In 2012, Cal biochemistry and molecular biology professor Jennifer Doudna and microbiologist Emmanuelle Charpentier, now of the Max Planck Institute, changed the world. They invented CRISPR-Cas9, a gene editing tool that uses a protein found in Streptococcus bacteria to chop up and rearrange viral DNA with precision. The implications of the technology were immediately apparent, astonishing, and perhaps just a wee bit scary. Ultimately, CRISPR applications might be developed to wipe out genetic diseases, produce bespoke bacteria that could pump out everything from hormones to biofuels, and engineer exotic animal chimeras.
Then in 2013, MIT bioengineer Feng Zhang published a paper in the journal Science that outlined a CRISPR process specifically for eukaryotic cells, i.e., those from higher plants and animals, including primates like Homo sapiens. At that point, the CRISPR saga bifurcated into two parts: the research narrative and the legal fight. The legal dispute pitted Cal against the Broad Institute (supported by both MIT and Harvard) over the patents to CRISPR. And since the patent battle could determine just who gets the gigabucks expected from CRISPR, that’s where most of the public attention has been focused.
Things seemed to move toward a resolution earlier this year when the U.S. Patent Trial and Appeal Board ruled that patents granted to Broad were significantly different from patents Doudna and her colleagues had applied for, and hence would stand. Berkeley’s position had been that the patents overlapped, and hence were the rightful property of the University of California. Berkeley has challenged the Patent Board’s ruling in the U.S. Court of Appeals for the Federal Circuit.
Broad representatives have stated they’re confident the institute will retain its patents, but the issue may not be as clear-cut as a CRISPR-edited gene; Cal’s researchers have been granted a patent for CRISPR applications to eukaryotic cells by the European Patent Office and the United Kingdom, and another may be pending.
Given that dueling patents can be as convoluted and confusing for the layperson as gene splicing, CALIFORNIA contacted Berkeley law professor and patent law authority Robert Merges for a gloss. Merges set it up this way: UC maintains that it has never been determined who first developed eukaryotic CRISPR applications, that CRISPR basically uses the same process for viruses and eukaryotic cells, and that the February decision should be reversed.
“But the patent trial court found that there ‘is no interference in fact,’ which in this case basically means the inventions are not the same,” said Merges. “In other words, there is no contest—the two processes are different. So for the time being, at least, Broad has its patent. We’ll have to see what happens with the appeal.”
That’s not to say it’s all sour grapes for Cal, adds Merges.
“The good news is that Berkeley has pending CRISPR patents of its own, and these have been delayed due to the patent trial court case,” Merges said. “With that resolved, it’s anticipated the patent office will move ahead with Cal’s patent approval.”
That’s not likely to be the end of the story, though, acknowledges Merges. Berkeley’s patent could very well be contested, just as Cal is challenging Broad’s patent. That’s pretty much standard operating procedure for any pioneering development like CRISPR, Merges says.
“Something like this has so much potential money at stake,” says Merges. “It usually takes quite a bit of time for patents [associated with groundbreaking technology] to settle out and determine who owns what. The [pending] Cal patent is very broad. If it’s issued and survives appeals, then the challenge will be in reconciling it with the Broad Institute patents.”
However, there is some risk to Broad if it contests Cal’s patent, Merges said. By arguing that other scientists were working on CRISPR techniques prior to Doudna’s work, “Broad could be hurt as much or more than Cal, because it could cast doubt on their own claims. They’re in a tricky situation. But MIT and Harvard play at a very high and sophisticated level, so I’m sure they’re considering that already. If they don’t challenge, it would tell me some interesting things about the relative strength of their own patent.”
Merges uses a baking metaphor to further explain the current patent brouhaha.
“It’s like Cal claims it invented cookies, and then Broad says it invented chocolate-chip cookies,” he says. “If Cal’s [pending] patent is verified and Broad’s also is upheld, you could end up with a situation where a biotech company would need licenses from both Cal and Broad for a CRISPR application. That kind of bundled license is very common in the world of patents.”
Another common scenario, says Merges, is shared entitlements, which means the profits are simply split between patent holders. That’s usually the case, he observes, for applications involving the Cohen-Boyer patents, which cover basic recombinant DNA technology.
“A tremendous number of biotech companies are using those patents, with the patent profits distributed through an entitlement agreement between the patent holders,” says Merges. “Once an entitlement structure is set up, the involved parties tend to agree on an equitable split. By the time it gets to that point, people are usually disinclined to spend more time and money in court.”
Still, patents aren’t all about money. They’re also about recognition. And in science, that’s at least as important as royalties.
“All things being equal, I’d say we’re probably a couple of years away from a resolution,” said Merges, “but when egos are involved—and they always are in scientific research—you can never be sure. Business logic may dictate settling things as expeditiously as possible, but there are two systems of currency operating here: money on the finance side, and legacy on the science side. That can be a volatile mix.”
But Merges also believes the CRISPR case has some profound social justice implications. The hard sciences, he observes, remains a male province to a great degree. History is rife with examples of women scientists being ignored or big-footed. And as lead researcher for Cal’s CRISPR work, Merges says, Doudna could be suffering from such institutional bias.
“I do have my suspicions that, once again, people are trying to push a woman scientist aside,” Merges says. “You can’t help draw parallels with Rosalind Franklin, who should’ve gotten shared credit for discovering the double helix configuration of DNA. I have a strong sense of something similar happening here, of an all-male, East Coast team at Broad trying to shoulder aside a pioneering female researcher at Cal. It’s an aspect you can’t ignore.”