How to get access to CRISPR after the patent battle

by Robert Kruse


The patent battle between the Broad Institute and the University of California was truly one for the ages, with the stakes for control of the CRISPR-Cas9 system of gene editing at stake. The court recently ruled in favor of the Broad Institute (a joint institution between Harvard & MIT) and Feng Zhang for being the inventor of Cas9 editing in eukaryotic cells, having shown sufficient evidence at the time that CRISPR could not only function in bacterial cells where it is normally found, but also in eukaryotic cells whose genomes are housed in the nucleus and whose DNA is wrapped in histones. This left Jennifer Doudna, Emanuelle Charptentier, and the University of California out in the cold, even though they filed their CRISPR patent first. Instead, the court said their applications are still limited to in vitro and bacterial applications. The University of California is appealing the decision and it is likely this court battle will continue on for years.

From the biotech side, at stake was the fortunes of a few companies. Caribou Biosciences and Intellia Therapeutics ($NTLA) had ownership of the University of California IP, while Editas Medicine ($EDIT) owned the Broad IP rights. These companies have also made other deals with companies for other downstream applications and therapeutic targets. The fallout and ramifications for these companies are still being determined. Clearly being in Editas' position would be favorable, but it should be noted that all these companies have continued making innovations and improvements on the CRISPR platform in the years since the original description. The applications that are key to CRISPR are likely tied up now, so even if Editas might want to push forward with a certain application, they must make sure they aren't blocked from an IP perspective in doing it. An example would be an application for CCR5 deletion in T cells for HIV therapy, or in PD-1 editing in T cells for cancer immunotherapy, which in both cases may have been patented by an investigator at a university or a different company. Interestingly, companies like Sangamo Biosciences which specializes in zinc finger nucleases have also filed patents on CRISPR, showing that they may have a similar strategy.

However, this strategy does still not truly allow free access to gene editing, which would be desired by many companies right now. Here, I will briefly outline my advice to invent around the Broad patent and allow one to freely pursue their CRISPR therapeutic applications.

My advice focuses on one simple aspect: The patent estate of the Broad patent is very specific to the Cas9 protein and the sequences of Cas9 proteins from the different organisms described at that time. It will not be easy for any patent lawyers or judges to claim that the Broad patent extends years in the future to a new Cas9-like protein, or even more preferably, a novel RNA-guided cutting enzyme with little sequence homology to Cas9. This is because the Broad patent has to describe in detail how the guide RNA sequences could be engineered, which part of the DNA nuclease enzyme is required, and how to engineer for better efficacy in human cells. The RNA sequences binding to the protein are unique, the length of the recognition domain in RNA is unique, etc. Simply put, there is no way the Broad patent could prevent someone from using their newly discovered Cas9-like system from doing human gene therapy studies.

The advice that is likely already being pursued by companies around the world is to find these new CRISPR systems that would be unique and not under patent protection. What's funny is that Editas Medicine itself would have been in best position to have lost the CRISPR patent battle since it already owns a Cas9 alternative system. Feng Zhang has published an alternative Cpf1 system that is uniquely distinct from CRISPR-Cas9, but can functionally accomplish the same thing with RNA-guided DNA editing. Editas could have easily shifted their entire programs toward Cpf1 and not missed a beat with their clinical programs.

CRISPR systems appear to be operant in bacteria species across all different phylums on the planet. If one could pull a Craig Venter and begin sequencing the oceans and soils, it is likely that you could find unique Cas9-like systems. As opposed to the original discovery of CRISPR, which took two decades of figuring out what these repeat DNA sequences meant, and trying to figure out what the protein partners could be, new DNA algorithms should be more efficient at picking a signature repeat pattern out, and researchers could take these RNA candidates and use them to pull down in affinity assays protein partners. Yes, it would take a significant amount of time working in isolation, as opposed to dozens of Cas9 groups helping to facilitate the understanding of how the original CRISPR works, but that would be the trade off for having a unique platform. The cost of this endeavor might preclude individual researchers from pursuing this path, and make it the domain of a biotech company willing to throw significant funds and resources toward it. From an academic perspective, the focus will likely remain on using Cas9 as the main platform since those researchers are focused on the applications of CRISPR and don't want to mess around with optimizing a brand new system.

In conclusion, the widespread nature of the CRISPR system in bacteria makes it inherently difficult to control from an IP perspective, since nature has created different variations on CRISPR's theme. This differs significantly from the previous discoveries of programmable zinc finger and TALE domains, which generated so much excitement just because they were perceived to be rare in nature. It is likely that new systems will continue to be discovered, meaning gene editing in the future will have open access, from both an academic and a biotech perspective. The merits of the clinical potential of gene editing will rest then on if it is useful in actually ameliorating disease, rather than owning an entire platform.