Alex Philippidis Senior News Editor Genetic Engineering & Biotechnology News

Cpf1 Discovery Unlikely to Affect the Legal Battle-Royal over Patent Ownership

The murky intellectual property landscape for CRISPR will likely get cloudier following the discovery of a new slicing protein for the genome-editing system hailed as the most significant genetic engineering advance in a generation—yet stuck at the center of a legal battle-royal over patent ownership.

Feng Zhang, Ph.D., and researchers centered at the Broad Institute of MIT and Harvard last week published details of their CRISPR-Cpf1 editing technology. Cpf1 is a newly characterized class II nuclease that promises to deliver simpler and more precise genome engineering since it is more compact than Cas9, relies on just one RNA, cuts DNA relatively far from the PAM target sequence, and results in DNA with staggered, offset ends, compared with the blunt, mutation-vulnerable ends left by Cas9. These features suggest that genetic editing via CRISPR-Cpf1 could be even more flexible and powerful than genetic editing via CRISPR-Cas9, Dr. Zhang and colleagues added.

The disclosure of Cpf1 comes as Dr. Zhang, the Broad Institute, and MIT fight off a challenge by two CRISPR co-developers to the technology’s first patent. It lists Dr. Zhang as inventor and was assigned to both institutions. Dr. Zhang was awarded No. 8,697,359 for “systems, methods, and compositions for altering expression of target gene sequences and related gene products” six months after filing, following fast-track review by the U.S. Patent and Trademark Office (USPTO).

Perhaps more significantly, his patent was awarded ahead of an earlier application, still pending, listing as inventors Jennifer Doudna, Ph.D., of the University of California, Berkeley, and Emmanuelle Charpentier, Ph.D., of the Helmholtz Centre for Infection Research. They were among six co-authors of the first paper on CRISPR published in Science in 2012. UC Berkeley has requested the USPTO reopen Dr. Zhang’s application through a patent interference proceeding. Dr. Zhang has said he learned little from the 2012 paper—and submitted photos of his lab notebooks in persuading USPTO that his lab was first to show inventive steps by applying CRISPR, ahead of Drs. Doudna and Charpentier.

The discovery of Cpf1 appears unlikely to affect the legal battle-royal over who owns Dr. Zhang’s patent related to CRISPR, which stands for Clustered Regularly Interspaced Short Palindromic Repeats. That patent’s claims are based on CRISPR-Cas9; even claims that speak more broadly to “guide RNAs” are based on key claims that specifically name CRISPR-Cas9.

“I do not believe the Cpf1 improvement will resolve the relevance of the dispute over inventorship and ownership of the CRISPR gene splicing technology,” William L. Warren, J.D., a partner and leader of the Intellectual Property Practice Group at the law firm Sutherland Asbill & Brennan, told GEN.

He added: “There may well be additional CRISPR patents issuing in the near future that are not limited to the Cas-9 enzyme.”

Greg Aharorian, director of the Center for Global Innovation/Patent Metrics, told GEN the patent wrangle between MIT and UC Berkeley could go one of two ways. In one scenario, UC Berkeley asks to settle over Cas9 but MIT refuses and drags the case out in the USPTO and the courts. 

“As long as the MIT/Berkeley Cas9 battle drags out, and ownership is unclear, it encourages people to switch over to CRISPR-Cpf1, which is solely MIT's, which is also a reason for MIT not to settle. The uncertainty with Cas9 adds value to their future Cpf1 patent,” Aharonian said. “MIT probably has more money to play this game than state-funded Berkeley.”

In Aharonian’s second scenario, UC Berkeley threatens to challenge the obviousness of the new Cpf1 technique, which its co-discoverers said emerged following databases searches for protein sequences similar to Cas9.  UC Berkeley would argue that given public knowledge of the original Cas9 work, the searching and tweaking represent obvious activity—a serious hurdle to MIT gaining a patent for Cpf1.

“If MIT keeps battling over Cas9, and loses, it could end up with nothing: No Cas9 patent, no Cpf1 patent.  But if it settles, it at least gets to split the current Cas9 sales with Berkeley, while solely profiting from those who switch to Cpf1,” Aharonian said.

“If Cas9 was the only CRISPR process, then it would probably be worth it for both sides to fight and fight,” Aharonian added. “Now that there are two processes, Cas9 and Cpf1, there are probably more than two.  So if MIT and Berkeley are distracted over Cas9, it could encourage others—who are already doing so—to look for yet other proteins beyond Cas9 and Cpf1, which could steal market share from MIT and Berkeley.”

The resulting third-party competition, Aharonian said, could encourage MIT and Berkeley to settle, with the greater legal certainty reducing the need for a third or fourth CRISPR process: “It could be 50-50, and probably a generous concession on the part of MIT, in light of the second Cpf1 system which they own outright.”

Jacob S. Sherkow, J.D., associate professor of law at New York Law School, earlier this year proposed in Nature Biotechnology that the ownership dispute over CRISPR-Cas9 could be resolved through licensing.

“The history of licensing patents on earlier foundational technologies—recombinant DNA, small interfering RNA (siRNA), and PCR—provide several avenues for deploying CRISPR-Cas9 without lengthy patent fights,” concluded Sherkow, an affiliated faculty member at the law school’s Innovation Center for Law and Technology.

Watching the legal battle closely are several startups founded to commercialize CRISPR technology. They include Editas Medicine (co-founded by Drs. Zhang and Doudna, who is no longer part of the company), which raised $120 million in August and $43 million in 2013; Intellia Therapeutics (where Dr. Doudna is a founding member and scientific advisor), which raised $70 million last month and $15 million last year; and Caribou Biosciences (where Dr. Doudna is a co-founder and investor), which raised $11 million in April.

Editas and Juno launched an up-to-$737 million-plus cancer therapy collaboration in May, while Novartis has partnerships of undisclosed value with Intellia and Caribou.

Cpf1 appears to portend a future for genomics in which researchers will have any number of editing tools depending on the material being edited.

“I picture this as a building block set,” Lisa Haile, J.D., Ph.D., a partner at the law firm DLA Piper, told GEN. “CRISPR is the main block onto which many other blocks can be connected, including Cas9 and Cpf1. But CRISPR will be the main building block so one of the patents would have to issue more broadly.”


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