In late 2024, EPO Appeal Board 3.3. 04 issued written decision T0294/20 after more than a year from the oral proceedings resulting in revocation of medical use claims for lack of sufficiency. It is a decision which has been worth waiting for as its aim is evident – to provide in the eyes of the Board clear guidance on a question which seems to arise still frequently: how much data do you need to file on a new medical use of a compound for compliance with the sufficiency requirement of Article 83 EPC? Into the case law on this issue has come Enlarged Board Decision G2/21, a decision concerned with ability to use post-filing data to support inventive step but noted by Board 3.3.04 as additionally relevant to applicability of post-filing data to support compliance with Article 83 EPC.
The claims under scrutiny were the granted claims of EP2397156B (Dana-Farber et al.) which derived from a divisional filing based on WO2006/133396 concerning inhibiting the programmed cell death 1 (PD1) pathway for treatment of persistent infections and cancers. It was known at the priority date that PD1 expressed at the surface of CD8+ T cells interacts with the ligand PD-L1 and that such interaction negatively regulates T cell activation, normally a welcome interaction to limit the magnitude and duration of T cell responses but not so welcome in some disease situations. Earlier issued claims of the same EPO family related to inhibition of such interaction in the context of specified infections. Such claims had been found to lack inventive step.
EP237156B focussed on a treatment of a particular cancer type, nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). Claim 1 was drafted in the form of a purpose-limited product claim pursuant to Article 54(5) EPC and was directed to a compound that reduces the activity or expression of PD-1 for use in the treatment of NLPHL. The compound was further defined as an anti-PD1 or anti-PD-L1 antibody, RNAi or antisense.
The therapeutic rational behind this claim is as shown diagrammatically below:
As with all such medical use claims, validity consideration requires consideration of sufficiency of disclosure in relation to the functional limitation – the alleged therapeutic contribution to the state of the art. As noted by Board 3.3.04., this accords with the comments in Enlarged Board decision G01/3 at clauses 2.5.2- 2.5.3. However, equally it is well recognised that such claims cannot require absolute certainty. This in the past has led to such terms as ‘plausible’ being used to in effect argue acceptable extrapolation of actual disclosure of a specification. Against this background, Board 3.3.04 saw opportunity and need to re-assess this evidential issue.
The problem seen by the Board was that the only exemplification deemed relevant to claim 1 (Example 9) showed merely that PD-1 could be detected in T cells of the tumour microenvironment in all samples representative of NLPHL. However, they considered that detection of such PD-1 expression alone did not necessarily correlate with T cell exhaustion of relevance for NLPHL treatment; it might be simply accounted for by activated T cells and germinal-centre origin of T cells in such samples. Notably, there was no reported testing for PD-L1 in NLPHL nor results indicative that interference with PD-1/PD-L1 interaction would be therapeutically beneficial for such cancer. The only results in the specification on interference of such interaction with benefit of alleviating CD8+ T cell exhaustion were from a mouse model for chronic viral infection. However, such results were held irrelevant to NLPHL. It was common general knowledge that antibody blockade of PD1/PD-L1 engagement could be helpful in inhibiting growth of certain tumours, but this was known to be dependent on cancer type. Against this background, the Board upheld lack of sufficiency which could not be remedied by any auxiliary request.
Interestingly, in their written decision they firstly refer to part of paragraph 77 in G2/21:
“In order to meet the requirement that the disclosure of the invention be sufficiently clear and complete for it to be carried out by the person skilled in the art, the proof of a claimed therapeutic effect has to be provided in the application as filed, in particular if, in the absence of experimental data in the application as filed, it would not be credible to the skilled person that the therapeutic effect is achieved. A lack in this respect cannot be remedied by post- published evidence.”
They see this ‘intermediate conclusion’ of the Enlarged Board as endorsing established case law that post-published evidence cannot be used to remedy a lack of sufficient disclosure but emphasise that they see no requirement that the claimed therapeutic effect must be actually demonstrated in the application as filed by direct experimental evidence. They do not see G2/21 as raising the evidential hurdle since:
“in decision G2/21 the Enlarged Board of Appeal focussed on the issue of whether or not post- published evidence can be used by an applicant or patent proprietor in the assessment of Articles 83 and 56 EPC, but did not address the question of the level of proof in an application as filed required to substantiate a therapeutic effect as a pre-requisite for using post-published evidence for assessing the requirements of Article 83 EPC “ (emphasis added).
Rather they see G2/21 as having “qualified the term ‘plausibility’ merely as a generic catchword” but not quashing the principles of T609/02 based on recognition of need for a balance to be struck “between enabling early patent protection for therapeutic uses and avoiding that the claimed invention is only completed at a later point in time.” Suitability of the product for the claimed therapeutic use must be derivable from the disclosure but as noted in point 9 of T609/02 (and endorsed by Board 3.3.04 in T0895/13) this can be equated with technical teaching that “the claimed compound has a direct effect on a metabolic mechanism specifically involved in the disease.” This is to be distinguished from mere disclosure of a ‘technical concept’ and consequent argument in effect that “the suitability of the claimed compounds for the claimed therapeutic application is “plausible” as long as it not shown to be “implausible”. The Board emphasise in point 11 that a ‘plausible technical concept’ “may not be stretched to include a mere hypothesis which has not been supported by any evidence” with further quotation of principles developed in decision T609/02:
“it is not always necessary that results of applying the claimed composition in clinical trials, or at least to animals are reported. Yet, this does not mean that a simple verbal statement […] is enough to ensure sufficiency of disclosure [….]. It is required that the patent provides some information in the form of, for example, experimental tests, to the avail that the claimed compound has a direct effect on a metabolic mechanism specifically involved in the disease, this mechanism either being known from the prior art or demonstrated in the patent per se.”
In reviewing case law, the Board finally return to G1/03 with statement that the burden to show the suitability for the claimed therapeutic use is on the applicant referring to point 2.5.3 of the reasons of that decision:
“When an application for a patent is filed, the process of making the invention has to be completed. The requirement of sufficiency of disclosure ensures that a patent is only granted if there is a corresponding contribution to the state of the art. Such a contribution is not present as long as the person skilled in the art is not able to carry out the invention. Therefore, the decisive date for fulfilling the requirement has to be the date of filing or priority, as the case may be. Deficiencies in this respect cannot be remedied during the proceedings before the EPO.” This burden cannot be discharged or shifted to the EPO or public by merely alleging that a claimed therapeutic effect has to be regarded as demonstrated as long as it has not been disproven.”
As regards the claims under consideration, the Board did not see Example 9 as enabling the skilled person to conclude a mechanistic link between PD-1 inhibitors and exhausted T cells of relevance to treatment of NLPHL. Nor could they accept such mechanistic link being extrapolated from mouse model studies concerning chronic viral infection. On this basis, a post-published document confirming expression of PD-L1 by the tumour cells in NLPHL could not be taken into account; it could not remedy the finding of insufficiency on the basis of insufficient data in the specification.
Concluding comment
The message from Board 3.3.04 is evident – Enlarged Board Decision G2/21 may have banished the term ‘plausible’ from the vocabulary of European patent attorneys in arguing sufficient disclosure for a medical use claim, but T 609/02 remains as good advice on when experimental data is enough to first file. One cannot merely set a research project to establish a sound mechanistic foundation for the use. It remains the case that a technical concept is just that and not a taught therapeutic route for the purpose of Article 83 EPC. However, this does not remove entirely room for argument over how much data is enough for the skilled person to see the functional limitation as a made invention and the value on occasions of post-filing evidence on achieving the desired end-point- a new treatment benefiting patients.
Practical advice
To obtain a patent at the EPO directed to a medical use, the application must provide sufficient experimental evidence at the time of filing to show that the treatment is likely to work. While data from clinical trials is not required, there must be sufficient data to prove a compound has an effect or mechanism of action which could treat the disease.
If you would like further information please contact Claire Irvine, one of our life sciences team or Ben Muir, head of the life sciences team.
