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A Nobel Prize, a Global Pandemic, and a Patent Dispute walk into a bar… stop me if you’ve heard this one before

Richard Gaugeler, Patent Attorney at Cedar White Bradley, explains how a Noble Prize, the Pandemic and a Patent Dispute are all inextricably linked to the CRISPR-Cas9 Technology.

ust as the three individuals who walk into a The functioning of the CRISPR-Cas9 technology bar seemingly appear independent from is as follows: First, the faulty sequence in the Jone another, they nevertheless always turn DNA is identified by a scientist. In this case the out to be inextricably linked through some faulty sequence refers to a defective gene common thread. And our Nobel Prize, Pandemic, which codes for Sickle-Cell anaemia. Second, and Dispute are no different. The thread? Of course, CRISPR uses guideRNA to identify, and bind to I must be talking about CRISPR-Cas9 Technology. the sequence. The guideRNA binds to and The revolutionary gene editing tool that can be used unravels the faulty sequence in the DNA molecule. to make precise incisions in genetic material to Third, Cas9 cuts the faulty sequence to either edit or even delete unwanted genetic code. deactivate the gene or replace the faulty sequence COPYRIGHT CTC LEGAL MEDIA The story of CRISPR-Cas9 Technology began with a new correct one. In editing the sequence, in 2002, when Emmanuelle Charpentier began Richard Gaugeler the gene is repaired and the resulting disease, her research into pathogenic bacteria. A later sickle-cell anaemia, is removed from the genome meeting between herself and fellow scientist altogether. Jennifer Doudna in 2011 at a café in Puerto Rico, The CRISPR-Cas9 Technology has near endless led to a discovery previously only imagined in possibilities for use and, has been deemed a movies and sci-fi novels. It is from this date that platform technology providing the springboard their discovery changes all our lives forever. for further advancements in gene editing. Gene editing techniques tend to raise questions CRISPR-Cas9 around the ethical use of technology. CRISPR-Cas9 allows us, for the first time, to One such ethical debate began in November accurately alter the genetic sequence of human 2018 when He Jiankui used CRISPR to produce cells. The alteration may be the deletion of a CRISPR- the world’s first “designer-baby” which was edited certain portion of DNA, effectively neutralizing a “ to remove a gene which produces a HIV receptor particular gene, or editing a portion of DNA, with Cas9 allows effectively making the baby immune to HIV. the effect of changing the gene altogether. us, for the While the debate surrounding the ethics of a CRISPR (Clustered Regularly Interspaced gene editing tool continues, so too will its use. Short Palindromic Repeats) refers to naturally first time, to Good or bad, so revolutionary was this invention, occurring nucleotide sequences found in the accurately that its inventors were awarded one of the genome of certain bacteria. These nucleotide highest accolades in the world. sequences play a role in the bacteria’s anti-viral alter the defence mechanisms. The sequences are genetic The Nobel Prize in Chemistry 2020 separated by spacer sequences which correspond On 7 October 2020, Emmanuelle Charpentier to sequences found in various viral genomes. sequence and Jennifer Doudna were awarded the Nobel Cas9 is a DNA cutting protein and makes up of human Prize in Chemistry for their invention “a method the other half of the technology and, when coupled for genome editing” (CRISPR-Cas9 Technology). with guideRNA, is guided to the DNA sequence cells. The Nobel Prize in Chemistry has been awarded to be cut. RNA is similar to DNA but comprises a 112 times to 186 Nobel Laureates, starting in 1901. single ribbon of molecules, unlike DNA’s double Until 2020 only five women, including Marie helix ribbon. Curie who won the Nobel Prize in both chemistry

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0 2 0 2 / 2 1 / 5 115/12/2020 15:14 31 Cas9 First-to-Invent First-to-Invent cell, while the cell, ed patents before before ed patents any THE PATENT LAWYER system. technology for gene editing in for technology Cas9 First-to-File i.e. without any specificity to bacterial bacterial to specificity any without i.e. technology and its use in gene editing. and its technology A First-to-File system relates to the actual the actual to relates system First-to-File A No sooner had UC filed their patent applications patent UC filed their had sooner No first, claim applications, although filed UC’s in dispute patents the of, all not if of, Most UC argued that their technology creates the creates technology that their UC argued vention by filing multiple U.S patent applications. patent filing multiple U.S by vention their respective institutions, namely; the the institutions, namely; respective their Vienna of the University California, of University referred Umeå (collectively of and the University rights in the their secure to as “UC”) looked to in filing date on when an application is presented when an application is presented on filing date The applications are directed to the CRISPR- to directed The applications are Cas9 a which represents Institute, that the Broad filed and Harvard, MIT between collaboration the same technology. applications to patent their the CRISPR- invention claim their however, Institute The Broad CRISPR- gene editing capabilities of the to cells are that eukaryotic argue Institute Broad cells and than prokaryotic complex more far cells as claimed that editing genes in eukaryotic complex. more applications is far patent in their edit successfully to ability that their Additionally, had previously others where cells eukaryotic and the the patent entitles them to failed, rights. accompanying the where 16, 2013 been filed pre-March have a from switched system patent a to system in mammalian (eukaryotic) cells. According to to According cells. in mammalian (eukaryotic) specific and is a more this invention Broad, The the technology. challenging use of more their fast-track decided to also Institute Broad grant applications and receive UC. applications of filed the earlier gene editing in for platform cells, cells. mammalian (eukaryotic) or (prokaryotic)

” COPYRIGHT CTC LEGAL MEDIA LEGAL CTC COPYRIGHT Résumé Attorney Patent Gaugeler, Richard Richard joined CWB as a Patent Attorney in 2016. In this role, Richard works with inventors, entrepreneurs, and start-ups in creating IP to provide registrable IP rights throughout the MENA region and beyond. He also assists R&D teams at large oil & gas organizations in the evaluation and development of new inventions and potential new patents. Richard works closely with UAE inventors through his work on the Takamul Program and innovation programs. As part of these programs, he provides patent and commercialization support to local inventors, entrepreneurs, academic institutions, private sector, and government bodies. Richard routinely advises clients on patent and design preparation, registration, prosecution, and maintenance. He prepares and prosecutes patents in various jurisdictions, including the European Patent Office, The United States Patent and Trademark Office, and the World Intellectual Property Office. Richard performs novelty and patents searches, as well as patentability and Freedom- to-Operate opinions. I. Fonfara, M. Hauer, J.A. Doudna, and E. Charpentier, A Programmable Dual- RNA-Guided DNA Endonuclease in Adapted Bacterial Immunity, 337(6096) Science 816-21 (Aug. 17, 2012). M. Jinek, K. Chylinski, 1 Jiankui used Jiankui CRISPR to produce the first world’s “designer- baby”. “

RNA RNA tracr technology technology interference. interference. . The seemingly was discovered. discovered. was Cas9. Cas9 Cas can cut DNA into two two into can cut DNA are very similar to the the to similar very are requires just one protein just one protein requires bacteria. bacteria. omes great litigation, and litigation, and omes great Cas9 , they combine the , they 1 1 3

Technology is no exception with is no exception Technology d d n i . paper Streptococcus Pyogenes Streptococcus 4 S. Pyogenes flesh-eating v S. Pyogenes _ Cas9 1 -genes are similar to other genes which genes other to similar -genes are 5 L P T Cas _ y In 2009 Emmanuelle, while working at Umeå working while In 2009 Emmanuelle, Back in 2012 when Emmanuelle and Jennifer Jennifer and when Emmanuelle Back in 2012 The origin of the CRISPR- of The origin The idea was that once the bacteria had had that once the bacteria was The idea During her studies into RNA Jennifer heard of of heard Jennifer RNA into studies During her The repeated sequences are dubbed Clustered sequences are The repeated between continued, an association the research As In 2006 at the University of California, Jennifer Jennifer California, of In 2006 at the University Emmanuelle’s work focused on understanding on focused work Emmanuelle’s Continued research shows that is the CRISPR shows Continued research findings in 2012, in the publishing their to Prior After continued testing and experimentation and experimentation continued testing After In 2011, Emmanuelle and Jennifer combine combine Jennifer and In 2011, Emmanuelle e l d and CRISPR-RNA to form ‘guide-RNA’, to cut cut to ‘guide-RNA’, form to and CRISPR-RNA choosing. their at a location of DNA CTC Legal Media The and unravel whose job it is to proteins code for genome. in an organism’s strands cut DNA studied small, gene in Sweden, University research molecules. During her RNA regulating RNAs that the small discovers Emmanuelle in found CRISPR and proteins called CRISPR and proteins disputes taking place in both the US and Europe. the taking place in both disputes Jinek paper, findings in the first publish their A patent dispute c patent, With great CRISPR- Regularly Interspaced Short Palindromic Repeats, Repeats, Short Palindromic Interspaced Regularly short. CRISPR for or dates back to 2002 when Emmanuelle Charpentier when Emmanuelle 2002 to back dates pathogenic bacteria, into research began her specifically and physics, had won or shared the win of the win of the shared or won had and physics, Chemistry. for Prize Nobel research into repeated sequences found in the sequences found repeated into research genetic sequences match appearing to bacteria, viruses. different of in the DNA found attack, a portion viral a off fended successfully the bacteria’s is coded into DNA viral the of a The coding provided sequence. DNA owns similar destroy and identify to on how memory in place take infections viruses should further the future. innocuous bacteria responsible for Strep throat throat Strep for responsible innocuous bacteria also fasciitis necrotizing severe and the more as known on RNA specifically focus to led her what made this bacterium so aggressive and and so aggressive what made this bacterium antibiotics. to resistant experience Jennifer’s studying RNA. was Doudna CRISPR sequence in the bacterium’s genome. in the bacterium’s CRISPR sequence in system parts. Jinek et al. their intellect to understand Cas9’s function in understand Cas9’s to intellect their S. Pyogenes. that discover they to cleave DNA, that protein is DNA, that protein cleave to a r B

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for filing at the patent office. Provided all the Interestingly, UC’s fresh proceedings have formal requirements are met the application will identified that most current applications of the receive the filing date on the date at which the CRIPSR system function using the single RNA- “With great application has been filed. This is the date from strand. which you may claim priority hence “First in time patent, equals first in right”. What about Europe... comes great However, the First-to-Invent system in the US Unlike the US, the proceedings before the worked differently. European Patent Office revolve around priority litigation. The first-to-invent system had two and whether the Broad Institute is entitled to it. requirements for establishing a filing date. The Although previously granting Broad several first requirement was ‘conception’, which related patents to CRISPR-Cas9, a request lodged with to the inventor’s innovative capacity, and was the Opposition Department to revoke the used to identify the inventor. The second patents was granted. In the appeal the decision ” requirement was ‘reduction to practice’, was was upheld by the EPO Board of Appeal (the obtained either, by developing a prototype or decision being handed down early in 2020). filing the application. Showing that you ‘reduced In the application UC objected to Broad’s patent your invention to practice’ before the filing date, on the basis that they were not entitled to an you could move the effective filing date of an earlier priority claim of one of their key European invention. Therefore, a later filed application Patents, namely; EP 2 771 468 B1 (the ‘468’ patent). could potentially predate an earlier filed one. Accordingly, the 468 patent claims priority, Thus, UC had to object to Broad’s earlier through a PCT application, to a US provisional granted patents before the Patent Trial and application filed on 12 December 2012. This Appeal Board (PTAB), through a process called provisional application listed 8 applicants, one interference proceedings. If Broad could show of which was Professor Luciano Marraffini of they reduced their invention to practice before Rockefeller University in New York, as owners of UC did, irrespective of their filing dates, Broad the invention. could be the rightful owners of the CRISPR- Prof. Marraffini was not named as an applicant Cas9 technology. on the European application, nor did his name In interference proceedings, UC showed the appear on the PCT application, when it was filed Jinek Paper rendered Broad’s applications obvious on 12 December 2013. An allegation which could COPYRIGHT CTC LEGAL MEDIA as it clearly showed the technology working in be easily discharged by providing an assignment cells, prokaryote and eukaryote alike. The from Marraffini. However, it is precisely that allegation was refuted by Broad, who countered assignment which is not available, thus there is that no such teaching was present in the Jinek no record of the transfer of right. Paper (or the UC applications for that matter), The outcome of the failed assignment is the and therefore their applications are not obvious. application of Article 87 of the EPO regulations, Broad did manage to convince the USPTO which requires a clear chain of priority. Without that as CRISPR-Cas9 was only found in prokaryotic such a chain the application cannot claim priority cells it was not unreasonable to conclude that to the original US provisional. Losing the earlier the technology would only be applicable to priority date, meant that other documents now prokaryote cells, despite UC’s allegations of became relevant as prior art. This prior art effectively working in cells. destroyed the novelty for Board’s application. The PTAB agreed with Broad and concluded The European patent was accordingly rejected. that their applications were non-obvious when read Not surprisingly Broad has appealed this in light of the Jinek paper and UC’s applications. decision, claiming that US priority should be A 2018 appeal by UC to the US Court of Appeals determined under US and not European law, upheld this decision. However, in 2019, a new but the Board of Appeal rejected this argument. interference proceeding was launched to decide With 9 out of 21 of Broad’s European patents the fate of the CRISPR patents between the two. being affected by the Board of Appeals decision, The latest in the interference proceedings it is unlikely these proceedings will end anytime occurred on 10 September 2020 when the PTAB soon. ruled in favour of the Broad Institute stating that A first attempt was made when Broad looked it had priority in its patents to the CRISPR system to correct the minutes from a hearing before the in eukaryotic cells. Board of Appeal where they claimed a procedural UC has since filed new claims to their defect had been noted. The type of defect which applications based on determining who invented would allow Broad to institute a Petition for Review. the CRISPR system to function in eukaryotic However, without the minutes showing the cells. The application turning on UC’s system procedural defect, and without a request in the which requires a single RNA-strand guide, minutes showing that a request to correct the whereas Broad teaches a double RNA-strand. defect at the time it was made, Broad had to

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rely on discussions outside of the official court comes to defeating the Virus. Including, record to prove their case. The outcome was that development of a vaccine and, whether a Broad was unable show such defect ever occurred. targeted antibiotic specifically designed for In April 2020, the Board of Appeal rejected Broad’s killing the virus could be developed. “Could request to amend the minutes shutting the door Developing vaccines takes time as the viral on their ability to seek a Petition for Review. DNA strands must be incubated. However, with CRIPSR CRISPR the incubator can actually be modified technology A global pandemic to increase the viral products. By increasing the The importance of a molecular tool capable of production rate of vaccine type viral DNA be the key reshaping DNA in stopping the spread of a virus strands per an incubation, the time required in in winning or fighting infections related to a global pandemic developing the vaccine can be reduced. is very clear. Another approach would be to use CRISPR the battle Severe Acute Respiratory Syndrome CoronaVirus technology to engineer B cells aka white blood 2 or SARS-CoV-2, the virus which causes COVID- cells, which produce antibodies to target and against the 19 or simply the Coronavirus has affected our destroy viruses. Using CRIPSR, B cells can be spread of lives in unprecedented ways. pre-programmed with COVID fighting genes Could CRIPSR technology be the key in and injected straight into the body to fight the this Virus winning the battle against the spread of this virus or even injected into patient before and if so, Virus and if so, how? infection occurs. So far CRISPR technology has been used in The targeted B cells are introduced into how? diagnosing patients with the Virus. The technology the bloodstream, thus skipping the immune uses Cas12 proteins, as opposed to Cas9. In fact, manufacturing process and move straight to a subsidiary of the Broad Institute recently received fighting the virus head-on. Emergency Use Authorization from the US Food This type of pre-emptive vaccine is referred and Drug Administration to use the CRISPR to as mRNA vaccines. Unfortunately, and until ” SARS-CoV-2 kit, dubbed SHERLOCK, which now, these types of vaccines have a very short they had developed for detecting the virus. life span. Meaning that regular ‘top-ups’ would The process involves programming CRISPR be required. machinery, to detect short genetic sequences of the virus, collected from the nose, throat, or What’s next? COPYRIGHT CTC LEGAL MEDIA fluid from the lungs. If the Virus is detected, the What effect CRIPSR technology and its associated CRIPSR enzyme emits a fluorescent glow in patents will have on this and future pandemics under an hour. Researchers in California2 claim remains to be seen. The value of such technology they can achieve similar results in just 40 minutes. may be difficult to quantify with any degree of Likewise, UC has also developed a quick accuracy. testing kit based on CRISPR technology for detecting Most, if not all, countries include compulsory the Virus called DETECTR. Unlike Broad’s licensing provisions in their Patent laws to allow SHERLOCK, it is yet to receive FDA approval. for use of patented products without the Jenifer Doudna3 was part of a team that recently permission of the owners. Such provisions being reported the development of a CRISPR diagnostic applicable only when the needs of the public test capable of detecting the Virus in just five minutes. outweigh the rights of the owners. Unlike other diagnostic tests using Countries such as France, Germany, and Italy, CRISPR technology, this test does not require which have been severely impacted by the amplification of any viral RNA in order to detect COVID-19 pandemic, have already taken to updating a positive result. The test is less accurate than their Patent acts when it comes to compulsory others and can only detect 100,000 viruses per licenses. The changes have the intention of making a microliter of solution compared to the above unilateral confiscation of patent rights less tests where 1 virus per a microliter can be stringent. 2 Broughton, J. P. et al. detected. An added benefit of this “Doudna test” While these provisions may appear to focus CRISPR-Cas12-based detection of SARS-CoV-2 is that it does not require the expensive lab on medicines, the French Patent Laws allow for Nature Biotechnol. 2020 equipment of the other tests. compulsory licenses covering either, a drug, Jul;38(7):870-874. doi: Additionally, the Doudna test can detect the medical device, or in vitro diagnostic device; the 10.1038/s41587-020-0513- amount of Virus present in a sample as measuring process for obtaining such products; or a 4. Epub 2020 Apr 16. the intensity of the fluorescent glow when the process of ex vivo diagnosis. 3 Fozouni, P. et al. Direct Virus is detected becomes proportional to the CRISPR technology appears to fall into all detection of SARS-CoV-2 amount of Virus present. This information may three of these categories for the issuance of a using CRISPR-Cas13a and a mobile phone medRxiv be used to tailor treatments for each patient. compulsory license in France and, is not limited 2020.09.28.20201947; to a pharmaceutical product. doi: https://doi. What about more than just detection… Italy recently enacted Law Decree No. 18/2020, org/10.1101/2020. CRISPR may have additional roles when it which included specific provisions under Article 09.28.20201947

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6 for dealing with the COVID-19 outbreak. The Conclusion Article allows for the requisition of medical What effect has the patent dispute, potential products and movable goods from private and compulsory licensing and a global pandemic “The public entities by the Civil Protection Department. had on our laureate winners? Well, seemingly Germany included similar provisions in its none, as the Royal Swedish Academy found question to Patent Laws under Section 13, while Japan themselves immune to all of it when awarding be asked provides for non-exclusive licenses to patented Emmanuelle and Jennifer with their highest products in the case of special necessity based accolade. In a world chaotically spinning out of may be how on the welfare of its public under Article 93 of control their Nobel Prize really became the eye high up the their Patent Laws. of the storm. As CRISPR spreads its wings and moves from patent chain virus detection to virus destruction you can expect the rights of its patent holders to be countries limited, or even lost, now that compulsory can grant license requirements are being relaxed worldwide in preparation for future pandemics. compulsory The question to be asked may be how high licenses. up the patent chain countries can grant compulsory licenses. Given the recent changes in compulsory license laws in European Contact countries, will the license stop at the product Cedar White Bradley (vaccines) or the manufacturing process itself Burj Al Salam, 47th Floor ” (platform). 2 Sheikh Zayed Road Of course, before the licensing question is Dubai, United Arab Emirates answered, we first need to determine whether Tel: +971 4 3816888 CRISPR technology can be classified as life- [email protected] saving. Under the current pandemic it probably www.cwblegal.com won’t be so hard to do so.

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