T 0979/23 (Dravet syndrome II/KATHOLIEKE UNIVERSITEIT LEUVEN) 01-10-2024

Admission of document D36 (Article 13(2) RPBA)

1. Document D36 was filed by the respondents with their letter dated 25 July 2024, i.e. after issuance of the board's communication pursuant to Article 15(1) RPBA, which was dated 6 June 2024. Admittance of the document is therefore subject to the provisions in Article 13(2) RPBA as in force since 1 January 2024. The respondents argued that the document was filed due to exceptional circumstances, namely the board's reference in its communication setting out its preliminary opinion to the reasoning given in the parent case (see decision T 1779/21). The respondents furthermore argued that obtaining declaration D36 from Dr Sullivan had required some time, i.e. the document was filed in a timely manner.

2. The board does not agree. The oral proceedings in which decision T 1779/21 was taken took place on 19 December 2023. The written reasoned decision was issued on 20 February 2024. Given the very similar wording of the claims of the granted parent patent and the present patent, the respondents must have been aware that the issues to be dealt with in the present case were very similar if not identical to the ones in the parent case. The respondents therefore could not be taken by surprise by decision T 1779/21 and the reasoning therein being considered relevant by the board in its preliminary opinion. In this regard, the board also notes that appellant II referred to the preliminary opinion of the board in case T 1779/21 (submitted as D35) in its statement of grounds of appeal and to written reasoned decision T 1779/21 in its letter dated 13 March 2024. If they considered it necessary, the respondents could therefore have responded to issuance of that decision in a timely manner.

3. The respondents' argument that the declaration did not introduce substantially new matter and was not detrimental to procedural efficiency because it was not complex is not relevant because Article 13(2) RPBA first and foremost requires there to be exceptional circumstances for a document to be admitted at such a late stage in the proceedings. The additional criteria of procedural efficiency and complexity as also mentioned in Article 13(1) RPBA may also be considered in the context of Article 13(2) RPBA, but, in the board's view, come into play only once the presence of exceptional circumstances has been acknowledged.

4. The board also disagrees with the respondents' further argument that, by referring to decision T 1779/21, the board's communication introduced new arguments which had not been raised before by any party in the proceedings.

5. The question of whether it was credible that a therapeutic effect was obtained by fenfluramine as a monotherapy had already been central to the discussion in the current case in the proceedings before the opposition division (see notices of opposition) and had also been reiterated by the appellants in their statements of grounds of appeal (see e.g. statement of grounds of appeal by appellant I, points 4.3 and 4.4 and statement of grounds of appeal by appellant II, point 1.2). The same applies to the discussion of the experiments in the patent and the relevance of the combination treatments reported therein.

6. The fact that the board in points 12 and 15 of the Reasons for decision T 1779/21 used wording which had not been used expressis verbis before in the proceedings does not change this.

7. Equally, alleged technical or legal errors in the written reasons for decision T 1779/21 cannot change the situation described in point 5. above (see also points 29. to 34. below).

8. In light of the above, document D36 was not admitted into the proceedings.

Disclosure (Article 100(b) EPC)

9. Present claim 1 differs from claim 1 in the parent patent only in that it does not require "oral administration" and in that it does not state "as the sole therapeutic agent". These features were, however, not crucial in decision T 1779/21 and the parties have also not provided arguments relating to a possible difference in the meaning of the term "monotherapy" in the absence of the phrase "as the sole therapeutic agent" or to the relevance of administration routes. The board's reasoning regarding the current case is thus similar to the reasoning of decision T 1779/21.

Decisions G 2/21 and G 1/03

10. Claim 1 is formulated as a purpose-limited product claim according to Article 54(5) EPC.

11. Point 74 of the Reasons for decision G 2/21 (OJ EPO 2023, A85) confirmed the relevant case law that "a technical effect, which in the case of for example a second medical use claim is usually a therapeutic effect, is a feature of the claim, so that the issue of whether it has been shown that this effect is achieved is a question of sufficiency of disclosure under Article 83 EPC" and that "it is necessary that the patent at the date of its filing renders it credible that the known therapeutic agent, i.e. the product, is suitable for the claimed therapeutic application".

12. It therefore had to be decided whether fenfluramine as a monotherapy, i.e. as the sole therapeutic agent, could be considered suitable for the treatment of Dravet syndrome at the relevant date. As decision G 2/21 further explains, in 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."

13. The Enlarged Board of Appeal endorsed the conclusions in decision T 609/02 (see G 2/21, point 75 of the Reasons) and decisions T 754/11 and T 887/14 (see point 76 of the Reasons). The expression "proof of a claimed therapeutic effect" in point 77 of the Reasons cannot therefore be interpreted as a deviation from the established case law in the context of second medical uses: it does not apply a stricter requirement than the established case law prior to decision G 2/21. Rather, by referring in the same sentence to a particular situation in which "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", the Enlarged Board confirmed that means other than experimental data in the application as filed can establish proof of a claimed therapeutic effect.

14. What is required, however, in the absence of experimental evidence, is for the patent or the application as filed to provide some information demonstrating 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 itself (see T 609/02, points 5 to 9 of the Reasons).

15. Decision G 1/03 (OJ EPO 2004, 413) notes in this regard, in point 2.5.3 of the Reasons, that "[w]hen 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."

16. The board concludes that a contribution to the state of the art which enables the skilled person to carry out the invention has to be present in the application as filed.

The teaching of the patent

17. The patent relates to the treatment of Dravet syndrome with fenfluramine. Dravet syndrome is a rare and catastrophic form of intractable epilepsy that begins in infancy. Children with Dravet syndrome are particularly susceptible to episodes of status epilepticus. This severe and intractable condition is categorised as a medical emergency requiring immediate medical intervention, typically involving hospitalisation. Status epilepticus can be fatal. It can also be associated with cerebral hypoxia, possibly leading to damage to brain tissue.

18. It was undisputed that the only example in the application as filed, "Comparative Example 1", does not relate to fenfluramine monotherapy, but reports administration together with valproate, a known anti-convulsant (see table 3). This combination treatment resulted in a seizure-free condition in 66.6% of test subjects, and in a slightly improved reduction in seizures (75%) as compared to the reduction in seizures in patients treated with valproate and stiripentol for two months (69.7%).

19. In the absence of experimental data for fenfluramine monotherapy in the application as filed, the board considered whether achieving the claimed therapeutic effect was made credible in the application as filed in any other way (see points 12. and 13. above). "Monotherapy" is explicitly mentioned in the application as filed on page 8, lines 11 to 13 and in claim 9, in both cases as an alternative to combination therapy. However, this mere statement is not in itself sufficient to provide any "proof" within the meaning of decision G 2/21. The application as filed furthermore states that "[f]enfluramine has been known to inhibit serotonin reuptake and to trigger the release of serotonin in the brain due to disruption of its vesicular storage. However, until the present invention was made, it was not known that fenfluramine's mechanism of action made it suitable for the treatment of Dravet Syndrome" (see page 7, first paragraph). The board notes that treatment by therapy does not per se require the disease to be completely cured or even that its cause be addressed, but does encompass the alleviation of symptoms (see also Case Law of the Boards of Appeal, 10th edition 2022, I.B.4.5.1).

Level of proof required

20. Although the skilled person could conclude, from the data in the patent or the application as filed, that fenfluramine in combination with valproate alleviated some symptoms of Dravet syndrome, it was not clear whether this also applied in the case of a monotherapy. In view of the serious nature of the disease, additional circumstances have to be borne in mind when deciding whether "proof of a claimed therapeutic effect" is provided in the application as filed. As noted in document D2: "Dravet syndrome is a truly catastrophic therapy-resistant epilepsy syndrome, and families faced with this disorder are required to cope with special circumstances" (see page 1136, left-hand column, penultimate paragraph). Discontinuation of treatment can lead to a greater number of seizures, potentially with adverse effects on mental development (see for example the case reported in document D17, right-hand column, lines 2 to 4 and D32, page 47, right-hand column, second full paragraph). According to several prior-art documents, including reviews authored by Charlotte Dravet, the physician after whom the disease is named, the standard first-line therapy for Dravet syndrome was valproate, a known anticonvulsant (see for example the upper part of the flowchart in D27). Depending on the response of the individual patient, this treatment was supplemented by additional medicaments (e.g. clobazam and stiripentol or topiramate, see the middle part of D27), while maintaining valproate as the basic medicament. Anti-epileptic drugs that target the sodium channel (e.g. carbamazepine, oxcarbazepine, phenytoin, lamotrigine) had to be avoided, because they were known to aggravate the condition, which could be associated with mutations in the sodium channel gene SCN1A (see D18, paragraph bridging columns on page 2 and paragraph bridging pages 3 and 4). The expert declaration submitted by the respondents (D25) states in point 13 that "removal of potentially efficacious compounds from a drug regimen is done with extreme caution and only with a rationale justifying the removal".

21. In this particular case, namely a very serious disease for which an established, albeit sub-optimal, therapy exists (only 16% of patients remained seizure-free, see D2, Summary) and where an incorrect therapeutic decision could lead to irreversible damage, the level of proof required has to be at least such that the skilled person has reason to assume that the standard valproate treatment could be discontinued and replaced by fenfluramine without worsening the patient's condition.

Mechanism of action

22. In the absence of experimental or clinical data in the application as filed that would indicate that fenfluramine monotherapy had a therapeutic effect, the board further considered whether the application as filed or the prior art established that fenfluramine had a direct effect on a metabolic mechanism specifically involved in the disease. The respondents argued that the inhibition of serotonin reuptake and triggering of the release of serotonin in the brain due to disruption of its vesicular storage, as reported in the application as filed (see page 7, first paragraph), was such a metabolic mechanism. The board does not agree, for the following reasons.

23. Document D2, published shortly before the priority date of the patent, refers to earlier in vitro studies (D19) which indicate that "serotonin-releasing drugs (like fenfluramine) could have an effect on the epileptic activity" (see page 1137, right-hand column, first full paragraph). However, D2 concludes that "although it is known that fenfluramine increases synaptic serotonin concentration, which has potential anticonvulsive effects, it is unclear whether the serotonin effects explain our favorable results". In summary, it was far from established at the filing date whether the greater number of seizure-free patients with Dravet syndrome who were treated with fenfluramine as an add-on therapy resulted from increased serotonin levels.

24. Furthermore, and importantly, the skilled person could not derive from the experimental data in the patent or the application as filed whether fenfluramine was able to exert its beneficial effect alone, or whether it was only acting in support of valproate, i.e. potentiating the effect of this established anti-convulsant.

The teaching of the prior art

25. Since "proof of a claimed therapeutic effect" is not provided in the application as filed, the board also considered whether the teaching of the prior art provided the skilled person with any indication of a therapeutic effect of fenfluramine as a monotherapy for Dravet syndrome.

26. Most of the documents cited relate to combination treatments (see for example D4 and D6 to D8). It was undisputed that the only prior-art documents which relate to monotherapy with fenfluramine, D5 and D11, concern distantly related epileptic diseases. Document D5 refers to a single case in which fenfluramine was given - as a monotherapy - to treat self-induced apnoeic syncopes and true epileptic absence seizures. The patient "responded favorably to treatment with fenfluramine hydrochloride, as already reported in cases of compulsively self-induced syncopes" (see page 923, left-hand column). In document D11, a single patient with temporal lobe epilepsy was treated with fenfluramine monotherapy. The document also refers to experimental data in rats and mice as a possible mechanistic explanation for the effect of fenfluramine (see paragraph bridging pages 1139 and 1140 and references cited therein). However, the conclusion in document D11 of an "involvement of serotoninergic circuits in some forms of drug-resistant temporal lobe epilepsy" limits the teaching concerning fenfluramine to these particular conditions (page 1140, last paragraph).

27. In view of the established use of fenfluramine in combination with other anti-convulsive medicaments, and the very different nature and isolated cases of the two epileptic diseases for which monotherapy with fenfluramine was reported, the skilled person could not draw any conclusions as to the effectiveness of fenfluramine as a monotherapy for Dravet syndrome.

Decision T 1779/21 (parent case)

28. The facts of the present case differ from the case decided in T 1779/21. In particular, claim 1 in case T 1779/21 contained the features: "wherein the formulation is for oral administration" and "as the sole therapeutic agent" which are not present in claim 1 of the present patent. Thus, the principle of res judicata does not apply.

29. The respondents considered that legal and technical errors in decision T 1779/21 would prevent the application of similar reasoning to the present case. The first alleged legal error was that the board set a higher standard of proof than the established case law of the Boards of Appeal of the EPO by stating that "the level of proof required has to be at least such that the skilled person has reason to assume that the standard valproate treatment could be discontinued and replaced by fenfluramine without worsening the condition of the patient" (see decision T 1779/21, point 12 of the Reasons).

30. Decision G 2/21 states in point 77 of the Reasons, in respect of sufficiency of disclosure of second medical use claims, that "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 case dealt with in decision T 1779/21 relates to a situation where experimental data for the therapeutic effect of fenfluramine monotherapy of Dravet syndrome, i.e. the treatment in the claim, is absent from the application as filed. As set out in detail in that decision, it was also not credible from common general knowledge or the prior art that a therapeutic effect could be achieved (see decision T 1779/21, points 16 to 18 of the Reasons). Therefore, according to decision G 2/21, "proof of a claimed therapeutic effect has to be provided in the application as filed" and a "lack in this respect cannot be remedied by post-published evidence".

31. To express this requirement, decision T 1779/21 uses a formulation ("reason to assume ... without worsening the condition of the patient") which is adapted to the specific case in hand and thus does not introduce a different legal standard. To assess whether the skilled person had "reason to assume" does not require proof "beyond all reasonable doubt" or "absolute conviction" as alleged by the respondents, but rather the establishment of proof based on "the overall balance of probabilities" as can been seen from the detailed reasoning in decision T 1779/21 (see points 13. to 18. of the Reasons therein).

32. The respondents further alleged that a technical error had been made in decision T 1779/21 by referring to "standard valproate treatment" for Dravet syndrome and considering whether the skilled person would have replaced such treatment with fenfluramine monotherapy (see point 12 of the Reasons). The board does not agree because evidence on file in both the parent and the present case refers to this medicament as a first line treatment (see e.g. D2, D25, D27). The respondents' expert Dr Sullivan in document D25 states with regard to document D27 that valproate was "a typical treatment pathway taken by the majority of clinicians before the priority date of the patent. Here we can see that patients would be placed on valproate (VPA) monotherapy following the clinical symptoms of Dravet syndrome. In some cases, the first line therapy may be topiramate." It is self-evident that fenfluramine monotherapy requires any other treatment to be discontinued or that fenfluramine be started before any other treatment.

33. The respondents further alleged that the board incorrectly took the severity of the disease into account, which implied a higher standard. The board does not agree because what was assessed in decision T 1779/21 is whether it was credible that fenfluramine monotherapy could achieve a therapeutic effect in Dravet syndrome. Achieving a therapeutic effect means that the therapeutic treatment results at least in an amelioration of the patient's condition in some way. This is in particular the case if not treating the disease has irreversible consequences. If, however, it is not credible that fenfluramine monotherapy lowers the number of epileptic seizures (or other potentially catastrophic events, such as life threatening status epilepticus) in comparison to other established treatments, a relative worsening of the patient's condition has to be expected, since monotherapy means that no additional treatment is permitted.

34. The board therefore cannot recognise any legal or technical errors in decision T 1779/21.

Conclusion

35. From the technical teaching of the application as filed, even taking into account the prior art, it was not credible that fenfluramine achieved a therapeutic effect in Dravet syndrome patients when given as a monotherapy. In line with decision G 2/21, the board has not taken the post-published data (document D3) into account (see point 77 of the Reasons).

36. The claimed invention is not disclosed in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art. The ground of opposition under Article 100(b) EPC therefore prejudices maintenance of the patent.