This is an appeal against a refusal of an application by the Examining Division (ED), for lack of clarity and lack of novelty.
Independent claims 1 and 10 under consideration read:
1. Use of an anti-ErbB2 antibody in the preparation of a medicament for treatment to provide clinical benefit as measured by increased time to disease progression of malignant breast cancer characterised by overexpression of ErbB2 in a human patient, wherein said antibody binds to epitope 4D5 within the ErbB2 extracellular domain sequence as determined by a cross-blocking assay using said antibody and antibody 4D5 obtainable from deposit ATCC CRL 10463, and wherein the medicament is for combined administration of the antibody with a chemotherapeutic agent other than an anthracycline derivative and not in combination with an anthracycline derivative, wherein said chemotherapeutic agent is a taxoid, wherein the combined administration has clinical efficacy as measured by determining time to disease progression and reduced myocardial dysfunction compared with combined administration of the antibody and anthracycline derivatives.10. An anti-ErbB2 antibody for use in a method of treatment to provide clinical benefit as measured by increased time to disease progression of malignant breast cancer characterised by overexpression of ErbB2 in a human patient, wherein said antibody binds to epitope 4D5 within the ErbB2 extracellular domain sequence as determined by a cross-blocking assay using said antibody and antibody 4D5 obtainable from deposit ATCC CRL 10463, and wherein the method comprises combined administration of the antibody with a chemotherapeutic agent other than an anthracycline derivative and not in combination with an anthracycline derivative, wherein said chemotherapeutic agent is a taxoid, wherein the combined administration has clinical efficacy as measured by determining time to disease progression and reduced myocardial dysfunction compared with combined administration of the antibody and anthracycline derivatives.
The Board found the claims to be clear and then examined their novelty:
[6] [… I]ndependent claims 1 and 10 are in the form of medical use claims (“Swiss type” form or A 54(5) EPC 2000-type, respectively), where the novelty is derived from the intended medical use (see the “Case Law of the Boards of Appeal”, 6th edition 2010, Chapter I.C.5.2.4). As a consequence, all the technical features of the therapeutic indication specified in the claims must be taken into account when considering whether or not the claimed subject-matter is novel.
[7] In short, the intended medical use is the provision of a clinical benefit as measured by increased time to disease progression of malignant breast cancer characterised by overexpression of ErbB2 in a human patient, and wherein the method comprises combined administration of an anti-ErbB2 antibody with a taxoid to a human patient.
For the purpose of assessing novelty, it thus has to be examined whether or not the same therapeutic effect is directly and unambiguously derivable from a prior art document, upon using the same combination therapy in a human patient.
[8] It should be noted that the language “wherein said chemotherapeutic agent is a taxoid” in independent claims 1 and 10 […] requires that the chemotherapeutic agent to be used together with the antibody must be a taxoid. This requirement of necessity excludes the possibility that the chemotherapeutic agent be an anthracycline. By implication, any (deleterious or otherwise) side effect linked to anthracyclines is also excluded by the claim language.
In view of this, the further features in independent claims 1 and 10 represented by the wording “a chemotherapeutic agent other than an anthracycline derivative and not in combination with an anthracycline derivative … wherein the combined administration has clinical efficacy as measured by determining … reduced myocardial dysfunction compared with combined administration of the antibody and anthracycline derivatives” may be overlooked by the board for the purpose of assessing the novelty. The ED came to the same conclusion, albeit for other reasons […].
Moreover, anthracyclines have been known to be cardiotoxic since the sixties of the last century. Thus, the feature “...reduced myocardial dysfunction compared with combined administration of the antibody and anthracycline derivatives” is an implicit “non-hidden” feature.
[9] The ED held that the claimed subject- matter lacked novelty over document D1 because this document disclosed […] the treatment of cancer, particularly metastatic breast cancer, with the recombinant humanised monoclonal antibody (rhuMoAb) Her2 and the taxoid paclitaxel. Monoclonal antibody rhuMoAb Her2 exhibits the same capacity as murine monoclonal antibody 4D5 of targeting epitope 4D5 within the ErbB2 extracellular domain sequence […].
[10] [… D]ocument D1 describes investigations of the effects of antibody rhuMoAb Her2 combined with chemotherapy with the taxoid paclitaxel or with the anthracycline doxorubicin in monolayer culture soft agar (in vitro) or in xenografts of human breast cancer transplanted into nude mice (in vivo). No results are reported for the in vitro experiment. As regards the in vivo experiment, it is reported […] that the antitumor activity was markedly better than an equipotent dose of doxorubicin and antibody 4D5, and that disappearance of well-established xenografts took place.
[11] However, both studies did not involve humans, whereas the claims before the board are directed to the treatment of breast cancer in a human patient. Therefore, this passage of document D1 is not novelty-destroying for the claimed subject-matter.
[12] [… In] document D1, it is stated that a combination therapy based on an anti-ErbB2 antibody (anti-“p185HER2”)and the taxoid placlitaxel is “currently being explored”.
[13] However, a mere statement that a combination therapy is being explored does not amount to a novelty-destroying disclosure of what is claimed in claim 1, because claim 1 is a medical use claim which includes, as a technical feature of the claim, the achievement of a clinical benefit in breast cancer patients as measured by an increased time to disease progression.
The present “currently being explored” situation, where no clinical benefit is disclosed, falls within the rationale of decisions T 158/96 and T 715/03. According to these decisions, if a prior art document discloses clinical investigations such as phase I, II or III studies (or states that these investigations are ongoing), but the document fails to disclose the final result of these studies, this document is not novelty-destroying.
[14] The ED argued that by applying the combined therapy of document D1, one would inherently come to the claimed effect, which could not render a known therapy novel.
However, decision G 2/88 [10.1] states:
“Under A 54(2) EPC the question to be decided is what has been “made available” to the public: the question is not what may have been “inherent” in what was made available”.
Therefore, while it may be true that the claimed effect is inherent once applying the claimed therapy, the decisive question to be answered by the board remains whether or not this effect was a “hidden” one or was accessible to the skilled person before the priority date of the patent in suit.
[15] A further passage of document D1 relied upon by the ED for denying novelty […] refers to an earlier phase II clinical trial and describes a planned phase III clinical trial:
“Results from the phase II studies and the activity of rhuMoAb HER2 against xenografts when given in combination with doxorubicin and paclitaxel have been encouraging. These positive results have led to the design of a phase III multinational study of chemotherapy in combination with rhuMoAb HER2 in patients with HER2-overexpressmg breast tumors who have not received prior chemotherapy for metastatic disease (Figure 2).”
[16] In paragraph 1.2.b2 of the decision under appeal, the ED considered that the expression “Results from the phase II studies” […] did in fact relate to the claimed combination therapy (rhuMoAB Her2 combined with paclitaxel) administered to human patients. It also argued that the results of this study were encouraging to the extent that they led to the start of a phase III multinational investigation prior to the priority date of the present application.
Therefore, because it was disclosed in document D1 that these phase II studies had a positive outcome, i.e., a pharmacological effect was achieved, the first instance denied that the rationale of decisions T 158/96 and T 715/03 […] applied to both the phase II clinical and the planned phase III clinical trial referred to in the passage of document D1 cited in point [15] supra.
[17] The assumption by the first instance that the phase II trials had used the claimed combination has been a key factor in its finding of lack of novelty. The board will thus deal with elucidating the nature of these “encouraging” phase II studies referred to in the first sentence of the paragraph highlighted in point 15 supra.
[18] Document D1 describes a phase II trial with rhuMoAb HER2 […]. This study does not use any combination chemotherapy, as only the antibody is referred to.
A second, different, phase II trial is described […]. This study relates to the anti-ErbB2 antibody taken in combination with cisplatin in human patients. However, cisplatin is not a taxoid.
[19] There are two references to the phase II trials cited in document D1 […]. Upon consulting documents J and K, it becomes clear that the former relates to the rhuMoAb HER2 phase II clinical trial where the antibody is used as a single agent, whereas the latter document describes a phase II clinical trial wherein the only agents used were rhuMoAb HER2 and cisplatin (not a taxoid).
[20] In view of this, the board must agree with the appellant’s view that none of the phase II trial described in document D1 uses an anti-ErbB2 antibody in combination with a taxoid, as required by present claims 1 and 10. Thus, the wording “encouraging” could not relate to this combination. In any case, it cannot be derived from document D1 that the encouraging results translated into a clinical benefit as measured by increased time to disease progression.
[21] As for the planned or ongoing phase III clinical trial, it cannot be directly and unambiguously derived from these trials […] that a therapeutic effect is obtained, let alone one translating into an increased time to disease progression.
Moreover, since document D1 fails to disclose any encouraging phase II trial using an anti-ErbB2 antibody in combination with a taxoid, the rationale of decisions T 158/96 and T 715/03 […] applies also to the planned phase III clinical trial referred to in the passage of document D1 cited in point [15] supra, which is not novelty-destroying for claims 1 and 10.
[22] In conclusion, document D1 is not novelty-destroying for the subject-matter of claims 1 and 10 and dependent claims 2 to 9 and 11 to 14.
[23] Turning to the remaining documents before the board, both documents D2 and D3 deal with a rodent xenograft model wherein the antibody MoAb 4D5 (against the HER2 receptor) is used in combination with paclitaxel or doxorubicin chemotherapy. There is no description in these documents of the treatment of a human patient, nor any disclosure of a biological effect translating into an increased time to disease progression.
[24] Therefore, the claims of the main request satisfy the requirements of A 54.
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