T 0009/81 (Cytostatic Combination) of 25.1.1983

Summary of Facts and Submissions

I. Patent application number 78 101 583.9, filed on 6 December 1978, published on 21 June 1979 under publication number 0 002 495 and claiming priority of 14 December 1977 and 23 June 1978 from previous applications filed in the Federal Republic of Germany, was refused by decision of the Examining Division of the European Patent Office dated 29 October 1980. The patentability of the subject-matter of claims 6 to 10 was acknowledged in the decision, but claims 1 to 5 directed to uses of substances in cytostatic therapy were considered not patentable. Claims 1 and 6 are worded as follows:

"1. Use of pharmacologically acceptable salts of a mercapto- alkane-sulphonic acid with the general formula HS-alk-SO3H, where alk is a straight-chain or branched alkyl residue with 2 to 6 carbon atoms, in cytostatic therapy with alkylation agents.

6. Pharmaceutical products containing a pharmacologically acceptable salt of a mercapto-alkane-sulphonic acid with the general formula where alk is a straight-chain or branched alkyl residue with 2 to 6 carbon atoms, and an alkylating cytostatic agent.

II. The applicant lodged an appeal against this decision on 19 December 1980 with payment of the relevant fee and set out the grounds of appeal on 26 February 1981. In a letter dated 10 December 1982 the protection applied for was restricted to products for preventing the detrimental effects of oxazyphosphorin metabolites, which contain 2-mercapto-ethane-sulphonic acid either as sole active ingredient (claims 1 and 2) or together with an oxazaphosphorin cytostatic agent (claims 3 to 6). In the course of the oral proceedings on 25 January 1983 three claims were submitted with the following wording:

"1. Products containing an oxazaphosphorin cytostatic agent and the sodium salt of 2-mercapto-ethane-sulphonic acid as a combined preparation for simultaneous, separate or sequential use in cytostatic therapy.

2. Product as in claim 1, characterised in that it contains as the oxazaphosphorin cytostatic agent 2 - /N,N - bis -2 ( chloro - ethyl) - animo/ - 3 - (2 - chloro - ethyl) - 2 - oxo - 1,3,2 - oxazaphosphorinane (Trophosphamide), 2 -/N - (2 - chloroethyl) - amino/ - 3 - (2 - chloro - ethyl) - 2 - oxo - 1,3,2 - oxazaphosphorinane (Iphosphamide), 2 - /N,N - bis - (2 - chloro - ethyl) - amino/ - 2 - oxo - 1,3,2, - oxazaphosphorinane (Cyclophosphamide) or 2 - (2 - mesyl - oxy - ethyl - amino) - 3 - (2 - chloro - ethyl - 2 - oxo - 1,3,2 - oxazaphosphorinane (Suphosphamide).

3. Product as in claim 1, characterised in that they contain the sodium salt of 2-mercapto-ethane-sulphonic acid and the oxazaphosphorin cytostatic agent in a weight ratio of at least 0.2:1." The appellant has requested that the refusal be set aside and that a patent be granted on the basis of these three claims.

III. The grounds for appeal were finally set out as follows:

The invention in question is of great importance for chemotherapy with oxazaphosphorin cytostatic agents, used frequently in the treatment of cancer. Treatment of patients with such cytostatic agents leads to severe damage to the kidney, urinary passages and bladder, so that as a rule the therapy has to be interrupted or completely terminated. The invention is based on the finding that this damage does not occur when sodium 2-mercapto-ethane-sulphonate is also administered. The detoxicating function of this salt on the oxazaphosphoring metabolites can be observed, for example, when both components, are administrated simultaneously, but it is also beneficial to use these components separately or at intervals. The claimed product may therefore also contain the kit of the two active ingredients in ampoules for the intravenous injection. In view of this comprehensive, new and indisputably inventive teaching, adequate protection must be claimed for all these variants, at least in the form of product protection.

Reasons for the Decision

1. The appeal complies with Articles 106 to 108 and Rule 64 EPC and is therefore admissible.

2. In the present case, there are no procedural objections (Rule 86(3) in conjunction with Rule 66(1) EPC) to the acceptance of the claims submitted only in the oral proceedings on 25 January 1983, because they correspond to the category of claims on which, in the light of the statement in the letter dated 10 December 1982 (page 1), the Board exclusively had to base its preparations for the oral proceedings.

3. The presently effective version of the claims cannot be objected to from a formal point of view, because it is based on the originally filed description (cf. in particular claim 6: page 5, lines 19 to 29; page 1, lines 1 to 5; page 6, line 1 and claims 9 and 10). In addition the claims have been drawn up in the form stipulated in Article 54(5) EPC.

4. The present claim refers to a combined preparation containing an oxazaphosphorin cytostatic agent and the sodium salt of 2-mercapto-ethane-sulphonic acid as therapeutic active ingredients. The first-mentioned component of the product is known (cf. page 1 of the present application), and the second is a known mucolytic agent according to DE-A-1 620 629. Cytostatic agents are normally applied intravenously; sodium 2-mercapto-ethane-sulphonate is preferably applied in the form of an aerosol directly to the mucous membrane, but may also be administered orally and parenterally. The two active ingredients however have, according to the documentary prior art available to the Board, never been used together for a new joint effect and were unknown as a composition. The active ingredients which are administered preferably at the same time (cf. page 5, lines 14 and 15 of the application) according to the invention do not therefore represent a mere aggregate of known agents, but a new combination with the surprising, valuable property that the severe side-effects to be expected when administering the cytostatic agents are absent as a result of the detoxicating effect of the sodium 2-mercapto-ethane-sulphonate.

5. The combination of the two components has therefore already been justly acknowledged as inventive by the Examining Division (original claims 6 to 10). This combination would have been accorded absolute product protection, at least for all applications in the therapeutic field, because of the unlimited claim to the pharmaceutical preparation. However, such a preparation would have had to be envisaged as a narrow physical combination of the components, i.e. a union of mixture, to differentiate the product from a state of the art which includes the possibility of a medical kit, collection or package containing the two agents in separate but adjacent form for their known independent applications in medicine.

6. The present claim 1 however refers to a product which is limited to simultaneous, separate or sequential use in cytostatic therapy. It follows from this indication of purpose that the components are no longer necessarily present as a union e.g. in composition, since the components would not otherwise be available for separate or sequential application. This kind of side-by-side presentation of known drugs may nevertheless be susceptible of industrial application under Article 52(4) (second sentence) as a product for therapeutic use. As a kit-of-parts, however, it is not necessarily a true combination in view of the physical separation of the individual components. The mere loose association of known components does not in itself turn them into a functional unity in which a necessary and direct interaction between the components is a precondition for the purposive use (cf. e.g. lock and key, match and striking surface, two-component adhesive). Although the components in the claimed combination do not enter into such a direct interaction with each other, the indication of purpose for the combined therapy may re-establish the unity of the product as a functional amalgamation of its two components, if it represents a genuine restriction to the specified application.

7. An indication of purpose in claims is generally regarded as technically meaningful if the skilled person is thereby made aware of further, not expressly specified or yet to be specified characteristics of the product, or of additional conditions for a process, which are necessary for the intended use or operability (e.g. a particular selection, quality or inter-relation of the various components). Without such physical relevance the indication of purpose can remain completely meaningless and unrestrictive. By contrast, indications for therapeutic use under Article 54(5) EPC are necessarily significant and may under certain conditions even provide grounds for the novelty of a known product, without requiring any additional identifiable or verifiable physical characteristics. Such conditions must however restrict the subject-matter appropriately, so that already known applications of the subject-matter are excluded from the claim. Since the individual components of the combined product in the present claims have themselves known therapeutic applications, these claims, by expressly including the separate presentation of those components, are indeed to be regarded as limited to the joint use of the combined products, so that the individual applications according to the state of the art are excluded. The indication of purpose provided for in Article 54(5) EPC for such products serves this objective, so long as its formulation complies with the requirements of that Article.

8. Article 54(5) EPC refers to cases in which substances or compositions already belong to the state of the art. This permits particular types of known products to be claimed; however, the Board also takes the view that such claims in accordance with Article 54(5) EPC cannot be denied the applicant even if the product as such is new, as in this case to some extend (cf. mixtures), since this category of claims can serve as a fall-back position and protects, for example, against the consequences of incidental previous publications of the product in a non-medical field.

9. Article 54(5) EPC in the German version refers to "Stoffgemische" whereas the English and French texts choose the wider term "composition". According to the Oxford English Dictionary (Vol. III, page 736) "composition" is characterised as a product as follows: "A condition consisting in a combination or union of several things; a combination, aggregate or mixture". According to Le Robert, Dictionnaire Alphabétique et Analogique de la Langue Française (1980, pages 862 and 830) "composition" may also have the meaning of "combinaison" - especially in chemistry - or in general terms "assemblage". Since each of the three texts is equally authentic (Article 117(1) EPC) and under this regulation only one will on the part of the Contracting States can be expressed, the Board takes the view that this will is most clearly formulated by the two texts referred to. The Board also takes the view that combined products intented under Article 54(5) EPC for therapeutic, surgical or diagnostic methods also include compositions in which the components are presented side by side and can therefore be applied simultaneously, separately or at intervals to one and the same human or animal body. Insofar as the components cannot attain the advantageous effect according to the invention independently of each other, the joint effect justifies the unity of the combined product as a result of the limitation by the indication of purpose of the area of protection of the claim under the conditions laid down in Article 54(5) EPC, even if the components are presented side-by-side and not as a union. In the present case the subject-matter of claim 1 fulfils these conditions.

10. Protection for the combined product as a collection of essential components with a corresponding indication and with reference to joint use is, moreover, in the therapeutic field also exceptionally justified by the fact that certain active substances do not necessarily bring about their joint effect at the same time or directly. When administering orally, for example, one component may be absorbed in the stomach, whereas another merely passes into the intestine. The kit-of-parts of the essential components of the combination does not therefore need to appear in molecular or microscopic dimensions according to the inventive teaching. It would not be justified if such advantageous forms of solving the problem were not included in the protection. Modern medicine may move further and further in the direction of combined therapies which require special products with flexible methods of administering.

ORDER

For these reasons, it is decided that:

1. The decision of the Examining Division of the European Patent Office dated 29 October 1980 is set aside.

2. The case is remitted to the first instance with the order to grant a European patent on the basis of the description and claims filed on 25 January 1983.