The road ahead: potential challenges facing CRISPR/Cas patents

Since Anton van Leeuwenhoek first discovered bacteria, these tiny single-cell organisms have been pivotal to major scientific advances. In fact, some of the biggest advances in medicine can be attributed to these unicellular microorganisms.

One prime example making headlines today is the clustered regularly interspaced palindromic repeats (CRISPR)/Cas system. Although this technology has the potential to revolutionise gene editing (among other fields), existing law and changes in patent jurisprudence may complicate the determination of who is entitled to reap the benefits.

Looking to past successes by trailblazers in other biotechnological fields could assist potential patentees navigate legal bumps along the road.

Technology paves the way

Working on salt-resistant microbes off the coast of Spain in the 1990s, Francisco Mojica discovered an unexpected sequence of near-perfect palindromic repeats of 30 bases, with spacers interspersed between these repeats. (Eric S. Lander, The Heroes of CRISPR, 164 Cell at 18 (January 14, 2016)). Mojica discovered that these repeats exist in many different types of bacteria, but it took years of research from a number of labs to pin down the purpose for these repeats.

Further work in the scientific community revealed that when a bacterium survives an attack by a virus, it incorporates portions of the viral DNA into its own DNA sequence, to ensure that the next time the bacterium encounters the virus, it would be able to quickly recognise the virus and destroy it—in short, providing the bacterium with adaptive immunity. (Id. at 19).

The viral DNA corresponded to the short spacer sequences between the repeats. The RNA expressed from these repeated sequences and spacer sequences, together known as the CRISPR array, is what “sees” the viral DNA. Once the CRISPR array has found the offending virus, it triggers a CRISPR-associated (Cas) protein (of which there are several types) to cut up the virus, eliminating the threat, with the help of a small RNA sequence, tracrRNA.

Harnessing this adaptive immunity, researchers discovered that the CRISPR/Cas system could be used to edit the human genome. By using human DNA instead of viral DNA as the spacer sequences, the Cas protein could be brought in contact with human DNA to cleave, permitting disruption of the locus or insertion of new DNA.

This development has opened the door to a large number of potential applications, including use of CRISPR/Cas to alleviate genetic disorders and to treat human diseases, use as an antiviral to target human viruses such as HIV-1, herpes, and hepatitis B, and beyond. (Rodolphe Barrangou and Jennifer A. Doudna, Applications of CRISPR Technologies in Research and Beyond, 34 Nature Biotechnol 933-41 (2016)).

One advantage of using the CRISPR/Cas system is its efficiency—CRISPR/Cas is able to target an intended site with a high degree of accuracy relative to other methods by simply employing a complementary sequence. Further directed mutations in the Cas protein have led to other potential uses for this system, including gene activation, and gene visualisation.

Bumps in the road

As with other cutting-edge technologies of the past, the large number of researchers focused on the CRISPR/Cas system has led to questions of who first discovered what, and when. Most recently, two US-based research groups—one at the Broad Institute, and one at University of California, Berkeley—both alleged that they were the first to demonstrate that CRISPR/Cas9 could be used in eukaryotic cells. Starting in December 2012, Feng Zhang, of the Broad Institute, had filed 13 patent applications directed to CRISPR complex formation in eukaryotic cells, and use of the CRISPR/Cas system to introduce mutations into eukaryotic cells. The patent office granted patents to the Broad Institute in 2014.

Meanwhile, Jennifer Doudna of University of California, Berkeley had also filed an application directed to the use of CRISPR/Cas9. University of California, Berkeley used this application to bring an interference proceeding against the Broad Institute, arguing that while Doudna’s application did not specifically claim use in eukaryotic cells, Doudna had proved that the CRISPR/Cas9 system would work. From there, University of California, Berkeley argued, it was an easy hop to put the system into eukaryotic cells. In support of its arguments, University of California, Berkeley cited publications by the inventors predicting the “potential to exploit the [CRISPR-Cas9] system for RNA-programmable genome editing.” (Interference 106,048 Decision at 16).

The Broad Institute sought to convince the US Patent Trial and Appeal Board (PTAB) that its claims, limited to use of CRISPR/Cas9 in eukaryotes, were not directed to the same invention as University of California, Berkeley’s claims, which were not restricted to any environment, and further, that the use of CRISPR/Cas9 in eukaryotic cells would not have been obvious. The Broad Institute presented competing commentary from University of California, Berkeley’s inventors and interference witnesses demonstrating uncertainty at the applicability of the CRISPR/Cas9 system in eukaryotes, including language from Doudna herself that “[w]e weren’t sure if CRISPR/Cas9 would work in eukaryotes.” (id. at 15-18).

The PTAB ultimately determined that the claims did not interfere with one another—that is, University of California, Berkeley’s patent application did not obviate the utility of the CRISPR/Cas9 system in eukaryotic cells. Because there was no interference-in-fact, the proceeding was terminated without further determination on the patentability of the parties’ claims.

University of California, Berkeley has now appealed against the decision, arguing that it took a “narrow and restrictive approach that ignored certain key evidence,” including the fact that six laboratories had used a 2012 paper by Doudna to achieve gene editing, prior to the Broad Institute’s filing.

Briefing on appeal is currently scheduled to be completed by the end of November 2017. As it must to maximise its chances for success, University of California, Berkeley’s brief focuses on the legal errors that it contends the PTAB made and seeks remand to the PTAB.

The outcome of the appeal and decision on remand if University of California, Berkeley gets its way may alter the playing field. However, as things currently stand, the Broad Institute’s patents are intact and UC, Berkley can obtain issuance of its patent application.

The path to the future

As demonstrated by the dispute between University of California, Berkeley and the Broad Institute, the crowded and still-growing field of CRISPR/Cas systems may pose a challenge for those seeking to patent their work. But potential patentees will have to contend with more than just proceedings before the US Patent and Trademark Office (USPTO). Changes in patent law mean it may be harder for patentees to maintain the claims they are awarded by the patent office.

CRISPR/Cas systems are not the first breakthrough to face growing pains in IP. In the 1970s, two scientists studying the way bacteria incorporate DNA into their genomes—Stanley Cohen and Herbert Boyer—discovered they could use this technology to create recombinant proteins. The two eventually obtained patents covering their new method of splicing genes to make recombinant proteins.

Stanford University, assignee of the patents, reportedly reaped more than $200 million in licensing fees.  The Cohen-Boyer patents led to a series of patents that improved on and expanded the technology, including patents on vectors to modify organisms, genetically modified organisms, and recombinant proteins.

However, biotech patents that are issued on the crest of major breakthroughs are frequently litigated under different legal standards than existed at the time of issuance. Certainly the law has evolved since issuance of the Cohen/Boyer patents. For instance, in the wake of the Federal Circuit’s en banc opinion in Ariad Pharmaceuticals v Eli Lilly (2010), further case law has affirmed and clarified that court’s stance on what is needed to adequately “describe” a claimed invention.

Take, for example, situations where the patentee has used functional language in the claims, meaning that the patentee has described the invention through its function, rather than its structure. While such functional language is not prohibited, it may nevertheless be inadequate to meet the written description requirement.

The Federal Circuit in AbbVie Deutschland v Janssen Biotech (2014) explained that a patentee seeking claims covering a genus using functional language must provide enough of a description to make clear the correlation between the functional language used and the structure of the claimed product.

The Federal Circuit most recently affirmed its stance on this matter with respect to claims covering antibodies, described only by the antigens they bind to. In that case, Amgen v Sanofi, (2017), it stated that “the ‘newly characterised antigen’ test flouts basic legal principles of the written description requirement”. Patentees seeking claims covering CRISPR/Cas systems described solely by the target it binds to will likewise have to demonstrate adequate written descriptive support.

Patentees seeking claims covering CRISPR/Cas technology may also face non-enablement rejections. For example, Editas Medicine has filed US patent application no. 14/644,181, directed to CRISPR/Cas compositions and methods used to treat Leber’s congenital amaurosis 10 (LCA10), a severe form of retinal dystrophy. The USPTO examiner rejected the claims as lacking enablement for homology-directed repair of the LCA10 gene, or the administration of the construct, for instance in ex vivo therapies.

Specifically, the examiner took issue with the breadth of the target—noting that the CEP290 gene to which some of the claims are directed is over 8 kilobases in length, and that because of limitations in the CRISPR technology, one would not be able to alter every portion of the gene.

Also, one would not be able successfully to transfect the cells ex vivo, as claimed by the application, without undue experimentation. The examiner went so far as to cite an article titled “The gene editor CRISPR won’t fully fix sick people any time soon. Here’s why.” The examiner’s final rejection reasserted non-enablement of the claims, adding that merely exploring a gene by mutating it to see what the mutation does is not a patentable utility.

While Editas Medicine has yet to respond to this office action, the USPTO’s rejections may be a warning to patentees seeking broad claims covering multiple potential mutation sites and/or methods of treatment. First, although the US National Institutes of Health approved a small clinical trial on the safety of using of CRISPR/Cas9 in humans in June 2016, the USPTO may still look to patent applications on method of treatment claims with scepticism.

Second, somewhat akin to antibody claims described using the antigen to which the antibody binds, the USPTO may not accept claims directed to targeting domains complementary to large gene sequences.

More fundamentally, it remains to be seen whether patents covering CRISPR/Cas system technology will face challenges to patentability based on 35 USC §101. The law is far from settled on what is patent-eligible subject matter, despite the Federal Circuit’s ruling in Rapid Litigation Management v CellzDirect (2016), and the Supreme Court’s guidance in Alice v CLS Bank International (2014) and Mayo Collaborative Services v Prometheus Laboratories (2012).

Given the origins of the CRISPR/Cas systems—naturally-occurring bacteria—patentees may have to defend their claims by asserting that while CRISPR/Cas systems can be found in nature, the claimed inventions “employed their natural discovery to create a new and improved” way of conducting gene therapy. Transformation of the CRISPR/Cas systems for use in eukaryotic cells may be enough to meet the §101 requirement.

As always, as the scientific community expands its base of knowledge, patentees will face further prior art in obviousness challenges. For example, the Supreme Court’s ruling in KSR International v Teleflex (2007) has arguably lowered the bar for challengers alleging obviousness since the time of the Cohen-Boyer patents. Additionally, a quick search of PubMed for journal articles published in the last five years relating to ‘CRISPR’ resulted in more than 6,400 hits. Things seem only to be heating up, as startups such as Editas Medicine and CRISPR Therapeutics, with large amounts of funding, set their sights on the CRISPR/Cas system technology.

Advances in the technology also provide new opportunities to gain IP rights. The Chinese University of Hong Kong and the Broad Institute both currently hold patent applications directed to combinations of CRISPR with Cpf1, an endonuclease used in place of Cas9. Others have worked to mutate Cas9, for example to provide greater control over the system and reduce offsite activity, or to tag a sequence of the genome with fluorescence. And researchers may be able to obtain patents directed to improving on and expanding the technology, as with those following in the wake of the Cohen-Boyer patents.

A number of researchers involved in the CRISPR/Cas technology have already faced patent challenges before the PTAB but the fledgling nature of this already crowded field, as well as the changing nature of the law, means that potential patentees can expect to face further speedbumps along the road. And those legal speedbumps are likely to evolve between patent issuance and the time those patents face legal challenges.

The well-worn path

In the face of the foregoing legal challenges, in a crowded and growing field, those seeking to protect IP over CRISPR/Cas technology could look to Stanford’s treatment of the Cohen-Boyer patents for inspiration. Eight months after issuance of one of the Cohen-Boyer patents, Stanford announced the availability of licences covering the gene-splicing technology. (Sally Smith Hughes, Making Dollars Out of DNA, Isis 92:541-575 (2001) (“Hughes”) at 569).

Four months later, Stanford had already signed 72 companies to the technology. While the number of companies signing agreements with Stanford was surely due in part to the groundbreaking nature of the gene-splicing technology covered by the Cohen-Boyer patents, Stanford also offered an extremely reasonable rate for such licence agreements. Initially, companies owed a $10,000 licence issue fee, with another $10,000 due a few months laterOffering an affordable licensing fee also provided Stanford with protection over its coveted patents—those able to obtain a non-exclusive licence at such an affordable price (equal to roughly $56,000 today) did not have a reason to bring suit against the Cohen-Boyer patents. Whatever the reason, the trio of Cohen-Boyer patents survived until their expiration on December 2, 1997.

Stanford’s licensing scheme may prove attractive to those seeking to protect their CRISPR/Cas technology patents. As recognised by those who developed Stanford’s licensing plans, non-exclusive licensing was “generally held to be viable only when inventions were revolutionary or broadly enabling.” Given the fanfare and excitement surrounding CRISPR/Cas technology, it may very well fall within this category, allowing patentees potentially to avoid the legal hazards described above—if the price is right, and the market is willing.

Pat Carson is a partner in the Kirkland & Ellis New York office. She can be contacted at: patricia.carson@kirkland.com

Ashley Ross is an intellectual property associate at Kirkland & Ellis. She can be contacted at: ashley.ross@kirkland.com