In a much anticipated judgement handed down on 15 February 2017, the Patent Trial and Appeal Board (PTAB) of the US Patent and Trademark Office has terminated the interference between the University of California Berkeley (UCB) and the Broad Institute (the Broad) of MIT and Harvard, unanimously finding that there was no interference-in-fact.
Background to CRISPR
The CRISPR-Cas system was first discovered as a key component of horizontal gene transfer (HGT) pathway in bacteria and archaea. In prokaryotic cells, the acquisition of new genes that confer selective advantage is often mediated by HGT. Despite this, only a small amount of transferred genetic material will confer an actual selective advantage. Therefore, prokaryotic cells employ a number of molecular defences to reject invading DNA molecules. The CRISPR-Cas system is one such mechanism, which may be adapted and reprogrammed to target new and previously encountered invading DNA molecules.
Patents and Applications in Question
Jennifer Dounda, of UCB and her key collaborator, Emmanuelle Charpentier discovered that CRISPR-Cas9 system could be adapted for use as a gene editing tool. In their landmark article published in 2012 (Jinek et al. 2012, Science), Dounda and Charpentier demonstrated that CRISPR may be used to specifically edit prokaryotic DNA in vitro. The pending patent application (US Patent Application No. 13/842,859) relates to this discovery, but is not limited to prokaryotic or in vitro applications.
Following the discovery of CRISPR-Cas9 gene editing by Dounda and Charpentier, Feng Zhang of the Broad successfully adapted the technique for use in eukaryotic systems (Cong et al. 2013, Science). Thereafter, the Broad filed a number of patent applications based on the eukaryotic use of CRISPR and utilised the USPTO “fast-track” system to obtain early acceptance and grant of the applications. Therefore, despite the UC applications being filed first, the Broad was granted the first of its patents in April 2014, which opened the door for wide-ranging commercial development of the CRISPR-Cas9 system for the development of novel therapeutics, agricultural products and biotechnological processes.
The Inference Proceeding
Interference proceedings are a unique feature of the pre-America Invents Act (AIA) US patent system. Under the previous Act, the US was a first-to-invent system. Therefore, any disputes relating to any two or more patents or pending applications covering the same or substantially similar subject matter were resolved by determining who first invented the disputed subject matter in an interference proceeding. Although the US has now transitioned to a first-to-file system under the AIA, the previous Act still applies to patent claims with effective filing dates before 16 March 2013.
UCB initiated an interference proceeding with the USPTO in January 2016 in an effort to have the Broad’s patents revoked. In the interference proceedings a number of motions were filed by both UCB and the Broad, which included interference and lack thereof, priority and the unpatentability of UCB’s claims due to a lack of written description.
In determining interference, the PTAB can decide the motions in any order. In this instance, the PTAB first addressed the Broad’s second motion that there was no interference-in-fact, as resolution of this issue could determine the proceedings and render the other motions moot. The PTAB applied a “two-way test” for interference by comparing the claims of the two inventions to determine if the subject matter of the claims of one party would, if prior art, have anticipated or rendered obvious the subject matter of a claim of the opposing party and visa versa. Accordingly, in order to succeed in establishing no interference, the Broad had to establish at least one of the following:
- That, if considered to be prior art to UCB’s claims, the Broad’s claims would not anticipate or render obvious UCB’s claims; or
- That, if considered to be prior art to the Broad’s claims, UCB’s claims would not anticipate or render obvious the Broad’s claims.
The parties agreed that UCB’s claims, if treated as prior art, did not anticipate the Broad’s claims, as none of the claims included a limitation to eukaryotic cells. Therefore, the Broad was only required to persuade the PTAB that their claims would not have been obvious in view of UCB’s application.
The PTAB held that the skilled person would have had no reasonable expectation of success in modifying the in vitro prokaryotic CRISPR-Cas9 gene editing system to eukaryotic cells. In doing so, the PTAB relied heavily on statements made by Dounda and other inventors of the UCB invention to suggest that the adaptation of the in vitro prokaryotic CRISPR-Cas9 system to eukaryotic cells was a mere possibility and the person skilled in the art would not reasonably expect that the in vitro prokaryotic CRISPR-Cas9 system could be adapted for use in eukaryotic systems. Importantly, the PTAB has interpreted statements made by Dounda following their discovery of the CRISPR-Cas gene editing system as providing sufficient evidence to suggest that the person skilled in the art would have had no reasonable expectation of success when adapting the technique to eukaryotic cells. This interpretation disregards scientific convention in making conservative hypotheses in publications and expert evidence relied upon by UCB that it would have been fully expected that the system could be used in eukaryotic cells.
Given that the PTAB upheld the Broad’s motion in terminating the interference, there was no need for the PTAB to assess the merits of any additional motions. Therefore, any detailed assessment of priority or invalidity due to lack of written description was not undertaken by the PTAB.
Implications of the Decision
As a result of this decision, each of the patents and applications held by UCB and the Broad remain valid and/or enforceable. It should be noted, however, that UCB may appeal the decision to the US Court of Appeals for the Federal Circuit.
Importantly, the termination of interference also allows for prosecution of the UCB application to continue. With regard to US 13/842,859, UCB needs to overcome a number of formalities objections, a written description objection directed to the breadth of Cas9 modifications encompassed by the claims and a statutory double patenting objection in order to allow their pending application to proceed to acceptance. Significantly, no objections have been raised against the claims encompassing any cell.
In the event that the UCB application proceeds to acceptance with the present claim scope, it is likely that the commercial use by third parties of this technology in eukaryotic systems will require licences from both UCB and the Broad. Any such dual-licencing arrangement will increase the costs and complexity of commercialising the CRISPR-Cas9 technology.
Despite the resolution of the interference proceeding in the US, ownership of the CRISPR-Cas technology remains hotly contested. For example, in Europe, UCBs pending patent application is subject to nine different sets of pre-grant third-party observations. Furthermore, the Broad has been granted at least seven European patents, each of which are subject to active oppositions. Importantly, the Broad’s first granted patent (EP2771468) is currently under attack for lack of novelty and/or inventive step in view of UCB’s earlier filed patent application and the Jinek et al. publication. The priority right of the Broad’s patents has also been called into question due to differences in applicants listed in the US and European application, which may result in the loss of priority right.
Clearly, the international CRISPR patent wars are a long way from being over!