CRISPR: The Future.

CRISPR: The Future

In the first of a series of articles outlining the potentially transformative and life-changing technology, CRISPR, we take a look at the recently concluded and on-going patent disputes in the US and Europe respectively.

But first….

What is CRISPR?

CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats), a powerful gene editing technology, has grabbed the headlines, captured imaginations and created quite a buzz in the scientific community.

CRISPR enables geneticists and medical researchers to edit parts of the genome by removing, adding or altering DNA. CRISPR has the advantage over other gene editing technologies, such as TALEN and ZFN, in its simplicity, affordability and high degree of versatility.

For diseases caused by problems with a single gene, such as Cystic Fibrosis, CRISPR has the potential to “cut out” the faulty gene and “paste in” a healthy gene.

From reports of resurrecting the woolly mammoth to designer babies, quite simply, the possibilities and potential of this revolutionary technology are endless.

Or are they?

The Debate: Who ‘Owns’ CRISPR?

The million dollar question….

On one side there is University of California, Berkeley (UCB) and on the other, Broad Institute of MIT and Harvard.

Whilst UCB and Broad have received all the plaudits, many forget about Virginijus Šikšnys of Vilnius University. In what seems to be a bit of bad fortune, it took Šikšnys five months to publish his study as it was first rejected by Cell in April 2012 and then moved slowly to publication in PNAS on 25 September 2012. Meanwhile, Doudna and Charpentier had reported their findings in Science on 28 June 2012, after filing a patent application in May 2012.

The US –

The Berkeley team (Jennifer Doudna and Emmanuelle Charpentier) first filed a patent application in May 2012 for the basic CRISPR technology. In December of that year, Broad (Feng Zhang) filed an application but paid an extra fee for an expedited route to patent CRISPR in eukaryotic cells – those in plants, animals, and humans. Broad was granted several patents.

UCB challenged that decision, asking the US Patent & Trademark Office to reconsider. In a ruling last year, the office’s patent trial and appeal board decided in favour of Broad, saying the two teams’ discoveries didn’t overlap and that Broad’s patents covered a separate innovation.

The US Court of Appeals for the Federal Circuit upheld this decision by the US Patent and Trademark Office on 10 September 2018 and essentially, awarded ownership to Feng Zhang and Broad. It remains to be seen if UCB will appeal to the US Supreme Court and if the Supreme Court would accept this case.

Europe –

In January 2018, the patent dispute entered Europe for the first time. EP2771468, one of Broad Institute’s fundamental CRISPR patents, was revoked in its entirety at an Opposition hearing.

The fundamental issue for the EPO to consider was if the EPO had the power to decide on entitlement to priority. The two earliest priority documents (12 December 2012 and 2 January 2013), amongst others, named Luciano Marraffini of Rockefeller University as an inventor-applicant, but Marraffini was not an applicant on the later patent applications and had not assigned priority rights to Broad.

Marraffini does not appear as an applicant on the PCT application forming the basis of EP2771468, and no evidence was submitted to the EPO’s proceedings that Marraffini had assigned his rights to Broad Institute before the filing date of the PCT application.

Broad argued that national law should apply (in this case, US law), in that Marrafinni did not contribute to the later filed invention.

35 USC § 116 (2004 ) – When an invention is made by two or more persons jointly, they shall apply for patent jointly and each make the required oath, except as otherwise provided in this title. Inventors may apply for a patent jointly even though (1) they did not physically work together or at the same time, (2) each did not make the same type or amount of contribution, or (3) each did not make a contribution to the subject matter of every claim of the patent.

The opponents argued that the EPO was bound by Article 87 EPC, in that any person who has filed a patent in a state a party to the Paris Convention, or his successor in title, shall enjoy such a priority right to the same invention for a subsequent application.

Intervening Prior Art –

During the opposition proceedings, Broad tried to introduce a press release detailing the settlement agreement between Broad and Rockefeller University dated the day before the hearing. This was not admitted by the Opposition Division (OD) and the subsequent loss of priority meant that two key prior art documents D3 (Mali) and D4 (Hwang) could be admitted in relation to lack of novelty and lack of inventive step.

Interestingly, both of these papers were published out of MIT or Harvard, also the Patentee in this case, and Broad did not argue for novelty over these two publications.

This ultimately led to the self-inflicted demise of this patent (in Europe anyway) and raises a very important reminder for academic institutions when filing patent applications, ensuring they have valid priority.

The latest –

After a day and a half of oral proceedings, out of a scheduled four, the OD upheld their preliminary opinion that the priority claim was invalid. In a press release immediately after the proceedings had closed, Broad indicated that they would appeal the decision in order “to harmonize the international patent process, including that of the United States and Europe”.

The latest developments are that Broad officially submitted their statement of grounds of appeal on 1 August 2018 and also subsequently asked for formal acceleration on the appeal hearing because there are a number of other pending oppositions concerning patents (EP2896697, EP2784162, EP2931898, EP2921557 and EP2794103) that claim priority to the same priority documents.

However, on 15 March 2019, the Board of Appeal announced that their request for acceleration had not been granted and Oral Proceedings have subsequently been scheduled from 13 to 17 January 2020 in Munich.

Broad argued that “an early decision will significantly enhance procedural economy, all parties and the public have a strong interest in the accelerated handling of this appeal and the patent are part of a portfolio for which there is a strong interest from potential licensees”.

The opponents, now successfully argued that the Patentees’ conduct in the EP2771468 opposition and appeal proceedings thus far have not been consistent, referencing their attempts to delay the opposition proceedings, and failing to provide any evidence to support the asserted need for acceleration.

The saga, at least in Europe, continues.

Conclusion

The CRISPR revolution shows no signs of slowing down. To many, it appears to be only a matter of time that a Nobel Prize will be awarded for the discovery of CRISPR, but to whom?

Most recently, Doudna, Charpentier and Virginijus Šikšnys of (Vilnius University) shared the highly prestigious Kavli Prize in nanoscience and each shared the $1 million prize fund. Notably, without Šikšnys’s delayed publication, his share of a $1 million prize fund could have been substantially greater.

Doudna and Charpentier have also won most of the highly coveted awards for CRISPR including sharing the Breakthrough Prize in 2015, the 2015 Gruber Prize in genetics, the 2016 Warren Alpert Prize, and several others.

Meanwhile Zhang shared the 2016 Gairdner International Award with Doudna and Charpentier and two other scientists (interestingly for developing CRISPR-Cas “as a genome editing tool for eukaryotic cells”). The trio also shared the 2014 Gabbay Award and the 2016 Tang Prize.

The apparent disconnect between patent law and science only intensifies the current situation. After all that, Broad appears to have the upper-hand in the US after their triumph at the US Court of Appeals for the Federal Circuit.