Brian Nolan is a partner in the Life Sciences Group of Mayer Brown LLP.

The European Patent Office (EPO) and the United States Patent and Trademark Office (USPTO) have been thrust into a dispute pitting the University of California, Berkeley (UC) and the University of Vienna against the Broad Institute of MIT and Harvard University. The patent applications in the dispute disclose the genome editing tool called CRISPR/Cas9. Scientists and inventors have been watching the decisions of the EPO and USPTO because these decisions may leave one of these entities with a patent portfolio worth billions of dollars.

The Broad Institute scored the first victory at the USPTO, which held that the Institute is entitled to claims for the use of CRISPR-Cas9 in eukaryotic cells because that use is patentably distinct from UC's earlier disclosure showing the ability to use CRISPR-Cas9 in vitro. But just a few weeks later, the EPO informed the public that it intends to issue a patent to UC for the use of CRISPR-Cas9 in either prokaryotic or eukaryotic cells.

The CRISPR-Cas9 genome editing system finds its scientific roots in the observation that prokaryotes utilise CRISPR to identify and destroy viruses. Professor Jennifer Doudna of UC and Professor Emmanuelle Charpentier of the University of Vienna showed that the CRISPR-Cas9 system could use short strands of guide RNA that recognize and direct Cas9 to locate a specific target DNA sequence, and to cut it. In four preliminary patent applications filed between May 2012 and February 2013 and a related scientific paper published on 17 August, 2012, Professor Doudna and her colleagues Dr Martin Jinek of UC and Professor Charpentier disclosed a successful test of a prokaryotic CRISPR-Cas9 genome editing tool in vitro.

Around the same time, Dr Feng Zhang, a scientist at the Broad Institute, was working on creating and using various bacterial Cas9 in mammalian cells. Between December 2012 and June 2013, a few months after Professor Doudna and Dr Charpentier's publication, Professor Zhang and his colleagues filed several provisional patent applications showing the use of CRISPR-Cas9 with human and mouse cells. Professor Zhang and his colleagues requested and paid for expedited review. The expedited review resulted in US patents being issued to Professor Zhang and colleagues before the issuance of patents to Professor Doudna and her colleagues.

UC and the Broad Institute have been watching the progression of each other's patent applications through the USPTO and EPO. When UC saw that the USPTO had issued patents to the Institute for the use of CRISPR-Cas9 in eukaryotic cells, UC requested that the USPTO decide whether UC's patent disclosure showing the use of CRISPR-Cas9 genome editing system in vitro in prokaryotic cells evidenced that using CRISPR-Cas9 in eukaryotic cells was UC's invention. The USPTO instituted a proceeding called an 'interference' to review the parties' claims.

During this proceeding, UC alleged that Zhang's work was an obvious extension of that shown in Professor Doudna's article. Based upon an email from a former member of Professor Zhang's laboratory, Shuailiang Lin, to Professor Doudna, UC asserted that Professor Zhang began only meaningfully working on CRISPR-Cas9 after reading that article. The Institute responded by characterizing the email as that of a former employee seeking a new job and willing to tell a prospective employer what they wanted to hear.

In response to this, the Broad Institute responded that the USPTO should not have instituted this proceeding because its patent claims are distinct from UC's patent applications, which only show success of CRISPR-Cas9 in vitro. In February, the USPTO ruled in the Broad Institute's favour and held that 'the parties claim patentably distinct subject matter, rebutting the presumption created by declaration of this interference. [The] Broad [Institute] provided sufficient evidence to show that its claims, which are all limited to CRISPR-Cas9 systems in a eukaryotic environment, are not drawn to the same invention as UC's claims, which are all directed to CRISPR-Cas9 systems not restricted to any environment.'

The USPTO came to this conclusion because it determined that the evidence showed that a person of ordinary skill in the art would not have a reasonable expectation that CRISPR-Cas9 could be implemented successfully in a eukaryotic cell based upon the success UC achieved in vitro. To support its conclusion, the USPTO pointed to several statements by Professor Doudna and Dr Jinek, the UC inventors, that questioned whether the CRISPR-Cas9 genome editing system could be implemented in a eukaryotic environment. UC has appealed the USPTO's decision to a United States appellate court. Yet as the appellate court will make its decision on the same record presented to the USPTO, it may be difficult for UC to convince the appellate court that substantial evidence did not support the USPTO's determination. The appeal should be resolved with 10-12 months.

In parallel with the USPTO's review, the EPO was considering what, if any, patent protection it should grant UC. UC's European patent application was the subject of great interest, as several third-party observations were submitted to the EPO seeking to impede the issuance of the patent. These observations included arguments that the UC patent publications did not support a claim scope that encompassed CRISPR in a eukaryotic environment, similar to those presented in the United States. Despite these submissions, the EPO has notified the public that it intends to issue a patent to UC for the use of CRISPR-Cas9 in either prokaryotic or eukaryotic cells. Within nine months of issuance, this patent may be the subject of third-party oppositions that challenge whether the patent should have issued. If filed, an opposition will afford the third-party a substantive role in the arguments before the EPO than it had before, similar to the procedure in the US where a third-party cab remain involved during an interference proceeding. This may increase the likelihood of the EPO questioning a claim scope that includes use in a eukaryotic cell.

Either way, the EPO will be unlikely to resolve an opposition until late 2018 or 2019; so as with the patent situation in the United States, the dispute will continue in Europe. Unless the parties enter into a settlement, the industry should expect uncertainty with respect to ownership of the use of CRISPR-Cas9 in eukaryotic cells for the next two to four years, with the potential for various disputes to erupt in the patent offices and courts of the United States and Europe.

The decisions of the USPTO and the EPO to grant rights to the use of CRISPR-Cas9 systems in a eukaryotic cell to different parties has complicated commercialisation decisions for biopharma companies. It is thought that the more lucrative uses for CRISPR-Cas9 will be in a eukaryotic environment. Thus, if the status quo remains, throughout the duration of the patents that may last until 2033, companies will have to secure licensing rights from both UC and the Broad Institute if they plan on commercialising products in both the United States and Europe which is the likely plan for biopharma companies. Therefore, biopharma companies will continue to watch these CRISPR-Cas9 patent disputes until either the disputes are resolved - or a significantly different CRISPR system becomes the genome editing tool of choice.

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The CRISPR patent dispute - Europe and the US - BioNews

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