CONTENTS

6 EXECUTIVE SUMMARY
6 Gene editing technologies evolve and improve over time
6 Multiple researchers have contributed to key academic discoveries in CRISPR/Cas9
6 The dispute over foundational CRISPR/Cas9 patents carries on
7 Many challenges and controversies remain in advancing CRISPR/Cas9 technology
7 Many players, from small biotechs to Big Pharma, are developing gene editing drug candidates
8 The gene editing pipeline is a small proportion of regenerative medicine therapies, and is dominated by CRISPR/Cas9

9 EVOLUTION OF GENE EDITING TECHNOLOGY
9 Gene editing can radically change how diseases are targeted
9 Gene editing is an emerging modality within the broader regenerative medicine market
10 Zinc-finger nucleases
12 Transcription activator-like effector nucleases
14 CRISPR/Cas9
17 Bibliography

20 ORIGINS OF ACADEMIC RESEARCH IN CRISPR/CAS9
20 Academic research over the last 20 years has helped to advance CRISPR/Cas9 technology toward human therapeutic use
21 Many start-ups have been borne out of CRISPR/Cas9 academic research
22 Bibliography

24 CRISPR/CAS9 PATENT LITIGATION
24 Select key patent filings, issuances, and decisions
27 Patent pools and cross-licensing may help commercial drug developers avoid intellectual property barriers in the future
28 Bibliography

31 CHALLENGES AND CONTROVERSIES WITH GENE EDITING
31 Process challenges exist for gene editing tools
32 Editing human embryos pose ethical concerns
33 Safety issues plague gene editing
33 As is the case with many regenerative medicines, cost of gene editing therapies may be prohibitive
34 Bibliography

36 KEY COMPANIES IN GENE EDITING
36 Key players in gene editing span both biotech and large pharma companies
36 Profiles of select key gene editing companies
48 Through deal-making, large pharmaceutical companies have gotten involved in gene editing
52 Bibliography

54 GENE EDITING PIPELINE TRENDS
54 CRISPR/Cas9 gene editing candidates represent the majority of the gene editing pipeline
54 ZFN therapies are the most advanced by phase
55 Rare diseases lead gene editing therapy areas
57 CRISPR/Cas9 is now being tested in humans
58 Editas and Intellia are on deck to initiating CRISPR/Cas9 Phase I trials
58 Bibliography

60 APPENDIX
60 Scope
60 Methodology

LIST OF FIGURES
11 Figure 1: Zinc finger nuclease gene editing tool
12 Figure 2: Zinc-finger nuclease advantages and disadvantages
13 Figure 3: Transcription activator-like effector nuclease gene editing tool
14 Figure 4: Transcription activator-like effector nucleases advantages and disadvantages
17 Figure 5: CRISPR/Cas9 gene editing tool
17 Figure 6: CRISPR/Cas9 advantages and disadvantages
20 Figure 7: Timeline of select key academic research discoveries in CRISPR/Cas9 as it has evolved toward human therapeutic use, 1987–2013
24 Figure 8: Timeline of select key patent actions in CRISPR/Cas9 technology, 2012–17
31 Figure 9: Key challenges and controversies with gene editing
36 Figure 10: Editas Medicine and CRISPR Therapeutics lead the most active gene editing companies
54 Figure 11: CRISPR/Cas9 technology dominates the gene editing pipeline, preclinical–Phase II*
55 Figure 12: First-generation ZFN technology leads to more advanced candidates in the gene editing pipeline
56 Figure 13: Rare diseases are most often targeted by gene editing candidates
57 Figure 14: Gene editing pipeline volume by indication
LIST OF TABLES
9 Table 1: Overview of gene editing technologies
22 Table 2: CRISPR/cas9 start-up company academic origins
38 Table 3: Key gene editing companies
42 Table 4: Cellectis’ gene editing pipeline
43 Table 5: CRISPR Therapeutics’ gene editing pipeline
45 Table 6: Editas Medicine’ gene editing pipeline
46 Table 7: Intellia Therapeutics’ gene editing pipeline
47 Table 8: Sangamo Therapeutics’ gene editing pipeline
49 Table 9: Key gene editing deals involving large pharmaceutical companies, 2012–17*