LIQUID BIOPSY RESEARCH TOOLS, SERVICES AND DIAGNOSTICS: GLOBAL MARKETS

LIQUID BIOPSY RESEARCH TOOLS, SERVICES AND DIAGNOSTICS: GLOBAL MARKETS BIO150A January 2016 John Bergin Project Analyst ISBN: 1-62296-224-9 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 CONTRIBUTION OF THE STUDY AND FOR WHOM 3 SCOPE AND FORMAT 3 METHODOLOGY 4 INFORMATION SOURCES 4 ANALYST'S CREDENTIALS 4 RELATED BCC RESEARCH REPORTS 4 BCC RESEARCH WEBSITE 5 DISCLAIMER 5 CHAPTER 2 EXECUTIVE SUMMARY 7 SUMMARY TABLE GLOBAL LIQUID BIOPSY MARKET BY APPLICATION, THROUGH 2020 ($ SUMMARY FIGURE GLOBAL LIQUID BIOPSY MARKET BY APPLICATION, 2014-2020 ($ 7 8 CHAPTER 3 OVERVIEW 11 INTRODUCTION 11 TABLE 1 LIQUID BIOPSY SAMPLE TYPES 11 REPORT SCOPE 12 TABLE 2 LIQUID BIOPSY REPORT SCOPE 12 LIQUID BIOPSY VERSUS TRADITIONAL BIOPSY 12 MARKETS 13 TABLE 3 LIQUID BIOPSY MARKET BY ANALYSIS TYPE, THROUGH 2020 ($ 13 GROWTH DRIVING FORCES 14 TABLE 4 GROWTH DRIVING FORCES 14 KEY TRENDS 15 TABLE 5 KEY TRENDS IN LIQUID BIOPSY 15 INDUSTRY 16 TABLE 6 SINGLE CELL ANALYSIS INDUSTRY SUBSECTORS 16 CHAPTER 4 TECHNOLOGIES 18 LIQUID BIOPSY BIOMARKERS 18 TABLE 7 LIQUID BIOPSY BIOMARKER CLASSES 18 CANCER GENOMICS 19 FIGURE 1 HOW CANCER GENOMICS DRIVES LIQUID BIOPSY 19 TABLE 8 SINGLE CELL ANALYSIS TO IDENTIFY CANCER DRIVER MUTATIONS 20 TABLE 9 GENOMICS-BASED ONCOLOGY WORKFLOW 21 NONINVASIVE PRENATAL TESTING 22 TABLE 10 CELL-FREE DNA ANALYSIS APPROACHES 23 CIRCULATING TUMOR CELL (CTC) TECHNOLOGIES 24 TABLE 11 UNIQUE TECHNICAL CHALLENGES OF CTC CAPTURE AND ANALYSIS 24 CTC WORKFLOW 25 TABLE 12 CTC WORKFLOW 25

CELL ISOLATION TECHNOLOGIES 26 TABLE 13 CELL DIFFERENTIATORS 26 TABLE 14 CELL ISOLATION TECHNOLOGIES 27 CTC SAMPLE PREPARATION TECHNOLOGIES 28 TABLE 15 CTC SAMPLE PREPARATION TECHNOLOGIES 29 CTC DOWNSTREAM ANALYSIS TECHNOLOGIES 29 TABLE 16 SINGLE CELL ANALYSIS TECHNOLOGIES 30 COMPARISON OF LIQUID BIOPSY WITH CONVENTIONAL BIOPSY 30 CANCER TESTING 31 TABLE 17 ESTIMATED ANNUAL BIOPSY PROCEDURES PERFORMED IN THE U.S. FOR SELECTED CANCERS TABLE 18 MAIN RISKS FOR NEEDLE-BASED TISSUE BIOPSIES 31 TABLE 19 FACTORS IN TISSUE BIOPSY 33 PRENATAL TESTING 33 TABLE 20 INVASIVE PRENATAL TESTING TECHNOLOGIES 34 TABLE 21 INVASIVE VERSUS NONINVASIVE PRENATAL TECHNOLOGIES 35 31 CHAPTER 5 LIQUID BIOPSY INITIATIVES 37 KEY COLLABORATIVE INITIATIVES 37 TABLE 22 KEY LIQUID BIOPSY RESEARCH AND DEVELOPMENT PROGRAMS 37 CAMBRIDGE SINGLE CELL ANALYSIS CORE FACILITY 37 CANCER-ID 38 CTC TRAP CONSORTIUM 38 EARLY CANCER DETECTION CONSORTIUM 38 HEMATOLOGIC ONCOLOGY CONSORTIUM 38 NATIONAL CENTER FOR SINGLE CELL BIOLOGY 39 PRECISION MEDICINE INITIATIVE 39 SINGLE CELL ANALYSIS PROGRAM 39 WORLDWIDE INNOVATIVE NETWORKING (WIN) CONSORTIUM 40 CHAPTER 6 LIQUID BIOPSY APPLICATIONS 42 INTRODUCTION 42 TABLE 23 SOURCE OF FOREIGN BIOMARKERS FOR LIQUID BIOPSY APPLICATIONS 42 CANCER APPLICATIONS 42 PRECISION MEDICINE 42 TABLE 24 PERSONALIZED MEDICINE DRIVEN BY CANCER COMMON GENETIC MUTATIONS CANCER BIOMARKER STATUS 43 TABLE 25 CANCER LIQUID BIOPSY BIOMARKER CLINICAL STATUS 44 CANCER MARKET SEGMENTS 45 TABLE 26 CANCER LIQUID BIOPSY MARKET SEGMENTS 45 REPRODUCTIVE HEALTH APPLICATIONS 47 TABLE 27 NIPT AS A SCREENING APPLICATION 47 TABLE 28 ETHICAL ISSUES ASSOCIATED WITH PRENATAL AND NEWBORN SCREENING TRANSPLANT DIAGNOSTICS APPLICATIONS 49 TABLE 29 TRANSPLANT DIAGNOSTICS APPLICATIONS 49 42 48

CHAPTER 7 LIQUID BIOPSY INDUSTRY 51 INTRODUCTION 51 TABLE 30 KEY SEGMENTS WITHIN THE LIQUID BIOPSY INDUSTRY 51 NGS INSTRUMENT INDUSTRY 52 TABLE 31 NEXT-GENERATION SEQUENCING INSTRUMENT COMPANIES SUMMARY 52 DROPLET DIGITAL PCR (DDPCR) INDUSTRY 55 TABLE 32 ADVANTAGES OF DDPCR FOR SINGLE CELL ANALYSIS 55 TABLE 33 DDPCR INDUSTRY 56 TARGET ENRICHMENT AND AMPLIFICATION INDUSTRY 56 TABLE 34 SINGLE CELL TARGET ENRICHMENT INDUSTRY 57 SINGLE CELL DNA POLYMERASE INDUSTRY 58 TABLE 35 SINGLE CELL DNA POLYMERASE INDUSTRY 58 NONINVASIVE PRENATAL TESTING INDUSTRY 59 TABLE 36 NGS NIPT INDUSTRY 60 TABLE 37 GLOBAL NIPT MARKET BY REGION AND COMPANY BY NUMBER OF TESTS, 2015 TABLE 38 GERMANY NGS-BASED NONINVASIVE PRENATAL DIAGNOSTIC COMPANIES, 2015 LIQUID BIOPSY INDUSTRY 67 TABLE 39 LIQUID BIOPSY INDUSTRY COMPANY FOCUS 68 64 65 CHAPTER 8 ACQUISITIONS AND STRATEGIC ALLIANCES 77 ACQUISITIONS 77 TABLE 40 LIQUID BIOPSY INDUSTRY ACQUISITIONS, JANUARY 2013-OCTOBER 2015 77 STRATEGIC ALLIANCES 80 TABLE 41 SINGLE CELL INDUSTRY STRATEGIC ALLIANCES, JANUARY 2013-OCTOBER 2015 80 CHAPTER 9 MARKETS 90 GROWTH DRIVING FORCES 90 TABLE 42 LIQUID BIOPSY MARKET GROWTH DRIVING FORCES 90 LIQUID BIOPSY MARKET 91 BY INDICATION 91 TABLE 43 LIQUID BIOPSY MARKET BY INDICATION, THROUGH 2020 ($ 91 BY BIOMARKER TYPE 92 TABLE 44 LIQUID BIOPSY MARKET BY BIOMARKER TYPE, THROUGH 2020 ($ BY ANALYSIS PLATFORM 92 TABLE 45 LIQUID BIOPSY MARKET BY ANALYSIS PLATFORM, THROUGH 2020 ($ BY ANALYSIS PURPOSE 93 TABLE 46 LIQUID BIOPSY MARKET BY ANALYSIS PURPOSE, THROUGH 2020 ($ NONINVASIVE PRENATAL TESTING MARKET 94 TABLE 47 NIPT MARKET BY RISK TYPE, THROUGH 2020 ($ 95 TABLE 48 NIPT MARKET BY ANALYSIS PURPOSE, THROUGH 2020 ($ 96 TABLE 49 NIPT MARKET BY BIOMARKER CLASS, THROUGH 2020 ($ 98 TABLE 50 NIPT MARKET BY ANALYSIS METHOD, THROUGH 2020 ($ 99 TABLE 51 NGS NIPT MARKET BY INSTRUMENT TYPE, THROUGH 2020 ($ 100 92 93 93

CANCER MARKET 100 TABLE 52 CANCER MARKET BY INDICATION, THROUGH 2020 ($ 100 TABLE 53 CANCER MARKET BY ANALYSIS PURPOSE, THROUGH 2020 ($ 102 TABLE 54 EARLY CANCER DETECTION (MM/NO.) 103 TABLE 55 CANCER MARKET BY BIOMARKER CLASS, THROUGH 2020 ($ 105 TABLE 56 CANCER MARKET BY ANALYSIS METHOD, THROUGH 2020 ($ 106 CTC CANCER MARKET 107 TABLE 57 CTC CANCER MARKET BY INDICATION, THROUGH 2020 ($ 107 TABLE 58 CTC CANCER MARKET BY ANALYSIS METHOD, THROUGH 2020 ($ CFDNA CANCER MARKET 110 TABLE 59 CFDNA CANCER MARKET BY INDICATION, THROUGH 2020 ($ 110 TABLE 60 CFDNA CANCER MARKET BY ANALYSIS METHOD, THROUGH 2020 ($ EV CANCER MARKET 113 TABLE 61 EV CANCER MARKET BY INDICATION, THROUGH 2020 ($ 113 TABLE 62 EV CANCER MARKET BY ANALYSIS METHOD, THROUGH 2020 ($ TRANSPLANT MARKET 115 TABLE 63 TRANSPLANT MARKET BY ORGAN TYPE, THROUGH ($ 115 TABLE 64 U.S. LIQUID BIOPSY TRANSPLANT MARKET (PROCEDURES PER YEAR/NUMBER OF PATIENTS) TABLE 65 TRANSPLANT MARKET BY ANALYSIS PURPOSE, THROUGH 2020 ($ TABLE 66 TRANSPLANT MARKET BY BIOMARKER CLASS, THROUGH 2020 ($ TABLE 67 TRANSPLANT MARKET BY ANALYSIS METHOD, THROUGH 2020 ($ LIQUID BIOPSY MARKET BY REGION 119 TABLE 68 LIQUID BIOPSY MARKET BY REGION, THROUGH 2020 ($ 119 TABLE 69 CANCER MARKET BY REGION, THROUGH 2020 ($ 120 TABLE 70 NIPT MARKET BY REGION, THROUGH 2020 ($ 120 TABLE 71 TRANSPLANT MARKET BY REGION, THROUGH 2020 ($ 122 109 112 114 116 117 117 118 CHAPTER 10 PATENTS 125 CIRCULATING TUMOR CELL PATENTS 125 TABLE 72 CTC PATENTS, 2005-2015 125 CELL-FREE DNA PATENTS 126 TABLE 73 CELL-FREE DNA PATENTS, 2005-2015 126 CHAPTER 11 COMPANY PROFILES 128 AFFYMETRIX 128 AGILENT TECHNOLOGIES INC. 128 ANGLE PLC 130 ANNOROAD GENE TECHNOLOGY 131 APOCELL 132 ASURAGEN INC. 132 AVIVA BIOSCIENCES 133 BECTON, DICKINSON AND CO. 134

BERRY GENOMICS CO. LTD. 135 BGI SHENZHEN 136 BIOCARTIS NV 137 BIOCEPT INC. 138 BIOFLUIDICA INC. 139 BIO-RAD LABORATORIES INC. 140 BOREAL GENOMICS 140 CELL MICROSYSTEMS INC. 141 CELLSEE DIAGNOSTICS INC. 141 CELLULAR RESEARCH INC. 142 CHRONIX BIOMEDICAL 143 CIRCULOGENE THERANOSTICS 143 CIRCULOMICS INC. 144 CLONTECH LABORATORIES INC. 144 CYNVENIO BIOSYSTEMS INC. 144 CYTOTRACK APS 145 DANAHER CORP. 145 DIAGNOLOGIX LLC 146 DNA ELECTRONICS LTD. 147 EPIC SCIENCES 148 EXOSOME DIAGNOSTICS INC. 148 FLUIDIGM CORP. 149 FOUNDATION MEDICINE 150 FLUXION BIOSCIENCES INC. 151 GATC BIOTECH AG 151 GE HEALTHCARE 152 GENOMIC HEALTH INC. 153 GIGAGEN INC. 154 GOOD START GENETICS INC. 154 GUARDANT HEALTH INC. 155 HTG MOLECULAR DIAGNOSTICS INC. 156 ILLUMINA INC. 157 TABLE 74 NEW PLATFORMS INTRODUCED BY ILLUMINA, 2015 157 JOHNSON & JOHNSON 161 KELLBENX INC. 162 LABORATORY CORP. OF AMERICA INC. 163 MDX HEALTH INC. 164 MERCK KGAA 165 MYRIAD GENETICS INC. 165 NATERA INC. 167 NEOGENOMICS INC. 168 NEW ENGLAND BIOLABS 169 NEW ONCOLOGY AG 169 NUGEN TECHNOLOGIES INC. 170 OXFORD GENE TECHNOLOGY 171 OXFORD NANOPORE TECHNOLOGIES LTD. 171 PACIFIC BIOSCIENCES OF CALIFORNIA INC. 172

PATHWAY GENOMICS CORP. 174 PERSONAL GENOME DIAGNOSTICS INC. 175 PROVISTA DIAGNOSTICS INC. 176 QIAGEN NV 176 RAINDANCE TECHNOLOGIES INC. 178 RARECELLS SAS 179 RARECYTE INC. 179 RESOLUTION BIOSCIENCE INC. 179 ROCHE HOLDING AG 180 TABLE 75 COMMERCIAL SEQUENCER COMPETITIVE POSITIONING 181 RUBICON GENOMICS 183 SALVEO DX 183 SCREENCELL 183 SENGENICS INTERNATIONAL PTE LTD. 184 SEQUENOM INC. 184 SILICON BIOSYSTEMS 186 SPHERE FLUIDICS LTD. 186 STRAND LIFE SCIENCES 187 STRATEC BIOMEDICAL AG 187 SYGNIS AG 187 SYSMEX INOSTICS 188 TAI DIAGNOSTICS INC. 188 THERMO FISHER SCIENTIFIC INC. 188 THORNE DIAGNOSTICS INC. 190 TROVAGENE INC. 190 TRANSGENOMIC INC. 191 VITATEX INC. 191 WAFERGEN BIO-SYSTEMS INC. 192 TABLE 76 WAFERGEN STRATEGIC ALLIANCES 192 XCELL BIOSCIENCES INC. 193 YIKON GENOMICS CO. LTD. 193 ZEPHYRUS BIOSCIENCES INC. 194

LIST OF TABLES TABLE HEADING SUMMARY TABLE GLOBAL LIQUID BIOPSY MARKET BY APPLICATION, THROUGH 2020 ($ TABLE 1 LIQUID BIOPSY SAMPLE TYPES 11 TABLE 2 LIQUID BIOPSY REPORT SCOPE 12 TABLE 3 LIQUID BIOPSY MARKET BY ANALYSIS TYPE, THROUGH 2020 ($ 13 TABLE 4 GROWTH DRIVING FORCES 14 TABLE 5 KEY TRENDS IN LIQUID BIOPSY 15 TABLE 6 SINGLE CELL ANALYSIS INDUSTRY SUBSECTORS 16 TABLE 7 LIQUID BIOPSY BIOMARKER CLASSES 18 TABLE 8 SINGLE CELL ANALYSIS TO IDENTIFY CANCER DRIVER MUTATIONS 20 TABLE 9 GENOMICS-BASED ONCOLOGY WORKFLOW 21 TABLE 10 CELL-FREE DNA ANALYSIS APPROACHES 23 TABLE 11 UNIQUE TECHNICAL CHALLENGES OF CTC CAPTURE AND ANALYSIS 24 TABLE 12 CTC WORKFLOW 25 TABLE 13 CELL DIFFERENTIATORS 26 TABLE 14 CELL ISOLATION TECHNOLOGIES 27 TABLE 15 CTC SAMPLE PREPARATION TECHNOLOGIES 29 TABLE 16 SINGLE CELL ANALYSIS TECHNOLOGIES 30 TABLE 17 ESTIMATED ANNUAL BIOPSY PROCEDURES PERFORMED IN THE U.S. FOR SELECTED CANCERS TABLE 18 MAIN RISKS FOR NEEDLE-BASED TISSUE BIOPSIES 31 TABLE 19 FACTORS IN TISSUE BIOPSY 33 TABLE 20 INVASIVE PRENATAL TESTING TECHNOLOGIES 34 TABLE 21 INVASIVE VERSUS NONINVASIVE PRENATAL TECHNOLOGIES 35 TABLE 22 KEY LIQUID BIOPSY RESEARCH AND DEVELOPMENT PROGRAMS 37 TABLE 23 SOURCE OF FOREIGN BIOMARKERS FOR LIQUID BIOPSY APPLICATIONS 42 TABLE 24 PERSONALIZED MEDICINE DRIVEN BY CANCER COMMON GENETIC MUTATIONS TABLE 25 CANCER LIQUID BIOPSY BIOMARKER CLINICAL STATUS 44 TABLE 26 CANCER LIQUID BIOPSY MARKET SEGMENTS 45 TABLE 27 NIPT AS A SCREENING APPLICATION 47 TABLE 28 ETHICAL ISSUES ASSOCIATED WITH PRENATAL AND NEWBORN SCREENING TABLE 29 TRANSPLANT DIAGNOSTICS APPLICATIONS 49 TABLE 30 KEY SEGMENTS WITHIN THE LIQUID BIOPSY INDUSTRY 51 TABLE 31 NEXT-GENERATION SEQUENCING INSTRUMENT COMPANIES SUMMARY 52 TABLE 32 ADVANTAGES OF DDPCR FOR SINGLE CELL ANALYSIS 55 TABLE 33 DDPCR INDUSTRY 56 TABLE 34 SINGLE CELL TARGET ENRICHMENT INDUSTRY 57 TABLE 35 SINGLE CELL DNA POLYMERASE INDUSTRY 58 TABLE 36 NGS NIPT INDUSTRY 60 TABLE 37 GLOBAL NIPT MARKET BY REGION AND COMPANY BY NUMBER OF TESTS, 2015 TABLE 38 GERMANY NGS-BASED NONINVASIVE PRENATAL DIAGNOSTIC COMPANIES, 2015 TABLE 39 LIQUID BIOPSY INDUSTRY COMPANY FOCUS 68 TABLE 40 LIQUID BIOPSY INDUSTRY ACQUISITIONS, JANUARY 2013-OCTOBER 2015 77 7 31 42 48 64 65

TABLE HEADING TABLE 41 SINGLE CELL INDUSTRY STRATEGIC ALLIANCES, JANUARY 2013-OCTOBER 2015 TABLE 42 LIQUID BIOPSY MARKET GROWTH DRIVING FORCES 90 TABLE 43 LIQUID BIOPSY MARKET BY INDICATION, THROUGH 2020 ($ 91 TABLE 44 LIQUID BIOPSY MARKET BY BIOMARKER TYPE, THROUGH 2020 ($ TABLE 45 LIQUID BIOPSY MARKET BY ANALYSIS PLATFORM, THROUGH 2020 ($ TABLE 46 LIQUID BIOPSY MARKET BY ANALYSIS PURPOSE, THROUGH 2020 ($ TABLE 47 NIPT MARKET BY RISK TYPE, THROUGH 2020 ($ 95 TABLE 48 NIPT MARKET BY ANALYSIS PURPOSE, THROUGH 2020 ($ 96 TABLE 49 NIPT MARKET BY BIOMARKER CLASS, THROUGH 2020 ($ 98 TABLE 50 NIPT MARKET BY ANALYSIS METHOD, THROUGH 2020 ($ 99 TABLE 51 NGS NIPT MARKET BY INSTRUMENT TYPE, THROUGH 2020 ($ 100 TABLE 52 CANCER MARKET BY INDICATION, THROUGH 2020 ($ 100 TABLE 53 CANCER MARKET BY ANALYSIS PURPOSE, THROUGH 2020 ($ 102 TABLE 54 EARLY CANCER DETECTION (MM/NO.) 103 TABLE 55 CANCER MARKET BY BIOMARKER CLASS, THROUGH 2020 ($ 105 TABLE 56 CANCER MARKET BY ANALYSIS METHOD, THROUGH 2020 ($ 106 TABLE 57 CTC CANCER MARKET BY INDICATION, THROUGH 2020 ($ 107 TABLE 58 CTC CANCER MARKET BY ANALYSIS METHOD, THROUGH 2020 ($ TABLE 59 CFDNA CANCER MARKET BY INDICATION, THROUGH 2020 ($ 110 TABLE 60 CFDNA CANCER MARKET BY ANALYSIS METHOD, THROUGH 2020 ($ TABLE 61 EV CANCER MARKET BY INDICATION, THROUGH 2020 ($ 113 TABLE 62 EV CANCER MARKET BY ANALYSIS METHOD, THROUGH 2020 ($ 114 TABLE 63 TRANSPLANT MARKET BY ORGAN TYPE, THROUGH ($ 115 TABLE 64 U.S. LIQUID BIOPSY TRANSPLANT MARKET (PROCEDURES PER YEAR/NUMBER OF PATIENTS) TABLE 65 TRANSPLANT MARKET BY ANALYSIS PURPOSE, THROUGH 2020 ($ TABLE 66 TRANSPLANT MARKET BY BIOMARKER CLASS, THROUGH 2020 ($ TABLE 67 TRANSPLANT MARKET BY ANALYSIS METHOD, THROUGH 2020 ($ TABLE 68 LIQUID BIOPSY MARKET BY REGION, THROUGH 2020 ($ 119 TABLE 69 CANCER MARKET BY REGION, THROUGH 2020 ($ 120 TABLE 70 NIPT MARKET BY REGION, THROUGH 2020 ($ 120 TABLE 71 TRANSPLANT MARKET BY REGION, THROUGH 2020 ($ 122 TABLE 72 CTC PATENTS, 2005-2015 125 TABLE 73 CELL-FREE DNA PATENTS, 2005-2015 126 TABLE 74 NEW PLATFORMS INTRODUCED BY ILLUMINA, 2015 157 TABLE 75 COMMERCIAL SEQUENCER COMPETITIVE POSITIONING 181 TABLE 76 WAFERGEN STRATEGIC ALLIANCES 192 80 92 93 93 109 112 116 117 117 118

LIST OF FIGURES FIGURE TITLE SUMMARY FIGURE GLOBAL LIQUID BIOPSY MARKET BY APPLICATION, 2014-2020 ($ FIGURE 1 HOW CANCER GENOMICS DRIVES LIQUID BIOPSY 19 8