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3-2015 Law, History and Lessons in the CRISPR Patent Conflict Jacob S. Sherkow New York Law School

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Recommended Citation 33 Biotechnology 256-257 (March 2015)

This Article is brought to you for free and open access by the Faculty Scholarship at DigitalCommons@NYLS. It has been accepted for inclusion in Articles & Chapters by an authorized administrator of DigitalCommons@NYLS. PATENTS

Law, history and lessons in the CRISPR patent conflict

Jacob S Sherkow Predicting the outcome of the ongoing patent disputes surrounding -editing technology is equal parts patent analysis and history.

enome-editing technology based on patent application, which claims a priority date patent would be invalidated, although there Gclustered, regularly interspaced, short of May 25, 2012, includes 155 claims, encom- would be no guarantee that the Doudna- palindromic repeats (CRISPR) and CRISPR- passing numerous applications of the system Charpentier patent application would be associated 9 () has generated great for a variety of cell types2. The second comes granted. If Zhang were to win, he would keep excitement in both academia and industry. But from of MIT on a method for using his initial patent, and Doudna and Charpentier a potential patent dispute between two sets of CRISPR-Cas9 for in eukaryotic would likely walk away empty handed. inventors has left the biotech community pon- cells3. Zhang’s patent, which claims a priority The second challenge concerns the patents’ dering its fate. Understanding several facets of date of December 12, 2012, has already been scope. All of the CRISPR patent applications patent law and history may provide some les- issued4. filed thus far are drafted quite broadly. As a sons about the probable—and best—outcome Since these filings, there has been a flurry consequence, if the USPTO allows these pat- for the dispute. of patent applications related to CRISPR-Cas9. ent applications to move forward—and if the More than a dozen new patents and 100 patent patents are ultimately enforced—the patents CRISPR and the patent landscape applications have claimed or described appli- are likely to prevent even the most basic use The CRISPR-Cas9 genome-editing system is cations for the CRISPR-Cas9 system. Zhang of the CRISPR-Cas9 system without a license. based on an endogenous, prokaryotic immune alone has received eight CRISPR-Cas9 patents, General academic research would almost cer- response to foreign nucleic acids, such as viral all from ‘fast-tracked’ applications and drafted tainly be liable for patent infringement7. At

Nature America, Inc. All rights reserved. America, Inc. Nature or . When presented with to very broad applications of the technology. the same time, the patent statute immunizes 5 or plasmids, some prokaryotes inte- Some of these patents are directed to more spe- research performed in connection with sub- grate short fragments of the foreign sequence cific applications, such as the patent claiming mitting new drug or biologic information to © 201 into one or more CRISPR loci, and then tran- the use of the technology to treat Huntington’s the US Food and Drug Administration8. Thus, scribe the loci and process the output to form disease5. depending on the enforcement scheme and the short CRISPR (crRNAs). The newly cre- technology’s development, academic research npg ated crRNAs then direct Cas9, a DNA nucle- Challenges to the patents may be subject to claims of patent infringement ase, to cleave future foreign nucleic acids on the The breadth and competing claims of these while some commercial development may pro- basis of sequence complementarity. The sys- patents and patent applications pose several ceed unchecked. tem’s ability to precisely introduce foreign DNA challenges to their inventors—and to the Last, the patents themselves pose sev- sequences makes CRISPR-Cas9 an incredibly biotech community at large. The first con- eral questions concerning their validity. versatile, effective system for genomic editing. cerns the priority of the fomenting patent Specifically, patent claims that are “obvious” That versatility, and the potential to use dispute between Doudna and Charpentier, on may be declared “invalid” and may be freely CRISPR-Cas9 for practical (and profitable) one side, and Zhang on the other. Currently, used by others9. In the biotechnology context, in vivo applications, has led to two competing the patent application from Doudna and there has been a long-running and unresolved patent claims on the CRISPR-Cas9 system. The Charpentier appears to have priority over issue about whether certain applications of a first stems from work led by , Zhang’s earliest issued patent—theirs claims a technology are obvious once the fundamentals at the University of California, Berkeley (UC priority date of May 25, 2012, whereas Zhang’s of a technology (such as PCR) are known. Now Berkeley), and , at claims a priority date of December 12, 2012. that the mechanics of CRISPR-Cas9 are known, the Helmholtz Centre for Infection Research Assuming Zhang’s claims overlap with those have genome-editing applications become in Germany, for a method of exploiting the of Doudna and Charpentier, this may allow obvious? Answering that question in legal system for genome editing in vitro1. Their the Doudna-Charpentier team to petition the terms is immensely difficult, but the answer is US Patent and Trademark Office (USPTO) to likely to control the future of all CRISPR-Cas9 challenge Zhang’s initial patent through an patent disputes. Jacob S. Sherkow is at the Institute for “interference proceeding” if their application Information Law and Policy, New York Law is ultimately rejected6. The stakes for an inter- Historical precedents School, New York, New York, USA. ference proceeding would be high: if Doudna Whether and how these difficulties are e-mail: [email protected] and Charpentier were to win, Zhang’s earliest resolved will be largely up to the assignees of

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the dueling patent applications: UC Berkeley, versity currently allows academic scientists Conclusion the University of Vienna, the Massachusetts with laboratory-made versions of the molecu- CRISPR-Cas9 is a very promising tool in the Institute of Technology (MIT) and the Broad lar components to use the technology for free quest for genome editing. Whether the tech- Institute. The history of licensing patents and grants companies selling these molecu- nology is allowed to develop with patent pro- on earlier foundational technologies— lar components nonexclusive licenses11. The tection will be up to law and history, rather recombinant DNA, small interfering RNA startup Alnylam, however, has received an than science. (siRNA) and PCR—provide several avenues exclusive license to the technology for thera- COMPETING FINANCIAL INTERESTS for deploying CRISPR-Cas9 without lengthy peutic applications. The author declares no competing financial interests. patent fights. ’s manage- The PCR patents provide another option ment of the Cohen-Boyer patents on recombi- for licensing and deployment. Because the ACKNOWLEDGMENTS The author would like to thank Christopher Weyant nant DNA, for example, has become the gold technology was discovered in the context of for invaluable contributions to this paper. standard for university technology licens- industry, strong enforcement of PCR patents ing10. First, the patents’ assignee, Stanford, could have significantly hindered scientific 1. Jinek, M. et al. Science 337, 816–821 (2012). licensed the technology nonexclusively and progress. This problem was largely miti- 2. Jinek, M. et al. US Patent Application No. PCT/ US2013/032589 (2013). allowed nonprofit research institutions to gated, however, through the twin policies of 3. Cong, L. et al. Science 339, 819–823 (2013). use the technology without a license. Second, ‘rational forbearance’ from suing research- 4. Zhang, F. US Patent No. 8,697,359 (2014). 5. Miller, J.C., Rebar, E.J. & Zhang, S.H. US Patent the university developed a graduated royalty ers for patent infringement and the adoption Application No. 2014/0336133 (2014). system to ensure that smaller companies were of widespread corporate licensing, business 6. 35 USC § 135 (2010). not disadvantaged. And finally, Stanford pre- partnerships and adaptive licensing strate- 7. Madey v. Duke University, 357 F.3d 1351 (Fed. Cir. 12 2002). emptively consulted a wide variety of stake- gies . In this way, PCR was widely—and 8. 35 USC § 271(e) (2012). holders and experimented with different quickly—disseminated. 9. 35 USC § 103 (2010). licensing agreements, to much community Although these examples are quite different 10. Feldman, M.P. et al. Intellectual Property Management in Health and Agricultural Innovation: A Handbook of fanfare. from one another, in all cases, the assignees Best Practices (eds. Krattiger, A. et al.) 1797–1807 Another helpful example to consider is chose an appropriate and user-specific combi- (MIHR, Oxford, 2007). 11. Rojahn, S.Y. gets patent on revolu- MIT’s ‘Tuschl patents’ on siRNA technol- nation of enforcement and licensing. Choosing tionary gene-editing method. MIT Technology Review ogy. As with CRISPR-Cas9, overly restric- the right strategy or strategies may help the http://www.technologyreview.com/view/526726/broad- tive licensing could have significantly slowed CRISPR-Cas9 patent assignees to avert legal institute-gets-patent-on-revolutionary-gene-editing- method/ (2014). scientific progress. MIT, however, was able to challenges, realize significant revenue streams 12. Fore, J. Jr., Wiechers, I.R. & Cook-Deegan, R. J. Biomed. avert this problem through licensing. The uni- and promote scientific progress simultaneously. Discov. Collab. 1, 7 (2006). Nature America, Inc. All rights reserved. America, Inc. Nature 5 © 201 npg

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