CRISPR-cas9 Technology

CRISPR-cas9 technology has changed the landscape for what is possible in genomic engineering.  It is also the subject of a heated and ongoing patent dispute between the Broad Institute in Cambridge, Massachusetts and the University of California.  As the case winds its way through the U.S. and European patent and court systems, ownership of the technology, and the resulting financial opportunities, is up for debate.

The University of California filed its first provisional patent on CRISPR-cas9 technology in May 25, 2012. The Broad Institute filed its first provisional patent application on December 12, 2012. However, the Broad Institute paid for accelerated examination of the utility application and its patent issued first. 

In March 2013, the America Invents Act changed the requirement for patent applications from the first-to-invent to the first-to-file protocol. Because both the Broad Institute and the University of California’s  patent applications claim priority to provisional patent applications filed prior to March 2013, they fall under the first-to-invent provisions and the University of California instituted proceedings in front of the Patent Trial and Appeal Board (PTAB) in an effort to have the Broad Institute’s patents thrown out.  In February of 2017, the PTAB issued a judgement of no interference-in-fact concluding:

Broad has persuaded us that the parties claim patentably distinct subject matter, rebutting the presumption created by declaration of this interference. Broad provided sufficient evidence to show that its claims, which are all limited to CRISPR-Cas9 systems in a eukaryotic environment, are not drawn to the same invention as UC’s claims, which are all directed to CRISPR-Cas9 systems not restricted to any environment. Specifically, the evidence shows that the invention of such systems in eukaryotic cells would not have been obvious over the invention of CRISPR-Cas9 systems in any environment, including in prokaryotic cells or in vitro, because one of ordinary skill in the art would not have reasonably expected a CRISPR-Cas9 system to be successful in a eukaryotic environment. This evidence shows that the parties’ claims do not interfere. Accordingly, we terminate the interference.

The University of California filed an appeal of the PTAB’s decision with the U.S. Court of Appeals for the Federal Circuit in April 2017 and filed a brief in July of 2017.  The Broad Institute filed its reply brief in October 2017, and the case is expected to be heard soon.  Until a final decision is reached, who owns the technology, as well as the scope of that ownership, is unclear.

The status of the ownership of the CRISPR-cas9 technology is also up for debate in Europe.  In January, 2018, the European Patent Office revoked the Broad Institute’s European Patent No. 2771468 which claims priority to 12 U.S. provisional patent applications including the December 12, 2012 provisional application.  EP 2771468 was revoked in part because of an invalid priority claim due to a disagreement between Rockefeller University and The Broad Institute over the contributions of Luciano Marraffini who is listed as an inventor on the U.S. provisional patent applications, but not the European patent application claiming priority to the U.S. provisional patent application.  The Broad Institute has stated that it plans to appeal the decision, but it is unlikely that the European Patent Office will change its mind.

Nearly 4000 patent applications using or otherwise developing CRISPR-cas9 technology have been filed worldwide since 2014, and many of the commercial developments stemming from such patent applications will require licensing from the Broad Institute or the University of California, or both. The Broad Institute and the University of California both filed patent applications in the US, EU, China and Korea.  The question thus arises: what will need to be licensed, and from whom?

For academic research, the answer is clear.  The University of California, the Broad Institute and other institutions have all agreed to make their CRISPR constructs widely available through AddGene, a nonprofit repository and patent licensor of CRISPR technologies for academic organizations.  

However, for commercial products, the licensing requirements are much murkier.  Both the Broad Institute and the University of California have largely delegated licensing responsibilities to a for-profit surrogate company that is also in the therapeutic development business, but as ownership of the technology is unclear, so are the licensing requirements.

To further complicate matters, all 12 of the Broad Institute patents declare US federal funding and rights in the patents, as does the patent application from the University of California. Under the Bayh-Dole Act, the federal government has worldwide royalty free rights in federally funded patented inventions [35 USC 202(c)(4)], and the public has the ability to petition to government for “march-in” rights” [35 USC 203] to use the patents when the inventions are not made “available to the public on reasonable terms.” [35 USC 201(f)].

While the stock prices of the for-profit surrogate companies holding the respective CRISPR-cas9 patent portfolios fluctuate in part based on legal decisions regarding the validity of the patents, their overall valuation continues to increase.  However, in the U.S. and Europe at least, it is still unclear who owns what, calling any commercialization developments and licensing deals into question. 

Janina Malone