eneath the technical and legal jargon in the latest documents filed in the battle over CRISPR patents is a simple argument that, in only slightly exaggerated form, comes down to this:
Any idiot could have turned the rudimentary CRISPR genome-editing technology described by scientists at the University of California in 2012 into the powerful technique that has revolutionized biology. No, going from DNA floating around in a test tube, the UC experiment, to precisely editing genes in humans took the kind of skill wielded only by a scientist in the running for a Nobel Prize — say, the Broad Institute’s Feng Zhang.
The gloves are off.
Key patents on the CRISPR technology were awarded to the Broad and Harvard University based on Zhang’s research developing a CRISPR system that edited mouse and human genes — many of them at the same time, Zhang and his team reported in a 2013 paper. The University of California is challenging those patents on behalf of UC Berkeley biochemist Jennifer Doudna and one of her key collaborators on a seminal 2012 paper, which described editing the test tube DNA using CRISPR.
In one of the more incendiary claims in the hundreds of pages of filings submitted by UC and the Broad this week, UC quotes an email by a former member of Zhang’s lab who asked Doudna for a job. As first reported by MIT Technology Review on Wednesday, graduate student Shuailiang Lin emailed Doudna in February 2015, saying he was the only member of Zhang’s lab working on CRISPR in 2011. The technique “did not work,” the email continued, adding that Lin has lab notebooks and other documentation “of the lab’s failure process.”
That failure turned into success, according to Lin’s email quoted by the UC lawyers, only after Zhang and others saw Doudna’s 2012 paper.
He was telling Doudna this, Lin said, because “I think I may help the CRISPR patent interference process,” referring to UC’s claim that its scientists and not the Broad’s are the true inventors of CRISPR-based genome editing.
The Broad immediately pushed back on the Lin email. The student visited the Broad “for a brief period from a Peking University/Tsinghua University joint program,” it said in a statement Wednesday, working for Zhang on CRISPR projects from October 2011 to June 2012. His visa was set to expire on March 1, 2015, the Broad added, and because he was not hired by the Broad — something he learned in late February 2015 — he needed another employer to sponsor him. Lin’s email to Doudna, said the Broad in a statement, had the subject line, “The Broad CRISPR patent and Apply for a position in your lab.”
Whatever claims Lin made, said the Broad, there is no “evidence to support them.” Last year, Zhang and Le Cong, the junior scientist who did the most work on what became Zhang’s key 2013 paper, told STAT that they began trying to make CRISPR-Cas9 edit genomes in early 2011, which would contradict Lin’s claim that he was the only member of Zhang’s lab working on CRISPR-Cas9. By the spring of 2012, Zhang said, they had enough results for a paper, but not one he thought good enough to submit to a journal.
“I didn’t want to submit the paper just because the result was publishable,” he told STAT then, explaining that he wanted to wait until they had “a paper that can make a significant difference, not just to be first with something.”
When the US Patent and Trademark Office announced in January that it was reopening its decision to award key CRISPR-Cas9 patents to the Broad (technically, “declaring an interference proceeding”), many legal experts expected the case to turn on who made the key discoveries and inventions first. In fact, said intellectual property expert Jacob Sherkow of New York Law School, it may turn on something even more basic: whether the Doudna and Zhang CRISPR inventions are for the same thing, as almost everyone assumed.
In simplified terms, UC’s original application for a patent on Doudna’s work described DNA editing in simple organisms. The Broad’s described such editing in eukaryotes, animals like mice and people whose cells have a genome-containing nucleus.
UC, in its legal filings this week, argues that parlaying Doudna’s discoveries into a technique that would work in eukaryotes was “obvious.” That is, soon after Doudna’s discovery “became known,” UC argued, “Broad was just one of many groups that quickly confirmed, using conventional techniques, that [CRISPR] could be readily used in eukaryotic cells.”
Crucially, scientists of “ordinary skill in the art” — not off-the-charts brilliance — parlayed Doudna’s work in test-tube DNA into something that worked in higher-order cells, UC said in the filings. Neither Zhang’s nor other discoveries of how to make CRISPR-Cas9 work in eukaryotic cells “required any unusual reagents or techniques, but rather used conventional techniques in conventional ways to produce predictable and expected results.”
“They’re saying that, given what [Doudna] reported, any molecular biologist could do it in eukaryotes,” Sherkow said. “Broad is saying, no, this was actually a big cognitive and technical leap. It’s like, I’ve given you the recipe for a Western omelet; how good a chef do you have to be to use that to make a souffle?” According to UC, any hash slinger could have done it; ergo, any patent claims on the eukaryotic advance are without merit. According to the Broad, only a superstar like Zhang could have done it, so the the Broad and Harvard deserve the patents awarded based on his work.
It won’t be easy for the patent office judges to decide just how obvious it was to move from Doudna’s editing of DNA in a test tube to Zhang’s doing it in eukaryotic cells. “That leads me to believe this will be much harder to resolve than I thought,” Sherkow said.