The State Of CRISPR/Cas9: Patents And Possibilities

By Joe Stanganelli

October 25, 2017 | A lot has been happening in the CRISPR playing field. For starters, and perhaps the most significantly, the Patent Trial and Appeal Board (PTAB) of the United States Patent and Trademark Office (USPTO) entered into judgment on February 15 that there is "no interference-in-fact" between the respective subject matter of the CRISPR/Cas9 patent claims made by the Broad Institute, MIT, and Harvard University ("Broad") and that of the patent claims filed by Emmanuelle Charpentier, the Regents of the University of California ("UC"), and the University of Vienna ("UV").

The ruling was made pursuant to a motion by Broad to dissolve the Charpentier group's suggestion of interference, and the Broad and its joint stakeholders effectively won a major battle insofar as they got a judgment recognizing the separate validity of their CRISPR/Cas9 patent. At the same time, it was not a total loss for Charpentier and company; that group's provisional CRISPR/Cas9 patent applications were allowed to remain pending by virtue of the decision that their applications and the Broad patents do not interfere.

Still, as with most big-money cases, the administrative judgment is not the end of the story. Charpentier et. al filed a notice to appeal the USPTO's decision before the US Court of Appeals DC Federal Circuit—and has since filed its appellate brief.

The Broad Institute is not worried. "Given that the facts have not changed, we expect the outcome will once again be the same," said the Broad in a statement on the ongoing CRISPR/Cas9 patent litigation. "We are confident the Federal Circuit will affirm the PTAB decision and recognize the contribution of the Broad, MIT and Harvard in developing this transformative technology."

Appeals courts almost never reconsider factual findings by lower adjudicating bodies, absent severe procedural errors, abuses of discretion, or arbitrariness or caprice on the part of the lower body. Instead, the DC federal appeals court will review the PTAB's process and legal decisions for errors of law rather than errors of fact. The Broad has presented confidence in the decision being upheld—indeed, many appeals do tend to be Hail Mary's in nature—but the brief filed by Charpentier’s group seems to raise a couple of compelling arguments regarding legal standards that may have been improperly applied by the PTAB. The Broad's response brief is due today.

UCB and Broad Abroad

But even this is not the end of the Broad-Charpentier CRISPR/Cas9 conflict. Since Bio-IT World's last update, China's State Intellectual Property Office ("SIPO") has awarded a very broad CRISPR/Cas9 patent—for applications both cellular and non-cellular, both eukaryotic and prokaryotic—to both Charpentier's CRISPR Therapeutics and Doudna's Intellia Pharmaceuticals. For its part, however, the Broad cautions that this is not the end of the CRISPR/Cas9 story in China.

"[The SIPO] is currently considering patent applications of Broad Institute, MIT, and Harvard, which we expect will issue," said Lee McGuire, the Broad's Communications Director, in a statement. "In China, patents are subject to invalidation proceedings after they are issued."

The Charpentier team has also succeeded in Europe; UC and company having been awarded a patent in the EU by the European Patent Office ("EPO")—but even that patent might not be entirely safe from third parties. In addition to the Broad (which notes that the EPO "may adjust patents after issue") and Harvard, separately, three other entities have filed CRISPR/Cas9 patent applications before the EPO: Vilnius University, South Korean pharmaceutical company ToolGen, and Merck subsidiary MilliporeSigma.

For what it's worth, the former two have already seen their respective CRISPR/Cas9 patent applications denied by the USPTO, and the respective outlooks in Europe for those entities are uncertain, though ToolGen has been awarded two patents in its native South Korea for CRISPR/Cas9-based genome editing of eukaryotic cells. The latter entity, however, stands out.

Four months after the EPO did the same for UC, UV, and Charpentier, the EPO announced its notice of intent to similarly grant a patent award to MilliporeSigma for its CRISPR-based eukaryotic genomic editing patent application—for a gene knock-in technique which can be used in gene therapy for correction of diseased genes, among many other applications. MilliporeSigma has also gained intent to grant for similar received patent allowances for foundational CRISPR-integration claims in Australia and, most recently, Canada.

"Unlike other systems, the proxy-CRISPR technique allows cutting of previously unreachable cell locations, making CRISPR more efficient, flexible and specific—giving researchers more experimental options," reports MilliporeSigma in a company press release.

Whose Tennis Ball Is It Anyway?

In any event, it's not hard to see why the original US patent fight continues from a business perspective. While Charpentier and company's pending patent covers certain CRISPR/Cas9 manipulations to primitive microorganisms, the Broad's patent is for certain CRISPR/Cas9 editing of much more advanced eukaryotic cells—including mammalian lifeforms.

"The only difference between the parties' claims that the PTAB considered material to the interference proceeding is that UC's claims are genus claims directed to using CRISPR-Cas9 in any environment (i.e., in any of three environments: in eukaryotic and prokaryotic cells, or outside of cells), while Broad’s claims are species claims limited to using CRISPR-Cas9 in eukaryotic cells," Charpentier, UC, and UV note in their appellate brief.

"We’re actually anticipating getting our patent issued finally, one that has very broad claims," Jennifer Doudna, Charpentier's co-inventor at UC–Berkeley, told TechCrunch shortly after the PTAB's decision. "The analogy I’ve used to explain this is the Broad Institute’s patent is for green tennis balls but the patent we will have is for all tennis balls."

Doudna's analogy is a pithy PR soundbite, to be sure, but it might prove misleading and may not quite hold up from the perspective of US patent law.

For now, many CRISPR/Cas9-editing licensees have been seeking licenses from multiple parties on both sides of the patent equation as a risk-management maneuver, but this is unsustainable and will likely lead to additional filings before the USPTO seeking clarification as to who owns what and who can license what to whom.

Assuming the federal appeals court keeps the PTAB's ruling status quo, the whole thing potentially presents a problematic situation for both the Charpentier coalition and its licensees because further filings will likely result in rulings that most closely represent the Broad's narrative—that "UCB's work simply involved characterizing a purified enzyme in a test tube". Consequently, the UC/UV/Charpentier team will have their CRISPR/Cas9 patent application, US Provisional Patent Application No. 13/842,859 (the '859 patent application), presumably limited to prokaryotic applications, while the Harvard/MIT/Broad will have their separate CRISPR/Cas9 patent applicable to plant and animal life.

Therefore, several organizations on the Charpentier-Doudna side of the litigation—even aside from the University of California system and the University of Vienna—would stand to lose millions of dollars in licensing fees.

Caribou Biosciences and Intellia Therapeutics, both companies co-founded by Doudna and in which she appears to hold an ownership interest, are significantly involved in eukaryotic applications of CRISPR/Cas9 gene editing (although Caribou itself, at least, licenses some relevant technology from entities uninvolved in this particular litigation, such as Vilnius University).

Three of Charpentier's companies—CRISPR Therapeutics, ERS Genomics Ltd., and TRACR Hematology Ltd.—all heavily rely on Charpentier's intellectual property rights in the '859 patent application. Ditto for Casebia Therapeutics, a joint venture between CRISPR Therapeutics and Bayer AG formed to develop CRISPR-based human therapeutics. Similarly, TRACR Hematology, in particular, which is co-owned by both CRISPR Therapeutics and Charpentier individually, appears to have been fundamentally founded on licensing rights to human therapeutic applications of CRISPR/Cas9 gene editing—rights that would appear to be in serious jeopardy if the finding of no interference in fact stands up.

Conversely, if the federal appeals court (or, after that, possibly the US Supreme Court) compels a reversal of the PTAB's finding of no interference in fact, additional litigation will compel tedious parsing out of where interference lies. The Broad, Harvard, and MIT—not to mention Editas Medicine, which acts as a CRISPR/Cas9 licensing agent for that trinity—could be on the hook for millions in licensing dollars unless they make their own arrangement with those on the other side of the courtroom aisle.

Yet another alternative is a scenario driven by mutually assured destruction. If the USPTO and/or courts do agree that the Broad's patent is nothing more than a particular color of the Charpentier "tennis ball," the Broad's patent remains good—but both sides would have to enter into a licensing agreement so that the Broad could sell licenses to its "green tennis ball"—which good old capitalism and rational economic thought would compel to happen because the Charpentier side would be unable to license the green tennis balls of human and plant genetic engineering via CRISPR/Cas9 otherwise. In other words, in this scenario, all green tennis balls would belong to the Broad, but the Broad wouldn't be allowed to play with them unless the Charpentier side says it's okay.

Or the USPTO may go in the other direction, determining that the Charpentier patent is overly broad. In this scenario, the patent examination process would take additional time and money and require additional amendments (it would be unfathomable to think that the Charpentier team would abandon its patent application). The Broad patent could be largely unimpacted, but not necessarily.

In any case, all of this means years of various litigation filings, years of continued uncertainty, and years of duplicated licensing dollars being spent so that innovation may continue.

10/27/17: Additional details from MilliporeSigma were added in paragraphs 10 and 11.