Title: Continuing CRISPR Patent Disputes May Be Usurped by Its Potential Role in Fighting Global Pandemics
Abstract: Biotechnology Law ReportVol. 39, No. 3 Original ArticlesFree AccessContinuing CRISPR Patent Disputes May Be Usurped by Its Potential Role in Fighting Global PandemicsBy Asawari Churi and Sarah TaylorBy Asawari ChuriE-mail Address: [email protected] Churi and Sarah Taylor are both members of Pinsent Mason LLP's global IP Group in London, United Kingdom. Asawari Churi is a patent law expert in the Life Sciences team. She has experience in opposition proceedings before the European Patent Office in relation to CRISPR patents.Search for more papers by this author and Sarah TaylorE-mail Address: [email protected] Taylor is a Senior Practice Development Lawyer in Pinsent Masons' IP team, specializing in patent litigation. She worked as a practicing patent litigator for over 13 years, with experience in the life sciences and tech fields, before moving into a professional support role.Search for more papers by this authorPublished Online:3 Jun 2020https://doi.org/10.1089/blr.2020.29180.acAboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail The discovery of the simple, yet powerful, gene-editing CRISPR technology, and its wide and varied potential applications, is a true revolution in life sciences. While the best-known use of CRISPR is high precision editing of genes, it can also be used to modulate gene expression. Initially, the application of CRISPR focused on academic research, but its potential now goes way beyond this. Perhaps most importantly in the current climate is its potential to transform medicine and diagnose, treat, and prevent many diseases.The commercial value of the CRISPR platform technology and its future uses has meant that this is a hugely competitive field with a complex patent landscape. As the innovations begin to move more towards clinical testing, the disputes over the many background patents continue. The hype surrounding the enormous potential of the technology appears almost to be matched by the controversy surrounding the question of who owns it. At the root of the controversy are two warring groups, with each group seeking ownership of the patents covering CRISPR and the resultant financial rewards. It is this that has led to long-running global patent disputes, which have recently been revisited at the European Patent Office. We consider the current status of the challenge to some of the key CRISPR patents in Europe.The complexities posed by the patent landscape aside, a potential application of CRISPR-based technology that is at the forefront of everyone's mind in the current global health crisis, is its role in testing for and diagnosing infectious diseases. Here, we look at whether, despite all of the excitement concerning future applications, CRISPR's most immediate contribution to date may be in respect of tackling the global COVID-19 pandemic.Crispr: The TechnologyCRISPR is an almost universally applicable gene-editing tool capable of being customized easily, quickly, and economically. The acronym CRISPR is derived from "clustered regularly interspaced short palindromic repeats," which is a naturally occurring collection of short, repeating nucleotide sequences. These sequences are found in many bacterial genomes where they are known to play a role in antiviral defense. The sequences are separated by spacer sequences which correspond to sequences found in various viral genomes.In bacteria, in response to a viral threat, the spacer sequences are transcribed to RNA. The RNA forms an RNA-protein complex with a bacterial enzyme known as Cas (CRISPR-associated). The entire CRISPR/Cas complex is commonly referred to as "CRISPR."Although there are many different types of Cas enzymes, most of our understanding of CRISPR is based on one specific Cas enzyme, Cas9, found in the organism Streptococcus pyogenes. The RNA in the CRISPR/Cas9 complex binds to the corresponding sequence in the invading viral genome. Once bound, the Cas enzyme acts as a pair of molecular scissors and cuts the viral DNA at that site and thus disables the virus.Other key enzymes are Cas12 and Cas13, and our knowledge about these enzymes is developing. In contrast to Cas9 which creates blunt ends where it cuts the nucleic acid, Cas12 creates staggered ends, which aids in the incorporation of new DNA sequences, meaning that Cas12 is more efficient at introducing new genes than Cas9. Cas13 targets RNA instead of DNA.Although CRISPR was discovered in the late 1980s by Japanese scientists, its potential use as a programmable gene-editing tool has only been recognized in the last decade. It was found that by changing the sequence of the RNA in the CRISPR/Cas9 complex, the entire complex could be customized to target virtually any part of a genome containing a corresponding sequence. It is generally accepted that the first public disclosure of the CRISPR/Cas9 complex in targeted gene editing was made in a collaborative paper published by Jinek et al. from the University of California, University of Vienna, and Umeå University, Sweden.1The potential applications and the corresponding commercial value of CRISPR are staggering, with estimated market valuations for the technology in the billions. Whoever owns the intellectual property underpinning CRISPR will be well-placed to enjoy a substantial part of this lucrative market. With different research groups working simultaneously to further characterize and refine CRISPR, it is no wonder that the groups are jockeying for control of the technology.The Patent Landscape and DisputeThe dispute over ownership of the associated patents is currently under consideration in various courts and patent offices across the world, and has been for a number of years.In May 2012, prior to publishing the Jinek paper (referenced above), the University of California (along with the University of Vienna and Umeå University) (collectively "UC") filed a U.S. patent application covering the technology and its use in gene editing. Seven months later, the Broad Institute (partnered with MIT and Harvard) (collectively the "Broad Institute") filed a series of patent applications covering the technology more narrowly, namely the application of the CRISPR/Cas9 complex in editing mammalian genomes.Although the Broad Institute was evidently not the first to file its patent applications, it adopted an aggressive patenting strategy by paying an additional fee to have their applications fast-tracked at the U.S. Patent Office. This meant that the Broad Institute's patents, although filed after the UC application, were granted first.In many jurisdictions, it is a condition of grant that a patent application discloses the invention in sufficient detail so as to enable an appropriately skilled person to reproduce the invention without undue burden (i.e., it is not insufficient). Although the UC application shows that the CRISPR/Cas9 complex is capable of editing genes in prokaryotic (that is, bacterial) cells, it does not include data demonstrating use of the complex in eukaryotic cells. Such data are, however, included in the later-filed Broad Institute application.The importance of these data in the context of the underlying patents, and the high degree of complexity of eukaryotic cells in comparison to prokaryotic cells, is debated. On one hand, it has been suggested that the other inventors in the earliest UC patent application created the recipe for the technology that the inventors named in the Broad Institute patents simply followed without any inventive input. On the other hand, others take the view that the Broad Institute demonstrated that the recipe actually worked where others had failed and arguably deserves the credit.Unsurprisingly, UC has taken the position that its patent application makes it obvious that the CRISPR/Cas9 complex would work in eukaryotic cells. Accordingly, it says the Broad Institute patents should be invalidated as the techniques that they cover are not inventive in light of the disclosure made by UC in the Jinek paper. The Broad Institute has argued that the skilled person would not be able to make the invention work in eukaryotic cells simply by reading the UC patent application and therefore the UC application is insufficient and their own patents are not obvious.These arguments are being presented in patent offices in many jurisdictions including the U.S. and Europe. In the U.S., both the Broad Institute and UC patent applications were filed under the old U.S. patent law which awarded patents under a "first-to-invent" system rather than a "first-to-file" system common in most other jurisdictions. (The U.S. patent law adopted the first-to-file system in March 2013). The U.S. Patent and Trademark Office (USPTO) has awarded a number of patents to the Broad Institute as well as UC.Challenges in respect of the Broad Institute patents were brought by UC in a procedure known as interference proceedings before the USPTO's Patent Trial and Appeal Board (PTAB) to determine who invented CRISPR first.The Broad Institute succeeded in convincing the USPTO that CRISPR/Cas9 should not be compared with existing gene-editing techniques such as zinc finger nucleases or TALE nucleases because, unlike CRISPR/Cas9 which is naturally active only in prokaryotes, the other two were known to be naturally active in eukaryotic systems. Instead, the Broad Institute argued, CRISPR/Cas9 should be compared with other purely prokaryotic-based regulatory systems such as riboswitches, ribozymes, and Group II introns, none of which have been particularly successful in eukaryotic cells. If these have not worked in eukaryotes, why would the skilled person expect that CRISPR would?The PTAB confirmed that the Broad Institute's innovations were distinctly patentable subject matter from the UC patent filings. This decision was upheld by the U.S. Court of Appeals for the Federal Circuit in September 2018.2 However, in 2019, the PTAB restarted the dispute by declaring a new patent interference in relation to CRISPR patents belonging to the two parties.In the meantime, Sigma-Aldrich, a subsidiary of German pharmaceuticals giant Merck, has petitioned the PTAB to consider its own claims to ownership of rights in the CRISPR technology at the same time as they consider the two institutions' dispute.The outcome of these new proceedings is awaited.A Lack of Priority in EuropeTurning to Europe, the European Patent Office (EPO) has granted a number of key CRISPR patents to the Broad Institute. A number of parties (including UC) have opposed the Broad Institute patents and, in early 2020, the EPO Board of Appeal (BOA) upheld an earlier decision of the EPO Opposition Division (OD) which revoked one of the Broad Institute's key CRISPR patents (EP'468). EP'468 is derived from a Patent Cooperation Treaty (PCT) application (WO'712) claiming priority from a number of provisional applications filed in the U.S. The earliest of these provisional filings named Professor Luciano Marraffini, of Rockefeller University, New York, as one of the applicants. However, EP'468, and a number of subsequent patent applications, do not name him as an applicant.Entitlement to claim priority before the EPO is governed by Article 87 of the European Patent Convention (EPC). This states: "Any person who has duly filed … an application for a patent … or his successor in title, shall enjoy, for the purpose of filing a European patent application in respect of the same invention, a right of priority during a period of twelve months from the date of filing of the first application."It is established case law of the EPO that in order to validly claim priority from an earlier application, all applicants named on the earlier application must be named as applicants on the subsequent application. In the case of applicants who have transferred their rights to another entity, this transfer must have taken place in the priority year.In the case of EP'468, it means that in order for EP'468 to validly claim priority from the earlier applications which name Professor Marraffini as applicant, either WO'712 (from which EP'468 is derived) must name Professor Marraffini as applicant or, Professor Marraffini must have transferred his rights to another applicant before WO'712 was filed. It is clear that Professor Marraffini was not named as applicant on WO'712, and there does not seem to be any evidence that he transferred his rights to any of the other applicants before WO'712 was filed. Therefore, in accordance with Article 87 EPC and EPO case law, EP'468 cannot validly claim priority from the earliest priority applications. This loss of priority date meant that certain documents, which were novelty-destroying, became relevant. Accordingly, the patent was revoked on the ground of lack of novelty.On appeal,3 the Broad Institute argued that the EPO's approach to priority was incorrect and that U.S. law should govern the interpretation of certain provisions when the priority application is a U.S. provisional.The BOA dismissed the appeal holding that the EPO case law on priority was well established. The minutes of the hearing (which only contain the "essentials" of the oral proceedings) indicate that the BOA was of the opinion that the EPO was competent to assess whether an applicant was entitled to claim a priority right and that reference to national law was not required in order to interpret the Article 87 EPC phrase "any person who has duly filed." The formal decision of the BOA is still awaited.Petition For ReviewThe Broad Institute announced that nine of its 21 European CRISPR/Cas9 patents may be affected by the decision which, it said, "does not involve the actual scientific merits of the patent application, but the interpretation of rules that dictate what happens when the names of inventors differ across international applications."4 Given the number of patents involved and the value of this technology, it is unsurprising that the BOA's decision may not be the end of the matter.At the hearing, many observers expected the BOA to refer questions on the correct approach to priority to the Enlarged Board of Appeal (EBA), and in fact, the minutes of the hearing record that during the hearing, the BOA indicated that it was minded to do so. Ultimately, however, it did not, and it held that this was a clear case of lack of priority, following many years of established case law.Now, the only recourse left to the Broad Institute in relation to EP'468 is to institute a petition for review (PFR). A PFR is a formal request to the EBA to review a decision by the BOA, and is only permitted under certain circumstances, including a problem concerning the composition of the Board, a procedural violation or defect, or a criminal act that occurred which may have had an effect on the decision.If a PFR relates to a procedural violation or defect, it is only considered allowable in situations where either an objection was raised by the petitioner during appeal proceedings and dismissed by the BOA without due consideration, or where an objection could not be raised by the petitioner during appeal proceedings.Many PFRs have been dismissed on the ground that it could not be proven that the BOA had been made aware of the procedural defect which was alleged to have occurred during the appeal proceedings. The approach to this is quite strict: it is not enough for a party to state during oral proceedings that it disagrees with the BOA's view, rather, an explicit request should be made so that it is noted in the minutes of the oral proceedings that a certain question has not been considered. In a previous case,5 the request for a PFR was not allowed because the minutes of oral proceedings did not mention that the petitioner had raised their objection with the BOA. The petitioner argued that the minutes were incorrect and that they had in fact raised the objection at the hearing. However, the petition was not allowed because the petitioner had not requested correction of the minutes.The Broad Institute has requested a correction of the minutes of the oral proceedings to record that the minutes do not accurately reflect the discussion during the hearing. In particular, they argued that, contrary to what the minutes seem to imply, the question of whether a referral should be made to the EBA was not adequately discussed during the hearing, and that the Broad Institute had requested a referral to the EBA in case the BOA was minded to decide that priority was not validly claimed. This seems to suggest that the Broad Institute intends to file a PFR. A PFR must be filed within two months of the parties being notified of the BOA's written decision which, as mentioned above, is still pending at the time of writing.On April 15, 2020, the BOA issued a communication rejecting Broad's request to amend the minutes. In light of this communication and the very high bar for successfully instituting a PFR, it looks increasingly unlikely that the Broad Institute will be able to rescue EP'468.The consequence of the BOA's decision is that, as the Broad Institute itself has explained, some of its other European patents will also be vulnerable on this same priority point. EP'468 has one pending and five granted divisional applications. It is therefore highly likely that these patents, as well as any other patents affected by the same problem, will also be substantially or wholly revoked. However, the Broad Institute has other patents covering later, more specific inventions, including different Cas proteins. This, and the potential uses of such platforms, may, as we will see below, result in a change in focus of the CRISPR-based technology disputes.In the meantime, UC's European patents, while not suffering from the same priority problem, are also under attack from various parties before the EPO, with oral proceedings in respect of one of the patents scheduled to take place in October this year.A Checkered LandscapeThe USPTO has already issued over 300 patents which relate to the CRISPR/Cas9 technology, and the EPO has granted over 100 patents. The dispute between the Broad Institute and UC focusses on the underlying CRISPR/Cas9 platform technology. Despite the priority issues facing some of the Broad Institute's European patents, other European patent applications from both the Broad Institute and UC are still undergoing examination. Due to differences in patent laws across the globe, different parties, and not just UC and the Broad Institute, may end up with patents, and may therefore have a stronger hold on the relevant market, in different jurisdictions. For example, in China, which is a serious contender in the race to further develop CRISPR, the vast majority of CRISPR patents have been awarded to Chinese applicants. Other, less high-profile research groups have been awarded patents in different territories.Thus, this checkered patent landscape could lead to different groups having monopoly positions in different parts of the world. This could lead to positive collaborations, but also legal complexities and disputes, if access to different markets is sought. As the different patent estates cover different aspects of the technology, a third party wishing to exploit it may need to take licenses from more than one of the patentees.Platform Technology PatentsCRISPR has emerged as an attractive tool not only for scientific research but also for the development of medicinal products. Most current CRISPR patents, such as those owned by UC and the Broad Institute, are the core and supporting platform technology patents which relate to fundamental components of the CRISPR system, including the Cas9 protein itself and general protocols for use. These are, of course, revenue-generating patents and given the extensive patent coverage, are likely to remain important and of huge commercial value for some years to come. However, it may be a number of years before many of the proposed clinical applications of the technology can be fully exploited.Clinical Applications of CrisprCRISPR-based technologies and their clinical applications are currently in their infancy. Indeed, further discoveries are being made all the time, in particular in relation to the potential uses of other Cas enzymes. The first patents which are the subject of the dispute between the Broad Institute and UC are narrow in scope, the majority of which relate to the CRISPR/Cas9 complex. Recently, a number of new Cas enzymes have been identified and their potential applications investigated. Such enzymes include Cas12 and Cas13 (described above), which, as we will discuss below, may have useful diagnostic applications. These will, of course, be underpinned by patents, but the present dispute may be put into context and become less important as the clinical uses of these enzymes become clear.CRISPR-based innovations with clinical applications may, therefore, ultimately prove to be the most commercially valuable innovations and, consequently, patents which underpin these may ultimately provide the most commercially relevant IP rights.Application in the Covid-19 PandemicThe clinical application of CRISPR may have immediate benefits, particularly in the light of the current health crisis. At the time of writing, many countries are subject to strict lockdown provisions as a result of the global coronavirus pandemic. Certainly in the UK, questions are being asked as to what the exit strategies from these draconian measures are—herd immunity, increased testing and diagnosis, or vaccine? It is in relation to diagnostics that CRISPR may play a key role.Several laboratories have reported progress in developing diagnostic kits which may be used to detect infectious diseases such as COVID-19. At the forefront of these are groups led by leading individuals from the two main players in the CRISPR patent dispute—the Broad Institute and UC.The Broad Institute has recently issued a protocol for using the CRISPR-based SHERLOCK (Specific High Sensitivity Enzymatic Reporter UnLOCKing)6 technique, using Cas12, for the detection of COVID-19. Sherlock Biosciences, a spin-out of the Broad Institute, which has licensed certain CRISPR platforms, has received Emergency Use Authorization (EMU) from the US Food and Drug Administration (FDA) for its Sherlock CRISPR SARS-CoV-2 kit for the detection of the virus that causes Covid-19. This is the first FDA-approved use of CRISPR technology.7Mammoth Biosciences, a spin-off of UC, has issued a protocol to validate a CRISPR-based approach called DETECTR,8 using Cas12, for the diagnosis of COVID-19. Again, this does not have Food and Drug Administration (FDA) approval and has not yet been tested on patients.But, unsurprisingly, the Broad Institute and UC and their associated laboratories and companies are not the only entities who are using CRISPR-based approaches to develop viable diagnostics for COVID-19. The lab of Dr. Changchun Liu at the University of Connecticut Health Center9 has recently reported progress in this area, with a preprint describing a simple, low-cost, CRISPR-based method, which could be used to detect infectious diseases such as COVID-19.10 This method, called the All-In-One Dual CRISPR-Cas12a (AIOD-CRISPR) assay, involves incubation of all of the reagents for nucleic acid detection in one-pot, and therefore enables simple, rapid, sensitive, and specific nucleic acid detection. It is particularly attractive because it is highly sensitive and can be used with only a few copies of nucleic acids, and was successfully used to detect SARS-CoV-2 and HIV.Further, Dr. Neville Sanjana's team at the New York Genome Center and at New York University have developed CRISPR RNA screening technology based on the CRISPR-Cas13 enzyme.11 The technique is currently designed for use on humans, but may be used on RNA containing bacteria and viruses, such as COVID-19.Such tests do not, at the time of writing, have clinical approval. What is clear, however, is that this is a rapidly developing area and, while a certain degree of collaboration is expected because we are in the midst of a global pandemic, there may well be future disputes relating to any patents which cover such techniques.Advanced Therapy Medicinal ProductsAnother consideration for any medicinal product or clinical application that is developed using CRISPR is, of course, the need for robust legislative framework to properly govern the approval and use of such applications. Any product developed using CRISPR will be classified as an advanced therapy medicinal product (ATMP). ATMPs are innovative and complex medicines for human use that are based on genes, tissues, or cells. They offer groundbreaking new opportunities for the treatment of disease and injury, but, because of their nature and how they are developed, are subject to rigorous legislation and a complex clinical approval regime.One challenge in getting such innovations to market is likely to be the lack of harmonization in the legislative regimes across the globe. In particular, the regimes are different in Europe and the U.S., increasing the complexities, cost, and timescales for obtaining approval, along with ethical considerations. This may be one of the reasons why there are only a handful of approved ATMPs: only 13 ATMPs have been approved so far by the European Medicines Agency. Therefore, despite the excitement in the scientific world and the media hype, it may be a while before the clinical benefit of such technology is recognized.ConclusionCurrently, there is no end in sight to the dispute regarding the ownership and validity of the current key patents protecting CRISPR. Given the checkered patent landscape, it is likely that different groups end up with monopoly positions in different parts of the world.However, the application of the technology to the race to develop therapies which have real and immediate clinical, and no doubt commercial, value may usurp this battle.1 M. Jinek, K. Chylinski, I. Fonfara, M. Hauer, J.A. Doudna, and E. Charpentier, A Programmable Dual-RNA-Guided DNA Endonuclease in Adaptive Bacterial Immunity, 337(6096) Science 816–21 (Aug. 17, 2012).2 Regents of the University of California v. Broad Institute, 903 F.3d 1286 (Fed. Cir. 2018).3 Case T 844/18 (Jan. 16, 2020).4 Press Release, Broad Communications, For Journalists: Statement and Background on the CRISPR Patent Process (Jan. 16, 2020), https://www.broadinstitute.org/crispr/journalists-statement-and-background-crispr-patent-process5 Case R 7/08 (June 22, 2009).6 F. Zhang, Omar O. Abudayyeh, and Jonathan S. Gootenberg, A Protocol for Detection of COVID-19 Using CRISPR Diagnostics, Broad Institute (Feb. 14, 2020), https://www.broadinstitute.org/files/publications/special/COVID-19%20detection%20(updated).pdf7 Sherlock Biosciences. Sherlock Biosciences Receives FDA Emergency Use Authorization for CRISPR SARS-CoV-2 Rapid Diagnostic. https://sherlock.bio/sherlock-biosciences-receives-fda-emergency-use-authorization-for-crispr-sars-cov-2-rapid-diagnostic/8 J.P. Broughton, W. Deng, C.L. Fasching, J. Singh, C.Y. Chiu, and J.S. Chen, A Protocol for Rapid Detection of the 2019 Novel Coronavirus SARS-CoV-2 Using CRISPR Diagnostics: SARS-CoV-2 DETECTR, Mammoth Biosciences (Feb. 18, 2020), https://mammoth.bio/wp-content/uploads/2020/02/A-protocol-for-rapid-detection-of-the-2019-novel-coronavirus-SARS-CoV-2-using-CRISPR-diagnostics-SARS-CoV-2-DETECTR.pdf9 Smart Medical Devices and Systems (SMDS) Laboratory, https://smds.engr.uconn.edu/10 Anna MacDonald, A Point-of-Care CRISPR-Based COVID-19 Diagnostic Could Be on the Horizon, Technology Networks (Mar. 31, 2020), https://www.technologynetworks.com/diagnostics/articles/a-point-of-care-crispr-based-covid-19-diagnostic-on-the-horizon-33279411 Hannah Balfour, CRISPR RNA-Targeted Genetic Screen Could Be Used for COVID-19 Therapy, Drug Target Rev. (Mar. 18, 2020), https://www.drugtargetreview.com/news/57578/crispr-rna-targeted-genetic-screen-could-be-used-for-covid-19-therapy/FiguresReferencesRelatedDetailsCited ByDiversification of the CRISPR Toolbox: Applications of CRISPR-Cas Systems Beyond Genome Editing Sarah Balderston, Gabrielle Clouse, Juan-José Ripoll, Grace K. Pratt, Giedrius Gasiunas, Jens-Ole Bock, Eric Paul Bennett, and Kiana Aran16 June 2021 | The CRISPR Journal, Vol. 4, No. 3CRISPR – Bacterial immune system Volume 39Issue 3Jun 2020 InformationCopyright 2020, Mary Ann Liebert, Inc., publishersTo cite this article:By Asawari Churi and Sarah Taylor.Biotechnology Law Report.Jun 2020.184-189.http://doi.org/10.1089/blr.2020.29180.acPublished in Volume: 39 Issue 3: June 3, 2020Online Ahead of Print:May 8, 2020KeywordsCRISPRcoronavirusCOVIDpatentgene editingEuropean Patent OfficePDF download
Publication Year: 2020
Publication Date: 2020-05-08
Language: en
Type: article
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