Intellectual Property of CRISPR-Cas9 - Prioritising monopoly over innovation?

US patents grant inventors a 20 year monopoly over the technology in return for disclosing the details of how it works. [1]  This fuels innovation by allowing others to build on technology already invented while protecting the rights of the inventor. However, this monopoly can backfire and prevent those ‘reasonably filled in the art’ from building on patented technology. [1]   Whoever owns the commercial or intellectual property rights to CRISPR-Cas9 will generate millions of dollar in royalties [2] and will be able to have complete monopoly over who gets to use it.[3]  As a result fo the complexity of CRISPR,  many different patents have been filed and awarded, meaning that if one was to use CRISPR technology, they have the potential to infringe multiple patents of multiple high-profile organisations. This fear stops gene-editing innovation in its tracks. 

Clustered regularly interspaced short palindromic repeats or ‘CRISPR’ paired with the associated protein 9 (Cas9) system. Is a ‘powerful RNA-guided DNA targeting platform for genome editing, transcriptional perturbation, epigenetic modulation, and genome imaging’ [4], allowing precise manipulation of virtually any genomic sequence. [4]

This paper outlines the legal battle that brought us to the complicated position we find ourselves in currently regarding CRISPR and its intellectual property. 

Origins of CRISPR

In 1987, Yoshizumi Ishino, a Japanese Student, discovered clusters of regular, interspaced, palindromic repeats of sections of DNA within bacteria. [5], [6] He noted that the ‘iap’ gene within E.Coli bugs contained repeating sequences of 29 base pairs, noting that “the biological significance of these sequences is not known”. He published his findings in the Journal of Bacteriology.

In 1995, Francisco Mojica of the University of Alicante discovered similar structures within the Haloferax Mediterranei, he is widely regarded as the person responsible for discovering CRISPR as he discovered the mechanism at the core of the tool and came up with the name ‘CRISPR’. 

By 2003, genetic sequences had been discovered in many species, these sequences were first named in 2002 as Spacers Interspersed Direct Repeats (SPIDR), however Mojica’s name was the one which stuck: Clustered regularly interspaced short palindromic repeats, or CRISPR for short. [5], [7] It was understood by this point that when a virus infects a bacteria, CRISPR associated enzymes cut out a section of the viral DNA called a protospacer. [5] This protospacer is stored in the CRISPR section of the bacterial  genome, between the repeated sections of DNA that Ishino and Mojica originally identified. If the virus infects the cell again, the bacteria use these sequences to defend themselves.  [5] The sections of viral DNA are transcribed to generate short sections of RNA. The RNA’s then search the cell for viral DNA or RNA with CRISPR associated DNA cutting enzymes, known as CAS. [5]

If this CRISPR RNA-CAS complex finds a matching sequence from an invading virus, it cuts through the viral DNA or RNA. [5] This is essentially how CRISPR operates. 

Patent dispute regarding CRISPR

Up to this point, no one had isolated the molecular components of CRISPR, this was important to understand how many of them functioned on a molecular level.

In 2011, Professor Jennifer Doudna from the University of California, Berkeley and Professor Emmanuelle Charpentier from the University of Vienna found that a CRISPR associated enzyme called Cas 9 was a dual RNA guided protein. [5] These universities together are known as the ‘CVC group’.  It was discovered that Cas 9 was a programmable and sequence-specific endonuclease which introduces double-strand breaks in DNA, these breaks can then be exploited to modify the DNA sequence. The break site is determined by a small RNA molecule, known as guide RNA. This pairs with the target DNA and binds to Cas9, this initiates the site-specific break. [8]  As an RNA-guided dsDNA-binding protein, the Cas9 effector nuclease is the first known example of a programmable unifying factor capable of colocalizing all three types of sequence-defined biological polymers, a capability with tremendous potential for engineering living systems. [9] Proteins can be targeted to any DNA sequence by simply fusing them to a nuclease-null Cas9 [9] showing the possibilities of CRISPR.

Professor Doudna’s team filed its first patent application for CRISPR -Cas9 in May 2012 [10]

However, in January 2013, a team of scientists from the Broad Institute of the Massachusetts Institute of Technology and Harvard University, claimed they had found a way to use CRISPR-Cas9 to edit the cells of mammals. The broad researchers had filed a patent application in December 2012, paying for a fast-track review. [3]  Eleven additional patent applications were filed to bolster the claim that they were the first to invent a CRISPR system to edit mammalian cells, Jon Cohen notes. In April 2014, the United States Patent and Trademark Office (USPTO) granted the Broad team a patent on their CRISPR technology. [3] As is usually the case in patent disputes both institutions filed multiple secret patent applications, which came to light 18 months after the priority date. [10]

Unlike EU patent law, at the time the patents were filed, the USPTO awarded patents on the basis of who was the first to invent a technology [2], rather than awarding patents based on priority date. It is important to note that the USPTO changed it procedures in 2013 to match the EU’s standard of awarding patents based on priority date. 

Once the US patent applications were sent, European patents were filed almost simultaneously. UC Berkley’s application with the European Patent Office was filed in March 2013, claiming priority by citing the US patent priority date of May 2012. [10] The Broad Institute filed their EU patent application in December 2013. [10]

In 2020 the Broad institute lost on appeal at the European Patent Office on the grounds that, under EU patent law, the priority date is the date in which the patent is filed, since the Broad Institute filed their EU patent application months after Berkley, their invention was already prior art.  This was further argued by the fact that Luciano Marrafini, a man listed as an applicant in the provision patent applications, had failed to transfer his priority rights to the Broard Institute. His priorty rights were assigned to Rockefeller University. [11]

“This is important because if the rights were not sufficiently transferred to the Broad Institute then the filing date of the patent application would not have been the filing date of the provisional application, but the later filing date of the non-provisional application,” said Ulrich Storz, Senior Partner at Michalski Hütterman Patent Attorneys. [11]

“This meant that journal articles that have been published in between those dates became novelty-destroying prior art.” [11]

While this decision is unlikely to weaken the stance of The Broad Institute while this patent battle continues within Europe, it will strengthen the position of US Berkeley within Europe going forward.

As a result of the differing laws surrounding the significance of the priority date, the issue of novelty and prior art. The Broad Institute issued a press release stating that the position of the European courts was ‘inconsistent with treaties designed to harmonise the international patent process’, [12], [13] following this they appealed the decision immediately on January 18, 2018. Starting that they hoped that the European patent office would ‘use this case as an opportunity to review and resolve this international inconsistency, not just for CRISPR patents, but for a wider range of European patents and applications that originated as U.S. provisional applications’. [13]

In 2021 the Us Court of Appeals for the Federal Circuit  decided to invalidate The tribunal said that there was ‘no dispute’ that the University of California and Vienna new the first to conceive the CRISPR system, however it was held that they failed to demonstrate that the had created a system that works with eukaryotic cells before the Broad’s priority date. [14]

Analysis

I’m sure many legal academics, had the same gut-reaction as I to the Broad Institute's press release: ignorantia juris non excusat. While the US patent law reforming and becoming more unified with the European approach in regards to novelty and priority date is a positive thing as it will simplify the process of filing multiple patents, it is not the responsibility of the European courts to cater to applications filed prior to the reforms. The law is the law and ignorance of the laws of another area of the world is simply that, it will not change the outcome of the case.

In an ideal legal world, there would be a single patent pool, therefore allowing anybody would want to use CRISPR technology can acquire a license covering the intellectual property of all parties with CRPSR patents. The broad Institute itself is behind the idea of a patent pool for all intellectual property regarding CRISPR, outlining thier support for the idea in a statement released in February 2022, claiming they had pushed for a patent pool for the ‘last eight years’. The statement also states that discussions are ‘underway’ as of 2022. Berkley University and the university of Vienna are yet to release a statement regarding the potential patent pool. 

As far as myself and many others see it, this is the only way forward, what is important here is the innovations that will come as a result of CRISPR, and the lives it will improve. The developments of this dispute are ongoing and do not seem to be slowing down.

Endnotes

[1] Nat Biotechnol, 'Licensing for profit and for good' (Nature, 2022) <https://doi.org/10.1038/s41587-022-01296-0> accessed 9 November 2023

[2] Heidi Ledford, 'Major CRISPR patent decision won’t end tangled dispute' (Nature, March 9) <https://www.nature.com/articles/d41586-022-00629-y> accessed 29 November 2023

[3] Catherine Jewell, 'The battle to own the CRISPR–Cas9 gene-editing tool' (Wipo Magazine , April) <https://www.wipo.int/wipo_magazine/en/2017/02/article_0005.html> accessed 29 November 2023

[4] Fuguo Jiang and Jennifer Doudna, 'CRISPR–Cas9 Structures and Mechanisms' [2017] 46(1) Annual Review of Biophysics <doi.org/10.1146/annurev-biophys-062215-010822> accessed 29 November 2023

[5] 'Hello CRISPR' (Genetics Unzipped, 8 April 2022) <https://geneticsunzipped.com/transcripts/2021/4/8/hello-crispr> accessed 9 November 2023

[6] Irina Gostimskaya, 'CRISPR-Cas9: A History of Its Discovery and Ethical Considerations of Its Use in Genome Editing' [2022] 87(8) Biochemistry (Mosc) <http://dx.doi.org/ 10.1134/S0006297922080090> accessed 29 November 2023

[7] Ruud Jansen and others, 'Identification of genes that are associated with DNA repeats in prokaryotes' [2002] 43(6) Molecular Microbiology <doi.org/10.1046/j.1365-2958.2002.02839.x> accessed 29 November 2023

[8] André Schneider, 'A short history of guide RNAs' [2020] 21(12) EMBO Reports <http://dx.doi.org/ 10.15252/embr.202051918> accessed 29 November 2023

[9] Prashant Mali and others, 'Cas9 as a versatile tool for engineering biology' [2013] 10(10) Nat Methods <http://dx.doi.org/10.1038/nmeth.2649> accessed 29 November 2023

[10] Felicia Lozon, 'Making sense of the battle for the CRISPR-Cas9 patent rights' (Osler, 15 March 2021) <https://www.osler.com/en/resources/critical-situations/2021/making-sense-of-the-battle-for-the-crispr-cas9-patent-rights> accessed 9 November 2023

[11] ClaraRodríguez Fernández, 'Broad Institute Loses Appeal on European CRISPR Patent' (Labiotech, January 24) <https://www.labiotech.eu/trends-news/crispr-patent-europe/> accessed 29 November 2023

[12] Ulrich Storz, 'CRISPR Cas9–Licensing What Can't Be Licensed' [2018] 3(2) Journal of the Licensing Executives Society

[13] Lee Mcguire, 'Broad Institute [McGuire, Lee) (1/17/18) "News Release: For Journalists – Statement and Background on the CRISPR Patent Process Update on Patent Processs In Europe"' (Life Sciences USA, 2018) <https://www.life-sciences-usa.com/news/broad-institute-update-patent-mit-harvard-massachusetts-technology-2001-112197.html> accessed 9 November 2023

[14] Jonathan Stempel, 'Breakthrough gene-editing technology belongs to Harvard, MIT -US tribunal' (Reuters, 1 March 2022) <https://www.reuters.com/business/healthcare-pharmaceuticals/breakthrough-gene-editing-technology-belongs-harvard-mit-us-tribunal-2022-03-01/> accessed 9 November 2023