EP 2 397 156 relates to “Methods and compositions for the treatment of persistent infections and cancer by inhibiting the programmed cell death 1 (PD-1) pathway”.
Claim 1 is drafted in the form of a purpose-limited product claim, pursuant to Art 54(5), and is directed to a compound that reduces the activity or expression of a Programmed Cell Death-1 (PD-1) polypeptide=”PD-1 inhibitor”, for use in the treatment of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)
Brief outline of the case
The OD revoked the patent for lack of sufficiency and the proprietors appealed.
The board confirmed the lack of sufficiency.
The proprietors’ point of view
No evidence had been filed by the opponents to the effect that the invention was not reproducible, i.e. that the claimed compounds did not treat nodular lymphocyte predominant Hodgkin lymphoma (NLPHL).
The requirement developed in the case law applying specifically to claims directed to medical uses, in particular in decision T 609/02, was that the suitability of the compound to the claimed therapeutic effect required that the patent showed a metabolic mechanism specifically involved in the disease (see Case Law Book II.C.7.2.1 and 7.2.2). This could be demonstrated by a plausible technical concept, see in particular T 578/06 and T 950/13. A concept was plausible if it was not implausible.
Moreover, it was not required that the patent contained evidence showing a direct effect of the compound on the specific disease, only that it had a direct effect on the immune system. In the present case, an increase in T cell activity, by reactivation of the exhausted T cells, increased the immune response.
G 2/21 did not change the established case law concerning the level of evidence required for a sufficient disclosure in the context of a claim relating to a therapeutic effect.
It was part of the common general knowledge at the relevant date that lymphoma was a specific type of cancer and that NLPHL differed greatly from other lymphomas.
It was also part of the common general knowledge that the PD-1 pathway had been implicated in other types of cancer.
The patent described that, by contacting T cells with a compound reducing the expression or activity of PD-1, T cell cytotoxicity was increased and the immune response specific to an infectious agent was enhanced.
The opponents’ point of view
The opponents contested that the burden of proof was on the opponents to show that the invention was not reproducible. Rather, according to the case law, the application had to disclose the suitability of the claimed compounds for the treatment of NLPHL.
The patent relied on an indirect effect of the claimed compounds, which was that they enhanced T cell function. However, a mechanistic link between enhancement of T cell function and treatment of NLPHL was not shown in the patent. The expression of PD-1 alone did not make a therapeutic effect on NLPHL plausible.
It was common general knowledge that antibody blockade for inhibiting growth in certain tumours relied on inhibition of engagement of PD-1 with its ligand.
The expression of PD-1 alone did not necessarily correlate with T cell exhaustion, since PD-1 was also expressed by activated T cells and germinal centre-associated cells.
It was not correct that in a tumour environment the T cells were necessarily exhausted. The PD-1 pathway was not involved in every cancer type and its involvement could not be extrapolated from one cancer type to another.
The board’s decision
According to G 2/21, OJ EPO 2023, A85, Reasons 77, “[i]n 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”.
The statement by the EBA might be understood to suggest a high standard of proof, i.e. “beyond reasonable doubt” rather than on “the balance of probabilities“, which would require that the claimed therapeutic effect must, as a rule, be demonstrated in the application as filed by direct experimental evidence.
However, in G 2/21 the EBA focussed on the issue of whether or not post-published evidence can be used by an applicant or patent proprietor in the assessment of Art 83 and 56, but did not address the question of the level of proof in an application as filed required to substantiate a therapeutic effect as a prerequisite for using post-published evidence for assessing the requirements of Art 83.
The present board therefore did not understand G 2/21 to have quashed the principles established by leading decision T 609/02 despite having qualified the term “plausibility” merely as a generic catchword.
Indeed, as decision T 609/02 clearly sets out, a balance should 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.
As a consequence, in order to fulfil the requirements of Art 83, the suitability of the product for the claimed therapeutic application must be derivable from the application, unless this is already known to the skilled person at the priority date, cf. T 609/02, Reasons 9 and T 895/13, Reasons 3 to 5.
It was undisputed that the patent does not report any testing of the suitability of a PD-1 inhibitor in an animal model of cancer or in cancer cells in vitro.
A central issue in this appeal concerns thus the information that the patent must contain about a direct effect of PD-1 inhibition on a mechanism specifically involved in NLPHL.
The board considered that a “plausible technical concept“, as found in T 950/03, may not be stretched to include a mere hypothesis which has not to be supported by any evidence.
Instead, the board confirmed the principles developed in T 609/02, that, “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 being either known from the prior art or demonstrated in the patent per se”, see Reasons 9.
The board could not accept the proprietors’ line of argument, that “plausible” in this context means that the “technical concept” and hence the suitability of the claimed compounds for the claimed therapeutic application is “plausible” as long as it is not shown to be “implausible“. That would be in direct contradiction with the principles set out in decision T 609/12.
This burden cannot be discharged or shifted to the EPO or the public by merely alleging that a claimed therapeutic effect has to be regarded as having been demonstrated as long as it has not been disproven.
Comments
The present decision reminds that when it comes to a purpose-limited product claim under Art 54(5), G 2/21 excluded post-published evidence to demonstrate a therapeutic effect.
The proof of a claimed therapeutic effect has to be provided in the application as filed. When it comes to sufficiency, the burden to show the suitability is on the applicant, cf. G 1/03, OJ EPO 2004, 413, Reasons 2.5.3.
Another teaching of the present decision is that an effect is not necessarily plausible if it is not implausible, and that the level of proof of a therapeutic effect is certainly above that of “balance of probabilities” and rather nearer to “beyond reasonable doubt“.
G 2/21 actually wanted to abolish the use of “plausible” or “implausible”. We are far from it.
The leading decision in the matter remains T 609/12 and not T 950/03.
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