DUBLIN – The epic CRISPR/Cas9 patent wars took another intriguing twist this week, when the European Patent Office (EPO) revoked a Broad Institute European patent, EP 2771468 B1, on the basis that it lacked priority over novel art. The Broad Institute, of Cambridge, Mass., immediately stated its intention to appeal the decision, which imposes a stay of execution on the EPO decision.

The patent, known in other jurisdictions as US 20140242664 A1 and WO 2014093712 A1, among other designations, is titled "Engineering of systems, methods and optimized guide compositions for sequence manipulation," and claimed a priority date of Dec. 12, 2012. It is one of the foundational patents claimed by the Broad Institute, based on Feng Zhang's work in translating the CRISPR/Cas9 genome editing tools to a eukaryotic background.

It was overturned on a technicality, based on the omission of Luciano Marraffini of the Rockefeller University in New York, who was originally named as co-inventor on earlier filings but omitted from later filings following the emergence of an IP dispute – since settled – between the two institutions.

The Broad Institute stated that the decision is based on a difference in interpretation between the U.S. Patent and Trademark Office (USPTO) and the EPO on the rules that govern the naming of inventors on patent applications. "The Broad Institute is confident that the EPO will, on appeal, harmonize the EPO procedures to be consistent with international treaties and compatible with the fundamental principles of the Paris Convention – and that it will recognize the same priority dates for the inventions as those the USPTO has repeatedly affirmed for the Broad's U.S. applications," it said in a statement.

"The Broad statement only addressed the priority position," Daniel Lim, senior associate at the London-based law firm Allen & Overy, told BioWorld. Lim, who stressed he was speaking in a personal capacity, attended the EPO hearing in Munich and noted in his own published account of the hearing that "the findings in the arbitration and subsequent settlement [between the Broad and Rockefeller] did not have retroactive effect and could not cure that key deficiency at the time of filing after the fact."

Opponents countered that the EPO is not going to change its procedures – or more than 100 years of case law – on foot of an appeal.

"The Broad has multiple patents in Europe. Most of them suffer from the same defect that this first one was rejected for," Eric Rhodes, CEO of Dublin-based ERS Genomics Ltd., told BioWorld. The company is part of the mini-ecosystem of biotech firms that has emerged from the work of CRISPR/Cas9 co-inventors Emmanuelle Charpentier, of the Max Planck Institute for Infection Biology in Berlin, and Jennifer Doudna, of the University of California, Berkeley.

The Berkeley and the Broad groupings have been locked in patent disputes on both sides of the Atlantic.

This week's outcome, although by no means a final resolution, resets the balance of power between the two sides.

"We're on the backfoot in the U.S. I think the Broad is on the backfoot in most of the rest of the world," Rhodes said. The Berkeley side has patents with broad sets of claims issued in Europe and China and expects a Japanese grant soon, he said.

The Berkeley side has long maintained that the Broad Institute played no role in the invention of the CRISPR/Cas9 genome editing toolset – that they merely were the first to implement it in a eukaryotic system using standard molecular biology methods. "They got it to work and got it to work quickly, but they didn't do anything novel," said Rhodes.

The USPTO does not share that position, however. It found no interference between the claims granted to the Broad Institute and those granted to the Berkeley group, in a ruling handed down in February 2017. That is currently the subject of an appeal, but the Berkeley group faces an uphill struggle to convince the appeal court that the USPTO erred in law.

"It is going to be difficult – and it always is difficult on appeal when you have a case that ultimately turns on factual findings," said Lim.

More opposition to follow

The Broad's line of argument this week may have been influenced by its legal argument in the USPTO appeal, noted Corinne Le Buhan, founder and principal consultant at IP Studies Sarl, of Neuchâtel, Switzerland, which maintains a database on the CRISPR IP landscape: "By focusing on the EU law 'technicality' problem, attention gets diverted from the core scientific issue of whether the Broad (and more specifically Feng Zhang) invented CRISPR/Cas9 for eukaryotes, and when did this invention actually occur, as this core question is also key to the parallel U.S. patent interference procedure currently in favor of the Broad, yet subject to appeal by the other camp," she told BioWorld by email.

"Overall, we think yesterday's decision was still good news for ERS Genomics and its licensees because it clears their most visible IP competition on CRISPR/Cas9 licensing in Europe," she added. "It's not definitive, though, as there will for sure be an appeal, but we know some prospective CRISPR end users were waiting for this decision to decide which licenses to take."

There is no real end in sight to the ongoing legal campaigns that parallel the development of commercial products based on CRISPR/Cas9. This week's hearing in Munich was the first CRISPR patent opposition to be heard in Europe, Lim noted, but oppositions to patents held by Berkeley, the Milliporesigma life sciences arm of Darmstadt, Germany-based Merck KGaA and Paris-based Cellectis SA are likely to follow.

And if the current Berkeley appeal fails, Rhodes noted, a second interference could follow, based on additional allowed claims in the Berkeley patent covering the use of CRISPR/Cas9 in any cell type.