JAK AND PI3K SIGNALING PATHWAY MARKETS

Transcription

1 JAK AND PI3K SIGNALING PATHWAY MARKETS PHM168A April 2014 Shalini Shahani Dewan 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 OBJECTIVES 2 REASONS FOR DOING THIS STUDY 2 CONTRIBUTIONS OF THE STUDY AND FOR WHOM 3 SCOPE OF THE STUDY 3 METHODOLOGY 3 INFORMATION SOURCES 3 ABOUT THE AUTHOR 4 RELATED BCC RESEARCH REPORTS 4 BCC RESEARCH WEBSITE 5 DISCLAIMER 5 CHAPTER 2 EXECUTIVE SUMMARY 7 SUMMARY TABLE GLOBAL REVENUE OF SIGNAL TRANSDUCTION THERAPIES/INHIBITORS (JAK AND PI3K), THROUGH 2018 ($ MILLIONS) SUMMARY FIGURE GLOBAL REVENUE OF SIGNAL TRANSDUCTION THERAPIES/INHIBITORS (JAK AND PI3K), ) ($ MILLIONS) 8 8 CHAPTER 3 OVERVIEW 11 JANUS KINASE (JAK) AND PHOSPHOINOSITIDE 3-KINASES (PI3K) 11 SIGNAL TRANSDUCTION THERAPIES/INHIBITORS FOR JAK AND PI3K 11 MECHANISM OF ACTION 12 Janus Kinase Therapies/Inhibitors 12 Phosphoinositide 3-kinases (PI3K) Therapies/Inhibitors 12 APPROVED HISTONE DEACETYLASE INHIBITORS 12 CLASSIFICATION 13 JANUS KINASE (JAK) 13 TABLE 1 CLASSIFICATION OF JANUS KINASE (JAK) 13 PHOSPHOINOSITIDE 3-KINASES (PI3K) 13 TABLE 2 CLASSIFICATION OF PHOSPHOINOSITIDE 3-KINASES (PI3K) 14 JANUS KINASE THERAPIES/INHIBITORS 14 Ruxolitinib (INC424/INCB18424) 15 FIGURE 1 STRUCTURE OF INC424 (RUXOLITINIB) 15 Tofacitinib (CP-690,550) 15 FIGURE 2 STRUCTURE OF CP-690,550 (TOFACITINIB) 16 Baricitinib (INC28050/LY ) 16 FIGURE 3 STRUCTURE OF BARICITINIB (INC28050/LY ) 16 NS Momelotinib (CYT-387) 17 FIGURE 4 STRUCTURE OF MOMELOTINIB (CYT-387) 17 AT FIGURE 5 STRUCTURE OF AT Pacritinib (SB1518) 18 FIGURE 6 STRUCTURE OF PACRITINIB (SB1518) 18 LY FIGURE 7 STRUCTURE OF LY

3 TG (SAR302503) 19 FIGURE 8 STRUCTURE OF TG (SAR302503) 19 BMS FIGURE 9 STRUCTURE OF BMS Lestaurtinib (CEP-701) 20 FIGURE 10 STRUCTURE OF LESTAURTINIB (CEP-701) 20 LS WP FIGURE 11 STRUCTURE OF WP AG FIGURE 12 STRUCTURE OF AG AZD FIGURE 13 STRUCTURE OF AZD INCB INCB PHOSPHOINOSITIDE 3-KINASES (PI3K) THERAPIES/INHIBITORS 23 Wortmannin 24 FIGURE 14 STRUCTURE OF WORTMANNIN 24 Perifosine (KRX-0401) 25 FIGURE 15 STRUCTURE OF PERIFOSINE (KRX-0401) 25 LY FIGURE 16 STRUCTURE OF LY Idelalisib (GS-1101, CAL-101) 26 FIGURE 17 STRUCTURE OF IDELALISIB (GS-1101, CAL-101) 26 PX FIGURE 18 STRUCTURE OF PX IPI FIGURE 19 STRUCTURE OF IPI BKM FIGURE 20 STRUCTURE OF BKM Copanlisib (BAY ) 29 FIGURE 21 STRUCTURE OF COPANLISIB (BAY ) 29 PF (PKI-587) 29 FIGURE 22 STRUCTURE OF PF (PKI-587) 30 Pictilisib (GDC-0941) 30 FIGURE 23 STRUCTURE OF PICTILISIB (GDC-0941) 30 Dactolisib (BEZ235) 31 FIGURE 24 STRUCTURE OF DACTOLISIB (BEZ235) 31 Apitolisib (GDC-0980) 31 FIGURE 25 STRUCTURE OF APITOLISIB (GDC-0980) 31 ZSTK FIGURE 26 STRUCTURE OF ZSTK SAR (XL765) 32 FIGURE 27 STRUCTURE OF SAR (XL765) 33 SAR (XL147) 33 FIGURE 28 STRUCTURE OF APITOLISIB SAR (XL147) 33 BYL719 34

4 FIGURE 29 STRUCTURE OF APITOLISIB BYL SIGNAL TRANSDUCTION BIOMARKERS FOR JAK AND PI3K 34 PROSPECTIVE DISEASE TARGETS FOR JAK AND PI3K THERAPIES 35 TABLE 3 SIGNAL TRANSDUCTION THERAPIES/INHIBITORS - PROSPECTIVE DISEASE TARGETS 36 CHAPTER 4 REGULATORY ASPECTS 42 RUXOLITINIB (INC424) 43 DOSING INFORMATION 43 Dose Modifications 43 SAFETY INFORMATION 43 Safety of Ruxolitinib in Specific Population 44 RISK OF INFECTION 45 Tuberculosis 45 Progressive Multifocal Leukoencephalopathy (PML) 45 Herpes Zoster 45 TOFACITINIB (CP-690,550) 45 DOSING INFORMATION 45 Dose Modifications 45 SAFETY INFORMATION 46 Safety of Tofacitinib in Specific Populations 46 RISK OF INFECTION 47 Tuberculosis 47 REGULATORY DEVELOPMENTS OF SIGNAL TRANSDUCTION THERAPIES/INHIBITORS/BIOMARKERS 47 CHAPTER 5 NEW DEVELOPMENTS 50 NEW DEVELOPMENTS 50 TABLE 4 NEW DEVELOPMENTS IN THE RESEARCH PIPELINE OF SIGNAL TRANSDUCTION THERAPIES (JAK AND PI3K) AS SINGLE AGENT TABLE 5 NEW DEVELOPMENTS IN THE RESEARCH PIPELINE OF SIGNAL TRANSDUCTION THERAPIES (JAK AND PI3K) IN COMBINATION WITH OTHER AGENTS TABLE 6 NUMBER OF ONGOING TRIALS FOR MAJOR SIGNAL TRANSDUCTION THERAPIES (JAK AND PI3K) AS SINGLE AGENT AND COMBINATION THERAPY COLLABORATIVE TRIALS AND FUTURE ACTIVITIES CHAPTER 6 MARKET ANALYSIS-SIGNAL TRANSDUCTION THERAPIES (JAK AND PI3K) 70 MARKET BY THE TYPE 71 TABLE 7 GLOBAL MARKET FOR SIGNAL TRANSDUCTION THERAPIES/INHIBITORS/BIOMARKERS BY TYPE, THROUGH 2018 ($ MILLIONS) FIGURE 30 GLOBAL MARKET FOR SIGNAL TRANSDUCTION THERAPIES/INHIBITORS/BIOMARKERS BY TYPE, RUXOLITINIB (INC424, INCB18424)-JANUS KINASE (JAK) INHIBITOR 72 Market Overview 72 Market Revenue 73 TABLE 8 GLOBAL MARKET FOR RUXOLITINIB (INC424, INCB18424, JAKAFI) BY REGION, THROUGH 2018 ($ MILLIONS) FIGURE 31 GLOBAL MARKET FOR RUXOLITINIB (INC424, INCB18424, JAKAFI) BY REGION, ($ MILLIONS)

5 TOFACITINIB (CP-690,550)-JANUS KINASE (JAK) INHIBITOR 74 Market Overview 75 Market Revenue 75 TABLE 9 GLOBAL MARKET FOR TOFACITINIB (CP-690,550) BY REGION, THROUGH 2018 ($ MILLIONS) FIGURE 32 GLOBAL MARKET FOR TOFACITINIB (CP-690,550) BY REGION, ($ MILLIONS) MARKET SHARE 77 TABLE 10 MARKET SHARE OF SIGNAL TRANSDUCTION THERAPIES/INHIBITORS/BIOMARKERS BY TYPE, 2013 (%) FIGURE 33 MARKET SHARE OF SIGNAL TRANSDUCTION THERAPIES/INHIBITORS/BIOMARKERS BY TYPE, 2013 (%) MARKET BY REGION 77 MARKET OVERVIEW 78 MARKET REVENUE 79 TABLE 11 REGIONAL BREAKDOWN FOR SALES OF SIGNAL TRANSDUCTION THERAPIES/INHIBITORS/BIOMARKERS, THROUGH 2018 ($ MILLIONS) FIGURE 34 REGIONAL BREAKDOWN FOR SALES OF SIGNAL TRANSDUCTION THERAPIES/INHIBITORS/BIOMARKERS, ($ MILLIONS) MARKET SHARE 80 TABLE 12 MARKET SHARE OF SIGNAL TRANSDUCTION THERAPIES/INHIBITORS/BIOMARKERS BY REGION, 2013 ($ MILLIONS) FIGURE 35 MARKET SHARE OF SIGNAL TRANSDUCTION THERAPIES/ INHIBITORS/BIOMARKERS BY REGION, 2013 ($ MILLIONS) PROSPECTIVE FUTURE MARKET FOR SIGNAL TRANSDUCTION THERAPIES (JAK AND PI3K) INDUSTRY STRUCTURE 81 MARKET LEADERS 82 TABLE 13 LEADING MANUFACTURERS/SUPPLIERS OF SIGNAL TRANSDUCTION THERAPIES/INHIBITORS/BIOMARKERS MARKET SHARES 83 TABLE 14 MARKET SHARES OF MANUFACTURERS FOR SIGNAL TRANSDUCTION THERAPIES/INHIBITORS/BIOMARKERS, 2013 (%) FIGURE 36 MARKET SHARES OF MANUFACTURERS FOR SIGNAL TRANSDUCTION THERAPIES/INHIBITORS/BIOMARKERS, 2013 (%) MARKET APPLICATIONS 84 TABLE 15 APPLICATION AREAS OF COMBINATION THERAPY OF SIGNAL TRANSDUCTION THERAPIES/INHIBITORS (FOR JAK AND PI3K) WITH OTHER THERAPIES MYELOFIBROSIS 86 RHEUMATOID ARTHRITIS 86 MARKET OVERVIEW 87 MARKET REVENUE 89 TABLE 16 GLOBAL MARKET FOR SIGNAL TRANSDUCTION THERAPIES/INHIBITORS/BIOMARKERS (JAK AND PI3K) BY TYPE, THROUGH 2018 ($ MILLIONS) FIGURE 37 GLOBAL MARKET FOR SIGNAL TRANSDUCTION THERAPIES/INHIBITORS/BIOMARKERS (JAK AND PI3K) BY TYPE, ($ MILLIONS) MARKET SHARE

6 TABLE 17 MARKET SHARE OF SIGNAL TRANSDUCTION THERAPIES/INHIBITORS/BIOMARKERS (JAK AND PI3K) BY APPLICATION, 2013 (%) FIGURE 38 MARKET SHARE OF SIGNAL TRANSDUCTION THERAPIES/ INHIBITORS/BIOMARKERS (JAK AND PI3K) BY APPLICATION, 2013 (%) PROSPECTIVE APPLICATION OF SIGNAL TRANDUCTION THERAPIES/INHIBITORS/BIOMARKERS (JAK AND PI3K) CANCER 91 INFLAMMATORY DISEASES 92 CARDIAC AILMENTS 92 OTHERS CHAPTER 7 PATENT ANALYSIS 95 PATENTS BY YEAR 96 TABLE 18 TOTAL NUMBER OF PATENTS EACH YEAR, FIGURE 39 TOTAL NUMBER OF PATENTS EACH YEAR, PATENTS BY SIGNAL TRANSDUCTION THERAPIES CATEGORY (JAK AND PI3K) 96 TABLE 19 NUMBER OF PATENTS BY SIGNAL TRANSDUCTION THERAPIES/ INHIBITORS/BIOMARKERS CATEGORY, FIGURE 40 NUMBER OF PATENTS BY SIGNAL TRANSDUCTION THERAPIES/ INHIBITORS/BIOMARKERS CATEGORY, PATENTS BY SIGNAL TRANSDUCTION THERAPIES TYPE 97 PATENTS BY JANUS KINASE (JAK) BASED THERAPIES/ INHIBITORS/BIOMARKERS TABLE 20 PATENTS BY TYPES OF JANUS KINASE (JAK) BASED FIGURE 41 PATENTS BY TYPES OF JANUS KINASE (JAK) BASED THERAPIES/ INHIBITORS/BIOMARKERS, PATENTS BY PHOSPHOINOSITIDE 3-KINASES (PI3K) BASED THERAPIES/INHIBITORS/BIOMARKERS TABLE 21 PATENTS BY TYPES OF PHOSPHOINOSITIDE 3-KINASES (PI3K) BASED FIGURE 42 PATENTS BY TYPES OF PHOSPHOINOSITIDE 3-KINASES (PI3K) BASED PATENTS BY COUNTRY 99 JANUS KINASE (JAK) BASED THERAPIES/INHIBITORS/BIOMARKERS 99 TABLE 22 NUMBER OF PATENTS BY COUNTRY FOR JANUS KINASE (JAK) BASED FIGURE 43 NUMBER OF PATENTS BY COUNTRY FOR JANUS KINASE (JAK) BASED TABLE 23 PATENT SHARES BY COUNTRY FOR JANUS KINASE BASED (%) FIGURE 44 PATENT SHARES BY COUNTRY FOR JANUS KINASE BASED (%) PHOSPHOINOSITIDE 3-KINASES (PI3K) BASED THERAPIES/ INHIBITORS/BIOMARKERS TABLE 24 NUMBER OF PATENTS BY COUNTRY FOR PHOSPHOINOSITIDE 3-KINASES (PI3K) BASED FIGURE 45 NUMBER OF PATENTS BY COUNTRY FOR PHOSPHOINOSITIDE 3-KINASES (PI3K) BASED TABLE 25 PATENT SHARES BY COUNTRY FOR PHOSPHOINOSITIDE 3-KINASES (PI3K) BASED (%)

7 FIGURE 46 PATENT SHARES BY COUNTRY FOR PHOSPHOINOSITIDE 3-KINASES (PI3K) BASED (%) PATENTS BY COMPANY 103 JANUS KINASE (JAK) BASED THERAPIES/INHIBITORS/BIOMARKERS 103 TABLE 26 NUMBER OF U.S. PATENTS BY COMPANY FOR JANUS KINASE (JAK) BASED PHOSPHOINOSITIDE 3-KINASES (PI3K) BASED THERAPIES/ INHIBITORS/BIOMARKERS TABLE 27 NUMBER OF U.S. PATENTS BY COMPANY FOR PHOSPHOINOSITIDE 3-KINASES (PI3K) BASED PATENTS BY ASSIGNEE 106 JANUS KINASE (JAK) BASED THERAPIES/INHIBITORS/BIOMARKERS 106 TABLE 28 PATENTS BY ASSIGNEE FOR JANUS KINASE (JAK) BASED FIGURE 47 PATENTS BY ASSIGNEE FOR JANUS KINASE (JAK) BASED PHOSPHOINOSITIDE 3-KINASES (PI3K) BASED THERAPIES/INHIBITORS/BIOMARKERS TABLE 29 PATENTS BY ASSIGNEE FOR PHOSPHOINOSITIDE 3-KINASES (PI3K) BASED FIGURE 48 PATENTS BY ASSGINEE FOR PHOSPHOINOSITIDE 3-KINASES (PI3K) BASED CHAPTER 8 CURRENT SITUATION 110 NEW TECHNOLOGIES AND PLATFORMS IN SIGNAL TRANSDUCTION THERAPIES (JAK AND PI3K) SCREENING TECHNOLOGY 111 PYRAMID 111 BIOMARKERS 111 FACTORS AFFECTING THE SIGNAL TRANSDUCTION THERAPIES (JAK AND PI3K) MARKET CURRENT DRIVERS OF SIGNAL TRANSDUCTION THERAPIES (JAK AND PI3K) MARKET COLLABORATIONS/ACQUISITIONS 113 TABLE 30 FUNDINGS IN SIGNAL TRANDUCTION THERAPIES/INHIBITORS/BIOMARKERS (JAK AND PI3K) CHAPTER 9 COMPANY PROFILES 117 ABBVIE INC. 117 AETERNA ZENTARIS INC. 117 AMGEN INC 119 ASTELLAS PHARMA INC. 119 ASTEX PHARMACEUTICALS INC 120 ASTRAZENECA PLC 121 BAYER HEALTHCARE PHARMACEUTICALS 121 CELL THERAPEUTICS INC 122 CURIS INC. 124 DAIICHI SANKYO CO. LTD 124 ELI LILLY AND CO. 125 EXELIXIS INC. 126

8 GALAPAGOS NV 126 GENENTECH INC 128 GILEAD SCIENCES INC. 128 GLAXOSMITHKLINE 129 INCYTE CORP. 130 INFINITY PHARMACEUTICALS INC. 132 ITALFARMACO S.P.A. 133 JANSSEN BIOTECH INC. 134 MEI PHARMA INC. 134 MERCK & CO. INC. 135 MILLENNIUM 135 NATIONAL CANCER INSTITUTE 136 NIPPON ZENYAKU KOGYO CO., LTD. 137 NOVARTIS INTERNATIONAL AG 138 NS PHARMA, INC 139 ONCOTHYREON INC 139 PATHWAY THERAPEUTICS LTD 140 PFIZER 141 PIRAMAL ENTERPRISES LIMITED 142 PORTOLA PHARMACEUTICALS INC 142 RIGEL PHARMACEUTICALS INC. 143 SANOFI ONCOLOGY 144 TEVA PHARMACEUTICALS INDUSTRIES LTD 145 TG THERAPEUTICS INC. 146 VERASTEM INC. 146 VERTEX PHARMACEUTICALS INC 147 WILEX AG 148 XCOVERY HOLDING COMPANY, LLC 148 CHAPTER 10 APPENDIX I-ABBREVIATIONS 151

9 LIST OF TABLES TABLE HEADING SUMMARY TABLE GLOBAL REVENUE OF SIGNAL TRANSDUCTION THERAPIES/INHIBITORS (JAK AND PI3K), THROUGH 2018 ($ MILLIONS) TABLE 1 CLASSIFICATION OF JANUS KINASE (JAK) 13 TABLE 2 CLASSIFICATION OF PHOSPHOINOSITIDE 3-KINASES (PI3K) 14 TABLE 3 SIGNAL TRANSDUCTION THERAPIES/INHIBITORS - PROSPECTIVE DISEASE TARGETS TABLE 4 NEW DEVELOPMENTS IN THE RESEARCH PIPELINE OF SIGNAL TRANSDUCTION THERAPIES (JAK AND PI3K) AS SINGLE AGENT TABLE 5 NEW DEVELOPMENTS IN THE RESEARCH PIPELINE OF SIGNAL TRANSDUCTION THERAPIES (JAK AND PI3K) IN COMBINATION WITH OTHER AGENTS TABLE 6 NUMBER OF ONGOING TRIALS FOR MAJOR SIGNAL TRANSDUCTION THERAPIES (JAK AND PI3K) AS SINGLE AGENT AND COMBINATION THERAPY TABLE 7 GLOBAL MARKET FOR SIGNAL TRANSDUCTION THERAPIES/INHIBITORS/BIOMARKERS BY TYPE, THROUGH 2018 ($ MILLIONS) TABLE 8 GLOBAL MARKET FOR RUXOLITINIB (INC424, INCB18424, JAKAFI) BY REGION, THROUGH 2018 ($ MILLIONS) TABLE 9 GLOBAL MARKET FOR TOFACITINIB (CP-690,550) BY REGION, THROUGH 2018 ($ MILLIONS) TABLE 10 MARKET SHARE OF SIGNAL TRANSDUCTION THERAPIES/INHIBITORS/BIOMARKERS BY TYPE, 2013 (%) TABLE 11 REGIONAL BREAKDOWN FOR SALES OF SIGNAL TRANSDUCTION THERAPIES/INHIBITORS/BIOMARKERS, THROUGH 2018 ($ MILLIONS) TABLE 12 MARKET SHARE OF SIGNAL TRANSDUCTION THERAPIES/INHIBITORS/BIOMARKERS BY REGION, 2013 ($ MILLIONS) TABLE 13 LEADING MANUFACTURERS/SUPPLIERS OF SIGNAL TRANSDUCTION THERAPIES/INHIBITORS/BIOMARKERS TABLE 14 MARKET SHARES OF MANUFACTURERS FOR SIGNAL TRANSDUCTION THERAPIES/INHIBITORS/BIOMARKERS, 2013 (%) TABLE 15 APPLICATION AREAS OF COMBINATION THERAPY OF SIGNAL TRANSDUCTION THERAPIES/INHIBITORS (FOR JAK AND PI3K) WITH OTHER THERAPIES TABLE 16 GLOBAL MARKET FOR SIGNAL TRANSDUCTION THERAPIES/INHIBITORS/BIOMARKERS (JAK AND PI3K) BY TYPE, THROUGH 2018 ($ MILLIONS) TABLE 17 MARKET SHARE OF SIGNAL TRANSDUCTION THERAPIES/INHIBITORS/BIOMARKERS (JAK AND PI3K) BY APPLICATION, 2013 (%) TABLE 18 TOTAL NUMBER OF PATENTS EACH YEAR, TABLE 19 NUMBER OF PATENTS BY SIGNAL TRANSDUCTION THERAPIES/ INHIBITORS/BIOMARKERS CATEGORY, TABLE 20 PATENTS BY TYPES OF JANUS KINASE (JAK) BASED TABLE 21 PATENTS BY TYPES OF PHOSPHOINOSITIDE 3-KINASES (PI3K) BASED TABLE 22 NUMBER OF PATENTS BY COUNTRY FOR JANUS KINASE (JAK) BASED TABLE 23 PATENT SHARES BY COUNTRY FOR JANUS KINASE BASED (%) TABLE 24 NUMBER OF PATENTS BY COUNTRY FOR PHOSPHOINOSITIDE 3-KINASES (PI3K) BASED TABLE 25 PATENT SHARES BY COUNTRY FOR PHOSPHOINOSITIDE 3-KINASES (PI3K) BASED (%)

10 TABLE HEADING TABLE 26 NUMBER OF U.S. PATENTS BY COMPANY FOR JANUS KINASE (JAK) BASED TABLE 27 NUMBER OF U.S. PATENTS BY COMPANY FOR PHOSPHOINOSITIDE 3-KINASES (PI3K) BASED TABLE 28 PATENTS BY ASSIGNEE FOR JANUS KINASE (JAK) BASED TABLE 29 PATENTS BY ASSIGNEE FOR PHOSPHOINOSITIDE 3-KINASES (PI3K) BASED TABLE 30 FUNDINGS IN SIGNAL TRANDUCTION THERAPIES/INHIBITORS/BIOMARKERS (JAK AND PI3K)

11 LIST OF FIGURES FIGURE TITLE SUMMARY FIGURE GLOBAL REVENUE OF SIGNAL TRANSDUCTION THERAPIES/INHIBITORS (JAK AND PI3K), ) ($ MILLIONS) FIGURE 1 STRUCTURE OF INC424 (RUXOLITINIB) 15 FIGURE 2 STRUCTURE OF CP-690,550 (TOFACITINIB) 16 FIGURE 3 STRUCTURE OF BARICITINIB (INC28050/LY ) 16 FIGURE 4 STRUCTURE OF MOMELOTINIB (CYT-387) 17 FIGURE 5 STRUCTURE OF AT FIGURE 6 STRUCTURE OF PACRITINIB (SB1518) 18 FIGURE 7 STRUCTURE OF LY FIGURE 8 STRUCTURE OF TG (SAR302503) 19 FIGURE 9 STRUCTURE OF BMS FIGURE 10 STRUCTURE OF LESTAURTINIB (CEP-701) 20 FIGURE 11 STRUCTURE OF WP FIGURE 12 STRUCTURE OF AG FIGURE 13 STRUCTURE OF AZD FIGURE 14 STRUCTURE OF WORTMANNIN 24 FIGURE 15 STRUCTURE OF PERIFOSINE (KRX-0401) 25 FIGURE 16 STRUCTURE OF LY FIGURE 17 STRUCTURE OF IDELALISIB (GS-1101, CAL-101) 26 FIGURE 18 STRUCTURE OF PX FIGURE 19 STRUCTURE OF IPI FIGURE 20 STRUCTURE OF BKM FIGURE 21 STRUCTURE OF COPANLISIB (BAY ) 29 FIGURE 22 STRUCTURE OF PF (PKI-587) 30 FIGURE 23 STRUCTURE OF PICTILISIB (GDC-0941) 30 FIGURE 24 STRUCTURE OF DACTOLISIB (BEZ235) 31 FIGURE 25 STRUCTURE OF APITOLISIB (GDC-0980) 31 FIGURE 26 STRUCTURE OF ZSTK FIGURE 27 STRUCTURE OF SAR (XL765) 33 FIGURE 28 STRUCTURE OF APITOLISIB SAR (XL147) 33 FIGURE 29 STRUCTURE OF APITOLISIB BYL FIGURE 30 GLOBAL MARKET FOR SIGNAL TRANSDUCTION THERAPIES/INHIBITORS/BIOMARKERS BY TYPE, FIGURE 31 GLOBAL MARKET FOR RUXOLITINIB (INC424, INCB18424, JAKAFI) BY REGION, ($ MILLIONS) FIGURE 32 GLOBAL MARKET FOR TOFACITINIB (CP-690,550) BY REGION, ($ MILLIONS) FIGURE 33 MARKET SHARE OF SIGNAL TRANSDUCTION THERAPIES/INHIBITORS/BIOMARKERS BY TYPE, 2013 (%) FIGURE 34 REGIONAL BREAKDOWN FOR SALES OF SIGNAL TRANSDUCTION THERAPIES/INHIBITORS/BIOMARKERS, ($ MILLIONS) FIGURE 35 MARKET SHARE OF SIGNAL TRANSDUCTION THERAPIES/ INHIBITORS/BIOMARKERS BY REGION, 2013 ($ MILLIONS) FIGURE 36 MARKET SHARES OF MANUFACTURERS FOR SIGNAL TRANSDUCTION THERAPIES/INHIBITORS/BIOMARKERS, 2013 (%) FIGURE 37 GLOBAL MARKET FOR SIGNAL TRANSDUCTION THERAPIES/INHIBITORS/BIOMARKERS (JAK AND PI3K) BY TYPE, ($ MILLIONS)

12 FIGURE TITLE FIGURE 38 MARKET SHARE OF SIGNAL TRANSDUCTION THERAPIES/ INHIBITORS/BIOMARKERS (JAK AND PI3K) BY APPLICATION, 2013 (%) FIGURE 39 TOTAL NUMBER OF PATENTS EACH YEAR, FIGURE 40 NUMBER OF PATENTS BY SIGNAL TRANSDUCTION THERAPIES/ INHIBITORS/BIOMARKERS CATEGORY, FIGURE 41 PATENTS BY TYPES OF JANUS KINASE (JAK) BASED THERAPIES/ INHIBITORS/BIOMARKERS, FIGURE 42 PATENTS BY TYPES OF PHOSPHOINOSITIDE 3-KINASES (PI3K) BASED FIGURE 43 NUMBER OF PATENTS BY COUNTRY FOR JANUS KINASE (JAK) BASED FIGURE 44 PATENT SHARES BY COUNTRY FOR JANUS KINASE BASED (%) FIGURE 45 NUMBER OF PATENTS BY COUNTRY FOR PHOSPHOINOSITIDE 3-KINASES (PI3K) BASED FIGURE 46 PATENT SHARES BY COUNTRY FOR PHOSPHOINOSITIDE 3-KINASES (PI3K) BASED (%) FIGURE 47 PATENTS BY ASSIGNEE FOR JANUS KINASE (JAK) BASED FIGURE 48 PATENTS BY ASSGINEE FOR PHOSPHOINOSITIDE 3-KINASES (PI3K) BASED