T 0007/86 (Xanthines) 16-09-1987
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Novelty of a specific compound from a generic formula
First medical use
Inventive step - Choice from numerous possibilities
Summary of Facts and Submissions
I. European patent No. 11 609 incorporating 4 claims was granted to the Respondent on 13 April 1983 on the basis of European patent application No. 79 850 091.4, filed on 28 September 1979 and claiming a priority of 21 October 1978 (SE 7 810 946).
II. The Appellant filed opposition to the grant on 9 January 1984 on the basis of new documents, and requested that the patent be revoked in its entirety on grounds of lack of novelty and inventive step.
III. By its interlocutory decision of 21 October 1985 the Opposition Division maintained the patent in an amended form, incorporating 2 claims.
The independent Claims 1 and 2 read as follows: ;p. "1.A pharmaceutical preparation for use in the treatment of chronic obstructive airway disease or cardiac disease comprising as active ingredient an effective amount of a compound of the formula
Formula
or a therapeutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier
Formula
or a therapeutically acceptable salt thereof, for use in the treatment of chronic obstructive airway disease or cardiac disease."
IV. The decision to maintain the patent as amended was based on the finding that the subject-matter of both claims is novel with respect to the cited documents. In particular, 3-propylxanthine is disclosed in Bull. Chem. Soc. Jap., 1973, Vol. 46, pages 506-509, (a document cited in the patent) but no pharmalogical data or use is given therefor.
It was further considered that an inventive step is present over the closest prior art, represented by documents (12) and (13) (see the list in paragraph VII below), in which 3-methylxanthine is disclosed, in particular because 3-propylxanthine (enprofylline) has considerably fewer side effects than 1,3-dimethylxanthine (theophylline).
V. A Notice of Appeal was filed by the Appellant against this decision on 17 December 1985, and the appeal fee was paid. A Statement of Grounds of Appeal was filed on 15 February 1986.
The submissions of the Appellant run essentially as follows:
The subject-matter of the patent-in-suit is obvious because the skilled man would expect enprofylline qualitatively to possess the same activity as that known for 3-methylxanthine: enprofylline was therefore an obvious candidate to test. Furthermore: (i) it is not clearly apparent that 3-methylxanthine has similar side-effects to theophylline; and (ii) it is questioned whether enprofylline has fewer side- effects than theophylline, rather it is suggested that the two compounds possess different patterns of side effects. Furthermore, the subject-matter of the patent-in-suit is not novel, because document (20) discloses the diuretic use of enprofylline.
VI. The Respondent filed a response to the Appellant's Statement in which he argued that the problem underlying the invention is not only to make available a compound having favourable bronchodilator and cardiac potency in comparison with theophylline, but a compound which has a combination of these favourable activities without the unfavourable side-effects of theophylline. He submitted that the choice of enprofylline for solving this problem was not obvious since the nearest structurally related compound, i.e. 3-butylxanthine was known to be a strong diuretic (see document (9), page 4, Table I and page 6, Table II).
Reasons for the Decision
3.In the view of the Board, the closest prior art is represented by document (12). This document discloses that 1,3-dimethylxanthine (theophylline) and its metabolite 3- methylxanthine are known to have bronchodilator activity and that the former is widely used in the treatment of obstructive airway disease (see page 534, last paragraph). Document (12) further discloses that theophylline is more potent than 3-methylxanthine (see page 531, Table 1; page 533, second paragraph and page 535). In the light of this document, and in view of the fact that 3-methylxanthine has not actually been proposed as a medicine in the therapy of chronic obstructive airway disease, it appears not to be sensible to use this compound as the starting point for an attack on the ground of obviousness, as is suggested by the Appellant. This view is also independently supported by the authors of document (18) who used theophylline as a standard for comparing the pharmacological activity of enprofylline. However, this document does teach that theophylline causes certain serious side-effects, particularly seizures or convulsions which may lead to death (see the description, page 2, line 11) and CNS-stimulating activity resulting in restlessness and tremor, which must be considered as a drawback in the therapy of chronic obstructive airway disease.
4.The technical problem underlying the invention with respect to document (12) is, therefore, making available a pharmaceutical preparation for use in the treatment of chronic obstructive airway disease, which is at least as effective as theophylline but does not cause the above adverse side-effects. In order to solve this technical problem the Patentees propose 3-propylxanthine (enprofylline) for use in the treatment of chronic obstructive airway disease or cardiac disease.
4.1 The Board is satisfied that this technical problem has been solved. Documents (7), page 337, last three lines; (8), Abstract; and, (17), page 400, right hand column, lines 24-28, all published after the application date, prove that enprofylline is four to five times more potent as a bronchodilator than theophylline. Other subsequently published documents as set out below contain evidence that enprofylline not only lacks the above-mentioned serious disadvantages but additionally has considerably fewer side-effects, e.g. diuretic and gastric secretory action, tremorgenic effect.
5.Examination of the cited prepublished documents has revealed that this technical teaching is not disclosed there. Consequently, the subject-matter of Claim 1 of the patent-in-suit is novel having regard to the prior art.
5.1 The Appellant alleged that document (20) describes the use of inter alia 3-propylxanthine as a diuretic, and suggested that this was a prior disclosure of the use of 3-propylxanthine for a method of treatment of the human or animal body by therapy, such as to deprive Claims 1 and 2 of novelty having regard to Article 54(5) EPC. Document (20) was not relied on before the Opposition Division, but will be considered by the Board under Article 114(1) EPC. The relevant part of the disclosure of document (20) is as follows: "Xanthines I (R = Me, Et, Pr, Bu, lower alkyl, R1 = H, lower alkyl), which are useful diuretics, were prepared by ...". Document (20) in fact discloses di-substituted xanthines wherein the substituents have to be chosen from two different lists. These lists comprise H and lower alkyl for position 8 and Me, Et, Pr, Bu and lower alkyl for position 3. In its decision T 12/81 (Diastereomers, OJ EPO 1982, 296) the Board stated by way of obiter dictum that if two classes of starting substances are required to prepare a product and examples of individual entities in each class are given in two lists of some length, then a substance resulting from the reaction of a specific pair from the two lists can nevertheless be regarded as new (see in particular, paragraph 13). In the Board's view, this principle is clearly applicable not only for starting substances in chemical reactions but also for polysubstituted chemical substances where the individual substituents have to be selected from two or more lists of some length, such as in the present case. Therefore, on this basis, document (20) cannot be interpreted either as a specific disclosure of 3-propylxanthine or consequently of a pharmacological use (as a diuretic) of this compound. Thus, in the Board's judgement, document (20) cannot be regarded as being detrimental to the novelty of the subject-matter of the claims. In the application of this principle in a previous case, the Board has refused to regard those compounds, which result from the reaction of one compound arbitrarily selected from a group of generically defined reactants with a single reaction partner, as being prior disclosed. Thus, N-propyl-2.2.4.4-tetramethyl-7-oxa-3.20-diaza-21- oxo-dispiro¦ 5.1.11.2 ¦heneicosane was considered to be novel since this compound (in contrast to the N-methyl compound) was not regarded as being disclosed merely by the description of the reaction of 2.2.4.4-tetramethyl-7- oxa-3.20-diaza-21-oxo-dispiro¦ 5.1.11.2 ¦heneicosane with one of the groups of compounds, C1-C4-alkyl bromides (cf. T 181/82 OJ EPO 1984, 401, 410). But if a mere precisely structurally defined (described by a chemical reaction) class of chemical compounds with only one generically defined substituent does not represent a prior disclosure of all the theoretical compounds encompassed by an arbitrary choice of a substituent definition, it must be clearly valid for a group of chemical substances, the general formula of which has two variable groups. Therefore, in the present case, a class of chemical compounds, defined only by a general structural formula having at least two variable groups does not specifically disclose each of the individual compounds which would result from the combination of all possible variants within such groups. ...
6.7 For the reasons given above, in view of the problem underlying the claimed method, the Board considers that the prior art cited and the common general knowledge did not provide any indication that the choice of enprofylline from the numerous available xanthines, would solve the technical problem underlying the invention. Thus the subject-matter of the patent-in-suit as defined in the Claims 1 or 2, is considered to involve an inventive step.
ORDER
For these reasons, it is decided that:
The appeal is dismissed.