The Broad Institute of MIT and Harvard on Monday withstood a second closely watched challenge to its CRISPR-Cas9 patents, as the Patent Trial and Appeal Board (PTAB) of the U.S. Patent and Trademark Office (USPTO) has sided with the Broad over the University of California (UC), the University of Vienna, and CRISPR pioneer and Nobel co-laureate Emmanuelle Charpentier, PhD, in the bitter battle royal over who invented the gene-editing technology in eukaryotic cells.

The PTAB has issued a judgment and decision in the second interference determining that the Broad Institute, MIT, and President and Fellows of Harvard College had priority over the Regents of the UC, University of Vienna, and Charpentier, who is director and scientific member at the Max Planck Institute of Infection Biology, Berlin—known collectively as CVC—in the invention of a single RNA CRISPR-Cas9 system that functions in eukaryotic cells.

“We base our decision on the facts that the CVC inventors encountered multiple experimental failures before they recognized any success, even as late as mid-October 2012,” the PTAB stated in its 84-page decision.

The PTAB cited the difficulty the labs of Charpetntier and Jennifer Doudna, PhD, of UC Berkeley, ran into getting their invention to work, starting in Zebrafish, where they found no cleavage in some cases even with codon optimization, raised doubts about whether CVC could have shown at the time that the technique had a “reasonable expectation of success.”

“Although the CVC inventors developed a system on 1 March 2012 that they hoped would work in eukaryotic cells, the preponderance of the evidence demonstrates that they did not have a definite and permanent idea of how to achieve that result as of that date, or by the later dates CVC asserts support that date because of their perception of these multiple failures,” the PTAB continued.

“CVC fails to provide sufficient, persuasive evidence of an earlier reduction to practice or conception, as they are legally defined, of each and every element of Count 1 before Broad’s evidence of reduction to practice. Thus, we determine that CVC’s currently involved claims are unpatentable.”

The board did acknowledge, however, that CVC conceived of a generic single guide RNA (sgRNA) CRISPR-Cas9 system by March 1: “CVC’s patent rights to that invention are not at issue here. Rather, the issue before us now is CVC inventor’s conception of a CRISPR-Cas9 system that works in eukaryotic cells.”

“The subsequent course of experimentation, especially repeated failures, reveal the inventor’s uncertainty, which undermines a definite and permanent idea,” the PTAB concluded.

In its decision, the PTAB added that it was unpersuaded by CVC’s counter-argument that the Broad’s claims were unpatentable, citing CVC’s raising the issue of the Broad failing to name the correct inventors, and would not take up CVC’s arguments regarding inequitable conduct by the Broad since they did not directly relate to the issue of priority for the single count.

“Our mandate is to determine priority, whereas determinations of unpatentability for other reasons is discretionary,” said PTAB. “We enter judgment against CVC, finally refusing CVC’s claims involved in this proceeding.”

Patents vs. Prize

Jacob Sherkow, Professor of Law at the College of Law and Affiliate of the Carl R. Woese Institute for Genomic Biology at the University of Illinois, commented in a Twitter thread that “the issue of priority between [Feng] Zhang [PhD, of the Broad Institute] and CVC is likely *finally* resolved at the USPTO, in Zhang’s favor.

“Thus we’re left with a situation—quite common in molecular biology—where one side gets the valuable patents and the other the Nobel Prize,” Sherkow added. That creates a situation, he said, where each side has something the other wants—clinical success and the Broad’s patents.

“This SHOULD counsel settlement. But that—like the interference—has been a long time coming,” Sherkow wrote. “Can CVC appeal? Sure. But remember the standard on appeal, again, is ‘substantial evidence’—and the PTAB decision, if nothing more, is based on substantial evidence. I don’t think an appeal is going anywhere.”

In 2020, Doudna and Charpentier were awarded the Nobel Prize in Chemistry “for the development of a method for genome editing,” notably the first time the Nobel Prize has been shared by two women.

The Broad in a statement hailed the decision as having “once again confirmed Broad’s patents were properly issued.”

“As the PTAB and U.S. federal courts have repeatedly established, the claims of Broad’s patents to methods for use in eukaryotic cells, such as for genome editing, are patentably distinct and not reasonably expected from results of biochemical ‘test tube’ experiments.”

In a statement last night, CVC said the University of California “is disappointed by the PTAB’s decision and believes the PTAB made a number of errors. CVC is considering various options to challenge this decision.”

In earlier statements and arguments, CVC asserted that it conceived of the use of CRISPR-Cas9 in eukaryotic cells by March 2012, with their conception documented in a March 1, 2012 lab notebook and also in an April 2012 lab notebook and an invention disclosure form and May 28, 2012 lab notebook

CVC argued that it diligently reduced the invention to practice, showing successful cleavage of DNA by the single-guide CRISPR Cas9 complex in multiple eukaryotic cells, including zebrafish and human cells—while Zhang and Broad Institute researchers were unaware of the basic requirements of the CRISPR-Cas9 DNA cutting complex until it learned of the single-guide CRISPR Cas9 complex components from the CVC team in June 2012.

CVC also contended that on June 26, 2012, Zhang’s research partner, Luciano Marraffini, PhD of The Rockefeller University, a reviewer of CVC’s confidential CRISPR Cas9 manuscript, shared the sequence of CVC’s single-guide construct from CVC’s then-confidential manuscript with Zhang. (Marraffini was among 10 co-authors of Zhang’s January 3, 2013, paper in Science reporting the first successful demonstration of Cas9-based genome editing in human cells).

However, the Broad countered at the time that Marraffini shared public information discussed at a CRISPR conference held a week before publication in Science of a paper by Doudna, Charpentier, and colleagues that was first to describe how CRISPR was capable of editing circular or short linear stretches of DNA.

The PTAB has echoed the U.S. Court of Appeals for the Federal Circuit (CAFC), which in 2018 sided with the Broad by upholding an earlier unanimous finding by a three-judge panel of the PTAB that there was “no interference in fact” between 12 patents related to CRISPR technology that list as inventor Zhang, and a patent application by Doudna and Charpentier.

A year later, however, the PTAB rekindled the bitter legal battle by declaring a patent interference between 10 separate U.S. Patent applications owned by CVC and 13 of the 15 patents held by the Broad Institute, Harvard, and MIT, plus one patent application.

In its statement, CVC noted that the 13 patents and one patent application owned by Broad that were the subject of the interference remain under challenge, and are also involved in separate interference proceedings with Toolgen and Sigma-Aldrich.

CVC said it has more than 40 issued U.S. patents that were not involved in the interference and that cover various guide formats of CRISPR-Cas9 genome editing systems with applications in all environments, including eukaryotic cells.

“In addition to the 40+ U.S. patents not involved in this interference, CVC also has issued patents to its foundational CRISPR-Cas9 systems in over 30 countries worldwide that are not affected by any U.S. interference proceedings,” CVC added.

CRISPR-Cas9 at Issue

At issue has been the CRISPR-Cas9 DNA-targeting technology invented by Charpentier as well as Doudna, Martin Jinek, PhD, of the University of Zurich, a onetime postdoctoral student of Doudna, and Krzysztof Chylinski, PhD, of the University of Vienna, a onetime graduate student of Charpentier.

Unlike the first interference process, requested by UC and partners, the latest interference was initiated by the USPTO. According to the Broad Institute, the latest interference challenged the validity of CVC’s eukaryotic claims, while the inventions of the Broad, MIT, and Harvard stretch back to 2011.

The Broad has contended that only its issued patents, and not those of CVC, cover genome editing and uses in eukaryotic cells, which includes cells from animals, humans, and plants. However, CVC has asserted that the application of CRISPR to eukaryotic systems covered by the Broad’s patents represented an obvious rather than an inventive invention, and was thus nonpatentable.

In April 2019, the Doudna-Charpentier-UC team was awarded U.S. Patent No. 10,266,850. That patent was based on U.S. Patent Application No. 13/842,859, which was involved in the first interference proceeding before the PTAB, in which the team challenged 12 patents related to CRISPR technology that listed as inventor Zhang of the Broad Institute.

The application broadly encompassed CRISPR-Cas9 genome-editing technology invented by the Doudna-Charpentier team and its applications in any setting, UC said, including in vitro, and cellular and non-cellular environments, as well as single molecule RNA guides, among other inventions.

The resulting patent, “Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription,” focuses on systems and methods for using CRISPR/Cas9 technology in a single guide format, including uses to target and edit or modulate genes.

“Since first disclosing their groundbreaking work in 2012, Doudna and Charpentier have each continued to lead the global development and ethical application of CRISPR technology,” CVC stated. “Their efforts have helped to establish a “CRISPR economy” of new, innovative companies and research projects for the betterment of humankind.”

The Broad‘s patents have been exclusively licensed to Editas Medicine, which joined the Broad in welcoming the PTAB decision.

“We are pleased with the U.S. Patent and Trademark Office’s decision, ending the interference, and determining the Broad Institute’s innovative work to discover and use the CRISPR/Cas9 technology in human cells,” said James C. Mullen, Editas’ chairman, president, and CEO. “The decision reaffirms the strength of our foundational intellectual property as we continue our work to develop life-changing medicines for people living with serious diseases.

Editas said it is using CRISPR technology covered by the Broad’s patents to develop its lead program EDIT-101 for the treatment of Leber congenital amaurosis-10 (LCA10).

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