CRISPR never ends

Patent Office: 1924

Another party to the dispute:

Fight for coveted CRISPR patents gets knottier, as MilliporeSigma makes new claims

STAT, Sharon Begley, 7-22-19

After nearly seven years of failing to win fundamental patents on the genome-editing technology CRISPR, a unit of one of the world’s largest life sciences companies has thrown a Hail Mary: Late last Friday, MilliporeSigma petitioned the U.S. Patent and Trademark office to open an interference proceeding between CRISPR-Cas9 patents that it applied for way back in 2012 and patents that the University of California has applied for or been awarded.

The unusual move — New York Law School patent expert Jacob Sherkow’s reaction was “holy s***,” and MilliporeSigma itself described the circumstances as “extraordinary” — seems to be the company’s last-ditch effort to pull out a CRISPR victory at the patent office, which it believes has treated its applications in a way that is inconsistent with how it has treated others.

“What we’re trying to do with this petition is highlight a fundamental unfairness in how Sigma-Aldrich’s patent applications” covering the use of CRISPR in plants and animals, or eukaryotes, “are being handled compared to others’,” company attorney Benjamin Sodey said, referring to the MilliporeSigma unit.

The move could have implications beyond intellectual property rights. MilliporeSigma argues that two scientists at its St. Louis lab, Greg Davis and Fuqiang Chen, were the first to get the CRISPR system to edit eukaryotes. That system is a “guide RNA” that finds a specific nucleotide sequence on a genome, paired with an enzyme that cuts the DNA so a disease-causing segment can be excised or a repair segment can be inserted.

“We have not been very visible” in discussions of CRISPR credit, said geneticist Supriya Shivakumar, head of strategy for gene editing at MilliporeSigma, a unit of Germany-based Merck KGaA. “We would like it to be recognized that our scientists did some amazing discovery work that led to the use of CRISPR in eukaryotes.”

The Broad Institute of MIT and Harvard pushed back hard against the implication that its scientists, led by Feng Zhang, came in second.

“Feng Zhang first used CRISPR in eukaryotic cells,” Broad spokesman David Cameron told STAT.

An interference proceeding determines whether two patents describe essentially the same invention. If so, then (under the law that prevailed when the disputed patents were all filed) the scientists who were the first to invent are awarded the patent.

Last month, the patent office declared an interference between UC and the Broad, meaning it believes that a dozen key CRISPR patents awarded to the Broad and 10 CRISPR patent applications by UC and its partners describe substantially similar  inventions.

MilliporeSigma is asking the patent office to conduct a parallel interference proceeding, between the company and UC, concurrent with its Broad/UC interference. The latter will determine whether Zhang’s invention of CRISPR-Cas9 to edit eukaryotes is essentially the same as inventions by UC’s Jennifer Doudna and her colleagues. Although the UC team showed that CRISPR can edit DNA floating in a test tube, and not in cells, its patents (eight so far) cover the use of CRISPR in all systems — inside cells, outside cells, genomes of eukaryotes and genomes of lower organisms.

A representative for UC’s attorney said she has no comment in the MilliporeSigma petition.

For years, the patent office has denied MilliporeSigma’s applications (including 15/188,911, 15/456,204, and 15/188,924) to patent CRISPR-Cas9 editing in eukaryotic genomes. The first of these was filed on December 6, 2012, six days before the Broad’s application on Zhang’s work.

MilliporeSigma has petitioned the patent office for an interference between it and UC, and not between it and the Broad, because the patent examiner has cited only the UC patents in denying the company’s applications.

The reason for the denial, according to MilliporeSigma’s petition, is the examiner’s conclusion that the Chen-Davis work in eukaryotes is obvious given Doudna’s on DNA in test tubes. As it happens, a previous interference between UC and the Broad revolved around this “obviousness” point. But last year a federal court upheld the patent office’s 2017 decision that Doudna’s test tube breakthrough did not make Zhang’s success getting CRISPR to edit genomes inside mammalian cells “obvious.” The Broad got to keep its key CRISPR patents.

MilliporeSigma argues that the same reasoning should clear the way for its patents on CRISPR in eukaryotes. That is, if the Broad’s eukaryote work was not obvious given UC’s, then Sigma-Aldrich’s isn’t either. “UC’s disclosure of CRISPR-Cas9 in in vitro cell-free and nucleus-free test tube environments … [does not] render obvious claims directed to CRISPR-Cas9 in eukaryotic cells,” its petition says.

The company is clearly aggrieved, sprinkling its petition with words such as “frustratingly,” a quote from Yogi Berra (“it’s like déjà vu all over again”), and assertions that the examiner “simply responds again and again that she finds Sigma-Aldrich’s evidence ‘unpersuasive’,” dismissed its arguments “in little more than a single paragraph, superficially,” and is guilty of “blatant inconsistency” and “demonstrable unfairness” to MilliporeSigma. In contrast, it has won CRISPR patents in Australia and Europe.

If the patent office conducts an interference proceeding between the company and UC, there are two possible outcomes. It can conclude that their CRISPR inventions are different enough that both can be granted patents, as happened with the first UC-Broad interference. Or, it can conclude that the two parties’ CRISPR inventions are substantially the same. In that case, the next step is to determine who invented it first. MilliporeSigma believes Davis and Chen did.

“If the patent office is deciding” who invented CRISPR in eukaryotes, MilliporeSigma’s lawyer Sodey said, “we believe [we] should be part of that conversation.”

That argument runs counter to all CRISPR histories. Numerous prizes have honored Doudna and her chief colleague, Emmanuelle Charpentier, as well as Zhang, for inventing CRISPR genome editing. One author who has extensively researched that history said none of the experts he interviewed ever mentioned Davis and Chen. The pair did not publish on CRISPR, though industry scientists often skip journals and file patent applications instead.

Attorneys who have worked on the seemingly endless CRISPR patent fights, who asked not to be named to preserve client confidentiality, called MilliporeSigma’s move “interesting” and even “fascinating.” But “I have never seen a parallel interference declared,” said one. “I don’t think the patent office will be moved.”

Source: Email from UC Daily News Notes of 7-22-19