MOLECULAR DIAGNOSTICS: TECHNOLOGIES AND GLOBAL MARKETS

MOLECULAR DIAGNOSTICS: TECHNOLOGIES AND GLOBAL MARKETS BIO063C June 2015 Jon Evans Project Analyst ISBN: 1-62296-110-2 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 SCOPE OF REPORT 2 INTENDED AUDIENCE 2 METHODOLOGY AND INFORMATION SOURCES 3 ANALYST'S CREDENTIALS 3 RELATED BCC RESEARCH REPORTS 3 BCC RESEARCH WEBSITE 4 DISCLAIMER 4 CHAPTER 2 SUMMARY 6 FORECASTS 6 SUMMARY TABLE GLOBAL MARKET FOR MOLECULAR DIAGNOSTICS BY TECHNOLOGY, SUMMARY FIGURE GLOBAL MARKET FOR MOLECULAR DIAGNOSTICS BY TECHNOLOGY, 2012-2020 ($ MILLIONS) VENDORS 7 6 6 CHAPTER 3 OVERVIEW 9 OVERVIEW 9 INTRODUCTION TO GENOMIC DIAGNOSTICS 9 EXPRESSION PROFILING AND DISEASE 11 EXPRESSION PROFILING AND INFECTIOUS DISEASE 12 DNA SEQUENCING FOR GENOTYPING AND DIAGNOSIS 12 CLINICAL PHARMACOLOGY 13 MUTATION DETECTION AND GENOTYPING FOR SPECIFIC GENES 13 IDENTIFICATION OF NEW DISEASE GENES 13 CHAPTER 4 REGULATIONS AND FINANCE 15 OVERVIEW 15 INSURANCE 15 FOOD AND DRUG ADMINISTRATION GUIDELINES 16 INTERNAL STANDARDS FOR DNA DIAGNOSTICS 17 TABLE 1 MINIMUM INFORMATION ABOUT A MICROARRAY EXPERIMENT - MIAME 2.0 18 TABLE 2 MICROARRAY QUALITY CONTROL (MAQC) PROJECT 19 CLINICAL LABORATORY IMPROVEMENT AMENDMENTS (CLIA) 20 TABLE 3 U.S. LABORATORIES CLIA-CERTIFIED FOR MOLECULAR DIAGNOSTICS AND NUMBER OF DISEASE TESTS, 2012 FIGURE 1 GROWTH IN CLINICAL LABORATORY SITES AND DISEASE TESTING, 1993-2015 TABLE 4 GENETIC TESTING PROCEDURES PERFORMED IN U.S. BY TYPE, 2015 22 PERSONALIZED MEDICINES AND COMPANION DIAGNOSTICS 23 FDA GUIDELINES FOR IN VITRO COMPANION DIAGNOSTICS 24 Definition and Use of an IVD Companion Diagnostic Device 24 21 21

Review and Approval of IVD Companion Diagnostic Devices and Therapeutic Products Novel Therapeutic Products 25 Approval of a Therapeutic Product without an Approved IVD Companion Diagnostic Device General Policies 26 FDA-APPROVED COMPANION DIAGNOSTICS 27 TABLE 5 FDA-APPROVED IN VITRO COMPANION DIAGNOSTIC DEVICES AS OF DEC. 23, 2014 TABLE 6 FDA-APPROVED IN VITRO COMPANION DIAGNOSTIC DEVICES, AS OF DECEMBER 2012 PHARMACOGENOMICS RESEARCH NETWORK 42 TABLE 7 CURRENT PGRN-RIKEN CGM COLLABORATIVE STUDIES 43 25 25 28 34 CHAPTER 5 COMMERCIAL MARKET TRENDS 50 MARKET CONDITIONS 50 HEALTHCARE, HOSPITALS, DOCTORS, GREATER REGULATION AND NEED FOR INSURANCE REIMBURSEMENT NEW REQUIREMENTS FOR SUCCESS 50 SALES AND MARKETING 50 MEDICAL AFFAIRS 51 REGULATORY COMPLIANCE 51 REIMBURSEMENT 51 ALLIANCES AND MERGERS 52 TABLE 8 DIAGNOSTICS MANUFACTURER MERGERS AND ACQUISITIONS, 2004-2014 52 50 CHAPTER 6 MARKET FOR MOLECULAR DIAGNOSTICS BY TECHNOLOGY 56 OVERVIEW 56 DESCRIPTION 56 REVENUES AND FORECASTS 57 TABLE 9 GLOBAL MARKET FOR MOLECULAR DIAGNOSTICS BY TECHNOLOGY, TABLE 10 GLOBAL MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY TECHNOLOGY, 2015 (%) FIGURE 2 GLOBAL MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY TECHNOLOGY, 2015 (%) MANUFACTURERS 58 TABLE 11 GLOBAL MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY MANUFACTURER, 2015 (%) FIGURE 3 GLOBAL MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY MANUFACTURER, 2015 (%) MICROARRAY 60 DESCRIPTION 60 Planar 60 Bead 60 REVENUES AND FORECASTS 61 TABLE 12 GLOBAL MICROARRAY MARKET FOR MOLECULAR DIAGNOSTICS BY APPLICATION, TABLE 13 GLOBAL MICROARRAY MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY 57 57 57 59 59 61 62

FIGURE 4 GLOBAL MICROARRAY MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY MANUFACTURERS AND PRODUCTS 63 Planar 63 TABLE 14 MAJOR SUPPLIERS OF PLANAR DNA MICROARRAYS 63 Bead 64 TABLE 15 MAJOR SUPPLIERS OF BEAD MICROARRAYS 64 PCR 64 DESCRIPTION 64 REVENUES AND FORECASTS 65 TABLE 16 GLOBAL PCR MARKET FOR MOLECULAR DIAGNOSTICS BY APPLICATION, TABLE 17 GLOBAL PCR MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY FIGURE 5 GLOBAL PCR MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY MANUFACTURERS AND PRODUCTS 66 TABLE 18 GLOBAL PCR MARKET SHARE BY MANUFACTURER, 2015 (%) 67 IN SITU HYBRIDIZATION (ISH) 67 DESCRIPTION 67 Labeling Techniques 68 Applications of In Situ Hybridization 68 FIBER FISH 69 HER2 FISH TESTING 70 REVENUES AND FORECASTS 71 TABLE 19 GLOBAL ISH MARKET FOR MOLECULAR DIAGNOSTICS BY APPLICATION, TABLE 20 GLOBAL ISH MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY FIGURE 6 GLOBAL ISH MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY LAB-ON-A-CHIP/BIOCHIPS 72 DESCRIPTION 72 Microfluidic Devices 74 PRODUCT DEVELOPMENT 75 REVENUES AND FORECASTS 76 TABLE 21 GLOBAL LAB-ON-A-CHIP/BIOCHIP MARKET FOR MOLECULAR DIAGNOSTICS BY APPLICATION, TABLE 22 GLOBAL LAB-ON-A-CHIP/BIOCHIP MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY FIGURE 7 GLOBAL LAB-ON-A-CHIP/BIOCHIP MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY EMERGING AND OTHER DIAGNOSTIC TECHNOLOGIES 77 DESCRIPTION 77 The Trend toward Single-Cell Measurements 78 Genetic Typing of Single Cells 78 Single-Cell Sequencing 78 Copy Number Variations in Single Cells 78 Combined Immunotyping and Single-Cell Expression Analysis 78 62 65 66 66 71 72 72 76 76 77

Diagnosing the Epigenome 79 REVENUES AND FORECASTS 79 TABLE 23 GLOBAL EMERGING/OTHER MOLECULAR DIAGNOSTICS MARKET BY APPLICATION, TABLE 24 GLOBAL EMERGING/OTHER MOLECULAR DIAGNOSTICS MARKET SHARE BY 79 80 CHAPTER 7 MARKETS FOR MOLECULAR DIAGNOSTICS BY APPLICATION AND PRODUCTS OVERVIEW 82 DESCRIPTION 82 REVENUES AND FORECASTS 82 TABLE 25 GLOBAL MARKET FOR MOLECULAR DIAGNOSTICS BY APPLICATION, TABLE 26 GLOBAL MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY FIGURE 8 GLOBAL MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY PRE-/POSTNATAL GENETIC SCREENING 84 DESCRIPTION 84 Carrier Screening 84 Prenatal Diagnostic Testing 85 Amniocentesis 85 Chorionic Villus Sampling 85 Genetic Counseling 86 Preimplantation Diagnosis 87 Newborn Screening 87 REVENUES AND FORECASTS 88 TABLE 27 GLOBAL PRE/POSTNATAL SCREENING MARKET FOR MOLECULAR DIAGNOSTICS BY APPLICATION, TABLE 28 GLOBAL PRE/POSTNATAL SCREENING MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY FIGURE 9 GLOBAL PRE/POSTNATAL SCREENING MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY INFECTIOUS DISEASE DIAGNOSTICS 89 DESCRIPTION 89 REVENUES AND FORECASTS 90 TABLE 29 GLOBAL INFECTIOUS DISEASES MARKET FOR MOLECULAR DIAGNOSTICS BY APPLICATION, TABLE 30 GLOBAL INFECTIOUS DISEASE SCREENING MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY FIGURE 10 GLOBAL INFECTIOUS DISEASE SCREENIN MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY ONCOLOGY DIAGNOSTICS 92 DESCRIPTION 92 Leukemias 92 Chronic Myeloid Leukemia 93 Genetic Marker of Chronic Myeloid Leukemia 93 REVENUES AND FORECASTS 94 82 82 83 83 88 88 88 91 91 91

TABLE 31 GLOBAL ONCOLOGY MARKET FOR MOLECULAR DIAGNOSTICS BY APPLICATION, TABLE 32 GLOBAL ONCOLOGY MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY FIGURE 11 GLOBAL ONCOLOGY MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY IDENTITY DIAGNOSTICS, FORENSICS AND PATERNITY 95 DESCRIPTION 95 Paternity Testing 96 Technology 96 Accreditation 96 Legal Issues 96 Veterinary Identity Testing 97 REVENUES AND FORECASTS 97 TABLE 33 GLOBAL IDENTITY TESTING MARKET FOR MOLECULAR DIAGNOSTICS BY APPLICATION, TABLE 34 GLOBAL IDENTITY TESTING MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY FIGURE 12 GLOBAL IDENTITY TESTING MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY PHARMACOGENOMICS/OTHER APPLICATIONS 99 DESCRIPTION 99 REVENUES AND FORECASTS 102 TABLE 35 GLOBAL PHARMACOGENOMICS AND OTHER MARKET FOR MOLECULAR DIAGNOSTICS BY APPLICATION, TABLE 36 GLOBAL PHARMACOGENOMICS AND OTHER MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY 94 95 95 98 98 98 103 103 CHAPTER 8 PATENT ANALYSIS 105 PCR 105 TABLE 37 SELECTED PCR PATENTS GRANTED FROM JANUARY 2013 TO JANUARY 2015 REAL TIME PCR DETECTION OF RESPIRATORY SYNCYTIAL VIRUS 107 NUCLEIC ACID AMPLIFICATION PRIMERS FOR PCR-BASED CLONALITY STUDIES 107 QUANTITATIVE MULTIPLEX METHYLATION SPECIFIC PCR METHOD- CMETHDNA, REAGENTS, AND ITS USE REAL-TIME PCR DETECTION OF STREPTOCOCCUS PYOGENES 108 REAL-TIME PCR FOR THE DETECTION OF PATHOGENS 108 QUANTITATIVE MULTIPLEX METHYLATION-SPECIFIC PCR 109 REAL-TIME PCR DETECTION OF MYCOBACTERIUM TUBERCULOSIS COMPLEX 109 REAL TIME PCR DETECTION OF M. TUBERCULOSIS RESISTANT/SUSCEPTIBLE TO RIFAMPICIN AND/OR ISONIAZID ABSOLUTE PCR QUANTIFICATION 110 COMPOSITIONS AND METHOD FOR MEASURING AND CALIBRATING AMPLIFICATION BIAS IN MULTIPLEXED PCR REACTIONS REAL-TIME PCR DETECTION OF SEASONAL INFLUENZA H1, H3 AND B SUBTYPES 110 MULTIMODAL PCR TARGET DETECTION 111 COMPOSITION TO OVERCOME INHIBITORS IN PCR AND GROWTH CULTURES 111 MAGNETIC IMMUNO DIGITAL PCR ASSAY 111 CUTOFF POINT DELTA CT. METHOD FOR HER2 PCR TESTING IN BREAST CANCER 112 105 107 109 110

METHODS AND COMPOSITIONS FOR PCR USING BLOCKED AND UNIVERSAL PRIMERS PCR ASSAYS AND REAGENTS FOR MOLECULAR DETECTION OF INFECTIOUS AGENTS RANDOM HOMOZYGOUS GENE PERTURBATION (RHGP) WITH THERMAL ASSYMETRIC INTERLACED (TAIL)-PCR MICRO RNA-BASED METHODS AND COMPOSITIONS FOR THE DIAGNOSIS, PROGNOSIS AND TREATMENT OF OVARIAN CANCER USING A REAL-TIME PCR PLATFORM PCR METHODS FOR CHARACTERIZING THE 5' UNTRANSLATED REGION OF THE FMR1 AND FMR2 GENES MULTIPLEX PCR-BASED TESTING OF CUTANEOUS SQUAMOUS CELL CARCINOMA AND PSEUDOEPITHELIOMATOUS HYPERPLASIA AND METHODS FOR DISTINGUISHING THE SAME IDENTIFICATION OF ANTIGEN-SPECIFIC ADAPTIVE IMMUNE RESPONSES USING ARM-PCR AND HIGH-THROUGHPUT SEQUENCING QUANTITATIVE MULTIPLEX METHYLATION-SPECIFIC PCR 115 PCR DIAGNOSTICS OF DERMATOPHYTES AND OTHER PATHOGENIC FUNGI 115 HIGHLY MULTIPLEX PCR METHODS AND COMPOSITIONS 115 SINGLE TUBE QUANTITATIVE POLYMERASE CHAIN REACTION (PCR) 116 HIGHLY MULTIPLEX PCR METHODS AND COMPOSITIONS 116 IDENTIFICATION OF LINKAGE USING MULTIPLEX DIGITAL PCR 116 METHODS AND COMPOSITIONS TO ENABLE MULTIPLEX COLD-PCR 117 METHODS OF DIAGNOSING DISEASE USING OVERLAP EXTENSION PCR 117 HOT-START DIGITAL PCR 117 METHOD FOR DETECTION, DIFFERENTIATION AND QUANTIFICATION OF T CELL POPULATIONS BY WAY OF REVERSE TRANSCRIPTION QUANTITATIVE REAL TIME PCR (RT-QPCR) TECHNOLOGY NDM-1 POLYMERASE CHAIN REACTION (PCR) ASSAY 118 DETECTION OF MICRO METASTASIS OF MELANOMA AND BREAST CANCER IN PARAFFIN-EMBEDDED TUMOR DRAINING LYMPH NODES BY MULTIMARKER QUANTITATIVE RT-PCR LATE-PCR 119 HEMOMOSAIC: HIGH-THROUGHPUT TECHNIQUE FOR RARE CELL DETECTION IN LIQUID SAMPLES BY MASSIVELY MULTIPLEXED PCR IN A PHOTOLITHOGRAPHIC MATRIX SERIAL QUANTITATIVE PCR ASSAY FOR DETECTION, SPECIES-DISCRIMINATION AND QUANTIFICATION OF LEISHMANIA SPP. IN HUMAN SAMPLES GENE DETECTING METHODS WITHOUT USING PCR 120 HIGHLY MULTIPLEX PCR METHODS AND COMPOSITIONS 120 PROCESS FOR DETECTION OF MULTIDRUG RESISTANT TUBERCULOSIS USING REAL-TIME PCR AND HIGH RESOLUTION MELT ANALYSIS ISOFORMS OF THE HUMAN SST5 RECEPTOR ORIGINATED BY ALTERNATIVE SPLICING AND OLIGONUCLEOTIDE PAIRS TO DETECT THEM BY PCR REAL TIME PCR ASSAY FOR DETECTION OF BACTERIAL RESPIRATORY PATHOGENS METHODS AND COMPOSITIONS RELATED TO CONTINUOUS FLOW THERMAL GRADIENT PCR METHOD FOR DETECTING MORE THAN ONE TARGET IN A PCR-BASED APPROACH APPLYING AN UN-SPECIFIC DYE WHICH IS NOT INTERFERING WITH THE EMISSION OF FLUOROPHORE-LABELED PROBES MICROARRAY 123 112 112 113 113 114 114 114 118 118 119 120 121 121 121 122 122

TABLE 38 SELECTED MICROARRAY PATENTS GRANTED, JANUARY 2013 TO MAY 2015 METHODS AND SYSTEMS FOR MANUFACTURE OF MICROARRAY ASSAY SYSTEMS, CONDUCTING MICROFLUIDIC ASSAYS, AND MONITORING AND SCANNING TO OBTAIN MICROFLUIDIC ASSAY RESULTS SYMMETRICALLY BRANCHED POLYMER CONJUGATES AND MICROARRAY ASSAYS 124 TWO-DIMENSIONAL PHOTONIC CRYSTAL MICROARRAY MEASUREMENT METHOD AND APPARATUS FOR HIGHLY-SENSITIVE LABEL-FREE MULTIPLE ANALYTE SENSING, BIOSENSING, AND DIAGNOSTIC ASSAY SOURCE CONTROLLED DECODABLE MICROARRAY SYSTEM AND METHODS FOR USE MICROARRAY BASED SAMPLE DETECTION SYSTEM 125 MICROARRAY FABRICATION SYSTEM AND METHOD 125 MICROARRAY FOR DETECTING VIABLE ORGANISMS 126 SERUM-BASED MIRNA MICROARRAY AND ITS USE IN DIAGNOSIS AND TREATMENT OF BARRETT'S ESOPHAGUS (BE) AND ESOPHAGEAL ADENOCARCINOMA (EAC) LUMINOPHORE-LABELED MOLECULES COUPLED WITH PARTICLES FOR MICROARRAY-BASED ASSAYS Y-SHAPED PROBE AND VARIANT THEREOF, AND DNA MICROARRAY, KIT AND GENETIC ANALYSIS METHOD USING THE SAME MICROARRAY-BASED ASSAY INTEGRATED WITH PARTICLES FOR ANALYZING MOLECULAR INTERACTIONS MICROARRAY FABRICATION SYSTEM AND METHOD 128 ALLERGEN MICROARRAY 128 PHOTONIC CRYSTAL MICROARRAY LAYOUTS FOR ENHANCED SENSITIVITY AND SPECIFICITY OF LABEL-FREE MULTIPLE ANALYTE SENSING, BIOSENSING AND DIAGNOSTIC ASSAY ISH 129 TABLE 39 SELECTED ISH PATENTS GRANTED, JANUARY 2013 TO MAY 2015 129 CELL PREPARATIONS AND CELL SUPPORTS AND THEIR USE IN THERANOSIS 129 ULTRA SENSITIVE METHOD FOR IN SITU DETECTION OF NUCLEIC ACIDS 129 BACH2 REPRESSION IN CELLS 130 IN SITU HYBRIDIZATION METHOD AND BUFFER 130 BIOCHIP 131 TABLE 40 SELECTED BIOCHIP PATENTS GRANTED, JANUARY 2013 TO MAY 2015 131 BIOCHIP AND TARGET DNA QUANTITATIVE METHOD 131 UNITARY BIOCHIP PROVIDING SAMPLE-IN TO RESULTS-OUT PROCESSING AND METHODS OF MANUFACTURE BIOCHIP AND FABRICATION THEREOF 132 UNITARY BIOCHIP PROVIDING SAMPLE-IN TO RESULTS-OUT PROCESSING AND METHODS OF MANUFACTURE BIOCHIP ASSEMBLY AND ASSAY METHOD THEREOF 133 BIOCHIP 133 123 124 124 125 126 126 127 127 128 132 132 CHAPTER 9 COMPANY PROFILES 135 ABBOTT MOLECULAR 135 PRODUCT CATEGORIES 136 PARTNERSHIPS 136 ADVANDX INC. 136

AFFYMETRIX INC. 137 PRODUCTS 138 Agrigenomics Genotyping Solutions 138 Chromogenic RNA in situ Hybridization 138 Fluorescence RNA in situ Hybridization 139 AGILENT TECHNOLOGIES INC. 139 PRODUCTS 140 PCR/qPCR 140 AUTOGENOMICS INC. 142 PRODUCTS 143 BECKMAN COULTER INC. (OWNED BY DANAHER) 143 PRODUCTS 144 Pipeline 144 BECTON DICKINSON AND COMPANY 144 BIOMERIEUX SA 145 PRODUCTS 147 Argene Molecular Biology Range 147 BIO-RAD LABORATORIES 148 LIFE SCIENCE RESEARCH 148 CLINICAL DIAGNOSTICS 149 PRODUCTS 149 Amplification/PCR 149 Digital PCR 149 PrimePCR Assays and Panels 149 Real-Time PCR Detection Systems 149 Thermal Cyclers 149 PX1 PCR Plate Sealer 149 PCR Reagents 150 PCR Plastic Consumables 150 Amplification Software 150 Nucleic Acid Sample Preparation and Purification 150 CALIPER LIFE SCIENCES INC. 150 PRODUCTS 151 Microfluidics, Laboratory Automation and Liquid Handling 151 THE CARLYLE GROUP 151 CEPHEID 152 PRODUCTS 153 CURAGEN CORP. (ACQUIRED BY CELLDEX) 154 DECODE GENETICS 154 PRODUCTS AND SERVICES 155 DNA DIAGNOSTICS CENTER 155 SERVICES 155 ELITECH GROUP 157 EMD MILLIPORE 157 PRODUCTS 158 EUROGENTEC (OWNED BY KANEKA CORP.) 158 PRODUCTS 159

SERVICES 159 EXACT SCIENCES CORP. 160 GE HEALTHCARE 160 HOLOGIC INC. 161 PRODUCTS 162 HTG MOLECULAR DIAGNOSTICS 163 SERVICES 164 PRODUCTS 164 ILLUMINA 164 PRODUCTS 165 LABORATORY CORP. OF AMERICA (LABCORP) 165 LIFE TECHNOLOGIES 166 PRODUCTS 166 LUMINEX CORP 167 PRODUCTS 167 xmap technology 167 xtag Technology 168 MultiCode Technology 168 MICRONICS INC. 168 PRODUCTS 169 MYRIAD GENETICS 169 PRODUCTS 170 PRODUCTS IN DEVELOPMENT 171 NOVARTIS MOLECULAR DIAGNOSTICS 171 PRODUCTS 172 Development Strategy 172 Novartis Diagnostics Division Products 172 OXFORD GENE TECHNOLOGY IP LTD. 173 PRODUCTS 173 PATHOGENETIX 174 PROMEGA 175 QIAGEN N.V. 176 PRODUCTS 176 COMPANION DIAGNOSTICS 177 QUEST DIAGNOSTICS 178 PRODUCTS 178 IN DEVELOPMENT 178 ROCHE 179 TABLE 41 ROCHE-COMPANION DIAGNOSTICS PIPELINE JOINT ONCOLOGY PHARMA AND DIAGNOSTICS SAVYON DIAGNOSTICS 181 PRODUCTS 181 SEQUENOM INC. 182 PRODUCTS 183 APPLICATIONS 183 SIEMENS 184 SORENSON GENOMICS INC. 185 THERMO FISHER SCIENTIFIC INC. 185 181

TRANSGENOMIC INC. 186 PRODUCTS AND PIPELINES 187 Genetic Testing Services 187 In Development 188

LIST OF TABLES TABLE HEADING SUMMARY TABLE GLOBAL MARKET FOR MOLECULAR DIAGNOSTICS BY TECHNOLOGY, TABLE 1 MINIMUM INFORMATION ABOUT A MICROARRAY EXPERIMENT - MIAME 2.0 18 TABLE 2 MICROARRAY QUALITY CONTROL (MAQC) PROJECT 19 TABLE 3 U.S. LABORATORIES CLIA-CERTIFIED FOR MOLECULAR DIAGNOSTICS AND NUMBER OF DISEASE TESTS, 2012 TABLE 4 GENETIC TESTING PROCEDURES PERFORMED IN U.S. BY TYPE, 2015 22 TABLE 5 FDA-APPROVED IN VITRO COMPANION DIAGNOSTIC DEVICES AS OF DEC. 23, 2014 TABLE 6 FDA-APPROVED IN VITRO COMPANION DIAGNOSTIC DEVICES, AS OF DECEMBER 2012 TABLE 7 CURRENT PGRN-RIKEN CGM COLLABORATIVE STUDIES 43 TABLE 8 DIAGNOSTICS MANUFACTURER MERGERS AND ACQUISITIONS, 2004-2014 52 TABLE 9 GLOBAL MARKET FOR MOLECULAR DIAGNOSTICS BY TECHNOLOGY, TABLE 10 GLOBAL MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY TECHNOLOGY, 2015 (%) TABLE 11 GLOBAL MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY MANUFACTURER, 2015 (%) TABLE 12 GLOBAL MICROARRAY MARKET FOR MOLECULAR DIAGNOSTICS BY APPLICATION, TABLE 13 GLOBAL MICROARRAY MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY TABLE 14 MAJOR SUPPLIERS OF PLANAR DNA MICROARRAYS 63 TABLE 15 MAJOR SUPPLIERS OF BEAD MICROARRAYS 64 TABLE 16 GLOBAL PCR MARKET FOR MOLECULAR DIAGNOSTICS BY APPLICATION, TABLE 17 GLOBAL PCR MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY TABLE 18 GLOBAL PCR MARKET SHARE BY MANUFACTURER, 2015 (%) 67 TABLE 19 GLOBAL ISH MARKET FOR MOLECULAR DIAGNOSTICS BY APPLICATION, TABLE 20 GLOBAL ISH MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY TABLE 21 GLOBAL LAB-ON-A-CHIP/BIOCHIP MARKET FOR MOLECULAR DIAGNOSTICS BY APPLICATION, TABLE 22 GLOBAL LAB-ON-A-CHIP/BIOCHIP MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY TABLE 23 GLOBAL EMERGING/OTHER MOLECULAR DIAGNOSTICS MARKET BY APPLICATION, TABLE 24 GLOBAL EMERGING/OTHER MOLECULAR DIAGNOSTICS MARKET SHARE BY TABLE 25 GLOBAL MARKET FOR MOLECULAR DIAGNOSTICS BY APPLICATION, TABLE 26 GLOBAL MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY APPLICATION, 2015 (%) TABLE 27 GLOBAL PRE/POSTNATAL SCREENING MARKET FOR MOLECULAR DIAGNOSTICS BY APPLICATION, TABLE 28 GLOBAL PRE/POSTNATAL SCREENING MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY 6 21 28 34 57 57 59 61 62 65 66 71 72 76 76 79 80 82 83 88 88

TABLE HEADING TABLE 29 GLOBAL INFECTIOUS DISEASES MARKET FOR MOLECULAR DIAGNOSTICS BY APPLICATION, TABLE 30 GLOBAL INFECTIOUS DISEASE SCREENING MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY TABLE 31 GLOBAL ONCOLOGY MARKET FOR MOLECULAR DIAGNOSTICS BY APPLICATION, TABLE 32 GLOBAL ONCOLOGY MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY TABLE 33 GLOBAL IDENTITY TESTING MARKET FOR MOLECULAR DIAGNOSTICS BY APPLICATION, TABLE 34 GLOBAL IDENTITY TESTING MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY TABLE 35 GLOBAL PHARMACOGENOMICS AND OTHER MARKET FOR MOLECULAR DIAGNOSTICS BY APPLICATION, TABLE 36 GLOBAL PHARMACOGENOMICS AND OTHER MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY TABLE 37 SELECTED PCR PATENTS GRANTED FROM JANUARY 2013 TO JANUARY 2015 TABLE 38 SELECTED MICROARRAY PATENTS GRANTED, JANUARY 2013 TO MAY 2015 123 TABLE 39 SELECTED ISH PATENTS GRANTED, JANUARY 2013 TO MAY 2015 129 TABLE 40 SELECTED BIOCHIP PATENTS GRANTED, JANUARY 2013 TO MAY 2015 131 TABLE 41 ROCHE-COMPANION DIAGNOSTICS PIPELINE JOINT ONCOLOGY PHARMA AND DIAGNOSTICS 91 91 94 95 98 98 103 103 105 181

LIST OF FIGURES FIGURE TITLE SUMMARY FIGURE GLOBAL MARKET FOR MOLECULAR DIAGNOSTICS BY TECHNOLOGY, 2012-2020 ($ MILLIONS) FIGURE 1 GROWTH IN CLINICAL LABORATORY SITES AND DISEASE TESTING, 1993-2015 FIGURE 2 GLOBAL MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY TECHNOLOGY, 2015 (%) FIGURE 3 GLOBAL MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY MANUFACTURER, 2015 (%) FIGURE 4 GLOBAL MICROARRAY MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY FIGURE 5 GLOBAL PCR MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY FIGURE 6 GLOBAL ISH MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY FIGURE 7 GLOBAL LAB-ON-A-CHIP/BIOCHIP MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY FIGURE 8 GLOBAL MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY APPLICATION, 2015 (%) FIGURE 9 GLOBAL PRE/POSTNATAL SCREENING MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY FIGURE 10 GLOBAL INFECTIOUS DISEASE SCREENIN MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY FIGURE 11 GLOBAL ONCOLOGY MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY FIGURE 12 GLOBAL IDENTITY TESTING MARKET SHARE FOR MOLECULAR DIAGNOSTICS BY 6 21 57 59 62 66 72 77 83 88 91 95 98