In this case the Board spent quite some time on the definition of the problem solved and reminds us of some limits to re-formulation.
Object of the invention
[2.1] The present invention concerns the provision of a composition for administering a taxane to patients suffering from a proliferative disease, in particular malignant melanoma, wherein the toxicity of the taxane should be reduced […].
Closest prior art
[2.2.1] At the oral proceedings before the board, the [applicant] initially defined document D15, which discloses the use of DTIC for treating malignant melanoma, as closest prior art. In contrast thereto, the examining division started from document D3, which discloses the use of protein coated taxane particles such as CapxolR (protein coated paclitaxel), which are identical to the particles according to the present invention, for the treatment of diseases such as prostate cancer, orchidectomy, pancreatic cancer and brain tumour […].
[2.2.2] The board, however, notes that in the present case a document should be selected as closest prior art which discloses the use of a taxane for the treatment of malignant melanoma. As a consequence, document D5 constitutes the closest prior art.
Document D5 concerns a study in which 25 patients with metastatic melanoma who were previously untreated received Taxol, which contains paclitaxel as active agent […] at a starting dose of 250 mg/m² delivered as a continuous intravenous infusion over 24 hours, at 3-week intervals […]. In contrast to the protein coated taxane particles of the present invention, Taxol according to document D5 was a conventional formulation in which the active agent was stabilised by Cremaphore. As was correctly pointed out by the [applicant] […], the results did not live up to the high expectations of the physicians carrying out this study because of a response rate of below 20% despite a very favourable patient population […]. The authors of document D5 did, however, not conclude therefrom that treatment of such melanoma with Taxol should be discontinued. On the contrary: taking into account the “paucity of other drugs with similar or better activity against melanoma” […], it was recommended to use a Taxol dose of 200 mg/m² as a single agent for the treatment of patients with metastatic melanoma […]. This statement was followed by the conclusions that “Taxol is an interesting drug which, besides showing activity against melanoma, has also shown activity against refractory carcinoma of the ovary” and that “there is considerable potential for Taxol to be a drug with good future”. As a consequence, document D5 qualifies as closest prior art.
Problem to be solved
[2.3.1] When formulating the problem to be solved with regard to document D5, it has to be evaluated what further effects, if any, are achieved by the selection of protein coated taxane in addition to the reduced toxicity. One direct consequence of the reduced toxicity consists in the possibility to administer higher taxane doses. According to […] the application, the dose administered is “typically larger than doses administered as part of conventional formulation”. This teaching is confirmed by example 27 which concerns a phase I clinical study in which 17 patients suffering from metastatic malignant melanoma are treated with CapxolR. In this study the maximum single dose administered was 375 mg/m², which is much higher than the approved dose of 175 mg/m² for paclitaxel, when administered as Taxol […], and higher than the dose of 250 mg/m², administered in the study according to document D5. However, this aspect cannot be taken into consideration for the definition of the problem to be solved, as claim 1 of the main request does not define the concentration of the taxane to be administered to the patient. As a consequence, the problem to be solved would have to be defined as provision of a taxane composition for treating melanoma, which is characterised by less unwanted side effects.
[2.3.2] The [applicant], making reference to post-published document D11 alleged an increased drug efficacy as a further effect that had to be taken into consideration for the assessment of inventive step. In document D11 previously treated patients and CN patients were treated with 100 mg/m² and 150 mg/m² Abraxane (= protein coated paclitaxel corresponding to CapxolR), yielding an overall response of 38% for pretreated patients of 49% for CN patients. This was much higher than the response rates in document D5, which had been achieved with 250 mg/m² of Taxol. It could not be predicted that the same or even lower doses of taxanes would lead to such a significant increase in efficacy of the therapy, in particular with regard to the previously treated patients, who usually showed limited response. Similar results were shown in documents D9 and D10 for docetaxel as active agent. As a consequence, the problem to be solved with regard to document D5 concerned the provision of a less toxic and more efficient taxane composition for treating melanoma.
[2.3.3] In this context, the question arises whether this aspect is encompassed by the technical teaching of the original application, which in a primary aspect is concerned with methods for the in vivo delivery of substantially water insoluble pharmacologically active agents in general as well as the provision of dispersible colloidal systems containing water insoluble pharmacologically active agents […]. The treatment of melanoma is a marginal point of the broad and general teaching of the original application and is first mentioned on page 36, where the treatment of proliferative diseases such as psoriasis, multiple sclerosis, vascular restinosis […] or cancers such as malignant melanoma […] can be treated with suitable pharmacologically active agents including taxanes such as paclitaxel or docetaxel […]. It is important to note that this passage also contains the information that the protein coated particles of the present invention reduce myelosuppression and neurotoxicity […], so that the dose of suitable pharmacologically active agent administered to the patient is “typically larger than doses administered as part of conventional formulations” […], which means that this aspect of the original teaching, i.e. treatment of melanoma by administration of protein coated taxane, is linked to the administration of higher than the usual doses.
This teaching is put into practice in example 27, which is the only example relevant for the treatment of melanoma by administering protein coated taxane. The board notes in this context that examples 28 and 29, though also mentioning treatment of melanoma, are not relevant for the following reasons: example 28 primarily concerns intra-arterial administration of CapxolR for the treatment of liver tumours and/or solid tumours with local-regional involvement […]. Although the long list of patients suffering from various types of cancers includes patients suffering from melanoma […], these patients do not figure in the list of patients for which a response to the treatment had been observed […]. As a consequence, example 28 is not relevant for the subject-matter claimed in the main request. Example 29 is not relevant, as it relates to a combination therapy of CapxolR with IL-2.
Example 27 concerns a phase I clinical study in which 17 patients exhibiting advanced matastases were treated with CapxolR (containing the taxane paclitaxel). Six patients were suffering from malignant melanoma, the remaining 11 subjects from breast cancer. Starting from an initial dose level of 135 mg/m², the subsequent doses were increased to the next higher paclitaxel single dose level if there were no significant adverse effects in the subject. The maximum single dose administered in this study was 375 mg/m², for which no significant adverse effects were noted. Administration of paclitaxel as protein coated particle at single dose levels as high as from 500 mg/m² or 2000 mg/m² and beyond are contemplated in example 1.
[2.3.4] To summarise:
the teaching of the original application, which is put into practice in example 27, tells the skilled person to use as high as possible doses of protein coated taxane for the treatment of melanoma. These doses are higher than the doses used for the administration of taxane in conventional galenic forms.
[2.3.5] The board notes that redefinition of the problem to be solved is usually permissible, it is even necessary in cases in which prior art is found which is closer to the claimed invention than the prior art cited in the application as filed. Usually, it is also possible to base such a newly defined problem on post-published evidence provided that it is linked to and in line with the original technical teaching. Such a redefinition is, however, not acceptable in cases where the teaching of post-published evidence is used for defining a new technical problem which is in contradiction to the original teaching of the application as filed (T 155/85  and T 115/89 [4, 4th §]). This being the case in view of the fact that the original teaching does not foresee the use of conventional taxane doses for the treatment of melanoma, the problem to be solved concerns, as previously indicated, the provision of a taxane composition for treating melanoma, which is characterised by less unwanted side effects.
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