It is just over 10 years since the Science publication of Jinek et al. showed for the first time that DNA cleavage could be achieved in vitro with a Cas9 enzyme of a bacterial CRISPR system using a single guide RNA thereby laying the foundation for a Nobel prize and a revolution in gene modification, yet the patenting situation covering the use of CRISPR-Cas systems remains unclear both in the US and Europe.
Suggestions following a second PTAB interference decision between patent claims of the Broad Institute and others ('Broad') and patent claims of the University of California/University of Vienna/Emmanuelle Charpentier (CVC) that Broad had won in the US as regards use of Cas9 in eukaryotic cells have proved premature. There is an on-going appeal before the Federal Circuit in which eminent scientists have filed an amici curiae brief criticising the approach of the PTAB as not properly acknowledging 'scientific method'. This has been further supported by an amicus curiae brief on behalf of Regeneron. In Europe, Broad are down following loss of their lead European patent (EP2771468) as a result of the Appeal Board Decision T0844/18 over the Marraffini priority issue (lack of consistency of the applicants on the first two priority filings and the applicants/successors in title at the PCT filing stage).
However, the latest combined referrals to the EPO Enlarged Board of Appeal on a priority matter (G1/22 & G2/22) raise new issues, essentially questioning whether the EPO had proper jurisdiction to rule as it did in T0844/18. This arises since the first question referred reads:
Does the EPC confer jurisdiction on the EPO to determine whether a party validly claims to be a successor in title as referred to in Article 87(1)(b) EPC?
In view of this, several of Broad's related appeals have been stayed. Moreover, it should not be overlooked that Broad have a number of related European applications which are free of the same priority issue, e.g. EP3252160B (under opposition), which covers in broad terms a CRISPR-Cas9 composition for use in eukaryotic cells. In the meantime, CVC's basic European Patent, EP2800811B, covering use of single guide RNA (sgRNA), and the related divisional EP3401400B covering use of a DNA-targeting RNA, remain under heavy attack in pending opposition appeals.
In the face of such IP confusion, many find themselves needing to address the question: what to do about FTO? The Broad Institute website make clear that Broad requires no written licence for any CRISPR-Cas9 use for academic or non-profit research. However, this is no help for use of CRISPR-Cas9 for commercial purposes. The research exemption of UK Patent Law only applies to research for experimental purposes related to the subject matter of the invention.
The four 'FTO' options:
- Seek licences off both the Broad and CVC or those with exclusive licences to the Broad and CVC portfolios, as appropriate.
- Make a choice on siding with one 'camp'.
- Carry out initial research with CRISPR-Cas9 but aim to switch to alternative non– CRISPR gene-editing, e.g. TALENs.
- Do nothing.
Option 3 may be frequently dismissed as not commercially viable. Option 4 raises another immediate question: will investors and/or collaborators tolerate this? If use of CRISPR-Cas9 is being considered in the therapeutic or diagnostic field, there is additional need to note the Broad 'inclusive innovation model' which means exclusive licensees of Broad such as Editas Medicine control additional licensing. How to deal with this may be vital to determine at an early stage of therapeutic concept development.
For research by companies or for the sale of tools and reagents for gene-editing, Broad offers non-exclusive licensing. Moreover, helpfully, the portfolio of Sigma-Aldrich is now joined with the Broad portfolio for licensing. That portfolio is now somewhat diminished by a number of European patents being revoked in opposition proceedings, but is still significant.
As regards the CVC 'camp', licensing is at least simplified by the fact that ERS Genomics, CRISPR Therapeutics, Caribou Biosciences and Intellia Therapeutics concluded a global cross-consent and invention management agreement. As two of the three relevant IP owners, the University of California and the University of Vienna gave one exclusive licence for all fields to a single company, Caribou Biosciences, which has since exclusively sub-licensed IP for human therapeutics to Intellia Therapeutics. Emmanuelle Charpentier has seemingly assigned her rights exclusively to two companies: CRISPR Therapeutics for human therapeutics and ERS Genomics for everything else.
What has become clear is that the aim of Broad and the CVC camps is to foster use of CRISPR-Cas technology so far as it does not interfere with their own commercial projects and hence option 4 as the route of managing risk has been favoured now by many. For those in the agricultural field, this is further simplified by the agricultural joint non-exclusive licensing framework originally agreed between Broad and Du Pont Pioneer (now operated by Broad and Corteva Agriscience), subject to ethical restrictions in relation to, for example, gene drive. Nevertheless, the 'wait and see' option can appear attractive still for some, especially those early on the road to commercialisation.
It is oft overlooked, but Toolgen was in fact the first to file on use of CRISPR-Cas9 in eukaryotic cells. However, this was little more than a draft journal paper – a fact that has determined Toolgen's problems over Cas9-related claims at the EPO – but, nonetheless, it does have issued claims in Europe, including the claims of EP3346003B relevant to plant gene editing (now under opposition). Moreover, Toolgen is involved in relevant interference proceedings in the US. Hence, it remains as a contributor to the murkiness to be clarified over CRISPR-Cas9 IP in both Europe and the US.
Can CRISPR-Cas9 foundational IP be side-stepped?
An oft asked question by those reluctant to seek licences under the foundational CRISPR IP of Broad and CVC is not surprisingly: is there any benefit to changing Cas enzyme?
The answer is generally 'not really' – one still needs a licence; one just swaps problems. However, the new problems may be less intractable. For example, change to Cas12a (previously known as Cpf1) means addressing a simpler IP position but, as things stand, one would still need a licence off Broad for any commercial research use under EP 3009511B (upheld in opposition proceedings without appeal) and related patents.
Moreover, it remains an unanswered question how broadly the scope of claims referring to 'Cas9' will be construed in the future. The English courts will need to apply the three questions of the UK Supreme Court in Actavis v Eli Lilly in considering claim scope. What exactly is a 'Cas9 polypeptide' was raised as a clarity issue in third party observations in relation to CVC's EPO divisional application issued as EP3401400B. Independent composition claim 11 of Auxiliary Request 10 as upheld in opposition proceedings for that patent refers to (a) a Cas9 polypeptide (or encoding polynucleotide) and (b) a two molecule DNA-targeting RNA (or one or more encoding DNA polynucleotides) but nothing in the claim requires ability to cleave DNA. Again the fate of this claim remains to be determined in appeal proceedings. In the meantime, the foundational CRISPR-Cas9 IP continues to raise many questions which many patent attorneys enjoy debating, but many in the commercial world would prefer to disappear.
Might there be patent pooling to ease the licensing issues?
This may come in the future, but at present the focus of those needing to consider such issues must be on important EPO appeal decisions and US decisions known to be coming in the next 12 months or so. It remains feasible that the current messy IP situation may have different winners in different countries depending on the law to be applied.
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