A legal dispute over the fundamental patent rights to CRISPR-Cas9 gene editing technology (CRISPR-Cas9 technology) might be coming to an end. On Monday, September 10, the U.S. Court of Appeals for the Federal Circuit affirmed the decision of the U.S. Patent and Trademark Office (USPTO), dismissing a challenge by University of California, Berkeley (UC) on CRISPR-Cas9 technology.
In its decision in favor of the Broad Institute, the Federal Circuit determined that “the [USPTO] did not err in concluding that Broad [Institute of MIT and Harvard]’s claims would not have been obvious over UC’s claims.” The decision will have wide implications — both for researchers and biotech companies.
CRISPR-Cas9: Overview and Case Background
CRISPR-Cas9 technology is a novel, cost effective, and relatively accurate genome-editing tool that can be used to delete, modify, and replace genes in almost any type of cells — including human cells. “CRISPR” refers to Clustered Regularly Interspaced Short Palindromic Repeats occurring in the genome of certain bacteria and other microorganisms. Cas9 is a CRISPR-associated endonuclease, a type of “molecular scissors” that can be programmed to cut and edit, or correct any segment of DNA in any gene from bacteria to humans. Using a guide RNA (gRNA), researchers can design a specific location at which the Cas9 molecular scissors is able to cut DNA. For example, a gRNA can direct the molecular scissors to cut DNA at the exact site of a specific mutation present in the genome of a patient with a genetic disease caused by a defective gene. Once the molecular scissors make a cut in DNA, a piece of DNA can be deleted, modified, or replaced with a new segment of DNA using the cell’s own “repair” machinery, for example, to correct a genetic defect.
Although still not approved for clinical use, researchers have demonstrated in the laboratory that CRISPR-Cas9 technology can be used to correct the genetic defects responsible for sickle-cell anemia, muscular dystrophy, and certain genetic defects associated with cystic fibrosis and blindness. Researchers have also demonstrated that this technology can be used to target cancer cells to stop cancer cells from multiplying, and to render human cells impervious to the virus that causes AIDS — thereby reducing or eliminating infection by the virus. Researchers have also claimed to have successfully modified human embryos in vitro to edit defective genes using the CRISPR-Cas9 technology.
Upon discovery, Dr. Jennifer Doudna and her colleagues at UC and Dr. Feng Zhang at the Broad Institute independently published methods for using CRISPR-Case9 technology. In the pre-America Invents Act (pre-AIA) first-to-invent period of American patent law, both UC and the Broad Institute filed respective U.S. patent applications, with UC filing its application first. The Broad Institute took advantage of an accelerated patent prosecution process before the USPTO and the Broad Institute’s application issued as a U.S. patent before UC’s application was fully examined. Soon after learning of the Broad Institute’s patent application, UC petitioned the USPTO’s Board of Patent Appeals and Interferences to declare an interference between the claims of the UC and the Broad Institute’s patent applications. UC argued that the claims of the two applications were patentably indistinct; because UC was the first to invent, the Broad Institute’s patent should have never been issued.
At this juncture, the USPTO sided with the Broad Institute, finding that the claims of the UC application and the Broad Institute’s patent were patentably distinct, and it refused to revisit the patentability of the Broad Institute’s patent. UC appealed this decision to the U.S. Court of Appeals for the Federal Circuit.
The Federal Circuit’s Decision
In its opinion confirming the USPTO’s decision, the Federal Circuit noted that “CRISPR-Cas systems occur naturally in prokaryotes such as bacteria … but have not been found to naturally exist in eukaryotes, such as plants and animals … It is undisputed that the Jinek 2012 article [published by the UC researchers] did not report the results of experiments using CRISPR-Cas9 in a eukaryotic cell, and the claims in UC’s ’859 application do not refer to a particular cell type or environment.”
The Federal Circuit used Claim 165 of UC’s U.S. Patent Application No. 13/842,859 as representative of UC’s claims:
165. A method of cleaving a nucleic acid comprising contacting a target DNA molecule having a target sequence with an engineered and/or nonnaturally-occurring Type II Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)— CRISPR associated (Cas) (CRISPRCas) system comprising a) a Cas9 protein; and b) a single molecule DNA-targeting RNA comprising i) a targeter-RNA that hybridizes with the target sequence, and ii) an activator-RNA that hybridizes with the targeter-RNA to form a double-stranded RNA duplex of a protein-binding segment, wherein the activator-RNA and the targeter-RNA are covalently linked to one another with intervening nucleotides, wherein the single molecule DNA-targeting RNA forms a complex with the Cas9 protein, whereby the single molecule DNA-targeting RNA targets the target sequence, and the Cas9 protein cleaves the target DNA molecule.
The Federal Circuit used Claim 1 of Broad Institute’s U.S. Patent No. 8,697,359 as representative of Broad Institute’s claims:
1. A method of altering expression of at least one gene product comprising introducing into a eukaryotic cell containing and expressing a DNA molecule having a target sequence and encoding the gene product an engineered, non-naturally occurring Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)—CRISPR associated (Cas) (CRISPR-Cas) system comprising one or more vectors comprising: a) a first regulatory element operable in a eukaryotic cell operably linked to at least one nucleotide sequence encoding a CRISPR-Cas system guide RNA that hybridizes with the target sequence, and b) a second regulatory element operable in a eukaryotic cell operably linked to a nucleotide sequence encoding a Type-II Cas9 protein, wherein components (a) and (b) are located on same or different vectors of the system, whereby the guide RNA targets the target sequence and the Cas9 protein cleaves the DNA molecule, whereby expression of the at least one gene product is altered; and, wherein the Cas9 protein and the guide RNA do not naturally occur together. (Emphasis added.)
The Federal Circuit provided the following basis for its decision, which relied upon 1) previous expert testimony, 2) contemporaneous statements made by skilled artisans, 3) statements by the UC inventors themselves (including Dr. Doudna), and 4) the USPTO Board’s fact-finding:
- Broad Institute’s expert Dr. Paul Simons cited some of the differences between prokaryotic systems and eukaryotic systems that would render the application of the CRISPR-Cas9 system in eukaryotic cells unpredictable. These included the differences between prokaryotic and eukaryotic cellular conditions such as “gene expression, protein folding, cellular compartmentalization, chromatin structure, cellular nucleases, intracellular temperature, intracellular ion concentrations, intracellular pH, and the types of molecules in prokaryotic versus eukaryotic cells.”
- UC’s expert witness Dr. Dana Carroll recognized many of the same issues that could arise in attempting to apply the CRISPR-Cas9 system in eukaryotic cells. Dr. Carroll further stated that “[t]here is no guarantee that Cas9 will work effectively on a chromatin target or that the required DNA-RNA hybrid can be stabilized in that context.” Ultimately, Dr. Carroll concluded that whether the CRISPR-Cas9 system will work in eukaryotes “remains to be seen” and “[o]nly attempts to apply the system in eukaryotes will address these concerns.”
- Dr. Doudna acknowledged the “huge bottleneck” in making genetic modifications in animals and humans, and after the publication of the initial UC research, she stated “[o]ur 2012 paper was a big success, but there was a problem. We weren’t sure if CRISPR/Cas9 would work in eukaryotes.” She also explained that she had “many frustrations” in getting CRISPR-Cas9 to work in human cells, and that she thought success in doing so would be “a profound discovery.” When a colleague contacted Dr. Doudna to inform her of Broad Institute’s success, he stated, “I hope you’re sitting down,” “CRISPR is turning out to be absolutely spectacular in [Broad Institute’s researcher] George Church’s hands.”
- The USPTO Board reviewed the statements by the UC inventors acknowledging doubts and frustrations about engineering CRISPR-Cas9 systems to function in eukaryotic cells and statements noting the significance of Broad’s success. The Broad Institute presented expert testimony that only a few other prokaryotic systems had been successfully adapted to work in eukaryotes, and a prior art article explained that differences in RNA folding in vivo versus in a cellular environment may prevent one such prokaryotic system, riboswitches, from working. Additionally, based on expert testimony and an earlier publication, the Board found that although some success was achieved using another type of prokaryotic system — ribozyme systems — that had been adapted for eukaryotic use, “that success required a specific strategy developed particularly for ribozymes.”
For the foregoing reasons, the Federal Circuit affirmed the USPTO’s finding that the claims of the UC application were “patentably distinct” from those in the Broad Institute’s patent. The Federal Circuit concluded that “[s]ubstantial evidence supports the Board’s finding that there would not have been a reasonable expectation of success” and even “if UC’s claims were prior art, they would not have rendered Broad’s claims obvious.” The Federal Circuit upheld the USPTO’s determination of no interference-in-fact.
UC is now evaluating potential litigation options. It could file a petition for rehearing en banc (i.e., before the entire bench) or appeal the decision to the U.S. Supreme Court.
The Broad Institute, on the other hand, has signaled that it is ready to move on. “It is time for all institutes to move beyond litigation … We should work together to ensure wide, open access to this transformative technology,” the Institute said in a statement.
Although the legal dispute between these two parties might be coming to an end, legal disputes involving CRISPR-Cas9 technology between other parties is likely just emerging. The Federal Circuit further hints such events by noting that “this case is about the scope of two sets of applied-for claims, and whether those claims are patentably distinct. It is not a ruling on the validity of either set of claims.” (Emphasis added.)
Immediate Consequences for the Biotech Industry?
This Federal Circuit decision does not appear to change anything for biotech companies because it cannot be interpreted to mean that the Broad Institute and UC own separate rights to use the CRISPR-Cas9 technology – e.g., prokaryotes vs. eukaryotes. Rather, the decision provides that the patents from both parties can co-exist. In theory, UC could get the patent for using the CRISPR-Cas9 technology in any living cell, “from bacteria to blue whales,” and the Broad Institute gets the patent in eukaryotic cells — e.g., plants and animals. As Dr. Doudna stated previously after the USPTO’s decision, “[Broad Institute] have a patent on green tennis balls. [UC] will have a patent on all tennis balls.”
Biotech companies using the CRISPR-Cas9 technology or intending to use this technology may find it prudent to take the licenses from both the Broad Institute and UC because “if you went with one, you could lose.” Because many biotech companies cannot afford to obtain licenses from both the Broad Institute and UC, interested parties had hoped that the Federal Circuit would render a decision that could clearly direct potential licenses to either the Broad Institute or UC. Unfortunately, the decision failed to provide a level of comfort in licensing from one party or the other.
UC’s U.S. patent application is still pending at the USPTO, and the examination has been stayed. Because both the USPTO and Federal Circuit sided with the Broad Institute and the statements made by UC played a key role in the decisions, whether UC will be awarded a patent on “all tennis balls” remains in question.