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9 July 2017Sectors

The global CRISPR battleground

Genetically modified humans are no longer in the realm of fantasy, and neither is the patenting of the technology that makes this possible.

While the well known CRISPR/Cas9 dispute between the Broad Institute of Harvard and MIT on one side, and the University of California, Berkeley (UCB) and the University of Vienna on the other, has mainly been centred in the US, the technology is used globally. Being an exciting emerging invention, more and more companies are claiming the patent rights to it.

The CRISPR dispute has been one of the biggest clashes in the life sciences industry in the past few years. But many from outside the life sciences industry might find it challenging to understand why this technology has been so important to the parties involved.

CRISPR is the acronym for clustered regularly interspaced short palindromic repeat, a description of the way short and repeated DNA sequences in the genomes of bacteria and other microorganisms are organised. CRISPR/Cas9 is a gene-editing technique that can target and modify DNA with high accuracy.

In February this year, the Patent Trial and Appeal Board (PTAB) at the US Patent and Trademark Office (USPTO) gave victory to the Broad Institute. The PTAB decision explained that the Broad Institute provided sufficient evidence to show that its claims, which are all limited to CRISPR systems in a eukaryotic environment, do not interfere with UCB’s claims, which are not restricted to any environment.

The PTAB decided that the inventions by the Broad Institute “would not have been obvious over the invention of CRISPR systems in any environment, including in prokaryotic cells or in vitro, because one of ordinary skill in the art would not have reasonably expected a CRISPR system to be successful in a eukaryotic environment.” The board therefore terminated the interference, which UCB had initiated.

CRISPR elsewhere

What is the landscape of CRISPR in other regions of the world? While the Broad may seem to have dominated the dispute with its win at the PTAB, its opponents appear to be leading the way in Europe. The European Patent Office (EPO) granted a patent covering CRISPR technology to UCB, the University of Vienna and Emmanuelle Charpentier. This was granted on May 10 this year and was separately opposed on May 10 and 12.

Marc Döring, partner at Allen & Overy, comments: “With the high-profile dispute in the UPSTO between the UCB and its co-proprietors on the one hand, and the Harvard University/MIT collaboration at the Broad Institute on the other occupying many of the headlines of late, one may be forgiven for thinking of CRISPR research as solely US-centric, but this is far from the truth.”

“In commercial terms, the entities leading the way in the licensing and development of CRISPR research are divided between three broad camps, each with one of the field’s pioneering researchers as its figurehead: UCB (Jennifer Doudna), Charpentier (who is a CRISPR patent co-owner in her own right) and the Broad Institute (Feng Zhang).”

"While the Broad may seem to have dominated the dispute with its win at the PTAB, its opponents appear to be leading the way in Europe."

In terms of commercial CRISPR activity, Döring explains that two of the three main offices of CRISPR Therapeutics, a gene-editing company, are based in Europe (London and Basel). Further, Novartis, Bayer and AstraZeneca are just three of the Europe-based multinational pharmaceutical companies that have already invested heavily in CRISPR technology collaborations.

James Fox, associate at Allen & Overy, explains that in terms of patents, the CRISPR landscape can be divided into three broad categories. The primary level is the foundation level patents relating to the CRISPR platform and its variants. The secondary level patents relate to the tools and processes necessary in the development of CRISPR-based products. The tertiary level patents relate to specific products born out of CRISPR research, such as novel therapeutic agents.

Fox says that the majority of patent families already granted in Europe relate to the primary-level patents described, which have been exclusively licensed by the big three institutions named above (main parties) to their own commercial spin-off companies. Fox adds that an array of secondary-level patent families have also been filed.

“The number of CRISPR-related patent filings, of which we expect most to be of the secondary-level variety, has been growing exponentially and we expect this growth only to continue,” he says.

Jim Wilson, partner at Penningtons Manches, says that in order to be protected from potential patent litigation in the future, it is sensible for organisations to take licences.

Wilson explains that UK-based organisation Horizon Discovery has announced that it has full access to CRISPR technology, although he stresses that this is for investigation in the lab and not for therapeutic applications.

Döring adds: “In Europe the IP landscape is in a relatively nascent phase and accordingly we are unlikely to see large-scale enforcement actions of CRISPR rights in the near term.” As it stands, Döring explains, there has been relatively little in terms of legal disputes relating to CRISPR in Europe to date and “certainly nothing on the scale of the recent high profile interference proceedings between UCB and the Broad before the USPTO”. He adds: “However, numerous opposition proceedings from other interested parties have been filed in respect of each European patent the Broad has been granted by the EPO. Similarly, two opposition proceedings have been filed by straw men; the first on the very day that the Charpentier/UCB/University of Vienna patent was granted on May 10, 2017, and the second just two days later on May 12.

A ‘straw man’ in this context, Döring says, is one where the opposition to the grant of the patent is filed in the name of another entity (usually the name of the external patent attorney firm) rather than the entity which is really opposing the patent.

He adds: “We expect this pattern of oppositions to continue and represent the first wave of CRISPR-related legal disputes likely to be seen in Europe.”

Getting a lead

As the CRISPR technology is expanding out of the US, it becomes increasingly important for organisations and companies to know what to do if they are to take advantage of this technology.

Kevin Noonan, partner at McDonnell Boehnen Hulbert & Berghoff, says that although the IP landscape of CRISPR is looking more uncertain internationally, he would advise any party wishing to use this technology to practise it in a place where it isn’t patented, or even better, get a licence.

Noonan adds: “At the moment the CRISPR technology is not yet patented in many countries around the world. Whether practising in a country where the patent is pending would get you into trouble once the patent grants is a question for the national patent law. But there is a risk that unlicensed use of the technology could raise issues with whatever is produced using it once commercialised.”

Looking further afield, in September last year, Toolgen of South Korea had two patent applications granted by the Korean Intellectual Property Office covering CRISPR. The two patents cover fundamental claims for CRISPR/Cas9-based genome editing in eukaryotic cells. The claims also covered modifications for improved specificity of CRISPR/Cas9 nucleases.

The CRISPR technology has also been patented in India. Hemant Singh of Inttl Advocare said in an article for LSIPR: “As expected Doudna, through Regents of the University of California, is the first to file an application in India as a national phase application.”

He explained that the claims essentially pertain to the structure (amino acid sequence) of the Cas9 enzyme (referred to as variant Cys4 endoribonuclease). Other claims are directed to use of the CRISPR/Cas9 system for regulating production and detecting the specific sequence of target RNAs in eukaryotic cells.

Singh added: “With Doudna’s application being the first filed at the Indian Patent Office, other applicants such as Fred Hutchinson Cancer Research Center, Vilnius University, Bayer CropScience, and Sigma-Aldrich have also entered India for securing patent rights for specific uses and modifications of CRISPR/Cas9 technology.”

As things stand, the international CRISPR landscape is becoming increasingly competitive, but in the US and Europe at least, the three main parties still dominate.

But according to Noonan, the parties would be in a better position if they joined forces.

“There could be situations where the technology would be in a better position to be commercialised, but so far unfortunately I don’t see a lot of evidence that any party is very interested in doing that,” he concludes.