Patent Law and Genome Engineering: A Short Guide to a Rapidly Changing Landscape
Authors: Ross Cloney
Journal: Molecular Therapy (2016)

The speed at which the genetic sciences have advanced is startling when you consider that less than one human lifetime separates the present day from the discovery of the double helix. A person born in 1953, the year of Watson and Crick's paper describing the structure of DNA,1Watson J Crick FHC A structure for deoxyribose nucleic acid.Nature. 1953; 171: 737-738Crossref PubMed Scopus (8400) Google Scholar has seen in her lifetime the first crude genetic manipulations with restriction enzymes and polymerase chain reaction opening the door to rationally designed gene sequences and modified organisms. In the last decade, the advance of science and technology has allowed ever more accurate changes to information at the genetic level in ever more complex organisms. Such is the potential for these new techniques that the focus is no longer on genetic engineering—manipulating DNA in vitro for introduction into a target organism—but on genome engineering and gene editing—the in vivo alteration of genes to correct mutations, introduce new genetic information, and remove desired sequences. Patent law in the biological sciences has had a history of being complex and controversial. The potential in academic, clinical, and commercial ventures of the emerging genome engineering technology, combined with their rapid advancement, has led to a complex patent law landscape. Classic patent law disputes concern infringement and validity of the patent in question, but disputes may, alternatively or in addition, concern issues of ownership (who has the right to the patent or invention). This commentary aims to give an overview of the patent law situation, primarily infringement and ownership issues, in regard to a key set of technologies: meganucleases, zinc-finger nucleases (ZFNs), transcription activator–like effector nucleases (TALENs), the piggyBac and Sleeping Beauty transposons, and clustered regularly interspaced short palindromic repeats (CRISPR, paired with its protein partner Cas9). It is important to be mindful that this article can be only a broad overview of a complicated and rapidly changing field, highlighting the well-known controversies for each technology. A full description and analysis would be a thesis in and of itself, and the reader is encouraged to consult professional patent lawyers if in-depth information is required. The patent publication numbers provided in the references are those of the international, i.e., PCT (Patent Cooperation Treaty (PCT), applications, although the most relevant patents are typically the national and regional patents derived therefrom. For relevant and related patents, the patent publication numbers here can be accessed at Espacenet (http://worldwide.espacenet.com); a patent publication number followed by an A indicates a published application and a B indicates a granted patent. Meganucleases The initial advance into genome editing emerged from the meganucleases, also known as homing endonucleases. These nucleases, such as the gold standard I-SceI, offered sequence specificity, recognizing and making only a single cut in a given genome. The patent situation of meganucleases2P Duchateau, F Paques 2006 I-CREI meganuclease variants with modified specificity, method of preparation and uses thereof. International patent WO2006097853Google Scholar,3S Arnould, 2004 Custom-made meganuclease and use thereof. International patent WO2004067736Google Scholar,4HW Hellinga, JJ Smith D Jantz 2007 Rationally-designed meganucleases with altered sequence specificity and DNA-binding affinity. International patent WO200704785Google Scholar was in dispute for years—a common occurrence—with the biotechnology companies Cellectis and Precision Biosciences in dispute over whether their respective commercial activities infringed on patents licenced from universities. This confrontation between broad and narrow patents is a common feature of biotechnology disputes. In 2013, after five years of legal battles, the two companies settled their claims and recognized the patent rights of each, allowing them to commercialize meganucleases.5Law360. Precision BioSciences, Cellectis settle longtime patent feud. 31 January 2014 http://www.law360.com/articles/505712/precision-biosciences-cellectis-settle-longtime-patent-feudGoogle Scholar This prolonged legal situation before resolution of the conflicts by cross-licensing I-CreI may offer guidance for the future of CRSPR/Cas applications. ZFNs ZFNs, which represented the first "programmable" method of gene editing, enable the targeting of specific sequences by mixing and matching the triplet recognizing zinc fingers. This opened up a huge portion of the genome to targeted and predictable editing, ushering in modern genome engineering and the beginnings of a potential revolution in research and treatment. The key intellectual property for ZFNs is held by Sangamo and protected by several broad patents owned outright, purchased or licensed from noncommercial institutions (6D Carroll, M Bibikova, GN Drews, KG Golic, MM Golic, 2003 Targeted chromosomal mutagenesis using zinc finger nucleases. International patent WO2003087341Google Scholar, 7Cox, GNI, Case, CC, Eisenberg, SP, Jarvis, EE and Spratt, SK (2000). Regulation of endogenous gene expression in cells using zinc finger proteins. International patent WO2000041566Google Scholar, 8Liljedahl, M, Aspland, SE and Segal, DJ (2003). Methods and compositions for using zinc finger endonucleases to enhance homologous recombination. International patent WO2003080809.Google Scholar, among other patents), and licensed to Sigma-Aldrich and other companies for therapeutic and commercial purposes. Sangamo has dozens of material transfer agreements with public research bodies for the use of its technology. While in theory anyone can use the known recognized triplets to design their own zinc fingers, the practicalities of designing, testing, and validating the engineered nucleases puts this option out of reach for many academic labs and small commercial entities.9Scott CT The zinc finger nuclease monopoly.Nat Biotechol. 2005; 23: 915-918Crossref PubMed Scopus (36) Google Scholar TALENs Whereas ZFNs' commercial intellectual property rights have been held by Sangamo and its partner Sigma-Aldrich, the companies Cellectis and Life Technologies (now Thermo-Fisher), along with the Two Blades Foundation, invested in the potential of TALENs after licensing the rights from patent holders at Martin Luther University,10Bonas, U, Boch, J, Schornack, S and Lahaye, T (2010). Modular DNA-binding domains and methods of use. International patent WO2010079430Google Scholar the University of Minnesota, and Iowa State University.11Voytas, DF et al. (2011). TAL effector-mediated DNA modification. International patents WO2010079430 and WO2011072246.Google Scholar However, in comparison with ZFNs, TALEN arrays to target specific sequences are far easier and less expensive to design and produce, putting them within the abilities of most molecular biologists to assemble and the budgets of academic and noncommercial entities who want to make their own custom proteins. Transposons Further potential genome engineering technologies developed in recent years are transposon systems such as piggBac and Sleeping Beauty. These are attractive tools because, owing to their long evolutionary history, much of the transposon machinery is "native" to eukaryotic cells.12Izsvak, Z and Ivics, Z (2004). Sleeping Beauty transposition: biology and applications for molecular therapy. Mol Ther 9: 147-156.Google Scholar Like other genome engineering tools, they are covered by a range of patents13Ivics, Z and Izsvak, Z (2001). Sleeping Beauty, a transposon vector with a broad host range for the genetic transformation in vertebrates. International patent WO2001081565.Google Scholar,14Hackett, PB, Ivics, Z, Izsvak, Z and Caldovic, L (1998). DNA-based transposon system for the introduction of nucleic acid into DNA of a cell. International patent WO1998040510.Google Scholar and licensed to companies such as Transposagen Biopharmaceuticals, Intrexon/Ziopharm, and Discovery Genomics for commercial development, but they do not seem to have attracted the same disputes as those for other technologies. In the case of the Sleeping Beauty transposon system, the initial intellectual property was clear because it was a synthetic element that was created rather than discovered, but, as with the site-specific nucleases, there were many derivative patents covering modifications and uses. Unlike the other tools highlighted in this article, the transposon systems lack sequence specificity. This makes them more similar to earlier but still widespread methods of manipulating genomes, such as the use of lentiviruses to introduce foreign genetic material into a host cell. CRISPR/Cas9 In comparison to the previous methods of genome engineering, CRISPR/Cas systems represent a substantial leap in terms of ease of use and availability. Unlike ZFNs or TALENs, with their need to optimize the nucleotide-recognizing proteins, CRISPR/Cas relies on a guide RNA to recognize potentially any sequence in a genome. Thus, the key stumbling block to effective design of site-specific nucleases could be addressed over a coffee break. Unsurprisingly, the versatility of this system has seen an explosion in interest in applying or modifying it for academic, commercial, and clinical applications. The first patents broadly describing the technology were filed in in the last few years, one from Feng Zhang at the Broad Institute15Zhang, F (2014). CRISPR-Cas systems and methods for altering expression of gene products. International patent WO2014093661.Google Scholar and a competing application from Emmanuelle Charpentier and Jennifer Doudna et al.16Charpentier, E. et al. (2013) Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription. International patent WO2013176772.Google Scholar As this dispute continues,17Sherkow JS Law, history and lessons in the CRISPR patent conflict.Nat Biotech. 2015; 33: 256-257Crossref PubMed Scopus (28) Google Scholar hundreds of patents related to the use of CRISPR/Cas (and similar systems) in more specific applications have been filed. The patent situation surrounding CRISPR/Cas9 is very complex, covering a range of patents, applications, and many jurisdictions.17Sherkow JS Law, history and lessons in the CRISPR patent conflict.Nat Biotech. 2015; 33: 256-257Crossref PubMed Scopus (28) Google Scholar,18Webber P Does CRISPR-Cas open new possibilities for patents or present a moral maze.Nat Biotechol. 2014; 32: 331-333Crossref PubMed Scopus (13) Google Scholar,19GenomeWeb. As CRISPR-Cas9 technology sets to take off, uncertainty swirls around IP landscape. 18 June 2014https://www.genomeweb.com/rnai/crispr-cas9-technology-sets-take-uncertainty-swirls-around-ip-landscapeGoogle Scholar,20Kupecz A Who owns CRISPR-Cas9 in Europe.Nat Biotech. 2014; 32: 1194-1196Crossref PubMed Scopus (8) Google Scholar,21Smith-Willis H San Martín B Revolutionizing genome editing with CRISPR/Cas9: patent battles and human embryosle.Cell Gene Ther Insights. 2015; 1: 253-262Crossref Google Scholar Conclusions and outlook The trend in biotechnology to date has been in rapid advancement of technology, often outpacing the attempts to codify these advances in patent law. Genome engineering has avoided one possible scenario: dispute over whether these technologies are patentable. Because of the therapeutic and commercial potential of genome engineering technologies, they are an area of intense research. The combination of rapid discovery and innovation with the large number of interest groups and companies has resulted in a complex patent landscape with conflicting arguments over ownership, infringement, and the validity of patents. The initial techniques have already been eclipsed by the rapid rise of CRISPR/Cas, and while the dispute over the patenting of ownership of the original discoveries continues, those same labs are making rapid progress in modified and orthogonal systems.22Zetsche B Gootenberg JS Abudayyeh OO Slaymaker IM Makarova KS Essletzbichler P et al.Cpf1 is a single RNA-guided endonuclease of a class 2 CRISPR-Cas System.Cell. 2015; 163: 759-771Abstract Full Text Full Text PDF PubMed Scopus (2518) Google Scholar Additionally, these technologies permit genome engineering with such ease that they are used by the burgeoning "do it yourself biology" (commonly called DIYBio) community, groups of "bio-hackers" who are neither academic nor commercial operators.23Ledford H Biohackers gear up for genome editing.Nature. 2015; 524: 398-399Crossref PubMed Scopus (22) Google Scholar Now that biology is programmable, there appears to be potential for the same debate around open source that has been seen in the software community.24Herrera S Profile: Richard Jefferson.Nat Biotechol. 2005; 23: 643Crossref Google Scholar,25Chandrasekharan S Kumar S Valley CM Rai A Proprietary science, open science and the role of patent disclosure: the case of zinc-finger proteins.Nat Biotechnol. 2009; 27: 140-144Crossref PubMed Scopus (34) Google Scholar It is also important to remember that patents do not last forever. Given the typical twenty-year life span of a patent, several of the earliest technologies will be passing into the public domain in the coming years.26World Trade Organization. Uruguay Round Agreement: Trips. Part II. Standards concerning the availability, scope and use of Intellectual Property Rights, Sections 5 and 6. https://www.wto.org/english/docs_e/legal_e/27-trips_04c_e.htmGoogle Scholar That said, it is standard practice for companies and academic laboratories to develop and patent more advanced and efficient versions of the technologies that most practitioners will want to use. In this way, the patenting of improvements effectively extends the commercial monopolies in the field. It is also important to recall that genome engineering techniques are not the first disruptive technology wherein the legal situation has important implications for academic and clinical work. Modern molecular biology, more so than its sibling sciences, seems prone to complicated legal situations27Rasmussen N Gene Jockeys: Life Science and the Rise of Biotech Enterprise. Johns Hopkins University Press, Baltimore, MD2014Google Scholar—especially since the techniques are both powerful and increasingly within the scope and price range of small organizations and individuals. While the legal situation regarding biotechnology patent law is nowhere near as headline-grabbing as the hundreds of claims and counterclaims that characterized the mobile phone patent wars, the law on what is and isn't patentable is constantly evolving. Much of this is due to the complexity of biological systems and the extraordinary length of time required to demonstrate applications of basic biology in commercial and biomedical fields. Here the advances that revolutionized mid- to late-twentieth-century molecular biology—recombinant DNA, RNA interference, and polymerase chain reaction—offer some guidance. In these cases, academic and noncommercial entities were able to freely use these technologies while commercial entities had access to nonexclusive licenses to use the technology, allowing for widespread adaptation of the new techniques.28Fore Jr, J Wiechers IR Cook-Deegan R The effects of business practices, licensing, and intellectual property on development and dissemination of the polymerase chain reaction: case study.J Biomed Discov Collab. 2006; 1: 7Crossref PubMed Scopus (38) Google Scholar Unsurprisingly, the potential academic, commercial, and therapeutic possibilities offered by genome engineering have seen it develop a complicated and shifting patent landscape. Often the nonacademic development of technologies is covered by several key patents held by a single entity, as in the case of Sangamo and ZFNs, or by competing entities, as in the recently resolved situation involving meganucleases. In the early stages of a new technology, it can be unclear to third parties which entity is the rightful owner of key intellectual property due to ownership disrupts, such as the continuing competing claims around CRISPR/Cas. Meanwhile, the ease of use is increasing in line with the specificity and power of each new technology. Much like the genome itself, the patent situation is complicated and evolving by the day.