 2012-2018 ($... 119 FIGURE 11 GLOBAL MARKET FOR CELL-BASED ASSAYS, 2012-2018 ($... 121 FIGURE 12 GLOBAL MARKET FOR CELL-BASED ASSAYS USED IN BASIC... 124 RESEARCH, 2012-2018 ($ FIGURE 13 GLOBAL MARKET FOR IN VITRO TOXICITY TESTS, 2012-2017 ($... 127 FIGURE 14 GLOBAL MARKET FOR SPECIALIZED CELL-BASED ASSAYS USED IN... 129 DRUG DISCOVERY, 2012-2018 ($ FIGURE 15 GLOBAL MARKET FOR ADME ASSAYS, 2012-2018 ($... 132 FIGURE 16 GLOBAL MARKET FOR CELL-BASED ASSAYS USED IN DRUG... 133 DISCOVERY BY SEGMENT, 2012-2018 ($ FIGURE 17 GLOBAL MARKET FOR HIGH-CONTENT SCREENING ASSAYS AND... 137 INSTRUMENTATION, 2012-2018 ($ FIGURE 18 GLOBAL MARKET FOR HIGH-CONTENT SCREENING INSTRUMENTS,... 146 2012-2018 ($ FIGURE 19 GLOBAL MARKET FOR CELL-BASED ASSAYS BY REGION, 2012-2018... 174 ($

FIGURE 20 U.S. MARKET FOR CELL-BASED ASSAYS, 2012-2018 ($... 176 FIGURE 21 EUROPEAN CELL-BASED ASSAY MARKET, 2012-2018 ($... 179 FIGURE 22 CHINA DRUG DISCOVERY OUTSOURCING MARKET, 2012-2018 ($... 181 FIGURE 23 INDIAN DRUG DISCOVERY MARKET, 2009-2010 ($... 182

Chapter 1 INTRODUCTION CELL-BASED ASSAYS: TECHNOLOGIES AND GLOBAL MARKETS BIO080B April 2014 Usha Nagavarapu Project Analyst ISBN: 1-56965-794-7 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

BIO080B - Cell-based Assays: Technologies and Global Markets CHAPTER 1 INTRODUCTION STUDY GOALS AND OBJECTIVES This BCC Research market report, Cell-Based Assays: Technologies and Global Markets, provides a detailed overview and thorough analysis of the present and future global market for cell-based techniques. This report analyzes in detail the cell-based assays available and currently used and their markets. This report includes current products in this market and detailed analyses of markets and competitive environments; market for cell assays in newly emerging regions, and instrumentation and robotics and their impact on the market. The report includes information about significant products and assays, key players, issues and trends, current market status of cell-based assays, strengths, weaknesses, opportunities and threats facing various assays and developments already on the market, major issues involved in the research and development (R&D) of more effective cell-based approaches, for drug discovery, and absorption, distribution, metabolism and excretion (ADME)/toxicity assays in development and in use. REASONS FOR DOING THE STUDY Cell-based assays have emerged as a more relevant alternative to biochemical assays involving the use of purified proteins especially in the field of drug discovery. There has been growth in demand for cell-based assays. A number of cell culture and liquid-handling instruments are available on the market that allows cell-based screening. The majority of compound screening programs performed by the biopharmaceutical industry are dependent on cell-based assays for functional measures of target activation. Label-free cellular assays are also driving this market forward, with their sensitivity, robustness, ease of use and flexibility. These assays are now used routinely throughout early drug discovery from target identification and validation to primary screening, lead identification, lead optimization and into safety and toxicology. There is a need to understand the trends in this market, currently available assays and latest developments for drug discovery. SCOPE AND FORMAT This report is an update on Cell-Based Assays: Technologies and Global Markets. It will review global markets for cell-based assays and new developments and will forecast trends for use of these assays for drug discovery and safety and toxicology through 2018. Important assays, technologies and the latest developments, market share by assay type, products on the market and market share by company, and statistical information for types of cancers prevalent worldwide, with a special emphasis on the U.S. market. Copyright BCC Research, Wellesley MA USA, Website: www.bccresearch.com 3

BIO080B - Cell-based Assays: Technologies and Global Markets The report also includes current issues and trends affecting the industry and costs, and factors influencing demand will be discussed. The report covers products in development, new technologies, trends, alliances and mergers. The report offers market data with respect to segments and geography. It also provides market trends with respect to drivers, restraints and opportunities. INTENDED AUDIENCE This report is an exhaustive study on the global market for cell-based assays, giving crucial statistics and analysis on existing technologies, latest trends, market structure, market size, key drug segments, important trends in technology development, major opportunities and market shares of key players and drugs. This report may prove crucial for the firms or investors seeking investments in the concerned sector. This report shows cell-based assays currently being used, new developments, spending trends and revenue prospects for cell-based assays in pharma. The report provides market data for 2012 to 2018 and also covers commercial prospects for cell assays in drug research and ADME/toxicity assays. METHODOLOGY Both primary and secondary research methodologies were used in preparing this report. Secondary sources include books, newspapers, trade journals, white papers, industry portals, government agencies, trade associations, monitoring industry news and developments and through access to paid databases. The base year of the report is 2012, with forecast data provided through 2018. Historical, base year and forecast data are provided for each market segment of this report. Growth rates are determined through a compilation of data, including past trends, future trends, demographics, incidence, mortality, products in R&D and current product growth. ANALYST CREDENTIALS Usha Nagavarapu is an experienced pharmaceutical professional with business development experience. She has preclinical, alliance management, discovery and technology development and marketing experience. Her strong focus areas include oncology and cardiovascular diseases, with expertise in molecular and cell biology and complex cell-based biological assays ranging from drug discovery, in vitro and in vivo screening, in vivo model development and pharmacokinetics. She has experience working with early start-ups. RELATED BCC RESEARCH REPORTS PHM017E In Vitro Toxicity Testing: Technologies and Global Markets. BIO049E Global Biochip Markets: Microarrays and Lab-on-a-Chip. HLC027B Cancer Therapies: Technologies and Global Markets. BIO061B Biomarkers: Technologies and Global Markets. Copyright BCC Research, Wellesley MA USA, Website: www.bccresearch.com 4