Mouse embryonic stem cells differentiated into motor neurons after a GFP tag was inserted in frame with the motor-neuron-specific transcription factor HB9, using CRISPR/Cas9 engineering. The Patent Trial and Appeal Board (PTAB) of the U.S. Patent and Trademark Office (USPTO) is taking up the issue of who invented CRISPR-Cas9 in eukaryotic cells, reigniting the long, bitter battle over who invented the gene editing technology. [T. Macfarlan, National Institute of Child Health and Human Development, NIH]
Eric Rhodes, CEO of ERS Genomics

The long, bitter legal wrangle over who invented CRISPR gene-editing technology is about to get even longer, now that the Patent Trial and Appeal Board (PTAB) of the U.S. Patent and Trademark Office (USPTO) has decided to take up the issue of who invented CRISPR-Cas9 in eukaryotic cells.

The PTAB has declared a patent interference between 10 separate U.S. Patent applications owned by the University of California (UC), the University of Vienna, and CRISPR pioneer Emmanuelle Charpentier, PhD, director and scientific member at the Max Planck Institute of Infection Biology, Berlin—and 13 of the 15 patents held by the Broad Institute, Harvard University, and the Massachusetts Institute of Technology (MIT), plus one patent application.

At issue is the CRISPR-Cas9 DNA-targeting technology invented by Charpentier as well as Jennifer Doudna, PhD, of UC Berkeley; Martin Jinek, PhD, of University of Zurich, a onetime postdoctoral student of Doudna; and Krzysztof Chylinski, PhD, of University of Vienna, a onetime postdoctoral 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 challenges the validity of UCB’s eukaryotic claims, and that the inventions of the Broad, MIT, and Harvard inventions go back to 2011.

“We welcome this action by the PTAB, which has previously ruled that the claims of the Broad patents, issued for methods for eukaryotic genome editing, were properly granted,” the Broad Institute said yesterday in a statement. “Broad Institute looks forward to participating in the interference process.”

The Broad contends that only its issued patents, and not those of UC and partners, cover genome editing and uses in eukaryotic cells, which includes cells from animals, humans, and plants. However, the Doudna-Charpentier-UC inventor team 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, 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 Feng Zhang, PhD, 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.

No interference, Appeals Court says

The first interference proceeding resulted in a ruling by the U.S. Court of Appeals in September 2018 that upheld a PTAB judgment finding no interference-in-fact between UC claims and patents already issued to Broad, stating that the claims were not directed to the same subject matter.

However, the appeals court ruling made no specific determination regarding priority of invention of genome editing within eukaryotic cells. Since then, UC and partners filed their series of applications.

“The patent office sidestepped the issue. UC wasn’t particularly satisfied with being asked whether they had invented it first and just hadn’t included the word eukaryotic specifically in the first filing,” Eric Rhodes, CEO of ERS Genomics, told GEN. “By following up with these applications, they’re forcing the hand of the patent office to now determine who did then invent first in eukaryotes.”

ERS holds an exclusive worldwide license from Charpentier for foundational intellectual property covering CRISPR-Cas9 for all applications other than use as a human therapeutic. ERS’ foundational IP covers broad and dominant claims covering CRISPR/Cas9 compositions and methods of genome editing in any organism.

Charpentier has licensed the technology to ERS Genomics as well as CRISPR Therapeutics.

UC has noted that it has encouraged widespread commercialization of its technology through its exclusive license with Caribou Biosciences. Caribou has sublicensed the UC’s patent family to numerous companies worldwide, including Intellia Therapeutics for certain human therapeutic applications.

Whether the new interference process upholds the Broad patents or upends them in favor of UC and its partners, Rhodes said, “I view that as a no-lose situation for UC. Obviously, they want to win, and believe that it’s worth going thru this interference process to prove that.”

Following the Court of Appeals ruling, UC and its partners were issued six U.S. patents for CRISPR technologies in other cellular or non-cellular settings, among more than 50 patents issued to the team worldwide. Six additional applications are set to issue in the coming weeks, according to UC.

The most recently-issued UC patent, announced June 4, was U.S. Patent No. 10,308,961, covering additional methods of using the CRISPR-Cas9 system. According to UC, the unique methods form a toolset for both editing genes and controlling gene expression, effectively enabling genes to be modified, activated, or repressed. The techniques are not limited to single guide RNA and can be applied to both prokaryotic and eukaryotic cells.

A week earlier, UC and partners were awarded U.S. Patent No. 10,301,651, covering techniques that enable sequence-specific repression or activation of gene expression in all types of cells, including both prokaryotic and eukaryotic cells.

In addition to those patents and U.S. 10,266,850, UC and partners have been awarded three earlier patents:

  • No. 10,227,611, which was issued in March and covers the use of single-molecule RNA guides and Cas9 protein in any cell, with the aim of creating efficient and effective ways for scientists to target and edit genes.
  • No. 10,113,167, which was issued October 30, 2018, and covers “Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription.”
  • No. 10,000,772, which was issued in June 2018, and covers methods of using optimized guide RNA formats (including single-guide and dual-guide formats) in certain environments, including eukaryotic cells (such as human, animal, and plant cells). The optimized formats modify the part of a guide RNA that interacts with the CRISPR-Cas9 nuclease.

Laying out a pathway

Importantly, according to the Broad, the USPTO designated Broad, MIT, and Harvard as the senior parties and UCB as the junior party in the latest interference: “This further underscores the significance of Broad’s prior claims. The senior party is presumed to be the ‘first to invent,’ and the junior party carries the burden of proof.”

Eldora L. Ellison, PhD, lead patent strategist on CRISPR matters for UC, said in a University statement that the initiation of the latest interference proceeding “highlights that previous decisions involving the Broad did not determine who was the first to invent this technology, and it lays out a pathway for resolving this important issue.”

“We are confident that the USPTO will ultimately recognize that the Doudna and Charpentier team hold the priority of invention specific to eukaryotic cells, as well as other settings covered by previous patents,” added Ellison, who is also a director at the law firm Sterne, Kessler, Goldstein & Fox.

Affected by the latest interference proceeding are UC patent applications: US 15/947,680; US 15/947,700; US 15/947,718; US 15/981,807; US 15/981,808; US 15/981,809; US 16/136,159; US 16/136,165; US 16/136,168; and US 16/136,175.

Also affected are Broad Institute patent Nos. 8,697,359; 8,771,945; 8,795,965; 8,865,406; 8,871,445; 8,889,356; 8,895,308; 8,906,616; 8,932,814; 8,945,839; 8,993,233; 8,999,641; 9,840,713; and application US 14/704,551.

At least one set of winners has emerged, Rhodes of ERS Genomics quipped: “The lawyers have already won, and are continuing to win.”

[Kevin Davies, PhD, and Alex Philippidis contributed to this report]

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