Controlling CRISPR. How the rapidly changing patent and regulatory environment may affect commercial applications of genome editing

Transcription

1 Controlling CRISPR How the rapidly changing patent and regulatory environment may affect commercial applications of genome editing Gregory Graff Agricultural & Resource Economics Colorado State University David Zilberman Agricultural & Resource Economics University of California, Berkeley Rocky Mountain Food Safety Conference Johnson & Wales University, Denver, CO May 24, 2017

2 The rise of CRISPR gene editing

3 Introduction Recent breakthroughs in gene editing, especially the introduction in 2012 of CRISPR, have led to an unprecedented proliferation in applications. Gene-edited agricultural and food applications are arising within an intellectual property (IP) and regulatory context shaped by previous technologies for creating genetically-modified organisms (GMOs). Yet, some major departures from the IP and regulatory conditions that characterized GMOs, could put gene-edited agricultural innovations on a very different trajectory toward market uptake.

4 From genetic transformation to gene editing Genetic transformation technologies: 1973 Cohen and Boyer Restriction enzymes and recombinant DNA in bacteria 1979 Wigler, Silverstein and Axel Co-transformation of eukaryotes 1982 Chilton; Schell Agrobacterium transformation of plants 1987 Sanford Biolistic ( gene gun ) transformation of plants Gene editing by nucleases: 1994 Zinc Finger Nucleases 2011 TALENS 2012 CRISPR-Cas9

5 CRISPR = Clustered, Regularly Interspaced, Short Palindromic Repeats Cas9 = CRISPR Associated nuclease 9 A molecular tool that can be programmed to target any possible matching DNA sequence in the genome of any species, and initiate a wide range of changes at that site.

6 CRISPR timeline: JENNIFER DOUDNA, UC Berkeley, and EMMANUEL CHARPENTIER, University of Vienna June 2012, paper in Science 1987 Unusual repeat DNA pattern first noticed in bacteria 2002 Associated protein identified; named CRISPR 2007 Found effective against viral pathogens: a microbial immune system Jan 2013, paper in Science FENG ZHANG et al, Broad Institute and MIT 2017

7 How the CRISPR-Cas system works In the gene editing version: 1. Guide RNAs are created by the researcher to target a specific location in the genome of a target organism 2. Guide RNA finds that specific genomic sequence in the target organism In bacteria s natural version: 1. Guide RNAs are created from the bacteria s CRISPR library 2. Guide RNA find genomic sequence specific to invading virus s genomic DNA, leading an attached Cas9 to that site. 3. Cas9 protien cuts the virus s genomic DNA at that site. 3. Guides a modified Cas9 or other nucleases such as Cpf1 to make customized edits: cut nick deletion insertion single-nucleotide substitution epigenetic modification: upregulation epigenetic modification: downregulation

8 CRISPR will affect almost every aspect of life, and provide inspiration for future technological breakthroughs Jennifer Doudna, professor, UC Berkeley, and one of the inventors of CRISPR editing

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15 Other possible applications in agriculture and food Sexual selection in livestock Female-only offspring in dairy cattle, layer hens Male-only offspring in beef cattle

16 Other possible applications in agriculture and food Introduction of gene drives into wild pest populations (e.g. engineering populations) to Reduce resistance / increase susceptibility to pest control tech Reduce damages caused Sterilize / eradicate Sources: Esvelt, OECD Genome Editing, Ottowa, ON Esvelt e al, elife, 2014

17 Research applications Characterizing gene regulatory networks controlling complex multi-genic traits, such as those involved in drought response photosynthesis etc Gene regulatory network of green leaf tissue. Genes related to CAM and their interaction partners are highlighted in yellow. Ming et al, Nature Genetics (2015)

18 The patent battle over CRISPR

19 CRISPR timeline: JENNIFER DOUDNA, UC Berkeley, and EMMANUEL CHARPENTIER, University of Vienna May 2012, filed first patent application June 2012, paper in Science Apr 2015, Berkeley initiates interference proceeding at USPTO 1987 Unusual repeat DNA pattern first noticed in bacteria 2002 Associated protein identified; named CRISPR 2007 Found effective against viral pathogens: a microbial immune system Apr 2014, first patent issued Jan 2013, paper in Science Dec 2012, filed first patent application FENG ZHANG, Broad Institute and MIT 2017 USPTO rules no interference.

20 The CRISPR patent conflict University of California Berkeley patent Broad Institute (MIT & Harvard) patents Claims a CRISPR-Cas9 gene editing tool based on the system found in Streptococcus bacteria, demonstrating its use in prokaryotic cells (e.g. microbes), and seeks to claim the general use of such tools to edit genes in other organisms. Claim a CRISPR-Cas9 process specifically for editing eukaryotic cells, i.e., cells from higher plants and animals (including humans) University of California alleged that the Broad Institute s patent claims overlapped with its own patent claims.

21 The US Patent Office ruled no interference on February 15, 2017 This means both Berkeley s and Broad s patents stand for now UC Berkeley has appealed the ruling in the U.S. Court of Appeals for the Federal Circuit. Similar filings at the European Patent Office are also contested.

22 Knut Egelie, Gregory Graff, Sabina Strand, & Berit Johansen, Nature Biotechnology, Oct 2016

23 CRISPR patenting worldwide 604 CRISPR inventions, by end of 2015, represented in 1,363 published patent applications 93 issued patent

24 Top CRISPR patent assignees

25 Conflict over the foundational CRISPR patents creates uncertainty Regarding who (if anyone) holds rights to the core CRISPR invention and controls the technology platform. During the formative period of technology development. Compounded by both parties use of new models of IP management.

26 CRISPR is already being widely used in academic laboratories leading academic institutions, including both the Broad Institute and UC Berkeley, offer free use for academic research purposes only under material transfer agreements (MTAs) offered through a nonprofit clearinghouse called Addgene.

27 But, options for commercial use are far more limited

28 Prior model of university IP management of biotech breakthroughs COHEN-BOYER patents (1973, 1979): recombinant DNA in bacteria Herbert Boyer, UC San Francisco Stanley Cohen, Stanford University THE AXEL PATENTS (1980, 1983): co-transformation of eukaryotic DNA Wigler, Silverstein, and Axel, Columbia University sirna PATENTS (2005): small interfering RNA (sirna) Were made widely available to industry through low-cost non-exclusive licenses.

29 Then Cohen-Boyer recombinant DNA and Now CRISPR gene editing Many competing non-exclusive licenses Founded by Zhang Few, field-specific exclusive licenses Few, field-specific exclusive licenses Founded by Doudna Founded by Boyer

30 What would the world have looked like if, in the 1970s, Genentech had been granted exclusive use of the Cohen-Boyer technology from Stanford, and Genentech itself was responsible for extending any commercial sub-licenses to other competing biotech companies? Knut Egelie, Gregory Graff, Sabina Strand, & Berit Johansen, Nature Biotechnology, Oct 2016

31 The big question: What happens when researchers at other universities, using the CRISPR research tool they obtained for nonprofit- or research-use only, make potentially valuable discoveries of their own? What are their options for commercializing follow-on inventions?

32 Critique of current IP licensing situation Everybody gets to keep their patents. This is maximum uncertainty for people because you don t know if you have to get licenses from both sides. Kevin Noonan, partner, McDonnell Boehnen Hulbert & Berghoff, Chicago, Illinois A large company wavered over whether to license University of Delaware patents on applications of CRISPR Cas9 in agriculture. Joy Goswami, technology-transfer officer, University of Delaware (from Ledford, Court rules on CRISPR, Nature Biotech, 23 Feb 2017) CRISPR based startups not a viable option for investments at this time. Brad Fabri PhD, Chief Science Office, TechAccel, Kansas City, Kansas (personal communication in meeting at CSU Ventures, Fall 2016)

33 Regulatory control of CRISPR

34 Current regulatory framework for gene edited crops, livestock, and other food ingredients In US, the Coordinated Framework for biotechnology regulation: USDA regulates plant pests, noxious weeds, and animal health EPA regulates chemical toxins release into the environment FDA regulates human food safety In Europe: regulations are based on use of the process of creating genetically engineered organisms (GMOs).

35 Alex Camacho, Allen Van Deynze, Cecilia Chi-Ham, & Alan B Bennett, Nature Biotechnology, Nov 2014

36 USDA APHIS review of DuPont Pioneer s waxy corn

37 USDA APHIS proposed regulatory changes: Federal Register, January Seeks to redefine what constitutes genetic engineering and genetically engineered organism, for purpose of triggering regulatory review: techniques that use recombinant or synthetic nucleic acids with the intent to create or alter a genome

38 USDA APHIS proposed regulatory changes: Federal Register, January Proposing a fundamental change: Would shift from a regulate first/analyze later system, to first assess new genetically engineered organisms to determine if they pose a risk to US agriculture. Regulatory trigger: WAS: strictly on basis of whether a GE organism was created using genetic material from a plant pest PROPOSED: whether a resulting GE organism poses a plant pest or noxious weed risk

39 USDA APHIS proposed regulatory changes: Federal Register, January Exclusions: Traditional breeding techniques including: marker assisted breeding tissue culture (protoplast, cell, or embryo fusion) chemical or radiation-based mutagenesis

40 USDA APHIS proposed regulatory changes: Federal Register, January Exclusions: Organisms created using techniques that fall within the scope of genetic engineering, but that could otherwise have been produced using traditional breeding techniques or chemical or radiation-based mutagenesis. Since such organisms are essentially identical, despite the method of creation. Including the following gene edits: solely a deletion (of any size) single base pair substitution introducing naturally-occurring DNA sequences from sexually compatible relatives traits introduced into breeding lines to simplify breeding without altering progeny DNA

41 USDA APHIS proposed regulatory changes: Federal Register, January Likely economic impacts: Savings to regulated community Reduced need to collect field data Fewer reporting requirements Lower management costs A broader range of gene edited organisms will require review; but, fewer will ultimately be subject to regulatory controls (e.g. permitting requirements).

42 USDA FDA request for input on regulatory changes: Federal Register, January On use of genome editing to product new plant varieties used for human or animal food 1. What categories are unlikely to present food safety risks? Therefore no reason to include in process. What is the basis for defining categories? 2. What categories are more likely to present food safety risk? What are the scientific bases? Nature of genome modifications? Phenotypes? 3. Mechanism through which plant developers may voluntarily notify FDA? What process? What kinds of information? 4. Economic question: What steps can we take to help small firms?

43 CRISPR challenges Europe s process-based definition and regulations of genetically engineered organisms (GMOs)

44 The lessons of GMOs for CRISPR gene editing

45 Wider public acceptance of medical biotech Medical biotechnology is much more accepted than agricultural and food biotechnology: In medicine, when benefits are obvious, risks are tolerated. In agriculture and food, public risk perceptions are more stringent!

46 Democratization of technology When access and use is limited by IP and regulatory conditions: The technology remains unfamiliar and suspect The technology is targeted by competitors Widespread access to the technology is important for its ongoing development and acceptance: Less people will be rooting against the technology. The technology will not be targeted by competitors.

47 Constraints, costs, and scale of applications With GMO technology, there was concern about ability to overcome IP and regulatory constraints to develop applications for The crops of the poor Small market orphan crops Many projects were not feasible because of Constrained permissions to use IP High costs of regulations These imposed both costs and uncertainty Still, when made available, the technology helped the poor (example, Bt cotton and smallholder farmers in India)

48 Private incentives shape deployment When a technology reaches a certain degree of maturity it moves to private hands. Private investors willingness to develop the technology depends on annual returns vs fixed costs (including R&D, IP and regulatory). There are many applications for improvement of small market applications that remained economically infeasible. Thus, GMO technology was used just for large commercial crops

49 The Precautionary Principle The Precautionary Principle sounds good, but it goes against the basic logic of science Adaptive learning: learn as you go Experimentation S-shape diffusion curve starts with low-hanging fruits Yes, risk matters! Selection and avoidance of bad outcomes are the essence of research but, scientists are not prophets We all avoid small risks and take big ones in our daily lives. In regulatory context, the Precautionary Principle reflects lack of trust desire to kill a technology

50 Industrialization and corporate control Many do not like GMO technology because it coincided with industrial farming rather than more natural farming. IP control combined with high cost of regulatory approval often made Monsanto or other large corporation the only game in town. They invested only in major crops. The bad image continues.

51 Lesson for gene editing Expected social benefits of gene editing are valued in the billions: More public acceptance = more applications As experience increases benefits increase risks decrease Gains to environment Land-saving effect (use less land) Input-saving effect (use less chemicals, water, energy, etc) The poor will benefit, if it is allowed to be used in developing countries. Otherwise it will contribute to a bigger income divide.

52 Conclusions: Similarities between transformation and editing Promise of the technology Potential disruption of incumbent industries Extensive overlap between the R&D activities of the public sector and private sectors and the role of technology transfer Issuance of overly-broad foundational patents, litigation over key patents Early contests over public perception and consumer acceptance, with invocation of risks and the precautionary principle by some stakeholders Need for regulatory harmonization between countries High regulatory costs = barriers to access for small markets and humanitarian applications

53 Conclusions: Difference between transformation and editing For editing, there are likely to be multiple categories of applications, governed under differing IP-regulatory policy paradigms: Some, will look like traditional breeding others will be more highly-regulated and/or proprietary

54 Conclusions Gene editing is a continuation of molecular biology and computer revolution It has benefits and some risks It offers huge potential for productivity, sustainability, and poverty alleviation It follows an underperforming sibling GMO technology but it is more precise and less risky. It need policies and communications that will enable the technology to grow and its benefits to be shared by all of humanity.

55 Thank you.