T 2735/19 - Post published evidence for sufficiency

Key points

• Claim 1 is a second medical use claims, "1. A cancer therapeutic drug, which is a composition comprising[ the compound FTD]  and [another compound] in a molar ratio of 1:0.5, for use in the treatment of cancer in a human patient in need thereof by orally administering the drug at a dose, as a dose of FTD, of 20 to 80mg/m**(2)/day twice daily.""
• The filing date was in 2006. (!)
• D11 is D11|Summary of clinical data filed on 19 March 2018 |
• "5. Sufficiency of disclosure - claim 1 of the main request
• 5.1 The appellants questioned whether the skilled person could carry out the subject-matter of claim 1 without undue burden. They argued that the use defined in claim 1 could not credibly treat every type of cancer, let alone at any dose within the range defined in claim 1. The Board disagrees.  ... Example 2 and Figure 2 (Trials 3 and 4) of the English translation of the application as filed showed that the oral administration of TAS-102 at a total daily dose of 60 or 50mg/m**(2) FTD, provided in two daily doses, effectively treated more than 70% of breast cancer patients for whom standard therapy had not worked. In this context, effectively treating meant that at least tumour progression was stopped and the disease remained stable. 

• The Board agrees with the respondent that, due to the direct action of FTD on DNA, TAS-102 could be expected to have a general effect on tumours and not to be limited to a single cancer type. Therefore, the consideration of the post-published evidence in document D11 confirming this effect on additional tumour types was in line with the principles established in G 2/21 (Reasons 77 and 93), namely that the purported effect is encompassed by the technical teaching of the application as filed and that it is embodied by the same originally disclosed invention."

• "The Board therefore concludes that the appellants did not raise serious doubts that the skilled person could carry out the subject-matter of claim 1 without undue burden. Consequently, claim 1 of the main request fulfils the requirements of Article 83 EPC."

• On inventive step: "In summary, the skilled person wanting to improve the efficacy and safety of the therapeutic indication disclosed in D4 would turn to D6. This combination would lead them to provide TAS-102 in multiple doses as an obvious solution. In particular, the skilled person would administer TAS-102 thrice daily, which is the regimen found in D6 to be optimum. The skilled person would have expected that administration twice daily, which was neither disclosed nor explicitly suggested in D6, would not be as good as thrice daily. It is even less likely that they would have expected twice daily administration to exhibit a comparable level of anticancer efficacy while considerably reducing the level of side effects. Therefore, the solution to the objective technical problem proposed in claim 1 was not obvious from the combination of D4 with D6. It constituted the selection of an undisclosed embodiment which was unexpectedly advantageous."

EPO 

The link to the decision is provided after the jump, as well as (an extract of) the decision text.

https://www.epo.org/en/boards-of-appeal/decisions/t192735eu1

5. Sufficiency of disclosure - claim 1 of the main request

5.1 The appellants questioned whether the skilled person could carry out the subject-matter of claim 1 without undue burden. They argued that the use defined in claim 1 could not credibly treat every type of cancer, let alone at any dose within the range defined in claim 1. The Board disagrees.

5.2 As acknowledged in paragraphs [0004] and [0005] of the English translation of the application as filed, which correspond to paragraphs [0003] and [0004] of the patent, the combination of FTD with 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride in a molar ratio of 1:0.5 was known in the art as TAS-102. The mode of action of the two active compounds constituting the composition was also known. Through its incorporation into DNA, FTD inhibited DNA replication. This mechanism circumvented the sensitivity problems arising from fluorouracil-based antitumour agents, which act on RNA. The main limitation of FTD was its fast degradation by thymidine phosphorylase. This limitation could be overcome by adding the thymidine phosphorylase inhibitor 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl) uracil hydrochloride, which extended FTD half-life.

Example 2 and Figure 2 (Trials 3 and 4) of the English translation of the application as filed showed that the oral administration of TAS-102 at a total daily dose of 60 or 50mg/m**(2) FTD, provided in two daily doses, effectively treated more than 70% of breast cancer patients for whom standard therapy had not worked. In this context, effectively treating meant that at least tumour progression was stopped and the disease remained stable.

The Board agrees with the respondent that, due to the direct action of FTD on DNA, TAS-102 could be expected to have a general effect on tumours and not to be limited to a single cancer type. Therefore, the consideration of the post-published evidence in document D11 confirming this effect on additional tumour types was in line with the principles established in G 2/21 (Reasons 77 and 93), namely that the purported effect is encompassed by the technical teaching of the application as filed and that it is embodied by the same originally disclosed invention.

D11 demonstrates that TAS-102 is able to treat a broad range of cancer types in a significant proportion of patients. The appellants tried to cast doubt by focusing on particular embodiments in D11 in which the disease control rate was of 0%. However, the embodiments selected by the appellants appeared to involve a very low number of patients and could not be considered to be statistically relevant. In the Board's view, a correct analysis of the data in D11 has to be based on the benefit provided by the anticancer agent to a population of patients, not to individual patients or a small group of them. A better overview of the data in D11 is presented on page 42 of the respondent's reply to the appeals, in which the results of the clinical trials according to claim 1 were summarised in a table. The content of this table was not contested by the appellants and is reproduced here below.

FORMULA/TABLE/GRAPHIC

In the table, N is the number of patients treated. Considering that trials involving too low a number of patients cannot be taken into consideration because they are not statistically relevant, the table shows that the therapeutic use of claim 1 is suitable for treating a significant portion of patients having colorectal, gastric, oesophageal, pancreatic, breast and lung cancer. The existence of non-responders in these trials is not a reason to deny sufficiency of disclosure. It is common in the treatment of cancer that a substantial portion of patients do not respond to the treatment. The cases of lung, pancreatic and oesophageal cancers are well known to be particularly difficult to treat, so that even a low portion of patients responding to the treatment may be considered to constitute a significant technical contribution. This is even more the case for patients at an advanced stage of the disease or who had not responded to previous treatments, as was the case for the patients in D11.

Therefore, in view of the common general knowledge on the mode of action of the active ingredients of TAS-102 and the evidence in the application as filed and D11, it is credible that the therapeutic use of claim 1 is generally suitable for treating cancer. The fact that there is no available evidence on blood cancer does not raise serious doubts since the interference in DNA replication exerted by FTD can also be expected to work in blood tumours.

5.3 With regard to the dosage range, it is common practice in oncology to adjust the dose depending on the circumstances of each patient. This does not entail an undue burden (see also expert opinion D10, page 3, first paragraph).

The appellants considered that post-published document D7 raised serious doubts that a patient can be treated with a dose at the upper end of the range of claim 1. D7 reports the results of a phase I study on the safety of TAS-102 administered twice daily to patients with metastatic breast cancer. It states that the recommended dose is that causing a limiting toxicity in no more than one third of patients, which in this case was 50mg/m**(2)/day. As D7 states that the dose of 80mg/m**(2)/day caused toxicity in two thirds of patients, the appellants argued that this dose could not be used.

This argument is not correct. The fact that a dose of 80mg/m**(2)/day administered in two daily doses causes higher toxicity than the recommended dose does not exclude this dose. It could be used depending on the circumstances since the skilled person would be able to adjust the dose to each patient's needs. As one third of patients did not experience toxicity, at least that third of patients could potentially benefit from the higher dose.

5.4 Appellant 1 raised three additional sufficiency objections, namely that: (i) the parameter "20 to 80 mg/m**(2)/day twice a day" was ill-defined; (ii) the skilled person would not know how to distribute the total daily dose between two partial doses; (iii) the therapeutic effect of claim 1 was not credibly achieved because the claim was not limited to the dosage regime applied in Example 2 of the patent - according to D10, a washout period was necessary for reducing side-effects.

The Board does not agree with appellant 1 on any of these three points.

The objection of point (i) is not a sufficiency but a clarity objection. As claim 1 is identical to claim 1 as granted, a clarity objection cannot be raised in opposition or its subsequent appeal proceedings (G 3/14, Order). Furthermore, as explained in point 3 above, the parameter "20 to 80 mg/m**(2)/day twice a day" is clear to the skilled person, who would know how to apply it in the context of claim 1.

The objection of point (ii) is not convincing. The Board finds it is difficult to imagine that the skilled person would not know how to divide the total daily amount of TAS-102 for twice daily administration. Appellant 1 has not provided any evidence casting doubt in this respect.

With regard to objection (iii), the situation is similar to that of the adaptation of the dosage. The skilled person would be able to determine, depending on the nature and intensity of the adverse effects experienced by the patient, whether a washout period is needed and of which length. Contrary to the opinion of appellant 1, this view is in line with the teaching in Exhibit Q, point 1.2, of D10, which explains how to manage adverse effects by introducing a washout period between treatment courses. Appellant 1 has not explained why in light of Exhibit Q a washout period of two days would be unavoidable.

5.5 The Board therefore concludes that the appellants did not raise serious doubts that the skilled person could carry out the subject-matter of claim 1 without undue burden. Consequently, claim 1 of the main request fulfils the requirements of Article 83 EPC.

6. Novelty over D1 - claim 1 of the main request