23 November 2015
On 26 October this year the CRISPR/Cas patent wars truly began with the filing of European oppositions against what appears to be the first patent granted in Europe for this revolutionary gene-editing technology. The patent was granted to the Broad Institute, MIT and Harvard College on 11 February this year (1), and at least nine different opponents filed oppositions against it before the deadline this month. The European opposition procedure that will now follow could result in the amendment or even the revocation of the patent, but it is likely to be at least five years before the final outcome is known.
CRISPR/Cas is a gene-editing system derived from prokaryotic cells that uses a target-specific guide RNA to direct a nuclease (e.g. Cas9) to a specific sequence within cellular DNA, where it creates a precise cut. The speed at which the system has been adopted by both academic and industry groups since it was first published in 2012 is quite staggering (2). It is already used extensively across the drug discovery and development pipeline of major pharmaceutical companies. The potential applications extend well beyond biological research, however, and many companies are already exploring applications in industrial biotechnology, agricultural biotechnology and therapeutic use (e.g. based on gene and cell therapy).
To provide some perspective on the patent landscape, the granting of the Broad Institute's patent was closely followed by the granting of two other European patents (3,4). These patents are still within the nine-month opposition period, and it seems likely that they too will be opposed by multiple parties. In the USA, the same patent family already includes at least 13 granted patents, the first of which was granted on 15 April 2014 (5). There are also many more European and US applications in this patent family that are currently pending.
One of the other important patent families directed to CRISPR/Cas currently includes a European patent application (6) and a US patent application (7). This patent family is in the name of the University of California, the University of Vienna and Emmanuelle Charpentier, and claims a priority date of 25 May 2012, which is more than six months earlier than the priority date claimed by the Broad Institute's patent family (i.e. 12 December 2012). The priority date of an invention is the date of filing of the patent application that discloses the invention or, if there is a valid priority claim, the date of filing of the priority application. It is an important date since the invention claimed in a patent must be novel and inventive over all public disclosures made before the priority date.
Why then have patents been granted to the Broad Institute? The answer is a complicated one, but relevant considerations include the scope of the claims of the Broad Institute patents and the extent of the disclosure regarding CRISPR/Cas in the University of California cases. In addition, while the University of California family claims an earlier priority date, none of the applications were published until after the priority date claimed by the Broad Institute family. This means that – at least in Europe – if the priority claims of both cases are valid, the University of California cases will only be relevant to the assessment of novelty (and not inventive step) of the Broad Institute's patents.
The interplay between the factors mentioned above is complex, to put it mildly, but one clear question does emerge. Since Jinek and co-workers at the University of California published the details of the CRISPR/Cas9 system before the priority date of the Broad Institute patents, for the claims of those patents to be valid they must define subject matter that is novel and inventive over that publication (2). One consideration in this respect is whether it would have been obvious, based on the disclosure of Jinek et al, that the CRISPR/Cas system would work in vivo in eukaryotic cells.
In the USA there is also the potential for a patent interference to determine who was the first to invent the technology. This possibility exists because the patent families mentioned above have priority dates prior to 16 March 2013 (patents and applications with effective filing dates on or after this date in the USA are now governed by a first-to-file system under the America Invents Act).
To date, there appear to have been attempts to initiate interference proceedings in relation to the CRISPR/Cas technology based on an alleged overlap between the claims of an application that is part of the University of California's patent family (7) and the claims of the Broad Institute's US patents. However, a formal interference procedure has not yet begun. Moreover, even if a patent interference is initiated, it is likely to be many years before the victor is declared.
In summary, CRISPR/Cas already has a complex patent landscape with many overlapping patent rights. This landscape includes patents and applications covering the basic CRISPR/Cas system and methods for its use, improvements to the system (e.g. the new nuclease Cpf1 (8)) and specific applications for its use (e.g. therapeutic uses). In addition to the Broad Institute and the University of California, there are of course many other parties with patents and patent applications relevant to this technology, and the relevant patent rights extend well beyond Europe and the USA. Furthermore, with so many teams of researchers now working on the system, the complexity of the patent landscape will only increase with time.
Faced with such complexity, those using CRISPR/Cas (or planning to do so) will need to adopt a pragmatic approach to freedom-to-operate (FTO) analysis. FTO is best viewed as a risk assessment and, in the case of CRISPR/Cas, the risks of patent infringement will need to be carefully considered against the undoubted benefits of using this technology.
The Progress Educational Trust's public conference 'From Three-Person IVF to Genome Editing: The Science and Ethics of Engineering the Embryo' is taking place in central London on Wednesday 9 December 2015. Find out more here.