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Biomedicine

CRISPR Patent Fight Now a Winner-Take-All Match

Lab notebooks could determine who was first to invent a revolutionary gene-editing technology.

Control over genome-editing tools could be worth billions.

In a legal maneuver with billion-dollar implications, the University of California has asked the U.S. Patent & Trademark Office to decide who was first to invent a powerful gene-editing tool called CRISPR-Cas9.

In a request filed Monday, the regents of California’s public university system asked the patent agency to reconsider ten patents issued starting last year to the MIT/Harvard Broad Institute, in Cambridge, Massachusetts, saying the hugely valuable rights should belong to them.

The technology, called CRISPR-Cas9, acts as a kind of molecular scissors, cutting and replacing DNA letters in an organism’s genome with exquisite precision and ease. The technique is revolutionizing the study of species from mice to potatoes, and is likely to open powerful new avenues in gene therapy to treat human disease as well (see “Genome Surgery”).

If the patent office approves it, the request for a “patent interference,” as the process is known, sets up a winner-takes-all challenge in which either the Broad Institute, or the University of California and two co-petitioners, including the University of Vienna, will come away with all the rights to the gene-editing system, leaving their rival with nothing.

“Expect this battle to be very expensive, very contentious, given the stakes involved,” says Greg Aharonian, director of the Center for Global Patent Quality, which works on patent issues. “I can see many hundreds of thousands of dollars being spent.”

The CRISPR-Cas9 editing technology was publicly described in the journal Science in 2012 by Jennifer Doudna, a biologist at the University of California, Berkeley, and the French microbiologist Emmanuelle Charpentier. But Feng Zhang, a scientist at the Broad Institute, was first to win a patent on the technique after submitting lab notebooks he says prove he invented it first (see “Who Owns the Biotech Discovery of the Century?”).

The system uses a cutting protein, Cas9, attached to a short RNA molecule that guides it to precise locations in a genome. Already, scientists have used it to disable HIV, cure muscular dystrophy in mice, and make wheat that’s resistant to crop diseases.

Under current rules, known as “first to file,” patent rights go to whoever submits a patent application first. That would mean an easy victory for Doudna and Charpentier, because their earliest application is dated May 2012, seven months before Zhang’s. But because of the dates of the discoveries, the case is being carried out under older “first to invent” rules, where the winner is whoever is able show—by any means—they were first to make an invention work, or simply conceive of it. “That person gets the patent,” says Aharonian.

Some experts say the confusion around CRISPR patents is slowing down commercial efforts. Tom Adams, vice president of global biotechnology at Monsanto, says his company had begun working with the technology to create plants with useful traits, but remained reluctant to employ it widely. “It’s a very complicated set of inventions,” says Adams. “Until we understand the intellectual property it’s hard to do much.”

If products or treatments are delayed, the high-profile legal fight could end up reflecting badly on the universities, who all used public tax dollars or philanthropic gifts to make the inventions.

UC Berkeley’s technology transfer office declined to comment, citing the legal case, as did Doudna. A spokesperson for the Broad Institute, Paul Goldsmith, said that Broad has made “repeated efforts and trips since the beginning of 2013 to resolve this situation outside the legal system.” 

Other technology disputes have been resolved by creating patent pools which offer wide access to basic innovations, or via cross-licensing. But that hasn’t happened yet with CRISPR-Cas9, precisely because it’s not clear who really owns the key rights. “It would be mutually beneficial to develop as many products as possible with the technology, because it’s the products that will generate the revenue,” says Dan Voytas, a gene-editing researcher at the University of Minnesota. “With CRISPR, it’s still anyone’s guess how it’s going to work out.”

The patent dispute started last April when Zhang, a scientist at the Broad, appeared as the lone inventor on a broad patent covering CRISPR-Cas9. To win it, he filed a declaration with the patent office saying he’d invented the idea on his own and offered lab notebooks to back up the claim. Zhang told MIT Technology Review in December that other evidence, like grant applications and correspondence, could offer further proof.

But lawyers for UC Berkeley, in counterclaims filed with the patent office this week, say pages and diagrams from Zhang’s lab notebooks show only some related experiments, and don’t prove he invented the system. “Dr. Zhang is wrong,” they conclude. Their conclusions rely, in part, on a technical analysis provided to the patent office by Dana Carroll, a gene-editing expert at the University of Utah. (A copy of the interference request is here, not including more than 100 exhibits.)

Broad says it will stick to its position. “It’s hardly shocking that Berkeley’s lawyers support Berkeley’s claim,” says Broad lawyer Ellen Law. “In fact, Dr. Zhang’s notebooks make it clear his invention of CRISPR-Cas9 dates back to 2011.”

Both Zhang and Doudna devote substantial time and effort to supporting and publicizing CRISPR. Doudna stars in an explanatory video being passed around social media sites, while Zhang’s lab has set up a website and made laboratory materials widely available to other scientists.

The stakes involved are huge. Not only does a Nobel Prize for gene editing seem likely, but several heavily financed startups have been created to start developing gene-therapy treatments. Zhang is involved in Editas Medicine, Doudna’s startup is called Caribou Biosciences, and Charpentier is a founder of CRISPR Therapeutics. The number of scientific publications on the technique has also been skyrocketing, and is likely to surpass 1,100 this year.

Ryan Honick, a spokesman for the patent office, says interference proceedings are decided by a special board of examiners, which hears evidence in about 100 cases a year. The process can take as much as two years to resolve, he says. Overall, the patent office approves about 300,000 patents annually.

Interferences have helped to decide control over some of the most lucrative inventions ever, including the telephone, the sewing machine, and television. In 1885, a competitor managed to strip Thomas Edison of a patent on a lightbulb with a paper filament, although by that time Edison had invented a better one.

Similarly, given the pace of innovation in gene editing, today’s legal fights could end up serving little purpose. Improved versions of CRISPR-Cas9 have already been invented, and entirely new methods are likely.

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