Ten years ago, two scientists drafted blueprints for CRISPR, a revolutionary gene editing technique that would enable them to make precise changes to DNA. The discovery won them a Nobel Prize and is now being used by biotech companies to develop cutting-edge treatments for genetic diseases ranging from inherited blindness to sickle cell disease.
Now those Nobel laureates — Jennifer Doudna of the University of California, Berkeley and Emmanuelle Charpentier of the Max Planck Institute for Infection Biology — find themselves on the losing side of a bitter patent brawl to determine who owns CRISPR in the United States.
A month ago, the US Patent and Trademark Office ruled that Feng Zhang and his colleagues at the Broad Institute of Harvard and MIT were the first to get CRISPR to work in the cells of organisms like yeast, plants, animals, and people. Investors consider agricultural and medical uses of CRISPR the most lucrative applications of the technology.
“This decision was the ticker tape, which says that Zhang crossed first,” said Jacob Sherkow, a professor of law at the University of Illinois, who has been following the CRISPR patent dispute since it began in 2015. The verdict was bad news for companies with the most advanced clinical programs, he added, including Crispr Therapeutics with its therapy for sickle cell disease, and Intellia Therapeutics with its treatment for a genetic form of nerve damage. Both companies, based in Cambridge, rely on licenses from Berkeley.
“They will need a license from the Broad Institute before they launch any product approved by the FDA,” Sherkow said. “This patent decision casts a shadow over whether and when the first CRISPR therapies will be launched onto the market.”
Scientists in Doudna’s lab originally developed a version of gene editing that relies on a bacterial enzyme called Cas9, which can be directed to turn specific genes on or off, or even add new DNA to a cell. Her team initially tested CRISPR-Cas9 in test tubes and bacteria, but struggled to get the technology to work in animal or human cells throughout the summer of 2012. Although they finally achieved this goal that fall, Zhang’s lab at the Broad got CRISPR to work in mouse and human cells first, allowing his team to claim victory. At least according to the patent office ruling.
The ruling was welcomed by Cambridge-based biotech firm Editas Medicine, which has an exclusive license for CRISPR-Cas9 therapies from the Broad. No one can say exactly how much the Broad’s patents are worth, but if CRISPR-based therapies are successful, experts believe they could easily bring the institute tens of millions of dollars.
“If CRISPR becomes a billion-dollar market, even a small royalty could become very significant to Broad, which is one of the reasons that everybody has been fighting so hard over this,” Zachary Silbersher, a partner at the intellectual property-focused New York law firm Kroub, Silbersher & Kolmykov.
But the ruling does not cover newer forms of gene editing that improve or expand upon what CRISPR-Cas9 can do, and it leaves unanswered lingering questions about a previously granted patent held by Berkeley that complicates the Broad’s advantage.
“This is just one battle in a much larger war, so stay tuned,” said David Silverstein, a patent attorney at Axinn in New York. “There are a lot of patents that each side has and a lot of other legal challenges each side is making.”
Berkeley is likely to appeal the case to federal court, although patent lawyers say its chances of success seem slim. The court is typically deferential to the patent office’s decisions on complex science, said Kevin Noonan, a biotechnology patent lawyer for the Chicago intellectual property law firm McDonnell Boehnen Hulbert & Berghoff. “As long as they didn’t misapply the law, the decision will be upheld.”
The Broad is also facing legal challenges from two companies — Sigma-Aldrich and ToolGen — that claim to have invented certain forms of gene editing. US patent courts are expected to hear arguments on both sides this year. “It is entirely possible that the Broad Institute could lose some patents,” Sherkow said. “To be clear, the Broad is not out of the woods.”
Berkeley has won patent disputes with the Broad in Europe, setting up a complex situation for companies hoping to commercialize their CRISPR products globally. Although some firms using gene editing in agriculture have lined up licenses from Berkeley and the Broad, most companies developing CRISPR therapies only have licenses from one side.
“We have this weird patchwork of global rights,” said Samantha Zyontz, an economist who studies innovation at Stanford University. “You would think that most companies would hedge their bets and just get licenses from both groups, but that isn’t what happened.”
So far, the various firms and institutions with a stake in CRISPR have shown little interest in cross-licensing their patents, and it’s unclear if the recent ruling will change that. “It does seem like they are ready to fight to the death, and I find that really peculiar,” said Arti Rai, director of the Center for Innovation Policy at Duke Law.
Further complicating the question of who owns the technology is one of Berkeley’s patents — shared with the University of Vienna and Emmanuelle Charpentier, a group collectively called CVC — is written to seemingly cover any use of CRISPR-Cas9. In a statement to the Globe, Crispr Therapeutics emphasized the importance of that broad patent. “As it stands today, parties commercializing gene editing medicines using CRISPR/Cas9 will need a license to the CVC portfolio.”
Lawyers are split on how to interpret Berkeley’s sweeping patent and say it could lead to more legal disputes. Katherine Ann Rubino, a life science patent attorney at Caldwell Intellectual Property Law in Boston, said that companies developing CRISPR-Cas9 therapies may need licenses from both Berkeley and the Broad.
Other experts, including Sherkow, say the patent court’s ruling could prevent Berkeley from enforcing the most valuable uses of its patent — plant, animal, and human applications of CRISPR-Cas9 — since those uses clash with the Broad’s patent.
Intellia chief executive Dr. John Leonard said in an e-mail that the patent dispute “has had no effect on our ability to discover, develop, or commercialize in the future potential CRISPR-based medicines.” He added that “we believe a business resolution should be possible between CVC and Broad and we would favor this outcome.”
The dispute between the Broad and Berkeley may yet trickle into other forms and applications of CRISPR. Sherlock Biosciences, founded by Broad scientists, and Mammoth Biosciences, founded by Berkeley scientists, are developing diagnostic tests based on CRISPR enzymes called Cas12 and Cas13. And both startups claim to have a dominant ownership of the technology.
“We have the first filing that blocks anyone from doing CRISPR-based diagnostics, so we are really the only CRISPR-based diagnostics company out there that has freedom to operate,” said Sherlock chief executive Bryan Dechairo.
Mammoth chief executive Trevor Martin rebutted Sherlock’s claims in an e-mail, saying, “That statement is false and we are confident we have the strongest IP portfolio in the space.”
For some academic researchers, the simmering patent disputes are just a distraction. Scientists can readily order CRISPR online for research, but as soon as they start making money from a product, they need a license. “The patent wars do not affect the fundamental basic research, and there are still a number of labs that don’t even want to talk about it,” said Eric Kmiec, executive director and chief scientific officer of the Gene Editing Institute at ChristianaCare in Delaware.
“While having access to the IP is important in the long run, it has not significantly hindered early stage innovation,” said CRISPR Therapeutics chief executive Samarth Kulkarni in an email. His comments are echoed by many researchers who say that the patent dispute hasn’t slowed down CRISPR research.
“CRISPR innovation has not disappeared while people wait for them to duke this out,” Zyontz said. But the dispute may have helped motivate scientists to discover or design new forms of gene editing that improve or expand upon what Cas9 can do. “It has definitely got people to think a little more creatively,” Zyontz added.
Only a few companies — namely Crispr Therapeutics, Editas, and Intellia — focus on Cas9 for their therapies. Many gene editing firms that have launched in the past five years are using next-generation gene editing tools.
Walter Strapps, former vice president of discovery biology at Intellia until 2018, said that startups moved away from Cas9 partly because they didn’t wait to get tied up in the patent war and partly because new tools could do things that Cas9 can’t do. The patent dispute over Cas9 spurred people “to see what else is out there,” he said.
Strapps is now chief executive and co-founder of a startup called Carver Bioscience, which is developing therapies for viral infections using the CRISPR enzyme Cas13. Although CRISPR patent fights have largely focused on Cas9 so far, experts expect that to change in the future.
“I hope that no one thinks this is the end of patent disputes over CRISPR generally,” Sherkow said. “There will be patent disputes over CRISPR as long as there is a market for CRISPR.”