The battle for CRISPR/Cas9 gene-editing technology: what patent applicants need to know

CRISPR, a powerful gene-editing technology, has been called a game changer by the scientific community and the biggest technology advance since the polymerase chain reaction (PCR).

CRISPR provides researchers with an easily accessible technique for making highly specific changes to DNA in viable cells. Interest in this gene-editing technique has been driven by its ease of use, potential for relative low cost and speed of implementation. Indeed, this technique is considered so easily accessible that it has recently been reported that ‘biohackers’ (hobbyists often with no formal training) are able to conduct gene-editing experiments using the CRISPR technique.

The potential upside from this gene-editing technique is significant. Companies are looking at potential applications in agriculture, industrial biotechnology and treatment of human diseases. There have been reports of its use on human cells, and recently, clinical trials were approved to begin to use the technique to treat a genetic disease.

However, there remains a great deal of debate over who will profit financially from CRISPR, as the United States Patent and Trademark Office (USPTO) investigates who has ownership over the patent on using CRISPR/Cas9 to edit genes. Currently, two groups have laid claim to this work: one group led by Professor Jennifer Doudna of the University of California, Berkeley and Professor Emmanuelle Charpentier of the Helmholtz Centre for Infection Research, Berlin, and another group lead by Professor Feng Zhang of the Broad Institute at MIT/Harvard University, Boston.

This article provides a brief overview of the CRISPR gene-editing technique and analyses the patent strategies employed by the two lead groups claiming this technique. We also provide some guidance for patent applicants based on our analysis of the patent strategies adopted by the CRISPR teams.

CRISPR: an overview of the science

The CRISPR gene-editing technique is based in part on the naturally occurring immune machinery of certain bacteria. The word ‘CRISPR’ is an acronym for clustered, regularly interspaced, short palindromic repeats, which was introduced to describe short sequences of DNA bases occurring in some bacteria. It has now been shown that when a bacterial virus (phage) infects these bacteria, a short sequence of the viral DNA is incorporated into the bacterial genome interspersed with these CRISPR nucleic acid base pairs. When the same virus tries to reinfect the bacteria, RNA transcripts of the genomic information stored between the CRISPR units form a complex with Cas9 (CRISPR associated protein 9) and act as a guide for the complex to identify, and bind, a corresponding sequence of the invading viral DNA and cleave it at a defined location. The CRISPR/Cas9 system therefore provides a mechanism for site-specific cleavage of DNA.

In a eukaryotic cell such as an animal or human cell, breaks in DNA are repaired by one of two mechanisms: non-homogenous end joining (NHEJ) or homology-directed repair (HDR). It has been shown that if CRISPR is conducted in the presence of a piece of DNA, when HDR occurs, that piece of DNA is incorporated into the cell.

There has been much ongoing work in terms of defining the precise conditions that will optimise the CRISPR/Cas9 system to avoid off-target DNA cleavage, modified forms of Cas9 that are better suited to laboratory gene editing, cofactors (including small molecules) that enhance the process, amongst many others. Academic Research Assistant Professor Doug Mortlock’s blog provides further detail on the development of each of these improvements.

The breakthrough work translating what was a small part of the bacterial immune system into the powerful in vivo gene-editing technique has largely been attributed to teams led by Professor Jennifer Doudna at the University of California, Berkeley and Professor Emmanuelle Charpentier, then of the University of Vienna (now at the Max Planck Institute for Infection Biology, Berlin), which we will refer to as the Doudna/Charpentier team. Another team led by Professor Feng Zheng at the Broad Institute at MIT/Harvard University, which we will refer to as the Zheng team, also claims to be the first to discover the use of the CRISPR/Cas9 system as applied to eukaryotic cells. Realising the commercial potential for this technique, both teams filed patent applications before publishing their work in academic journals. However, each team adopted a different patent strategy, which has led in the US (at least) to the current dispute over ownership rights.

Although not the focus of this article, in addition to the patents filed by the Doudna/Charpentier and Zhang teams, there have also been other patents granted relating to CRSIPR/Cas gene editing, either to modification of the technique or specific components used in the processes, by other groups, including Harvard University, the Broad Institute, DuPont, Agilent Technologies, University of Georgia Research Foundation, Institut Pasteur and Caribou Biosciences.

The United States patent landscape

The CRISPR/Cas9 patent dispute dates back to 2012, when the Doudna/Charpentier team published a paper showing that the Cas9 enzyme can be directed to cut specific sites in isolated DNA and filed a series of patent applications relating to the CRISPR/Cas9 technology including patent application US 13/842,859 filed 25 May 2012.

The Feng Zhang team filed their first patent application on 12 December 2012, and published a 2013 paper demonstrating the application of CRISPR–Cas9 in mammalian cells.

While Doudna and Charpentier filed their first application about seven months before Zhang, Zhang’s legal team elected to expedite examination and was granted the first patent relating to gene editing relying on the CRISPR technology (US 8,697,359 (‘359)) in April 2014. The Doudna/Charpentier team’s application has yet to be granted.

The key difference between the applications of the Zhang team and that of the Doudna/Charpentier team is that ‘359 specifically related to eukaryotic cells.

In January 2016, the USPTO launched an investigation (interference proceeding) following a request filed by the Doudna/Charpentier team into who was the first to invent CRISPR/Cas9. It appears that much of the outcome of this interference proceeding seems likely to turn on whether the invention claimed by the Zhang team in ‘359 would have been obvious over the methodology described in the Doudna/Charpentier team’s patent application.

What will happen next?

The interference proceeding is currently underway, with the first oral hearing completed at the end of 2016. Under this system a panel of administrative patent judges is appointed by the USPTO. These judges are tasked with deciding which team invented the application of CRISPR-Cas9 for gene editing in Eukaryotic cells first.

This interference proceeding may be the last widely publicised case of this type given the United States’ switch to a ‘first-to-file’ system in March 2013 (actually a ‘first inventor-to-file’). Given that several key CRISPR–Cas9 patents were filed before this change in US patent law, the implications of this case are significant. It is, therefore, being closely watched — so watch this space for updates on the case’s progress and implications.

The Australian patent landscape

Australia is already a first-to-file jurisdiction — meaning that the most important date to determine inventor’s rights is the filing date of a patent application, rather than the date of actual invention. Both of the Doudna/Charpentier and Zhang teams have filed patent applications in Australia that correspond to those involved in the interference proceeding. Doudna and Charpentier’s application, AU2013266968 (corresponding to US 13/842,859) is currently pending and has yet to be examined. The Zhang team’s later filed application, AU2013359123 (corresponding to US ‘359), was advertised as accepted on 27 June 2016 and proceeded to grant on 27 October 2016. It is therefore interesting to analyse how these two applications progressed in Australia, as this analysis may shed light on how corresponding applications in other countries might be treated.

Consistent with the strategy employed in the US to accelerate examination, the examination of the Zhang team’s patent application was expedited.

Interestingly, the Doudna/Charpentier team did not choose to oppose the grant of this application during the three-month opposition period between the date of advertisement of acceptance and grant.

The treatment of the Doudna/Charpentier team’s patent application by the Australian Examiner in the examination of Zhang’s Australian patent application provides an example of how these applications are considered in a first-to-file jurisdiction. Doudna and Charpentier’s earlier filed application, AU2013266968, was not published before the priority date of the claims of the Zhang team’s Australian application. Under Australian law, information disclosed in AU2013266968 could potentially be relevant to the novelty of the claims of the Zhang team’s application and was cited by the Australian Examiner. However, the Examiner accepted the Zhang team’s arguments that the Doudna/Charpentier team’s application did not disclose activity of the CRISPR/Cas9 technique in eukaryotic cells as defined in the now granted claims.

When AU2013266968 (the Doudna/Charpentier team’s Australian application) is eventually examined, the Examiner will not consider the Zhang team’s applications as prior art, unless the application loses its right to claim priority from the first filed application. This may lead to a scenario where the commercially useful scope of Zhang’s patent’s claims are also within the scope of the eventual granted claims of AU2013266968. When such a scenario occurs the two parties may require cross-licensing of their Australian patents to exploit their technology in Australia, and may require third parties to obtain licences from both teams.

It is also of note that the claims granted in AU2013359123 have different scope to those granted in US’359 (its US equivalent). The claims of US’359 may be found here and the claims of AU2013359123 may be found here. US’359 contains claims to (i) “a method of altering expression of at least one gene product” in eukaryotic cells (claims 1–7), (ii) “an engineered, non-naturally occurring CRISPR-Cas system” (claims 8–14) and (iii) “an engineered, programmable, non-naturally occurring Type II CRISPR-Cas system” (claims 15–20). AU2013266968 contains similar claims of the same type as (i)–(iii) of US’359, although the claims in each of these categories in AU2013266968 have different scope to those of US’359. AU2013266968 also includes claims to “a eukaryotic cell” (claims 26–27), “a cell line” (claim 28), “a multicellular organism” (claims 29–30), a “gene product” (claim 31) and “a plant” (claim 32). This is a common difference between Australian and counterpart US applications.

Finally, the US interference proceeding should have no impact on the validity of the Australian applications. However, should evidence emerge during the interference proceedings showing that one of the Doudna/Charpentier or Zhang teams is not entitled to their respectively claimed ‘inventions’, this may impact their counterpart Australian applications.

Issues to consider for patent applicants from the CRISPR patents

Expedited examination

It is possible to expedite examination of your patent application. If there is a particular jurisdiction of interest, and it is commercially and financially prudent to do so, accelerating examination can be an effective strategy to obtain early enforceable rights. However, it is key that this strategy be considered in the context of your commercial and business plan as it has the potential to limit future flexibility, eg, if you are in the stages of continual product development and thus require flexibility in terms of claim scope you may not want to finalise the scope of your claims earlier.

First-to-file jurisdictions

All major jurisdictions are now first-to-file. The timing of filing your first patent application needs to balance the potential for your patent application to be accepted with the market competitive dynamics; filing too early may mean you do not have all of the data needed to support your application, file too late and you could be ‘beaten’ to the Patent Office by a competitor.

The devil is in the detail

Patent systems in each jurisdiction have their own intricacies. It is important to find a patent adviser that you trust who can guide you through these complexities. This case study shows that the patent situation for CRISPR/Cas9 technologies varies in the United States and Australia due to differences in patent legislation and interpretation, which needs to be considered whenever you seek to commercialise an invention across multiple jurisdictions. Also, there may be opportunities available for broader claim scope, or different claim types in some jurisdictions and not in others.

UPDATE: On 15 February 2017, the Patent Trial and Appeal Board (PTAB) handed down their one line decision on the CRISPR interference, stating that there was “no interference in fact”.

This means that the patent applications of both the Doudna/Charpentier team and the Zhang team for the CRISPR/Cas9 technology will coexist. While the decision may be appealed, both sides have publicly stated that they respect this finding.

Further, this decision also means that the patent landscape for the CRISPR/Cas9 technology in the US will be similar to that in Australia. Assuming that the Doudna/Charpentier team’s patent application(s) proceed to grant, companies seeking to commercialise CRISPR/Cas9 technologies may need to license the patents from both teams.

Therefore, only time will tell who will be the real winners and losers of this dispute.

Dr Danny Gelman.

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