Talk in the Biotech Industry has Focused on the Broad Institute’s Big Win—But Will Continued Scientific Development Minimize Its Impact?
The CRISPR-Cas9 gene editing system has revolutionized genetic engineering. Over the last decade, this technology has exploded at a breathtaking pace due to its simplicity, scalability, affordability and adaptability. Currently, the CRISPR-Cas9 system is employed in molecular biology laboratories all around the world and has been used to edit the genomes of a myriad of organisms from bacteria to yeasts to plants to mammals. This is particularly true in the cancer immunotherapy sphere, where the CRISPR-Cas9 system has been successfully used to genetically enhance different cancer-killing properties of human immune cells. Pickar-Oliver and Gersbach, 2019, Nature Reviews Molecular Cell Biology 20(8), 490-507.
Considering the potential application of the CRISPR-Cas9 system in the immunotherapy space, it is helpful to stay abreast of developments concerning the patenting of this technology. While there are a plethora of patents and patent applications relating to CRISPR, the dispute between Nobel Prize winners Jennifer Doudna and Emmanuelle Charpentier associated with The Regents of the University of California and University of Vienna (collectively “CVC”), on the one hand, and Feng Zhang associated with The Broad Institute, Inc., Massachusetts Institute of Technology, and Presidents and Fellows of Harvard College (collectively “Broad Institute”), on the other hand, has received the most attention. This dispute focuses on which entity is entitled to patent claims (and associated ownership rights) that encompass the use of CRISPR-Cas9 in eukaryotic cells. The parties have participated in multiple proceedings before the United States Patent and Trademark Office’s Patent Trial and Appeal Board (“PTAB”) to decide which entity was entitled to claims specific to eukaryotic cells. The PTAB’s most recent decision resulted in a win for the Broad Institute. The PTAB’s decision focuses on which entity actually reduced to practice, or conceived of, the use of the CRISPR-Cas9 system with a single guided RNA able to edit DNA to affect gene expression in a eukaryotic cell. The question of reduction to practice requires proof that the inventors constructed an embodiment that met all of the claim limitations and that the inventors determined that the invention would work for its intended purpose. The Regents of the University of California, et. al. v. The Broad Institute, Inc., et al., Patent Interference No. 106,115 at 9 (PTAB Feb. 28, 2022). The question of conception requires both the idea of the invention’s structure and possession of an operative method of making it. The Regents of the University of California, et. al., Patent Interference No. 106,115 at 24-25.
After reviewing the evidence the PTAB concluded that the submission by Dr. Zhang on October 5, 2012 of a peer reviewed manuscript showed that Dr. Zhang appreciated that his results demonstrated successful use of a chimeric RNA CRISPR-Cas9 system to cleave DNA in a eukaryotic cell. The Regents of the University of California, et. al., Patent Interference No. 106,115 at 57. With respect to CVC the PTAB concluded that while it may have succeeded in editing the DNA of the embryo of a zebrafish before October 5, 2012, neither the scientists running the experiment nor the inventors appreciated the success. Thus, there was no reduction to practice. Absent this evidence, CVC could not meet the legal definition of actual reduction to practice that predated the Broad Institute’s actual reduction to practice of October 5, 2012.
The PTAB then moved onto the question of conception. It is undisputed that Drs. Doudna and Charpentier were first to conceive of a CRISPR-Cas9 system as a genetic engineering tool. It was this work that led to these scientists being awarded the 2020 Nobel Prize in Chemistry. But the legal framework provides a requirement that these scientists possess an operative method of modifying the DNA of eukaryotic cells for patent claims specific to that environment. The PTAB held that experimental failures by CVC showed just the opposite. Thus, the inventors did not have a definitive and permanent idea in June 2012 to support the legal requirements of conception. The Regents of the University of California, et. al., Patent Interference No. 106,115 at 42.
The Broad Institute’s success in establishing entitlement to use of a CRISPR-Cas9 system in eukaryotic cells in the United States is an important result for the Broad Institute and its licensees. In particular, companies that took a license from CVC will also need license rights from the Broad Institute to the extent they commercialize in the United States therapeutics based upon the use CRISPR-Cas9 in patients’ cells. But issues remain.
The Broad Institute has not fared as well in Europe. There CVC remains in a stronger patent position so companies will need to obtain licensing rights from CVC. The differing results in Europe and the United States continue to provide uncertainty as to the IP rights that companies should pursue when developing their products.
A final point to consider when assessing the value of the Broad Institute’s victory—and what may be the most important development in considering the value of the CRISPR-Cas9 patents that survive these disputes—is substitution of the Cas9 with Cas14 in order to allow the packaging of the CRISPER-Cas system in the tiny viruses routinely used for gene therapy. Ran et al, 2015, Nature 520, 186-191 and Nelson et al., 2016 Science 351 (6271), 403-407. It also includes the substitution of Cas9 with other Cas enzymes such as Cas12a(Cpf1), which displays greater target specificity than Cas9 and is more amenable to multiplex gene editing applications and Cas 13a(C2c2), which is capable of directly editing RNA transcripts and can be used to perform tissue specific transcript knockdowns. Zetsche et al., 2017, Nature Biotechnology 35(1), 31-34. At bottom, the greatest threat of all to the value of the foundational CRISPR-Cas9 technology patents might well be the emergence of entirely novel gene-editing technologies that may supersede CRISPR-Cas9, thereby rendering it obsolete. Cox et al., 2017, Science 358(6366), 1019-1027.
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