T 0012/81 (Diastereomers) of 9.2.1982

Summary of Facts and Submissions

1. European patent application No. 79104254.2, filed on 2. November 1979 and published on 28 May 1980 under Publication No. 0011 191, claiming the priority of the prior application in the Federal Republic of Germany of 18 November 1978, was refused by decision of the Examining Division of the European Patent Office of 30 December 1980. That decision was based on Claims 1 to 5 as originally filed.

II. The reasons given for the refusal was that the subject-matter of the claims was no longer new. DE-A 2 333 354 and 2 333 355 described a process for the reduction of alpha-phenoxy-alpha-(1-imid-azolyl)-ketones, including 1-(4-chloro-phenoxy) - 1-(imidazol-1-yl) - 3,3-dimethylbutan-2-one, in accordance with process variant b described on page 6 of the latter document using aluminium isopropylate as an agent, to the corresponding secondary alcohols, which could give rise to two diastereomeric forms. These documents anticipated all the technical features of Claim 2, so that the product of this reduction process, i.e. the substance according to Claim 1, also formed part of the state of the art. The applicant's view, that the latter document did not explicitly state the problem to be solved by the process according to the application, namely the production of a specific diastereomer, so that - the problem being novel - the whole of Claim 2 would have to be regarded as novel, was rejected. By implication, the process for reducing the ketone mentioned in Claim 2 by means of aluminium isopropylate defined the problem of preparing the resulting reduction product (cf. also the Guidelines for Examination in the European Patent Office, Chapter C-IV, 7.5). This known problem differed from the one to be solved by the application only in the way it was described but not in substance. The product to be prepared was adequately defined by the very fact of indicating the starting compound and how it was converted. The applicant had simply used other parameters to describe the same thing. It was furthermore stated that use Claim 5 contravened Article 52(4) EPC, since it was equivalent to a method of treatment of the human or animal body by therapy.

III. On 7 February 1981 the applicant lodged an appeal against this decision of 30 December 1980. In the statement of grounds, submitted on 2 April 1981, the appellant requested that Claim 5 be deleted and that the patent be granted on Claims 1 to 4. Oral proceedings were requested on 7 July 1981. At the oral proceedings, held on 9 February 1982, it was requested that the patent be granted on Claims 1 to 5 as set out in a document dated 4 February 1982 which, however, had not yet been placed on file and was accordingly tabled in a photocopy at the oral proceedings. The claims in question read as follows:

1. A compound having the formula (FORMULA) in the form of the diastereomer whose melting point is 158 - 159°C, and its physiologically tolerated acid addition salts.

2. The hydrophilic diastereomer from the diastereomer mixture having the formula (FORMULA) and its physiologically tolerated acid addition salts.

3. The diastereomer having the lower coupling constants of the (FORMULA) protons in the NMR spectrum from the diastereomer mixture having the formula (FORMULA) and its physiologically tolerated acid addition salts.

4. A process for preparing the compound according to Claim 1, characterised in that 1-(4-chlorophenoxy)-1-(1-imidazolyl) - 3,3-dimethyl -2-butanone, having the formula (FORMULA) is stereoselectively reduced with secondary alcoholates in the presence of a diluting agent and the product is optionally converted into the salts by reaction with acids.

5. Use of the compound according to Claim 1 or its physiologically tolerated acid addition salts in the treatment of mycoses.

IV. The only points made further to the statement of grounds were as follows: the substance claimed was a chemical entity distinguishable from the state of the art, described in the present application for the first time stating physico-chemical properties such as melting point, hydrophilic nature and data concerning the NMR spectrum; from this it followed that the compound was new. The two cited documents described azolyl phenoxyethanols of a general empirical formula, the threo- and eritho- forms also being claimed. Furthermore, Example 3 also described the p-chlorophenoxy derivatives having a melting point of 145° - 147°C, being the nearest approximation in the state of the art. As further work on it had shown, this was a mixture having a diastereomer ratio threo : erythro of roughly 1:1. The compound as claimed, however, differed from this in that its characteristic melting point was 158° - 159°C and the relative configuration of the enantiomer pair was pure threo. The novelty of this compound was also apparent from its superior effectivness as compared with the isomer mixture. Furthermore, it was not correct to allege that the threo form claimed had been implicitly described by the fact of giving the starting substance and the process used. While it was true that a list of over 20 starting substances also included the starting compound used to prepare the substance claimed, 5 alternative processes for reducing the ketone had also been given which, to a person skilled in the art, would hardly lend themselves to achieving a stereospecific reduction of the ketone. These facts were not, however, sufficient to prejudice the novelty of a product obtainable only by selecting one of more than 20 starting substances and using one of 5 processes. Even though the process disclosed in the application involved no additional technical features as compared with process b, in the cited documents, this did not mean that the former process had been exhaustively described in the latter documents.

Reasons for the Decision

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

2. Of the 5 claims on which it is requested that the decision be based, only the first four can be accepted as validly current claims, having formed the basis for the appeal proceedings from the outset (cf. the request in the document dated 31 March 1981 under point IV), although partly reworded. The same cannot be said for use Claim 5 which was withdrawn in the afore-mentioned document right at the commencement of proceedings before the Board was not adverted to by the appellant during those proceedings lasting just short of a year. A few days before the oral proceedings, the Board thus had every reason to believe that this claim would not be resurrected to be made an object of the oral proceedings and the decision. It therefore takes the view that Rule 86(3) EPC, which also applies to appeal proceedings (Rule 66(1) EPC) and which is intended to prevent the proceedings before the European Patent Office becoming unduly prolonged, should be applied where subject-matter is submitted late in this manner. It accordingly deems the reactivation of this claim to be inadmissible.

3. The present text of Claims 1 to 4 is covered by the original disclosure (Claim 1: cf. Claim 1 in conjunction with Example 1; Claims 2 and 3: cf. Claim 1 in conjunction with page 2, paragraph 3; Claim 4: cf. Claim 2) and there can thus be no objection to them on these grounds. The question whether the aforementioned claims comply inter alia with the requirements of Article 84 and Rules 29 and 30 EPC need not, however, be addressed in the present case, because the appeal fails anyway for other reasons.

4. DE-A-2 333 354 (hereinafter referred to as the "cited document") describes imidazolyl-O, N-acetals having a general formula, stated more precisely in Claims 1, as well as a number of individual compounds covered by that formula (cf. examples 1 to 12). Example 3 also mentions 1- (4-chlorophenoxy) - 1-(1-imidazolyl) - 3,3-dimethyl- 2-butanol, which is structurally identical to the claimed substance. The compound mentioned has two asymmetric carbon atoms and can thus occur in four different spatial configurations, i.e. in two pairs of enantiomers having two diastereomeric configurations, viz. the so-called erythro and threo forms (cf. cited document, p.2, lines 13 to 16 in conjunction with the applicant's observations in the document of 1 July 1981). This steric characteristic would seem to support the view that the compound according to Example 3 of the cited document having a melting point of 145° - 147°C is not identical with the compound claimed, which has a melting point of 158° - 159°C.

5. However, the concept of novelty must not be given such a narrow interpretation that only what has already been described in the same terms is prejudicial to it. The purpose of Article 54(1) EPC is to prevent the state of the art being patented again. Article 54(2) EPC defines the state of the art as comprising everything made available to the public before the date of filing in any way, including by written description. There are many ways of describing a substance in chemistry, and this is ususally done by giving its precise scientific designation. But the latter is not always available on the date of filing, and indeed the applicant initially (November 1978) did not choose this, the most concise and best description, for the compound claimed but only made it clear at the appeal stage (April 1981) that the claim related to the threo form.

6. It is clear from the wording of present Claims 1 to 3 that the applicant himself considers it legitimate in the present case to enlarge on the insufficiently precise structural formula by specifying additional substance parameters such as melting point, hydrophilic nature or NMR coupling constants. Furthermore, it is the practice of a number of patent offices to accept the process parameter, in the form of a product-by-process claim, for closer characterisation of inventions relating to chemical substances. To the Board's knowledge this is also the practice at the European Patent Office. If inventions relating to chemical substances defined by claims of this kind are patented, it necessarily follows that the resulting patent documents, once they enter the state of the art, will be prejudicial to the novelty of applications claiming the same substance although in a different and perhaps more closely defined form. This is the case with the present application.

7. The teaching of a cited document is not confined to the detailed information given in the examples of how the invention is carried out but embraces any information in the claims and description enabling a person skilled in the art to carry out the invention. The cited document gives 5 optional methods of reduction for preparing the imidazolyl-O, N-acetals, the common feature being the transfer of hydrogen to the corresponding starting ketone in forming the secondary alcohol. These methods are not only described in a very general way (cf. Claim 2) or using a graphic formuly (cf. bottom of page 3 to bottom of page 5), but also in considerable detail (cf. pages 8 - 10). They include Variant b which - and this is not disputed - contains all the technical details for preparing the compound according to the application (aluminium isopropylate in isopropanol at 20° - 120°, particularly 50° to 100°C). There is also a list of 20 starting ketones on pages 6 and 7 of the description, the fourth of which is the ketone used to prepare the claimed compound according to the application.

8. In the Board's view, this information taken as a whole constitutes a prior description of the claimed compound prejudicial to its novelty, because it supplies a person skilled in the art with all the information he needs regarding the starting substance and the reaction conditions for preparing the claimed substance. In other words, the teaching of the cited document also covers the substance which is the inevitable product of the reduction of the p-chloro-phenoxy ketone in the above mentioned list and Example 3 in Variant b.

9. For such a prior publication to have prejudicial effect, moreover, it is not necessary for the starting compound or the process variant to be given special prominence. The essential point is what a person skilled in the art, carrying out the invention, could be expected to deduce from it. Furthermore the cited document does give a degree of prominence to the p-chlorophenoxy ketone, in the list of 20 starting compounds given only by way of example, in that one of the 12 examples deals with the preparation of the corresponding secondary alcohol. While Example 3 employs Variant c (erroneously indicated as a and b) of the reduction process, the teaching of the description, that all five variants of the reduction process can be used to prepare the secondary alcohols, in conjunction with Example 3 means that the substance inevitably resulting from Variant b is also made available by written description to the person skilled in the art.

10. It is immaterial for the purposes of prejudice to novelty that the end product is not described in full detail but chiefly by the process parameters. Furthermore, the question of whether a person skilled in the art carrying out the invention would - as the appellant asserts - be surprised at the results does not enter into it, since the finding that, if reduction Variant b is substituted for reduction Variant c in Example 3 of the cited document, the ratio between threo and erythro form changes from approx. 1:1 to 90:1 could only be regarded as an unexpcted piece of knowledge about a known process and hence of no consequence for determining whether a cited document is prejudicial to novelty.

11. The appellant, however, asserts novelty of the substance by selection, on the grounds that - as in a typical selection - a very specific combination is chosen from an array of more than 20 alternative starting substances and 5 alternative processes, i.e. the chloro-phenoxy ketone No.4 from the list and process Variant b, yielding a surprising result. This argument cannot be accepted. The concept of substance selection pre-supposes the choosing of a single compound or a specific sub-group from a group of substances. Thus the felicitous choice of the claimed threo compound from among the multiplicity of substances covered by Formula 1 in the cited document would, of course, be a genuine selection if the cited document did not supply any further information. The compound or sub-group chosen must, of course, also be new; but that is not the case here, as shown under 7 and 8 above.

12. A substance selection can come about in various ways, e.g. if an unmentioned compound or group of compounds having a formula covered by the state of the art is found, in the absence of any information as to the starting substance or substances. The present subject-matter does not involve a selection of that kind in an area which, although marked out by the state of the art, is nonetheless virgin territory.

13. However, the disclosure by description in a cited document of the starting substance as well as the reaction process is always prejudicial to novelty because those data unalterably establish the end product. If on the other hand two classes of starting substances are required to prepare the end products 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 for patent purposes as a selection and hence as new.

14. The appellant argues, however, that this selection principle also applies in cases where the starting substance from a list is combined with one of the alternative process variants. The Board does not share this view. It is readily shown that a combination of two starting substances is quite a different matter from a combination between starting substances and process variants and that they are thus not comparable.

14.1 At its simplest, if the starting substances are regarded as fragments of the end product, then in the former case every conceivable combination of a given starting substance in the first list with any starting substance in a separate second list of additionally required starting substances involves a true substantive modification of the first starting substance, since in every combination it is supplemented by a different fragment of the second starting substance to become a different end product. Each end product is thus the result of two variable parameters.

14.2. Substances obtained in this way by selecting a specific pair of starting substances from the immense range of possibilities offered are in normal practice rightly regarded - in the absence of any additional information - as not having been anticipated by prior description but as being a new selection. The new element - indispensable if a substance selection is to be recognised as new for patent law purposes - is not attributable to the absence of a reference to the end products but to the fact fact that the combination actually selected from the wide range of possibilities has not been disclosed to the public. 14.3 The appellant is incorrect in applying the concept of the selection invention to the present subject-matter, which involves combining a given starting substance from a list of such substances with one of the methods of preparation given. In contrast to the case outlined above, such a combination does not result in a real substance alteration of the starting substance but only an "identical" alteration, since no matter which of the processes described in detail is used the end product is always the particular starting substance's hydro-genation product, which differs from the starting substance itself only in that it contains two additional hydrogen atoms. The process parameter is thus - seen in terms of the end product - not a variable parameter that would result in an immense widening of the range of possiblities, so that precisely in this case the end product is not the result of two variable parameters. The role of a new element - indispensable to a selection invention - cannot therefore be attributed to the process parameter. On the contrary, the teaching of the cited document, to the effect that each of the ketones listed in the document - including the p-chlorophenoxy ketone - is to be reduced by the methods described therein including method (b), has become available to the public. 14.4 Nor would the appellant have anything to gain from listing, instead of the five process variants, the even greater number of reducing agents described and combining them with the listed starting substances, since this likewise would not result in a more extended range of possible end products than could be expected on the basis of steric factors from the single variable parameter "starting substance". 14.5 The fact that of all the compounds concerned p-chlorophenoxy ketone in combination with reduction method (b) yields the virtually pure threo compound, whereas method (c) results in a mixture of the threo and erythro configuration, i.e. the ex post facto discovery that the prior art method (b) has a stereospecific influence on the particular end product involved, can be regarded merely - as already explained under 10 above - as a surprising piece of knowledge about a known process but not as a selection invention, since the latter would require the introduction of a new feature in addition to the known starting compound p-chlorophenoxy ketone and Method (b).

15. It follows that, where a cited document describes the starting ketone, it automatically co-describes the secondary alcohols in the sense of a product-by-process claim. In other words, by virtue of the teaching in the cited document that chlorophenoxy ketone is to be reduced optionally by any of the five process variants indicated, the product of the process according to each of these alternative reduction methods is to be regarded as having been made available to the public by written description.

16. At any rate this principle applies if - as in the present case - having meticulously followed the teaching in the state of the art, the result obtained is still, both in terms of structure and configuration, within the confines of the cited document and differs from the actual examples of how the invention is carried out only by a greater shift in the threo/erythro ratio.

17. Because substance and process are so closely intertwined in the present case, the foregoing considerations are essentially valid for process Claim 4 as well as for substance Claims 1 to 3. The former does not contain a specific technical feature, it is true, but simply directs that p-chlorophenoxy ketone be reduced "stereoselectively". What the applicant means by this emerges from Example 1 of the present application which - a point that is not in dispute - applies Variant b of the reduction method in the cited document. Thus the process claim likewise does not cover any new subject-matter within the meaning of Article 54(1) EPC.

ORDER

For these reasons, it is decided that:

The appeal against the decision of the Examining Division of the European Patent Office dated 30 December 1980 is dismissed.