Has a Federal Circuit Decision Ended the CRIPSR/Cas Patent Battle?

On September 10, 2018, the U.S. Court of Appeals for the Federal Circuit’s decision in Regents of the University of California v. Broad Institute, Inc. may have ended perhaps the most heated biotech patent battle today: who owns the fundamental patents for the powerful CRISPR/Cas gene-editing tool. Unless University of California, Berkeley (UCB) successfully appeals the decision to the U.S. Supreme Court, the Broad Institute will keep its patents on CRISPR/Cas technology.

 

History of the Dispute

CRIPSR/Cas is originally an immune system in bacteria and archaea, which are prokaryotes – organisms whose cells have no nucleus or chromosome – as opposed to eukaryotes, which include all the animals, plants, and fungi. The system employs special short RNA segments transcribed by prokaryotic DNA, to target specific DNA sequences and recruit the Cas nuclease to cut that DNA sequence, which usually comes from an invading virus.

After its 2012 disclosure in the first paper published by the UCB team, CRIPSR/Cas underwent a series of technical modifications and improvements. An important progress was made at the Broad Institute, where a research team led by Feng Zhang modified the system to be able to function in eukaryotic cells. Today, CRIPSR/Cas is widely used in life science research as a powerful gene editing tool due to its unprecedented precision and flexibility in making any desired changes to any gene sequence.  Its potential application in treating diseases like cancer and genetic diseases may bring another medical revolution. Though no CRIPSR/Cas-based treatment has received market approval, related clinical studies have already begun. Thus, it is no surprise that investors have been watching this case closely.

In 2013, the UCB research team, led by Jennifer Doudna, filed its first patent application for CRIPSR/Cas technology, seven months earlier than the Broad Institute team. However, despite several rounds of amendments, UCB’s original application is still pending, while the Broad Institute was granted a patent in 2014 after it filed an Accelerated Examination Request. Moreover, UCB cannot derive too much advantage from its earlier filing, because both sides claim a priority date in 2012, when the U.S. was still under the first-to-invent system; under the first-to-invent system, one party can initiate an interference proceeding against another party that applied for the same invention to determine priority issues. In this way, UCB formally started the patent battle in 2015. Yet, the Patent Trial and Appeal Board (PTAB) found no interference-in-fact because UCB’s application was based on studies in cell-free systems, while the Broad Institute’s patents are directed to genome editing in eukaryotic cells. After hearing an appeal from UCB, the Federal Circuit affirmed the PTAB decision.

 

Concerns Around the Fundamental Patent

Hundreds of patent families relating to CRIPSR/Cas have been filed worldwide. However, the Broad Institute’s patents remain fundamental for covering an enabling technology platform, based on which many improvements have been made. Feng Zhang’s team first adapted the bacterial-derived CRIPSR/Cas system to function in eukaryotic cells, which ushered in a new era of its use in agriculture and medicine.

Such fundamental patents may restrict access of the technology to other researchers. Though the Broad Institute has offered free research licenses through Addgene, its spin-off company, Editas, has been granted exclusive license for therapeutic applications. Considerable concerns and active discussions have been aroused among commentators and researchers as to how this arrangement would affect future endeavors in drug development and patient interests, as well as social responsibilities of academic institutions.  Committed to developing CRIPSR/Cas-based disease treatments, would Editas be willing to sublicense the technology to other competing companies at reasonable fees? Will this spur increased patent litigation when commercial products gradually emerge? Are such patent battles suitable for academic institutions, which has a tradition of open sharing of knowledge and are expected to contribute to societal good?

History is not without similar examples. The Cabilly patents, covering fundamental methods of producing recombinant antibodies, have become one of the most litigated patents of all time. The patented technology was the basis for the production of therapeutic monoclonal antibodies, bringing many of its developers into patent disputes with the patent holders, Genentech and City of Hope. In comparison, Stanford University and the UC system have developed a quite workable licensing program for their patents that cover recombinant DNA platform technologies. The program has not only generated substantial revenue for patent holders, but has also effectively avoided formal litigation. These examples may provide valuable insights in devising licensing and dispute resolution strategies for CRIPSR/Cas patents.

 

Patent Battle Again?

There are two main approaches to applying CRIPSR/Cas in human therapies. One approach involves using CRIPSR/Cas to genetically modify cells in vitro and inject them into the human body as therapeutic agents. This approach is likely covered by the Broad Institute’s patents, since the application in the patent is specific to eukaryotic cells. Another approach is to directly deliver the CRIPSR/Cas system into the human body to target the disease-causing genes. Will the second approach be covered by Broad Institute’s patents, since a living organism rather than isolated cells becomes the target of manipulation?

According to the Federal Circuit decision, due to the differences between eukaryotic and prokaryotic cells, a person of ordinary skill in the art would not have had a reasonable expectation of success in applying the CRISPR/Cas system in eukaryote cells. Thus, Broad Institute’s patents are not rendered obvious by UCB’s patent applications. If adapting a prokaryotic system to eukaryotic cells meets the nonobviousness requirement, could adapting that system to a living organism still be an obvious invention? After all, the human body is not a simple assembly of isolated eukaryotic cells, but a highly complicated system of cells and acellular matrices, which may bring significant challenges to the latter adaptation. Indeed, successful direct administration of gene therapy to the human body has led to several breakthrough therapies recently received market approval.

Moreover, for CRISPR/Cas’ therapeutic application, one major challenge involves off-target mutations, which are unwanted genetic alterations generated by CRISPR/Cas9. Though in vivo genome editing by CRISPR/Cas has been achieved in mouse livers and zebrafish, detecting off-target mutations in vivo was not feasible until recently. Without such effective in vivo detection, a safe therapy can hardly be developed. Yet, a research group from Massachusetts General Hospital recently disclosed a method of detecting off-target mutations in living organisms (see also patent application US15853275), which makes the aforementioned “second approach” possible. Will this new method infringe the Broad Institute’s patents? If it succeeds in clinical studies, could there be another fierce patent battle?

 

Conclusion

Though the Federal Circuit decision probably resolved a major patent dispute, future technological developments may still challenge the status of Broad Institute in the CRISPR/Cas patent landscape. Meanwhile, the trend of academic institutions becoming major patent holders of CRISPR/Cas technology has triggered increasing public concerns of how they would exploit these patents, especially when life-saving treatments are at stake. Thus, these potential legal and ethical battles will unlikely end with a single court decision.

 

 

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