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As patent disputes within the scientific community continue, drug developers consider the intellectual property unknowns associated with this emerging technology.
Technology utilizing clustered regularly interspaced short palindromic repeats, or CRISPR, has the potential to be one of the most revolutionary-or dangerous-genetic manipulation technologies ever developed. It provides researchers with the ability to edit genetic information-including both structural genes encoding proteins, as well as regulatory sequences that control when a gene is expressed, how much is expressed, and in what tissue-in ways heretofore only more crudely practiced, such as by introducing a heterologous gene into a new cellular environment. While these earlier methods were extremely useful, permitting, for example, the production of commercially sufficient quantities of proteins such as erythropoietin, interferon, and a variety of peptide hormones, CRISPR permits alteration of gene expression directly in a desired host to provide a desired effect. It thus has implications for agriculture to increase yield or reduce allergens, as well as human medicine.
CRISPR was first reported by Jennifer Doudna and Emmanuelle Charpentier in 2012 (1), as an outgrowth of their work on bacterial immunity against bacteriophage viruses at the University of California at Berkeley and the University of Vienna; they showed genetic editing could be achieved at specific sites in known genetic sequences in vitro. They did not explicitly show that CRISPR could edit genes in eukaryotic cells (i.e., almost every type and species of cell except bacteria) in their earliest published work, although applying CRISPR to eukaryotic DNA was envisioned and there is some evidence that the earliest efforts in achieving eukaryotic CRISPR were unsuccessful. The first scientific publication demonstrating that CRISPR could be effectively practiced in eukaryotic cells was by Zhang and colleagues at The Broad Institute, MIT, and Harvard University; thereafter, several groups reported successful eukaryotic CRISPR results (2).
Both The Broad Institute and California, Vienna, and Charpentier (CVC) groups accompanied their scientific work with patent applications. This is because both groups, and their universities, realized that in order to bring this technology to market there must be a reasonable likelihood of being able to recoup a sufficiently robust return on investment; this reasonable likelihood depends on having patent protection. Both groups claimed inventorship over CRISPR applications to eukaryotic cells, which encompasses the majority of the most promising applications of the technology, and in the face of their competing claims the US Patent and Trademark Office (PTO) instituted an interference proceeding to make the determination of who invented eukaryotic CRISPR first.
On Sept. 10, 2018, the outcome of the first of these interferences seemingly resolved the question, albeit imperfectly: the PTO decided (and the Court of Appeals for the Federal Circuit affirmed)(3) that Broad and their collaborators had the rights to eukaryotic CRISPR applications and rights to CRISPR more generally were owned by the University of California, Berkeley, the University of Vienna, and Emmanuelle Charpentier as an individual. PTO determined there was no interference between the parties because inventing eukaryotic CRISPR was a patentably distinct invention from inventing CRISPR in vitro or in bacterial cells. This outcome had the benefit of certainty in identifying who owned the rights to eukaryotic CRISPR but suffered from the consequence that any third party wishing to bring CRISPR-modified eukaryotic organisms to market (or products made by such organisms) would likely need a license from both The Broad Institute and CVC, which could result in delays in commercial development.
In June 2019, PTO declared another interference between these same parties, involving again who has the rights to eukaryotic applications of CRISPR (4). PTO did not change its mind or decide the first interference incorrectly. Rather, Broad and their collaborators had filed many patent applications directed to various aspects of eukaryotic CRISPR and had many of them granted as patents. The CVC group had filed patent applications more broadly to CRISPR without regard to the cell targeted in the method; however, these applications were not specifically directed to eukaryotic embodiments of CRISPR. After not prevailing in the first interference, the CVC group filed applications directed more narrowly at eukaryotic CRISPR embodiments, and PTO declared an interference between these applications and most of the same Broad patents and applications involved in the first interference. Meanwhile, broader patents on CRISPR technology not limited to any particular organismal milieu have been granted to the University of California, Berkeley and the University of Vienna, which it would appear, should be licensed by third parties wanting to practice CRISPR.
The current interference is in the early, so-called motions phase, where Broad has asserted its belief that the decision in the earlier interference should preclude the CVC party from pursuing their claims in this interference. CVC has responded by making its case that application of CRISPR to eukaryotic cells was within the ability of the ordinarily skilled artisan once CVC’s first provisional application disclosing CRISPR was filed. It will be several months until PTO renders a decision on that question; if the decision goes against Broad only then will PTO consider evidence regarding who invented CRISPR for use in eukaryotic cells. A decision on that question will take at least another 10 months; a decision on motions, including a decision that CVC is barred by the first interference from pursuing claims in this interference, should be forthcoming before the end of 2020. Any such decision will likely be appealed, adding at least another six-month delay in resolving the question. And that’s before PTO gets to the priority of invention question.
In addition, another party, SigmaAldrich, also has a claim to priority for eukaryotic CRISPR, although these claims are bottled up in a procedural morass in PTO that has prevented the company from joining the fray, despite their argument that joining them to the existing interference would give PTO and the parties a chance to resolve the ownership issue more expeditiously. And there is at least another party that may be heard from; however, those claims have not been allowed and no interference has been declared. These circumstances leave the ownership status of eukaryotic CRISPR technology in limbo for at least the foreseeable future. This state of affairs raises clear impediments to commercial development, at least until-and if-the parties decide some way to cross-license CRISPR to third parties.
The situation is also complicated in Europe, where, in 2019, the Opposition Division revoked one of Broad’s European patents on important procedural grounds (5). Specifically, the European Patent Convention requires that any application for patent establish at the filing date that the applicant properly owns the rights to the invention claimed in the application. In this case there was an inventor working at Rockefeller University who was named in certain of the priority documents relied upon in the European filing, but neither the inventor nor Rockefeller University was named in the application. Several third-party opponents took advantage of the opposition period (nine months after grant) and opposed the European patent on these priority grounds. The Opposition Division agreed, and its revocation of Broad’s European patent was upheld on appeal (6). In addition to losing this patent, Broad has eight additional patents that are at risk for being revoked on grounds of having the same priority infirmity. This leaves open the possibility that eukaryotic CRISPR might be practiced in Europe without the need for a license, but also without patent protection. While commercial development might continue under these circumstances, it might not flourish in view of developers’ reasonable fear that any commercial product could be copied without liability or risk in the absence of patent protection.
These are important considerations for the two greatest potential markets for eukaryotic CRISPR, agriculture and medicine. For agriculture, in addition to the development costs that companies wish to have defrayed, the volume of goods sold and the attendant profits to be made make patent exclusivity an important consideration. Another important consideration is in animal husbandry and the development of improved strains of livestock, which is expected to be facilitated by applying CRISPR to the task of stably generically modifying animals for human uses and consumption. These factors may be even more important in the pharmaceutical industry for similar reasons but different economic considerations; it can be expected that eukaryotic CRISPR might find its most profitable use involved with biologic drugs and the high costs of development and regulatory approval. Other considerations are the possibility that CRISPR-engineered agricultural sources might avoid the most vocal opposition by those against genetically modified organisms, in view of the relatively less intrusive genetic changes CRISPR enables.
In conclusion, while the challenges of developing CRISPR technology over the next decade will undoubtedly be predominantly scientific and technological, economic realities mandate that ownership considerations will have a practical effect on what companies commercialize various aspects of the technology, where this commercialization occurs, and the licensing costs and complexities that arise in the process.
1. M. Jinek, et al., Science 337 (6096) 816–821 (2012).
2. Cong, et al., Science 339 (6121) 819–823 (2013).
3. Regents of the University of California v. The Broad Institute, 903 F.3d. 1286 (Fed. Cir. 2018).
4. US Patent and Trademark Office, Regents of the University of California v. The Broad Institute, Declaration of Interference No. 106,155 (June 24, 2019).
5. European Patent Office, Decision Revoking European Patent EP-B- 2 771 468 (Art. 101(2) EPC) epo.org (March 26, 2018).
6. European Patent Office, Decision in Case T 844/18 on the CRISPR Gene Editing Technology, epo.org (Jan. 17, 2020).
Kevin E. Noonan is a partner with McDonnell Boehnen Hulbert & Berghoff LLP and serves as co-chair of the firm’s biotechnology and pharmaceuticals practice group.
Vol. 33, No. 3
When referring to this article, please cite it as: K. Noonan, “The Costs of Commercializing CRISPR,” BioPharm International, 33 (3) 2020.