by Jacqueline Sayyah
The CRISPR-Cas9 revolution is generating a lot of excitement and publicity for its ability to advance basic research, gene therapy, and personalized medicine. Scientists have taken advantage of the research opportunities presented by this simple and efficient technique, with over 3,000 labs having requested CRISPR plasmids (Gene editing at CRISPR speed, Nature Biotechnology, 1994, 309-312). Biotech, pharmaceutical companies, and universities are also capitalizing on the potential therapeutic applications of CRISPR with a number of recent licensing deals (detailed below). Interestingly, amidst all the scientific developments, a fierce patent battle is in progress between scientists and institutions over the rights to this valuable technology. The outcome of this complicated intellectual property (IP) situation could have huge impacts on the future of the CRISPR-Cas9 field and its commercial applications.
While CRISPR-Cas9 discoveries are moving at a fast pace, there is uncertainty surrounding the patent landscape for this technology. The University of California, Berkeley’s Jennifer Doudna along with Emmanuelle Charpentier at the Helmholtz Centre for Infection Research are currently in a patent dispute with Feng Zhang of the Broad Institute over the exclusive rights to the CRISPR-Cas9 technology. Although the CRISPR-Cas9 gene editing technology was first reported by Doudna and Charpentier in the journal Science in 2012, and their patent application was filed seven months before Zhang’s, Zhang was awarded the patent by submitting lab notebooks and claiming that he was the first to prove that the CRISPR-Cas9 technique works in mammalian systems. What makes this case interesting, according to Jacob Sherkow of the New York Law school, is that Zhang was awarded the patent because he had applied for a fast-track patent application, which awarded his intellectual property six months after he applied. Sherkow wrote that, without Zhang’s fast-track application approach, “the Patent and Trademark Office would have flagged it for being in conflict with Doudna’s earlier application.” (Sherkow, J.S., 2015, Nature Biotechnology, 33, 256-257)
Nevertheless, Jennifer Doudna and the Berkeley group have submitted a counterclaim or patent interference to the United States Patent and Trademark Office to have the CRISPR-Cas9 patent that was awarded to Broad Institute reconsidered, claiming that the technology was first invented by them. In the request for interference, the Berkeley group argued that Zhang lacked sufficient evidence to show that Cas9 cleaves DNA, since the use of tracrRNA was not disclosed in his lab notebooks. They also stated that Zhang’s notebooks were missing the key experimental information that would demonstrate the introduction of CRISPR-Cas9 system into animal cells. Finally, the Berkeley group has the backing of the gene-editing pioneer Dana Carroll, who has declared that he and other scientists were able to use the detailed descriptions provided in the Berkeley group’s paper and patent application to successfully perform their own CRISPR-Cas9 experiments. The patent interference, if approved, could set up a winner-takes-all scenario where either the University of California or the Broad Institute would be awarded all rights to the CRISPR-Cas9 gene-editing system.
Whatever the final resolution for the IP brawl would be, there is a lot at stake for both parties involved, given that the technology is potentially worth billions of dollars and a likely Nobel Prize for the scientists behind the seminal work. Venture capitalists have already recruited Doudna, Charpentier, and Zhang to form biotechnology startup companies to develop applications for CRISPR. Doudna has created Caribou Biosciences, which employs CRISPR-Cas9 as well as other Cas proteins for research, agricultural, and therapeutic use. Caribou Biosciences has established Intellia Therapeutics and through a partnership with Novartis, it plans to use CRISPR-Cas9 for ex vivo modification of cells for oncology applications. Zhang and Charpentier have each, respectively, founded Editas Medicine and CRISPR Therapeutics. These startups have been launched with multi-million-dollar Series A venture capital investments to develop CRISPR-Cas9 technology to therapeutically alter the underlying genetics of a variety of diseases.
In addition to the startups founded by Doudna, Charpentier and Zhang, other companies have also made use of the CRISPR technology. For example, Taconic has licensed Zhang’s patent to edit the genomes of mice and create constitutive knock-out and point mutation knock-in animal models. Similarly, Horizon Discovery has licensed Zhang’s patent to create genome-edited cell lines and animals using CRISPR-Cas9. Meanwhile, ToolGen has licensed to Thermo Fisher its intellectual property involving a modified synthetic guide RNA to enhance target specificity.
Key opinion leaders think that a lengthy CRISPR patent dispute could slow down commercial development efforts. In particular, the IP disagreement could have a large impact on biotechnology companies who are interested in making immediate use of this technology. Tom Adams, vice president of the global biotechnology firm Monsanto, indicates that, because of the complicated patent situation, his company has been hesitant to extensively employ the CRISPR-Cas9 technology to create genetic engineered plants with useful traits. Seokjoong Kim, ToolGen’s research director says, “The IP uncertainty is making it hard for customers to enter the CRISPR field.” Moreover, if the development of CRISPR products is delayed due to the legal battle, it could reflect poorly on UC Berkeley and the Broad Institute, who have used public tax dollars and gifts to invent the CRISPR-Cas9 technology. Contrary to Adams and Kim, CRISPR Therapeutics CEO, Rodger Novak, commented in Gene Silencing News that he does not believe the patent issue will hold back the field. He stated, “because of the broad applicability of this technology, there will be room for more than just one or two players.”
It could take years for the US patent office to resolve the CRISPR-Cas9 dispute. In the meantime, companies like Editas, Intellia, and CRISPR Therapeutics will continue their therapeutic development as they await the final outcome. While the ultimate owners of this technology stand to reap significant benefits, it is possible that improved versions of CRISPR-Cas9 or entirely new gene editing technologies could be developed due to the rapid pace of innovation in this area. In a recent article published in Nature Biotechnology (Chu, V.T. et al., 2015, Nature Biotechnology, 33, 543-548), scientists at Max Delbrück Center for Molecular Medicine were able to increase the precision of gene knock-ins using CRISPR-Cas9 by suppressing the non-homologous end-joining (NHEJ) pathway, which is suitable for generating gene deletions but not ideal for the insertion of precise genetic modifications. Using adenovirus 4 proteins, the scientists were able to degrade key molecules, such as DNA ligase IV and KU70, to shut off the NHEJ pathway and promote the homology directed pathway (HDR) to achieve the precision needed to knock in genes with greater efficiency. This and other useful strategies to improve the frequency of precise gene modifications using CRISPR will likely result in new patents and the formation of startup companies to apply this technology.
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