For my project, I decided to focus on CRISPR and its related patent issues. I will go through: (1) the fundamental science of CRISPR, (2) the so-called patent war of CRISPR, and (3) the patent licence issues for the recently approved CRISPR based therapy.
Casgevy, the first medical therapy using CRISPR to cure sickle cell disease and transfusion-dependent-beta-thalassemia was approved late last year in the UK and USA which inspired me to write on this topic.[1]
The Fundamental Science of CRISPR
Clustered regularly interspaced short palindromic repeats (“CRISPR”) is a biological phenomenon observed in bacterial and archaeal life (single-celled organisms e.g., E. Coli).[2] CRISPR is specifically a section of DNA on the genome of a bacterial or archaeal cells which can provide immunity against viruses. Within the CRISPR loci are sections of foreign DNA call spacers.[3] Spacers are either inherited from past generations or acquired during the life of the cell. These sections of DNA are transcribed into guide RNA (“gRNA”) and act to detect if the same sequence of DNA is present in the cell (e.g., repeat infection of a virus). These gRNA sequences also guide proteins called nucleases which are enzymes able to cut DNA.[4] If a repeat viral infection of a bacterial or archaeal cell occurs, the gRNA will bind to the DNA of the invading virus and the nuclease will cut the DNA, leading to disruption of the infection. CRISPR associated protein 9 (“Cas9”) is one such nuclease and is often utilize with CRISPR for genetic editing, leading to the moniker of the gene editing technique CRISPR/Cas9 (Other Cas proteins can be utilized with CRISPR).
The (Never-ending) Patent War for CRISPR
Patent war is a term used to describe the occurrence of parties engaging in expensive and extensive patent litigation often across jurisdictions. Patent wars are nothing new and go back to the Sewing Machine War of the 1850s.[5] The patent war for CRISPR has been primarily fought between two research groups and their associated institutions. Unsurprisingly, the war started at the US Patent and Trademark Office (“USPTO”). One of the parties to the war is CVC (for University of California, University of Vienna, and Emmanuelle Charpentier). A research team led by two scientists: Jennifer Doudna (of University of California, Berkely) whom collaborated with Emmanuelle Charpentier (formerly of University of Vienna now at the Max Planck Unit for the Science of Pathogens) published a pivotal study in 2012. Their study demonstrated the use of CRISPR to act as a tool to precisely cut a strand of DNA at a site of the researcher’s choosing.[6] Although their study was done in vitro (in test tubes), it highlighted the immense potential CRISPR had as a genetic editing technique. In March 2013 they filed a patent application with the USPTO for the use of CRISPR in any cell (human, animal, plant, bacteria, etc.).[7]
However, in 2013 another patent was filed with the USPTO. The Broad Institute, a organization located in Cambridge Massachusetts, is a research organization focused on genomic medicine (the use genetic information to inform medical decisions and treatments) and is composed of scientists from Massachusetts Institute of Technology (“MIT”), Harvard University, and Harvard University affiliated hospitals.[8] A research team from the Broad Institute led by Feng Zhang of MIT published in early 2013 a paper demonstrating the use of CRISPR to precisely cut DNA within the genome of both human and mouse cells.[9] They subsequently filed a patent application in October 2013 with the USPTO for the use of CRISPR in eukaryotes (eukaryotes is one of the three domains of life. Importantly it includes all multicellular life e.g., humans).[10] Although they filed their patent later than CVC, they paid the USPTO to fast track their application and received their patent while CVC’s application was still pending.[11]
The awarding of a patent to the Broad Institute and Feng Zhang set off an ongoing patent war between the two research groups and their affiliated companies set up to commercialize the scientific discovery. Premier scientific journals such as Nature and Science, prominent Canadian national law firms, and the general news media have detailed the ongoing global patent dispute blow-by-blow. The patent war does not seem to be fully over and given there has already been considerable licensing by the parties in dispute, this creates a potential legal minefield for licensees.[12] The reason it is worth fighting this patent war is due to the potential use of CRISPR in medical therapies, modification of crop genetics, and as a research tool, among other things.
In Canada, CVC received a patent in 2023 which discloses foundational aspects of the CRISPR technique, primarily the gRNA as a targeting sequence to modify DNA in a site-specific way.[13]
CRISPER, Licence to Cure
Coming full circle, the newly approved CRISPR derived therapy is subject to a complex legal landscape, where depending on the country the therapy is brought to market, different parties hold the patents which can also be pending appeals. Vertex Pharmaceuticals (The company which developed Casgevy) received its licence from CRISPR Therapeutics who received their licence from CVC.[14] However, last December Vertex Pharmaceuticals agreed to compensate a company called Editas Medicine up to $100 million in order to secure a non-exclusive licence to Editas Medicine’s CRISPR technology.[15] Currently the Broad Institute holds the foundational patents for human gene editing with CRISPR in the United States and granted an exclusive license to Editas Medicine. In order to market their therapy in the USA, the most lucrative pharmaceutical market in the world, Vertex was willing to pay Editas Medicine in order to avoid litigation and not be dragged into the patent war that currently has no end in sight.
[1]See https://www.cbc.ca/news/health/gene-therapy-sickle-cell-uk-1.7030109. See also https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease.
[2] Luciano A Marrafini, “CRISPR-Cas Immunity in Prokaryotes” (2015) 526 Nature 55 at 55.
[3] Ibid at 56.
[4] Ibid.
[5] Adam Mossoff, “The Rise and Fall of the First American Patent Thicket: The Sewing Machine War of the 1850s” (2011) 53 Arizona L Rev 165.
[6] Martin Jinek et al, “A Programmable Dual-RNA-Guided DNA Endonuclease in Adaptive Bacterial Immunity” (2012) 337 Science 16.
[7] Heidi Ledford, “Bitter Fight Over CRISPR Patent Heats Up” (2016) 529 Nature 265 at 265.
[8] See https://www.broadinstitute.org/about-us.
[9] Le Cong et al, “Multiplex Genome Engineering Using CRISPR/Cas Systems.
[10] Ledford Supra note 6 at 265.
[11] https://www.broadinstitute.org/files/shared/osap/pdf/US8697359.pdf.
[12] Heidi Ledford, “Major CRISPR Patent Decision Won’t End Tangled Dispute” (2022) 603 Nature 373.
[13] See “Methods and Compositions for RNA-Directed Target DNA Modification and for RNA-Directed Modulation of Transcription”, Can Patent No 2872241 (15 Mar 2015).
[14] See https://investors.vrtx.com/news-releases/news-release-details/vertex-and-crispr-therapeutics-announce-authorization-first.
[15] See https://www.fiercebiotech.com/biotech/after-long-standing-patent-battle-vertex-pays-100m-license-editas-gene-editing-tech.
Communications Law