T 0294/20 (NLPHL/DANA-FARBER) 26-10-2023

Admittance of documents D56 to D61

1. The appellants requested that documents D56 to D61 not be admitted into the appeal proceedings. Since the documents are not used by the board in reaching a decision and the appellants are not adversely affected by this decision, there is no need for the board to decide on this issue.

Document D64

2. The appellants filed this document in appeal proceedings in the context of sufficiency of disclosure, the issue decided on in this appeal. Moreover, admittance of this document into the appeal proceedings was disputed.

3. However at the oral proceedings before the board, the appellants stated that they no longer wished to rely on it. Therefore, the contents of this document and arguments relying on it have not been considered in this decision and there was no need for the board to decide on its admittance.

Main request - claim 1

Sufficiency of disclosure - Articles 100(b) and 83 EPC

4. Claim 1 is drafted in the form of a purpose-limited product claim, pursuant to Article 54(5) EPC, and is directed to a compound that reduces the activity or expression of a Programmed Cell Death-1 (PD-1) polypeptide (in the following "PD-1 inhibitor") for use in the treatment of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) (see point IX.).

5. According to decision G 2/21 (OJ EPO 2023, A85, point 77 of the Reasons), "[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." This intermediate conclusion of the Enlarged Board of Appeal can be understood as confirming the established case law that post-published evidence cannot be used to remedy a lack of sufficient disclosure in respect of a medical use (cf. T 609/02, headnote). By this statement, the Enlarged Board of Appeal can also be seen to have endorsed the jurisprudence of the boards of appeal that attaining a claimed therapeutic effect is a limiting functional technical feature of a claim directed to the use of a substance or composition in a method of treatment (see also G 2/21, point 74 of the Reasons). The above statement by the Enlarged Board of Appeal might also 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 decision G 2/21 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 prerequisite for using post-published evidence for assessing the requirements of Article 83 EPC.

The above question has nevertheless been part of considerations on "plausibility" in the assessment of sufficiency of disclosure of claims directed to the use of a substance or composition in a method of treatment in the case law cited by the Enlarged Board in G 2/21 (see point 74 to 76 of the Reasons) (see, e.g., T 609/02, point 9 of the Reasons: "The patent system takes account of the intrinsic difficulties for a compound to be officially certified as a drug by not requiring an absolute proof that the compound is approved as a drug before it may be claimed as such.").

6. The board therefore does 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 Article 83 EPC, 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 (see T 609/02, point 9 of the Reasons and T 895/13, points 3 to 5 of the Reasons).

7. On how the suitability may be derived from the patent or application, the board in decision T 609/02 held: "It is required ... the claimed compound has a direct effect on a metabolic mechanism specifically involved in the disease ..." (point 9 of the Reasons, emphasis added by the board).

8. Thus, in the case at hand it must be assessed whether the patent contains information on a direct effect of PD-1 inhibitors on a mechanism specifically involved in NLPHL.

9. It is 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.

10. A central issue in this appeal concerns the information that the patent must contain about a direct effect of PD-1 inhibition on a mechanism specifically involved in NLPHL.

11. The appellants relied on decision T 950/13 to argue that such information may be in the form of a "plausible technical concept". However, the board considers that a "plausible technical concept" may not be stretched to include a mere hypothesis which has not to be supported by any evidence. Instead, the board confirms the principles developed in decision T 609/02, quoted above, 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." (point 9 of the Reasons).

12. The board cannot accept the appellants' 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. The burden to show the suitability is on the applicant (see G 1/03, OJ EPO 2004, 413, point 2.5.3 of the Reasons: "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 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.

13. The board therefore assesses below what can be inferred from the information provided in the patent as to a direct effect of a PD-1 inhibitor on a metabolic mechanism specifically involved in NLPHL.

14. The patent proposes that CD8**(+) T cells expressing PD-1 no longer have the ability to proliferate and express cytokines (they are "exhausted T cells"). Because PD-1 expressing T cells were detected in the tumour microenvironment in NLPHL, these had to be exhausted CD8**(+) T cells. This exhausted state can be reversed by blockade of PD-1. It follows that reversing T cell exhaustion can be used to treat this cancer.

15. Example 9 is the only example that relates to proliferative disorders or mentions NLPHL. It shows the expression of PD-1 in samples of a number of B cell and T cell lymphoproliferative disorders. In NLPHL samples, there was no expression of PD-1 in the neoplastic cells, however, there was PD-1 expression in the T cells surrounding them ("rosettes" of T cells surrounding the neoplastic cells is a characteristic pattern in NLPHL). There is no report on expression of ligand PD-L1.

16. The appellants argued that the skilled person reading example 1 would learn that inhibition of PD-L1 has a direct effect on exhausted T cells and that, in a chronic infection environment, this effect leads to reversal of virus-specific T cell exhaustion and increased viral clearance. According to one line of argument, this reversal of T cell exhaustion by PD-1 inhibitor was suitable to treat NLPHL because the expression of PD-1 by T cells in this tumour microenvironment indicated T cell exhaustion.

17. The board notes however that example 1 does not concern cancer and the question of whether the reversal of T cell exhaustion is relevant for NLPHL is not investigated in the patent and is not derivable from the prior art either. Indeed, out of the examples in the patent, only example 9 refers to NLPHL, however it neither shows that cancer-specific CD8**(+) T cells were present in NLPHL nor that reversal of T cell exhaustion contributed to treatment of the NLPHL. Instead, as summarised above, Example 9 merely shows PD-1 expression in T cells surrounding the neoplastic cells.

18. Consequently, the skilled person reading the information contained in the patent at the relevant date, would not have concluded that an effect of PD-1 inhibitors on exhausted T cells was relevant to treatment of NLPHL. The board is therefore not persuaded by the appellants' argument that the patent shows that a compound as defined in the claim is suitable for alleviating or preventing a symptom of NLPHL. Indeed, the appellants on the one hand argued that tumours are characterised by T cell exhaustion and on the other hand that PD-1 expression is concomitant with T cell exhaustion. This explanation would lead to the conclusion that all cancers may be treated by PD-1 blockade, which manifestly is not the case. This is acknowledged in the declaration D55 submitted by the appellants:

"All cancers are distinct and it is not possible to predict that a specific pathway, such as the PD-1 pathway, is present in any given type of cancer"

(see point 10), and

"Lymphomas are a specific class of cancer, and NLPHL is a distinct type of lymphomas. NLPHL differs greatly from other lymphomas, such as classic Hodgkin's lymphoma and non-Hodgkin's lymphoma. Each type of lymphoma has its own unique tumour microenvironment, and you cannot predict which pathways will be present."

(see point 11)

This passage, also illustrates why it is justified to require that the patent contains a mechanistic explanation specific to the claimed therapeutic use, in the case at hand treatment of NLPHL.

This point is further illustrated in document D4, which provides an overview of the knowledge on the blockade of PD-1/PD-L1 interaction for cancer therapy in 2005, and shows that a potential therapy relied on the presence of tumour-specific CD8+ T cells and on the expression of ligand PD-L1 by the tumour cells:

"Clinical responses have been found to correlate with CD8**(+) lymphocyte infiltration of the carcinomas and with CD8**(+) T cells producing IFN-gamma [28, 30]. Interestingly, in vitro studies have revealed increased IFN-gamma production by CD8**(+) T cells upon stimulation with tumor cells when PD-L1 was blocked [7, 33]. Thus, the blockade of negative regulation via PD-L1/PD-1 might improve the induction of type I immune responses.

Despite the presence of tumor-specific T cells within the tumors [42], tumor cell lysis is often prevented, and the clinical outcome of adoptive T-cell therapies is often disappointing [13, 20]. It is thought that the tumor microenvironment can restrict the effectiveness of activated antitumor lymphocytes [26, 65]. The blockade of PD-L1 on the tumor cells might improve stimulation of T cells after infiltration and thus allow for improved lysis of target cells in vivo [7, 68]." (see "Implications of PD-L1 for immunotherapy", on page 312).

19. A further line of argument was that the suitability of PD-1 inhibitors for treatment of NLPHL could be extrapolated from Example 1. In the appellants' view, this was the case because an environment of exhausted T cells is common to both chronic infections (addressed in example 1) and cancer.

20. In the board's view, this line of argument must fail for the reasons set out above (see point 17.) which already considered and dismissed the argument that a direct effect on the immune system, in the case in hand on exhausted T cells, demonstrated the suitability of the claimed compound for the therapy of NLPHL.

21. In a still further line of argument, the appellants asserted that T cell expression of PD-1, as shown in Example 9 of the patent, was in itself evidence of an active PD-1/PD-L1 pathway, so that the absence of data concerning PD-L1 expression by the tumour cells in NLPHL did not affect the completeness of the disclosure.

However, as set out in point 15. above, the patent does not demonstrate that this is the case and it was not derivable from the art at the relevant date.

22. In a final line of argument the appellants put forward that post-published document D9 confirmed the expression of PD-L1 by the tumour cells in NLPHL.

23. However, in line with the established case law (see decision T 609/02, point 13 of the Reasons and T 1329/04, point 12 of the Reasons), in a case where the patent provides only a vague indication of the suitability of the claimed compound for the therapeutic effect, post-published evidence may not be taken into account to remedy the insufficiency of disclosure. In the present case, for the reasons set out above in point 15., document D9 would be the first disclosure of an interaction between PD-1 and its ligand PD-L1 in NLPHL, and therefore would be the first disclosure of a possible mechanism underlying the claimed therapeutic effect. This line of argument must fail.

Auxiliary requests 1 to 5 - claim 1

Sufficiency of disclosure - Article 83 EPC

24. Claim 1 of auxiliary requests 1 and 2 is identical to claim 1 of the main request. Accordingly, the conclusions above apply equally to auxiliary requests 1 and 2.

25. In comparison with claim 1 of the main request, in claim 1 of auxiliary requests 3 to 5 the compound is limited to an anti-PD-1 antibody, an anti-PD-1 RNAi or an anti-PD-1 antisense RNA. Since the reasoning above in the context of the main request relates to inhibitors targeting PD-1, it applies equally to claim 1 of auxiliary requests 3 to 5.

Conclusion

26. None of the claim requests is allowable.