T 0163/84 (Acetophenone derivates) 21-08-1986
Intermediate products for known end products
Protection of elements
I. European patent No. 15 456 was granted on 2 December 1981 on the basis of European patent application No. 80 100 882.2 filed on 22 February 1980 claiming the priority of a previous application (DE 2 907 972) of 1 March 1979. It has three claims reading as follows:
1. Omega-Halogeno-acetophenone oxime ethers of the general formula
in which R represents fluorine, chlorine, bromine, nitro and cyano, further represents alkyl and alkylsulphonyl with in either case 1 to 4 carbon atoms, alkoxy and alkylthio with 1 to 2 carbon atoms and halogenoalkyl with up to 2 carbon atoms and up to 3 halogen atoms, and in addition represents phenyl or phenoxy, it being possible for these two radicals to be substituted by halogen, cyano, nitro and halogenoalkyl with up to 2 carbon atoms and up to 3 halogen atoms, R' represents alkyl, alkenyl and alkynyl with in each case up to 4 carbon atoms and cycloalkylalkyl with 5 to 7 carbon atoms in the cycloalkyl part and 1 to 2 carbon atoms in the alkyl part, it being possible for the cycloalkyl part to be optionally substituted by alkyl with 1 to 4 carbon atoms, and also represents benzyl or styryl, it being possible for the indicated two radicals to be substituted by halogen, cyano, nitro, amino, alkyl with 1 to 4 carbon atoms, phenyl, phenoxy and halogenoalkyl with up to 2 carbon atoms and up to 3 halogen atoms, n represents the numbers 1 or 2 and Hal represents chlorine or bromine.
2. Process for the preparation of Omega -halogeno-acetophenone oxime ethers of the formula I in Claim 1, characterised in that Omega-halogeno-acetophenones of the formula
in which Hal, R and n have the meaning given in Claim 1, are reacted with substituted hydroxylamines of the formula
in which R' has the meaning given in Claim 1, in the presence of a diluent.
3. Use of Omeg -halogeno-acetophenone oxime ethers of the formula I in Claim 1 as intermediate products for the preparation of largely known-azolyl-acetophenone oxime ethers of the general formula
in which R, R' and n have the meaning given in Claim 1 and Z represents the CH group or a nitrogen atom, characterised in that the Omega-halogeno-acetophenone oxime ethers of the formula I in Claim 1 are reacted with azoles of the formula
in which Z has the above mentioned meaning, in the presence of an acidbinding agent and in the presence of a diluent.
II. The opponents filed notice of opposition to the grant of the European patent, requesting that it be revoked on grounds of lack of inventive step and citing new documents in support of this claim, including: (1) DE-A-2 657 578 (SIEGFRIED AG) (2) DE-A-2 723 942 (BASF AG) (3) DE-A-2 613 167 (BAYER AG) (4) Houben-Weyl, Methoden der Organischen Chemie, 4th edition, vol. 10/4, pp. 73 and 74 (1968) (5) Troxler et al., Helv.Chim.Acta, vol. 51, p. 1616 et seq. (1968) (6) Houben-Weyl, Methoden der Organischen Chemie, 4th edition, vol. 10/1, pp. 1181 and 1183 (1971) (7) Mixich, Thiele, Arzneim.-Forschung. vol. 29 (II), p. 1510 et seq. (1979) (8) Beilstein, 4th edition, Hauptwerk, vol. 7, p. 282 (1925) (9) DE-A-2 431 407 (BAYER AG) (10) Godefroi et. al. J. Med. Chem., vol. 12, pp. 784 - 791 (1969).
III. By decision dated 29 February 1984 (oral proceedings) the Opposition Division rejected the opposition, essentially on the grounds that further processing of the intermediate products (i) to the known end products (IV) did not have to involve an inventive step. What alone mattered was whether the new complete process in which the intermediates (i) were used involved an inventive step. According to the literature the known process involving azolation followed by a reaction with hydroxylamine gave an overall end product yield of only 60%. If the reaction was carried out with hydroxylamine ether instead of hydroxylamine, expectations were even lower (40%). By contrast, the yield from the process according to the patent lay in the region of 84%. Such an increase could not have been foreseen by the man skilled in the art since the opponent had indicated no prior art from which improved yields could be inferred either for the individual stages or for the complete process.
IV. The opponents duly appealed against this decision on 29 June 1984, submitting a statement of grounds on 9 October 1984. Following an interim communication from the Board oral proceedings were held on 21 August 1986.
V. In support of their appeal the appellants (opponents) finally submitted as follows: (a) The Opposition Division had based its approach on the "Bis- epoxy ethers/BASF" decision (T 22/82, OJ EPO 9/1982, p. 341), concluding that the inventiveness lay in the process as a whole. This latter, however, had not been claimed in the case under review; nor moreover was that decision applicable to the present case because there the intermediate product itself showed unexpected advantageous properties. (b) The supposedly low yield of the various citations compared with the corresponding procedural steps according to the patent was not decisive here. Examples in patents were generally only illustrations of possibilities rather than developed technical methods. The "yield" of a chemical process depended ultimately on the skill of the expert. It had been obvious to use these methods for the purpose intended here.
VI. The respondents (patent proprietors) countered these submissions, arguing that the complete process did not have to be specially claimed, since it was evident from the claims as they stood. The advantages shown by the process via the intermediate products were undisputed and substantial. Even stage 2 of the complete process revealed a wholly unexpected improvement in yields compared with the cited condensation reactions of the various azoles with acetophenone derivatives.
VII. The appellants requested that the contested decision be set aside and the European patent revoked. The respondents submitted that the appeal should be dismissed, failing which Claim 3 should preferably be limited by including the preparation stage or else dropped.
1. The appeal complies with Articles 106 to 108 and Rule 64 EPC and is therefore admissible.
2. There is no formal objection to the present claims, they being supported by the original documents.
3. Claim 1 is directed towards specific substituted Omega-halogeno-acetophenone oxime ethers. These are suitable for the preparation of known substituted Omega -azolyl-acetophenone oxime ethers by azolation (see use Claim 3). For this type of reaction citation (9) is in fact the nearest prior art since there a 2,4-chlorine- substituted Omega-bromine-acetophenone is condensed with 1,2,4- triazole to yield 60% of the theoretical value. Given this technique the technical problem therefore consisted in considerably improving condensation with an azole. The solution to the problem lies in preparing the claimed intermediates and in their use for the preparation of known azole derivatives.
4. The reaction according to the invention of 2,4-chloro-acetophenone oxime-0-methyl ethers with 1,2,4-triazole gives a yield of 84% (calculation per p. 11, lines 9-11, and p. 10, lines 29-31), which is considerably better than the corresponding azolation of the identically substituted ketone according to (9), example 3, p. 29 (60%). Although further examples in (10) also reveal yields of only 58 to 77%, these condensations use imidazole, i.e. a diazole instead of a triazole. The Board does not share the appellants' view that comparisons of this kind are not admissible because prior art examples represent only preliminary experiments and not developed processes. Without good cause for questioning the published examples the skilled person would in practice take them as his starting point. The Board is therefore satisfied that the technical problem is actually solved. The interpretation of a citation's teaching must be based on what it actually discloses, as representing complete and specific technical instructions (see "Spiro compounds/CIBA GEIGY", T 181/82, OJ EPO 9/1984, p. 401, specifically p. 411, point 8, or T 68/83, dated 21 March 1986, p. 11). As the novelty of the claimed intermediates is undisputed, their preparation and use as claimed in Claims 2 and 3 are also new.
5. It has to be examined whether the preparation of the intermediates involves an inventive step. The question is whether it was obvious to a skilled person to expect improved condensation from Omega- halogen-substituted acetophenone derivatives when the ketone is first converted into an O-substituted oxime. The appellants have themselves conceded that the skilled person could not with certainty expect reaction to be aided by replacing the oxo group by an oxime group. Although the first-named group might possibly increase the reactivity of the beta methylene group, there was nothing in the general knowledge of the art to indicate what effect the oxime group would have under reaction conditions. Furthermore, the use of triazoles instead of diazole was known to reduce the yield (compare (9) with compound 3 in Table 1, p. 785 (10)), so that the skilled person could not expect them to produce any improvement. Contrary to expectations the results using this reagent were surprisingly better.
6. The use of the intermediates themselves according to Claim 3 reveals a favourable, unexpected "process effect" (see "Bis-epoxy ethers/BASF" decision, p. 346, point 7). The structure of the intermediate is a direct factor in this reaction and the structural difference in the compound manifests itself in a valuable effect (loc. cit., p. 345, point 6). The process and also the new agent for it therefore involve an inventive step which is not derived from the possible patentability of the process as a whole. Such a complete process does not therefore need to be claimed. Although the preparation process could itself also be inventive by virtue of particular effects and advantages, Claim 2 is allowable anyway because the products themselves are patentable, even if an analogy process is involved.
7. A complete process may be inventive by virtue of the combination alone without there being any patentable individual stages. On the other hand the inventive character of the whole may be based on at least one inventive part. In the present case the Opposition Division accepted that the process as a whole involved an inventive step and from that inferred that the parts were necessarily patentable. The Board considers however that all the formally and substantively independent claim categories should be judged in the light of their particular purpose and the effects achieved.
8. There is no doubt that the complete process is also inventive as a combination compared with its own nearest prior art (i.e. the known complete process using azolation and oxime formation according to DE-A-2 431 407 and DE-A-2 723 942), notwithstanding the Board's view expressed above that the second stage is patentable in its own right. Comparison of the complete processes reveals a considerable and unexpected increase in yield (see patent specification p. 11, line 15, to p. 12, line 11, on the one hand, and p. 10, line 13, to p. 11, line 12, on the other). Despite the simple replacement of azolation by oxime formation the complete process is inventive because what matters is not whether the skilled person could have foreseen the possibility of the reaction stages but whether he would have done so in expectation of some improvement or advantage (see Simethicone Tablet/RIDER, T 2/83 in OJ EPO 6/1984, p. 265, Headnote II).
9. Nevertheless, the patentability of the intermediates in the present case cannot automatically be recognised on the basis of the above-mentioned "Bis-epoxy ethers/BASF" decision. In that particular case no direct comparison with a known multi-stage process was possible. Instead of a quantitative comparison with analogous reaction stages, consideration had to be given to the special qualitative properties of the intermediates. However, the use of new original intermediates was recognised as inventive (op. cit., p. 350, point 15). In that particular case the intermediates contributed to the inventiveness of the second stage of the complete process precisely because of their "structural difference" and the "effect" manifested thereby (p. 345, point 6). Without this contribution the advantageous complete process would have been inconceivable (p. 341, Headnote I, second paragraph).
10. In the case to be decided here the complete processes are quantitatively comparable both overall and in their individual stages. Whether the intermediates are themselves also patentable here depends on their contribution to the quantitative effect produced by them even at the azolation stage. The Board is in no doubt that the quantitative success is attributable to the intermediates, and hence that grant of a patent for them is justified. Parts of a patentable complete process are not per se automatically patentable. If they were, even non-inventive new products of an inventive process as intermediates could be made patentable by simply adding a trivial further processing stage to the process to form a "complete process". The Board therefore holds that a new chemical intermediate does not become inventive merely because it is prepared in the course of an inventive multi- stage process and is further processed to a known end product. There must also be other factors, such as that the process for preparing the new intermediate enabled it to be prepared for the first time and did so inventively and other methods of preparing it appeared to be ruled out (see, for example, the circumstances of the "Zeolites/BASF" case, T 219/83, OJ EPO 7/1986, p. 211, specifically p. 220, points 11 and 12). Such a product is at any rate patentable when its further processing is inventive, as here (further to "Bis-epoxy ethers/BASF", T 22/82).
For these reasons, it is decided that:
The appeal is dismissed.