The development of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein (Cas) systems for genome editing has greatly improved the efficiency of modifying eukaryotic genomes. This article discusses the key patent filings in 2013 that sought to capitalise on this development (with a focus on Australia) and references the seminal research articles published in 2012 and 2013 that paved the way for them.   

The greater the potential for a patent filing to prevent third parties from exploiting a new scientific development, the more likely they are to dispute its validity. To that end, most of the key early CRISPR/Cas patent filings were opposed in Australia (and elsewhere). The Australian Patent Office (APO) allows oppositions to be brought by 'straw people', which allows the true opponent to hide its identity (thereby potentially avoiding a patent infringement allegation at a later date). Consequently, it is often unclear which parties are actually in dispute.  So it was with the CRISPR/Cas oppositions discussed in this article.

As with most new technological developments, the financial rewards that CRISPR/Cas genome editing is expected to generate have not come quickly. For example, the first (and so far only) approved medical treatment to be developed using CRISPR/Cas genome editing was launched late in 2023.  Most likely due to this lack of resources, only one of the many oppositions to the key 2013 patent filings in Australia reached a final conclusion on the merits, and only one further opposition reached a first instance court decision. Consequently, and as discussed below, a number of broad CRISPR/Cas genome editing patents are in force in Australia (a 'patent thicket'), whose validity has not been properly tested. Those seeking to exploit CRISPR/Cas systems in Australia (including by, say, importing gene therapy compositions developed using CRISPR/Cas genome editing) should be aware of this patent landscape.  We discuss infringement issues relating to CRISPR/Cas patents in the concluding remarks at the end of this article.

Since 2013, many of the Australian CRISPR/Cas patent filings that have been opposed have related to the agribusiness sector. This is perhaps unsurprising given the significance of this sector to Australia. Yet, as discussed below, the situation is similar as above, in that none of these oppositions have to date reached a first instance court decision. 

2013 – Universities of Vienna and California

The first application (now patent) was filed by Emmanuelle Charpentier and Jennifer Doudna and their respective employers at the time, the University of Vienna and the University of California, in March 2013. Charpentier and Doudna would later share the 2020 Nobel Prize in Chemistry for developing the CRISPR/Cas9 genome editing system. This claims priority from several US provisional applications, the earliest of which was dated May 2012. This provisional was filed shortly before Charpentier and Doudna's research groups jointly published their seminal research article describing how CRISPR/Cas9 systems work and how they can be used in genome editing in June 2012[1]. The application was briefly opposed by a straw person, but it withdrew the opposition without filing any arguments or evidence. The patent was granted in 2017.    

At its broadest, the patent claims a method of modifying a target DNA by contacting it with a Cas9 endonuclease and a single (engineered) guide RNA (sgRNA), the sgRNA comprising (i) a targeting segment – a nucleotide sequence from a CRISPR RNA (crRNA) that is complementary to the target DNA sequence – and (ii) a Cas9 binding segment – complementary stretches of nucleotides from the crRNA and a trans-activating CRISPR RNA (tracrRNA) that hybridise to form a double-stranded, covalently-bound RNA duplex (dsRNA). There are two points worth noting about the scope of this claim. First, it encompasses the use of CRISPR/Cas9 in eukaryotic genome editing (it would be of limited utility if it did not). This is worth noting because there was a disagreement between Charpentier and Doudna on the one hand and Feng Zhang and the Broad Institute of Harvard and MIT on the other about who was first to demonstrate that CRISPR/Cas9 could be applied to edit the genomes of eukaryotes (see below).  Second, it encompasses CRISPR/Cas9 genome-editing systems derived from any species (see below).

2013 – ToolGen 

The second application (now patent) was filed by ToolGen Inc of South Korea in October 2013.  This application claimed priority from several US provisionals, the earliest of which was dated October 2012. The broadest claim was to a composition containing a type II CRISPR/Cas system for introducing a site-specific, double-stranded break into a target nucleic acid sequence in a eukaryotic cell, comprising (i) a nucleic acid encoding a Cas9 endonuclease with a nuclear localisation signal (NLS) and (ii) a Cas9 binding segment with similar characteristics as in the claims of the patent above.  ToolGen's application was opposed by two straw people, and this time, one was prepared to go the distance.  

The parties filed their evidence at the APO in 2017, and in 2018, the Deputy Commissioner of Patents decided that almost all of the application's claims were invalid. This decision primarily rested on a finding that the application was only entitled to claim priority from the third of its provisionals, which was filed in June 2013. Three research articles[2] published between October 2012 and June 2013 were determined by the Deputy Commissioner to anticipate most of the claims. These articles were published by research groups at Harvard University, Massachusetts Institute of Technology (MIT) and the Broad Institute of MIT and Harvard.

ToolGen appealed the decision to the Federal Court of Australia (FCA). In 2023, the FCA upheld the Deputy Commissioner's decision in relation to priority and anticipation. It also held that all claims that the Deputy Commissioner had not held to be anticipated were obvious and that all claims were insufficient and lacked support, essentially because only one CRISPR/Cas9 system (derived from Streptococcus pyogenes) was disclosed. In a further judgment in 2024, the FCA permitted ToolGen to limit its claims to a system comprising a nucleic acid coding for a Cas9 polypeptide and an sgRNA both derived from S. pyogenes[3]. The application was granted nearly eleven years after it was filed. 

2013 – Sigma-Aldrich

The third application (now patent) was filed by Sigma-Aldrich Co LLC in December 2013. This claims priority from several US provisionals, the earliest of which was dated December 2012. The broadest claim is to a method for modifying a chromosomal sequence in a eukaryotic cell by integrating a donor sequence, the method comprising (i) introducing into the cell an RNA-guided endonuclease with an NLS, a guide nucleic acid encoding an sgRNA and a polynucleotide donor sequence, and (ii) culturing the cell such that the sgRNA guides the endonuclease to the target chromosomal sequence, where it introduces a double-stranded break, which, when repaired, is modified by insertion or substitution of the donor sequence. This granted claim is broader than the broadest claim pursued by Toolgen; not only can the CRISPR/Cas system derive from any of numerous bacterial species, but the endonuclease may be selected from a list of Cas proteins and the CRISPR system may be of type I, II and III.   

The application was briefly opposed by four straw people, three of which withdrew their oppositions before filing arguments and the fourth of which withdrew its opposition before filing evidence. A patent including the above-referenced claim was granted in 2018. Two divisionals of this application with more modest claims were also opposed, both by a single straw person.  In respect of the first divisional, evidence was filed in 2019 and 2020, and in 2021, a Delegate of the Commissioner of Patents rejected all eight grounds of opposition. The straw person did not appeal against this decision, so a second patent was granted. In respect of the second divisional, the straw person withdrew its opposition after filing evidence, so a third patent was granted, also in 2021. 

2013 – Broad Institute, Harvard and MIT

The fourth application (now patent) was filed by the Broad Institute, Harvard and MIT, also in December 2013. This claims priority from numerous US provisionals, the earliest of which was dated December 2012.  This provisional was filed shortly before the research groups of Zhang of the Broad Institute and George Church of Harvard published their seminal research articles that describe the use of CRISPR/Cas9 systems to make modifications to the genome of human cells in January 2013 (Cong et al. (2013) and Mali et al. (2013)). These articles are different in scope to Jinek et al. (2012), hence the disagreement over who described the application of CRISPR/Cas9 to eukaryotic genome editing first. This disagreement is reflected in the groups' competing patent filings, as well as in patent office disputes, in particular at the Patent Trial and Appeal Board of the United States Patent and Trademark Office.   

The broadest claim granted from this application is long but essentially claims a method for treating a condition caused by a defect in a target genomic sequence in a eukaryotic subject by modifying the target sequence, where the condition is susceptible to treatment by such modification, the treatment comprising delivering to eukaryotic cells an engineered composition comprising one or more adeno-associated virus or lentivirus vectors comprising nucleotide sequences encoding an sgRNA and a Cas9 with an NLS, each sequence linked to a regulatory element. This claim is very broad (pun intended) in scope, particularly as it is not limited to any particular genetic defect or condition and the description of the patent includes pages of genes that are said to be suitable target sequences for the purpose of the invention.  

The application was opposed by a straw person, which withdrew its opposition after all of the parties' evidence had been filed but before a hearing had taken place. This was also the case in respect of a divisional that was filed with composition claims.  Both applications were granted as patents in 2021.

The fifth application (now patent) was filed by the same applicants as the fourth and on the same day in December 2013, with Rockefeller University as an additional applicant (two researchers from Rockefeller University were co-authors of Cong et al. (2013)). The application claims priority from several US provisionals, the earliest of which (dated December 2012) is the same provisional as is relied upon by the fourth application. The broadest granted claim is similar to that of the fourth application, except that it has composition claims rather than method of treatment claims. This application was opposed by a straw person, which withdrew its opposition after the applicants filed their evidence in answer to the opposition. It was also granted in 2021.          

Opposed applications filed since 2013

It is apparent based on data from the APO that patent applications claiming CRISPR/Cas genome editing systems filed after 2013 were less likely to be opposed or, if opposed, for the opposition to be withdrawn at an early stage. One opposed application (now patent) was filed in April 2017 by the Broad Institute, Harvard and MIT. Its broadest claim is directed to an sgRNA that interacts with Staphylococcus aureus Cas9.  The straw person that opposed this application withdrew before filing any arguments. Another opposed application was filed in May 2018 by the Chinese Academy of Sciences.  This application related to CRISPR/Cas genome editing of plants.  It was opposed by the New Zealand Institute for Plant and Food Research and the Academy withdrew its application after the opponent filed its evidence.

Several other opposed applications filed after 2013 refer to CRISPR/Cas genome editing, but it is not central to their claims. These include an application relating to a genetically modified opium poppy, which was withdrawn after the opponent filed arguments in support of its opposition, and an application relating to genetically modified diazotrophs (nitrogen-fixing prokaryotes), which proceeded to grant after the opponent withdrew its opposition. 

Lastly, two oppositions to applications referring to CRISPR/Cas genome editing are currently on foot. One of the applications relates to high amylose content wheat grains and the other relates to gender determination of avian (e.g., chicken) embryos in unhatched eggs.

Concluding remarks – infringement issues

Notwithstanding that many broad Australian patents relating to CRISPR/Cas genome editing are in force, as far as we are aware, no CRISPR/Cas patents have been enforced in Australia to date. It is unclear whether biotech companies using CRISPR/Cas to develop gene therapies: can do so using non-patented processes; will take licences under any relevant patents; or are confident that any such patents are invalid.    

Further to that, many of the patent claims referred to above are to CRISPR/Cas genome editing compositions themselves (i.e., product claims), rather than, say, the gene therapy compositions that result from a CRISPR/Cas genome editing process. If such a process were to take place overseas, as one might expect them to, such product claims may be avoided, as only the gene therapy compositions would be imported into (or otherwise exploited in) Australia, not the CRISPR/Cas genome editing compositions used to make them that are patented in Australia. It is not an act of infringement in Australia to import (or otherwise exploit) a product (i.e., the gene therapy composition) of a product that is patented in Australia (the CRISPR/Cas composition).

The situation may be different in the case of patent claims referred to above that are to methods of CRISPR/Cas genome editing. That is because importing into (or otherwise exploiting in) Australia the product of a method or process that is patented in Australia is an act of infringement, notwithstanding that the patented method or process was performed overseas.  This means that importing into (or otherwise exploiting in) Australia a gene therapy composition resulting from a CRISPR/Cas genome editing method or process performed overseas that is the subject of a method or process claim in Australia may infringe that claim.   

If any of the above issues are relevant to you, we recommend obtaining specialist advice as the infringement and validity issues involved are likely to be complex and to differ from one jurisdiction to another.  

Next week in our DLA Piper Genomics Series

Please tune in for next week’s feature, where we will be looking at the use of genomics in healthcare in the UAE.

[1] Jinek et al. (2012) A Programmable Dual-RNA-Guided DNA Endonuclease in Adaptive Bacterial Immunity. Science, 337, 816-821.

[2] Cong et al. (2013) Multiplex genome engineering using CRISPR/Cas systems. Science, 339, 819-23; Mali et al. (2013) RNA-guided human genome engineering via Cas9. Science, 339, 823-6; and Wang et al. (2013) One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell, 153, 910-8.

[3] The CRISPR/Cas9 system of S. pyogenes recognises a specific trinucleotide sequence and an sgRNA derived from S. pyogenes has a specific truncation, so the claims were further limited accordingly.