New frontiers in genome editing and an update on the CRISPR patent wars

The discovery of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) has revolutionized gene editing, allowing scientists to modify the genome of an organism by adding or subtracting segments of DNA. The most well-known CRISPR system uses CRISPR-associated protein 9 (CRISPR-Cas9) that precisely cuts DNA at a targeted location. The CRISPR-Cas9 system was first discovered in prokaryotic organisms and has since been adapted for use in eukaryotes. CRISPR-Cas9 can be used to create genetically modified plants and animal models and is now being clinically tested in patients suffering from certain genetic disorders, as well as HIV and several cancers.

In response to the rapid adoption of CRISPR-Cas9 to develop human therapeutics, the FDA has released a number of Draft Guidance documents, including recommendations for early-phase clinical trials and the implications of manufacturing changes. Last year, the FDA published a Draft Guidance titled “Human Gene Therapy Products Incorporating Human Genome Editing,” highlighting specific considerations for in vivo and ex vivo genomic modification. In vivo delivery requires administration of the gene editing system to the patient, typically through viral vectors or nanoparticles. Ex vivo modification involves modifying a cell’s genome, for example via CRISPR-Cas9, outside the body and then administering the modified cells to the patient.

Both ex vivo and in vivo administration have associated risks, including the risk of “off-target editing” in which Cas9 acts on genomic sites that were not targeted, resulting in unintended DNA cleavages. In vivo administration has additional potential risks that stem from the fact that the CRISPR-Cas9 system originates in prokaryotes. Administration of a CRISPR-based therapeutic could trigger immune reactions to the Cas9 enzyme, a large foreign protein. Guide RNAs and the viral vectors used for the delivery of the CRISPR-Cas9 also have immunogenic potential.

To mitigate these risks, the FDA suggests that the frequency of off-targeting editing be evaluated, along with an assessment of genomic integrity, the immunogenicity of the gene editing components and expressed gene product. The FDA’s focus on gene therapy products highlights the dramatic impact CRISPR continues to have in this field.

Fanzors

Until recently, the scientific community believed that these programmable RNA-guided systems existed only in prokaryotes. In a surprising twist, two research groups at the Massachusetts Institute of Technology have discovered CRISPR-like systems in eukaryotes. These proteins, dubbed Fanzors by Dr. Feng Zhang (a CRISPR pioneer) have been found in fungi, algae, amoebas, and even a species of quahog clam.

Dr. Zhang’s lab recently published an article in Nature showing how Fanzor proteins can be programmed to precisely target DNA using RNA as a guide. Much remains to be learned about Fanzor proteins. Importantly, given the relative smaller size of the Fanzor systems, they have the potential to be more efficiently delivered to cells. The Fanzor system may also trigger fewer immunogenic reactions, as it is derived from eukaryotes, not prokaryotes. Dr. Zhang and his colleagues have filed patent applications with claims to engineered Fanzor proteins, guide RNAs, and associated vector systems.

The other group, led by Drs. Omar Abudayyeh and Jonathan Gootenberg, also at MIT and former members of Dr. Zhang’s lab, recently published a scientific pre-print identifying Fanzor proteins (also known as TnpB homologs) across genomes of different eukaryotes. They’ve named this class of compounds HERMES, for Horizontally-transferred Eukaryotic RNA-guided Mobile Element Systems, to reflect their findings that these proteins likely jumped from prokaryotes to eukaryotes and then diversified. They also have demonstrated that these HERMES proteins can be programed to edit the genome of human cells, which suggests that this large class of eukaryotic RNA-guided nucleases could be designed for use in gene editing applications. Like Dr. Zhang, the Abudayyeh-Gootenberg group has filed patent applications on their inventions.

Update on CRISPR patent disputes

It remains to be seen if discovery of the Fanzor/HERMES class of proteins will result in protracted litigation, akin to what is happening with CRISPR-Cas9.

We’ve previously written about that ongoing litigation here. The most well-known CRISPR-Cas9 dispute is between The Broad Institute, Harvard University, and MIT (Broad) against the University of California, University of Vienna, and Emmanuelle Charpentier (CVC), centering on the use of CRISPR-Cas9 in eukaryotic cells.

This fight is far from settled. The USPTO granted priority to Broad in an initial interference proceeding and that decision was affirmed by the Federal Circuit in 2018. In 2022, the USPTO ruled in favor of Broad in a second interference proceeding, but both parties have appealed that decision to the Federal Circuit and a number of amici have filed briefs in support of CVC. The parties and amici all take aim at the USPTO’s application of the law of conception and reduction to practice, and the appeal presents the Federal Circuit with the opportunity to clarify the fundamental distinctions between conception and reduction to practice and the impact of experimental failures.

This past month, the Federal Circuit had another opportunity to weigh in on patents related to CRISPR in a dispute between SNIPR Technologies and The Rockefeller University. SNIPR owns five patents related to the use of CRISPR to selectively kill certain bacteria in a mixed-species population of bacteria. Rockefeller has a patent application directed to similar subject matter. The Rockefeller application claimed priority to February 7, 2013. This application was filed before the America Invents Act (AIA) was enacted. The AIA revised how patent priority is determined, changing from a “first-to-invent” to a “first-inventor-to-file” scheme. The SNIPR patents claim priority to May 3, 2016, and are post-AIA.

The USPTO declared an interference over SNIPR’s objection that interference proceedings are not available to post-AIA patents. The USPTO rejected SNIPR’s argument, determined Rockefeller had priority, and cancelled all the claims of SNIPR’s patents.

On appeal, the Federal Circuit reversed, agreeing with SNIPR and holding that post-AIA patents may not be part of an interference.

These cases highlight the interdependence of tactical patent prosecution and litigation strategies in developing strong IP portfolios in the rapidly changing gene editing space. Learn more by contacting either of the authors or your usual DLA Piper relationship attorney.