p at e n t s

Who owns CRISPR-Cas9 in Europe? András Kupecz Recent developments in the prosecution of the CRISPR-Cas9 patent in Europe highlight the differences between the intellectual property regimes of Europe and the United States.

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he evolution of the clustered, regularly interspaced, short palindromic repeats (CRISPR)–CRISPR-associated protein 9 (Cas9) system (CRISPR-Cas9) as a genome editing tool has undoubtedly been one of the hottest developments in biotech over the last few years1. With these developments came the filing of several patent applications by rival groups2. In April 2014, the first US patent was awarded to the Broad Institute and the Massachusetts Institute of Technology3. Meanwhile in Europe, the corresponding patent application was published as EP2764103 (ref. 4) and entered prosecution at the European Patent Office (EPO) in May 2014 (both the European patent application and the US patent are herein jointly referred to as ‘the Zhang patent’ after its inventor). Even before substantive examination of the patent began, anonymous parties filed so-called ‘third-party observations’ with the EPO, trying to prevent the grant of a European patent. This article discusses these recent developments in the prosecution of the Zhang patent in Europe and highlights some of the differences between the European and the American CRISPR-Cas9 intellectual property (IP) situation. Finally, I address how one deals with these and other pending CRISPR-Cas9 patent applications if one wants to use the CRISPR-Cas9 technology in Europe. Prosecution of the Zhang patent in Europe Third party observations and arguments. The Broad and MIT applied in Europe to get a patent granted with the following main claim: 1. An engineered, non-naturally occurring Clustered Regularly Interspersed Short András Kupecz is at Kupecz Intellectual Property, Amsterdam, the Netherlands. e-mail: [email protected]

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Palindromic Repeats (CRISPR)-CRISPR associated (Cas) (CRISPR-Cas) vector system comprising one or more vectors comprising: a) a first regulatory element operably linked to one or more nucleotide sequences encoding one or more CRISPRCas system guide RNAs that hybridize with target sequences in polynucleotide loci in a eukaryotic cell, b) a second regulatory element operably linked to a nucleotide sequence encoding a Type II Cas9 protein, wherein components (a) and (b) are located on same or different vectors of the system, whereby the one or more guide RNAs target the polynucleotide loci in a eukaryotic cell and the Cas9 protein cleaves the polynucleotide loci, whereby sequence of the polynucleotide loci is modified; and, wherein the Cas9 protein and the one or more guide RNAs do not naturally occur together.’ Since the filing of the Zhang-patent application with the EPO, there has not been any substantive examination of the application by the Examining Division. However, even before the EPO got to assess the application, a number of third-party observations were filed anonymously. Article 115 of the European Patent Convention (EPC) states that in proceedings before the EPO, any third party may present observations concerning the patentability of the invention to which the application or patent relates. In practice, third parties wanting to prevent the grant of a European Patent frequently use this opportunity to try to persuade the Examining Division to reject the patent application even before it proceeds to grant. In addition, the filing of third-party observa-

tions is likely to delay the examination process and thereby the grant of a patent. Obviously, the fact that one is allowed to file such observations anonymously makes it attractive for direct competitors or potential infringers wishing to stay below the radar of the prospective patentee. Third parties have so far filed more than 20 prior art references against the Zhang patent, some of which had already been identified in the international search carried out by the EPO. The third parties are disputing the patentability of the subject matter covered by the patent application, trying to prevent its grant on the grounds of lack of novelty and lack of inventive step. Novelty and inventive step. In Europe, novelty needs to be established over the prior art. In order to form prior art, a document must in principle be published before the valid priority date or the filing date, jointly referred to as the ‘effective date’ if no priority date is (validly) claimed. In the third-party observations against the Zhang patent, a number of arguments are made as to why the Zhang patent is not entitled to priority. If these arguments succeed, the effective date of the Zhang patent may become its filing date (i.e., December 12, 2013 instead of December 12, 2012), which will be relevant for determining which documents form part of the state of the art. As an important exception to this rule, the contents of European patent applications whose effective filing date is earlier than the effective filing date of the contested patent application, but that is published after that application, can still be cited as prior art against the application, albeit for the determination of novelty only5. Europe in this respect is quite different from the United States. For the Zhang patent application, the third parties are arguing that the patent lacks novelty over a number of patent applications

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patents Table 1 The Zhang patent: comparison of US granted claims and current EP claims (as of 17 November 2014). EP claim 1

US claim 1

1. An engineered, non-naturally occurring Clustered Regularly Interspersed Short Palindromic Repeats (CRISPR)-CRISPR associated (Cas) (CRISPR-Cas) vector system comprising one or more vectors comprising:

1. A method of altering expression of at least one gene product comprising introducing into a eukaryotic cell containing and expressing a DNA molecule having a target sequence and encoding the gene product an engineered, non-naturally occurring Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)—CRISPR associated (Cas) (CRISPR-Cas) system comprising one or more vectors comprising:

a) a first regulatory element operably linked to one or more nucleotide sequences encoding one or more CRISPR-Cas system guide RNAs that hybridize with target sequences in polynucleotide loci in a eukaryotic cell, b) a second regulatory element operably linked to a nucleotide sequence encoding a Type II Cas9 protein, wherein components (a) and (b) are located on same or different vectors of the system, wherein the guide RNA comprises a tracr sequence which is 30 or more nucleotides in length whereby the one or more guide RNAs target the polynucleotide loci in a eukaryotic cell and the Cas9 protein cleaves the polynucleotide loci, whereby sequence of the polynucleotide loci is modified; and, wherein the Cas9 protein and the one or more guide RNAs do not naturally occur together.

a) a first regulatory element operable in a eukaryotic cell operably linked to at least one nucleotide sequence encoding a CRISPR-Cas system guide RNA that hybridizes with the target sequence, and b) a second regulatory element operable in a eukaryotic cell operably linked to a nucleotide sequence encoding a Type-II Cas9 protein, wherein components (a) and (b) are located on same or different vectors of the system, whereby the guide RNA targets the target sequence and the Cas9 protein cleaves the DNA molecule, whereby expression of at least one gene product is altered; and, wherein the Cas9 protein and the guide RNA do not naturally occur together.

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The applicant is free to amend its claims throughout the examination process at the EPO, so further claim sets may be submitted. The most recent claims can be found in the EPO register 6.

which have been filed before the Zhang patent application was filed, but which were published after the filing of the Zhang application. Interestingly, one of the applications cited against the Zhang application is the University of California PCT-application WO 2013/176772 (‘the California application’), listing inter alia Jennifer Doudna and Emmanuelle Charpentier as inventors2. In their submissions, the third parties argue that the California application discloses all features of the above claim. In reply, the Broad and MIT argued that the California application does not disclose the application of the CRISPR-Cas9 technology in eukaryotic cells, but rather only in cell-free in vitro systems7. Inventive step in Europe is generally assessed using the so-called problem solution approach in which one document is considered to be the ‘closest prior art’. Inventive step, or obviousness, is subsequently determined by identifying the objective technical problem that is solved by invention in comparison to the closest prior art. The third parties take the position that the publication of Jinek et al.8 forms the closest state of the art. This publication, coauthored by Doudna and Charpentier, shows the ability of a trans-activating CRISPR (tracr) sequence–guided Cas9 to cut plasmid DNA and concludes by suggesting the usefulness of CRISPR-Cas9 as “an alternative methodology based on RNA-programmed Cas9 that could offer considerable potential for gene-targeting and genome editing applications.” The third parties argue that based on the disclosure of Jinek et al.8, one would obviously apply the technology to eukaryotic systems, especially in view of the known applicability of other genome editing tools, such as transcription activator-like effector nucleases, zinc-finger nucleases and the Argonaute RNA interference system, in eukaryotes. The applicants’

response to the assertion of lack of inventive step has been that the systems mentioned cannot be compared to CRISPR-Cas9 and do not teach the skilled person what is needed to successfully apply the system in eukaryotes. The applicants further refer to a declaration filed by the inventor, Feng Zhang, stating the same. In addition, new claims have been filed that limit the guide RNA to comprise a “tracr sequence which is 30 or more nucleotides in length”5. Further prosecution of the Zhang patent. It is now entirely up to the EPO’s Examining Division to decide how to deal with the further prosecution of the Zhang patent. The examiner may be satisfied with the patentee’s response and claims and may decide to grant the patent at once. Equally likely, the prosecution may continue with further patentability issues being identified by the examiner based on the third-party observations on file, additional third-party observations or based on grounds identified by the Examining Division itself. Both the patentee and the third parties may file further facts and evidence throughout the examination process. Based on what is on file currently, it is therefore very hard to make any sound predictions as to where the prosecution of the Zhang patent in Europe is going. At this point it does seem clear, however, that if the patent in Europe is granted, it will have substantially different claims than the US granted claims (Table 1). This adds to the uncertainty with regard to the freedom third parties have to operate in view of the Zhang patent. When will there be clarity? It is very unlikely that the uncertainty regarding the extent of the patent monopoly afforded by the Zhang patent in Europe will be resolved in the near future. If the grant of a European

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patent is refused by the Examining Division, the decision is open to appeal with the Board of Appeal of the EPO. This process will take two years at minimum. If the patent is granted (either by the Examining Division or by the boards of appeal) the granted patent will be open to opposition by third parties for a period of nine months. For the Zhang patent, it seems almost certain that one or more third parties will oppose the patent. Opposition proceedings in Europe (including appeal by the unsuccessful party) are likely to last three to five years. It should further be borne in mind that there is currently still not a ‘true’ European patent. This means that the patent centrally prosecuted and granted by the EPO will be split up in a bundle of national patents, each valid for the respective member state of the European Patent Convention. In the end, national courts will have the final say over validity and possible infringement of the patent claims. It could easily take another five years or more to resolve any conflict before a national court (which may or may not run, at least partly, in parallel with EPO opposition proceedings). In sum, there are many years to come before there is at least some degree of clarity with regard to the legal status and the scope of the Zhang patent in Europe. So what do you do if you want to use CRISPR-Cas9 in Europe? It is important to note that the preceding discussion concerns only the Zhang patent, clearly one of the basic patent applications relating to the CRISPRCas9 technology. The Zhang patent situation, however, is representative of the issues and timelines that one is likely to come across in prosecuting the many other CRISPR-Cas9– related patent applications in Europe, filed by the Broad and MIT and by multiple other players in the CRISPR-Cas9 arena, as well. Third parties that need to assess their freedom to 1195

operate should take due account of the many patent applications that have been filed. In most European countries, using patented research tools is unlikely to be covered by a research exemption. Third parties, nonetheless, wishing to use the CRISPR-Cas9 technology, especially commercial parties, therefore need to be aware that they may end up infringing a valid patent. Patentees, on the other hand, will very likely have to wait to enforce their patents until these have been granted by the EPO. Before grant there is provisional protection in many European countries in the form of a ‘reasonable royalty’ to be compensated by parties found to be infringing later on. In view of the great potential number of relevant rights and the highly uncertain IP situation surrounding the CRISPR-Cas9 technology, one strategy could well be for third parties to wait and see instead of actively pursuing licenses with the parties claiming to have

rights. At this point, it seems almost impossible to assess which party will end up ‘owning’ CRISPR-Cas9 in Europe, and it is not unlikely that there will be more than one relevant patent in the end. This may lead to commercially unattractive royalty stacking scenarios in which for a single use or product, royalties have to be paid to multiple parties. On the other hand, obtaining licenses this early in the game may prevent costly and time-consuming litigation later on and may secure access to the technology on reasonable terms. Conclusions The Zhang patent has recently been granted in the United States. In Europe, it will take a long time before the extent of the patent monopoly owned by the Broad and MIT is clear. This also applies to the other existing CRISPR-Cas9 patent applications. Moreover, as is illustrated here, the claims of the Zhang patent and others

may very well differ between the United States and Europe. All of this adds to the increasing uncertainty surrounding the CRISPR-Cas9 patent in Europe. Third parties in need of access to this scientifically promising technology should be aware and should carefully assess their legal and commercial options. COMPETING FINANCIAL INTERESTS The author declares no competing financial interests. 1. Hsu, P.D. et al. Cell 157, 1262–1278 (2014). 2. Sheridan, C. Nat. Biotechnol. 32, 599–601 (2014). 3. Zhang, F. CRISPR-Cas systems and methods for altering expression of gene products. US patent 8697359 (2014). 4. Zhang, F. CRISPR-Cas systems and methods for altering expression of gene products. EP2764103 (2014). 5. Article 54(3) European Patent Convention. 6. https://register.epo.org/application?number=EP13824 232&lng=en&tab=doclist 7. Letter of the applicant (the Broad Institute and MIT) dated 2 October, 2014. https://register.epo.org/applic ation?number=EP13824232&lng=en&tab=doclist 8. Jinek, M. et al. Science 337, 816–821 (2012).

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Who owns CRISPR-Cas9 in Europe?

Recent developments in the prosecution of the CRISPR-Cas9 patent in Europe highlight the differences between the intellectual property regimes of Euro...
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