T 2506/12 - Described but novel medical use

Key points

• The Board holds that anticipation of a claim for a second medical use requires a disclosure that that the treatment of the indicated disease with the compound(s) at issue is both effective and safe.
• The two cited prior art documents mentioning a clinical trial of the now claimed medical use therefore did not anticipate the claims.
• Nevertheless, inventive step was denied over the same documents because " The upshot is that the combination of ET-743 and PLD as disclosed in D2 looked promising in terms of efficacy, and that the aspect of safety of the combination treatment had yet to be assessed. While the outcome of a clinical trial could be success or failure, no particular reason was known which would have discouraged the person skilled in the art from carrying out an experimental evaluation to confirm the usefulness of the combination treatment. Finding out in this straightforward manner that useful dosage combinations providing both efficacy and safety indeed existed cannot be regarded as an invention." 

EPO T 2506/12 - link

2. Novelty - main request

2.1 Independent claims 1 and 2 of the main request concern the further therapeutic application of ET-743 (claim 1) or of PLD (claim 2) in the treatment of cancer of the human body by combination therapy employing an effective therapeutic amount of ET-743 with an effective therapeutic amount of PLD.

2.2 Both claims are in "Swiss-type" format, i.e. directed to the use of a substance for the manufacture of a medicament for a specified therapeutic application.

The novelty of the subject-matter of such a claim can be derived not only from the novelty of the substance or of the method of manufacture, but also from the novelty of the therapeutic application, which is regarded as a functional technical feature, as established by decision G 5/83 of the Enlarged Board of Appeal (OJ EPO 1985, 64, order: point 2, reasons: point 21; also see Case Law of the Boards of Appeal of the European Patent Office, 8th edition 2016, I.C.7.2.1).

This special concept of a purpose-limited process claim also applies in the present case, since the patent in suit was granted before the publication of decision G 2/08 of the Enlarged Board of Appeal, which abolished the Swiss-type format but had no retroactive effect (see G 2/08, OJ EPO 2010, 456, order: question 3, reasons: point 7.1.4).

2.3 Since both substances intended for the combination therapy were already known, and claims 1 and 2 of the main request do not define any specific manufacturing step, it follows that novelty may only be derived from the therapeutic application

"for an effective treatment for cancer of the human body by combination therapy employing an effective therapeutic amount of PLD with an effective therapeutic amount of ET-743",

as per the wording of claim 2, and analogous wording in claim 1.

This was not contested among the parties.

For the purpose of assessing novelty, it thus has to be examined whether the claim features which define the therapeutic application are anticipated in documents D1 or D2, and in particular whether it is directly and unambiguously derivable from at least one of those documents that a therapeutic effect, or clinical benefit, in the treatment of cancer is obtained in humans by administration of the combination therapy.

2.4 Documents D1 and D2 disclose that Yondelis (ET-743) had shown efficacy in the treatment of soft-tissue sarcoma and that its efficacy as sole agent in further types of cancer was being evaluated in twenty phase II studies (see D1: page 9, columns 3 and 4; D2a: slide 12, slide 19).

Both documents disclose that Yondelis monotherapy showed efficacy in advanced ovarian cancer in a phase II trial with data obtained from 55 patients (see D1: page 9, column 4; D2a: slides 12 and 21).

Both documents also disclose that the combination of Yondelis (ET-743) and Doxil (PLD) was being tested in a clinical phase I trial for the treatment of cancer (see D1: page 9, column 3; D2a: slide 17).

Document D2 further specifies that the medical indication targeted in that combination trial was ovarian cancer (see D2a: page 8, slide 17).

2.5 Since clinical phase I trials of anti-cancer medication are carried out on human cancer patients, it can be affirmed that the purpose of treating cancer of the human body is indeed disclosed in documents D1 and D2. Both documents also disclose that the study was designed to test ET-743 and PLD in combination (see point 2.4 above).

Hence it is decisive for the question of novelty to establish whether an effective treatment with effective amounts of each drug is disclosed in D1 and/or D2.

2.6 As neither document mentions further details or results of the phase I combination trial, no explicit disclosure of these elements can be found. It must therefore be examined whether there is an implicit disclosure, meaning that the person skilled in the art, in the light of common general knowledge, when reading the respective document at its publication date would have understood an effective treatment (i.e. the achievement of the desired clinical benefit), with effective amounts of each drug, to be part of its information content.

These considerations are in keeping with decision T 1859/08 cited by the patent proprietors, according to which a mere statement that a combination therapy is "currently being explored", or that a medicament is being evaluated in clinical studies, does not amount to a disclosure of the achievement of a clinical benefit in human patients. It is also not decisive whether the clinical benefit, or therapeutic effect, is inherent in the prior-art disclosure. The relevant criterion is whether it is accessible, i.e. disclosed, rather than "hidden" (see T 1859/08, reasons: points 13, 14).

2.7 With regard to this issue, the opponent took the position that, since both ET-743 and PLD were already known to have efficacy in the relevant therapeutic application, it would have been directly and unequivocally implicit to the reader of documents D1 and D2 that the combination treatment, too, must have the desired efficacy. The patent proprietors argued that it had not, however, previously been known that ET-743 used alone provided efficacy combined with acceptable safety; nor was it disclosed in documents D1 and D2 that the combination treatment provided efficacy combined with acceptable safety.

2.8 It is self-evident that, for a treatment to be effective, it must show efficacy in treating the targeted disease. The board agrees, however, with the patent proprietors' argument that an effective medical treatment has to meet not only the criterion of efficacy but also that of acceptable safety. A treatment which caused unacceptable harm to patients would not be considered an effective treatment within the usual meaning of the term.

Thus the aspects of both efficacy and safety have to be taken into account to determine whether an effective treatment is (implicitly) disclosed in the prior-art citations.

The board considers moreover that this concept of effective treatment would also apply if the claims only referred to a treatment without explicitly mentioning the word "effective".

2.9 It was not disputed by the patent proprietors that, at the time of the publication of documents D1 and D2, PLD in the form of Doxil was an approved drug authorised for the treatment of cancer, including ovarian cancer (see also document D16a, page 2420, "indications and usage"). Thus it was part of the common general knowledge of the person skilled in the art that PLD as a single agent provided efficacy, and also acceptable safety, in the treatment of cancer, in particular ovarian cancer.

2.10 As far as ET-743 is concerned, both document D1 and document D2 report favourable preliminary results of clinical phase II studies obtained with Yondelis in the treatment of advanced ovarian cancer in 55 human patients, with a global response rate of 26% (D2) or 28% (D1) in patients resistant to platins-taxanes and a response rate of 54% in refractory patients. While toxicity is not discussed in that context, it is not mentioned either that any safety concerns precluding such treatment were identified.

2.11 Since PLD and ET-743 were both known to be effective as monotherapy anti-cancer agents, in particular in the treatment of ovarian cancer, the person skilled in the art would have inferred from the disclosure of document D2 (where it is mentioned that the combination study targeted ovarian cancer) that a combination treatment carried out as a phase I trial with Yondelis (ET-743) and Doxil (PLD) would provide clinical efficacy in the treatment of ovarian cancer. The possibility that each drug might cancel out the other's pharmacological activity is remote and would not have been considered a realistic outcome without actual experimental evidence. Thus, assuming it can be inferred from the wording of document D2 that the combination treatment was carried out (see however point 2.14 below), there is some merit in the opponent's argument that the therapeutic efficacy of the claimed combination in the treatment of ovarian cancer was implicitly disclosed at least in document D2.

2.12 However, nothing was known or disclosed about the safety of the combination therapy. Phase I studies are normally carried out precisely for the purpose of identifying side effects and safe dosage ranges, and documents D1 and D2 do not mention any experimental results in that regard. Based on the available information, the person skilled in the art reading document D1 or D2 would thus not have been able to exclude the possibility that ET-743 and PLD might interact to produce unacceptable adverse effects, and in combination might reach dose-limiting toxicity before reaching the threshold of pharmacological efficacy.

2.13 Taking into account the criteria established in point 2.8 above, it cannot therefore be confirmed that documents D1 or D2 implicitly disclose an effective treatment by combination therapy (irrespective of the question whether these documents disclose effective therapeutic amounts of each drug).

2.14 An additional point concerns the actual wording used in documents D1 and D2 with regard to the combination trial. The relevant text passages read as follows:

D1: "There are ten additional Phase I trials in combination with other chemotherapy agents (...)"

D2: "abiertos 10 estudios de fase I en combinación con otros agentos", translated as: "10 Phase I studies in progress in combination with other substances" (D2a).

Since a clinical trial also involves a preliminary set-up stage required for organisational matters, it can, arguably, not be inferred with absolute certainty that the combination treatment of human patients had already been carried out at the time of writing or publication of documents D1 and D2.

2.15 For these reasons, the board finds that the therapeutic application as defined in claims 1 and 2 of the main request is not disclosed in documents D1 and D2, and that therefore the subject-matter of these claims is novel having regard to the disclosure of documents D1 and D2 (Articles 100(a), 52(1) and 54(1) and (2) EPC).