T 0566/91 (Nystatin/SQUIBB) 18-05-1994

1. The appeal is admissible.

2. Procedural matters

2.1. Document (1) as basis for the revocation of the patent by the first instance.

During discussion of (1) at the oral proceedings before the Board, it rapidly emerged that the text of (1), cited in the decision under appeal as DD-A-132 404, and a copy of which was present in the opposition file, contained substantially more than the text of (1) which both parties present at the oral proceedings had in their possession, and which had been cited by the Respondents as DD-C-132 404 when filing the opposition. The latter was in fact a reissue of the DDR Patent in an amended form, with claims limited to a film-like pharmaceutical carrier and a particular embodiment of the invention using Nystatin no longer appearing in the amended text. That different texts were being used appears to be the result of the fact that document (1) was not provided to the Opposition Division which ordered a copy for itself which turned out to be a different text. The differences might have been apparent on extremely careful examination from the fact that the line numbers cited by the Respondents for various passages did not correspond exactly with the position of those passages in the text used by the Opposition Division. But these dicrepancies did not spring to the eye, as the cited passages did appear close to the lines actually cited and the lines of the pages were not numbered. The version of (1) relied on by the Opposition Division, is the most relevant one. The decison of the first instance was thus based, albeit inadvertently, on evidence (the fuller version of document (1)) on which the parties concerned had not had the opportunity to comment, contrary to the requirements of Article 113 EPC.

To remedy this unfortunate situation, the Board offered a half hour suspension of the proceedings for the parties to consider the fuller version of (1) with the interpreters, present to translate the Respondents submissions from German to English, kindly agreeing to help the Appellants to understand the German language full version of (1). The Appellants and Respondents both accepted this offer. At the end of this suspension both parties were prepared to continue with the proceedings and deal with the full version of (1), so that in the proceedings before the Board Article 113 EPC was complied with. The Appellants withdrew their original main request that the patent be maintained as granted, proceeding only with the requests as stated in VII above.

2.2. Late-filed documents

At the oral proceedings the Board had to decide whether the Respondents' late-filed citation (15), the Appellants' expert opinion of Dr. M.V. Martin based on experimental work as well as the statement in response of Dr. Ulrich Schwantes subsequently submitted by the Respondents, a letter from Dr. Martin commenting briefly on Dr. Schwantes' statement, and the data submitted as evidence in support of a commercial success of the claimed invention, should be admitted for consideration.

(15) had been cited by the Respondents directly in response to the Statement of Grounds of appeal wherein the Appellants for the first time submitted a restricted main claim differing from the granted claims in that it related to a specific formulation reflecting the preferred soft nystatin formulation defined on page 3, lines 14 ff. of the patent in suit. As the technical content of this document could not be considered to be irrelevant for assessing inventive step of the said formulation, the Board made use of its discretion under Article 114(2) EPC to admit (15) into the appeal proceedings.

By contrast, the Board decided on the basis of the same provision not to admit for consideration the other documents submitted by the parties in the course of the appeal proceedings.

3. Allowability of amendments in the main and the auxiliary requests I and II

There are no formal objections on the basis of Articles 123(2) and (3) EPC to the three sets of claims (see point VII above) since these claims are adequately supported by the original description and do not extend the protection conferred when compared to the claims as granted. This was not contested by the Respondents.

4. Novelty

None of the documents considered in the present proceedings discloses a soft nystatin pastille formulation presenting all the features indicated in the claims in accordance with the main or the two auxiliary requests. This was not contested by the Respondents. The said claims must thus be regarded as novel.

5. Inventive step

5.1. In relation to the invention as claimed in all the requests, document (1) is regarded as constituting the closest prior art. It relates to a process for preparing a pharmaceutical carrier designed to provide a continuous release of an active pharmaceutical substance over a sustained period of time and in a much higher concentration than the usual carriers, thereby obviating the known deficiencies and drawbacks of the latter in terms of continuity and duration of the release to accessible mucous membranes, for example those of the buccal cavity of subjects suffering from mucosal lesions due to Candida albicans. This goal is achieved by incorporating an active substance into an organic, physiologically indifferent and swellable carrier mass under addition of a polar solvent or suspension agent (preferably water) and a softening agent (preferably glycerol) in an amount of 0% to 40%, whereby gelatin is considered to be a suitable carrier material. It can be used in an amount of 1,5% to 50%. Among the many groups of potential active substances to be used figure antifungal agents, in particular those active against Candida albicans such as nystatin. Although the amount of active substance in the carrier mass is not limited, in practice it ranges between 0.05 mg and 5.0 grams per carrier unit. The pharmaceutical carrier may actually have any shape depending on the body cavity and the mucosal membranes to be treated (mouth, ear, nose etc.), including an elliptical form or the shape as represented in figure 1, i.e. a film-like shape or strip if oral application to the mucosal membrane of the palate is envisaged. A single carrier unit may have a thickness from 0.5 mm to 4.0 mm and a surface ranging between 1. mm2 and 100 cm2, whereby the weight per unit is between 0.1. g and 20 g. If necessary, the formulation may contain additional ingredients such as flavouring and colouring agents (see claims; page 1, last paragraph to page 3, line 13; page 3, lines 19 ff.; page 4, lines 10 to 36; page 5, lines 10 to 13 and figure 1).

As can be seen from the example on page 6 of (1), a suitable pharmaceutical carrier formulation may have the following composition:

1. nystatin: 106 units (active substance)

2. citric acid: 0.04g (stabilising agent/ solubility promoter)

3. gelatin: 0.8g (carrier)

4. glycerol: 1.5g (softening agent)

5. water: 3.0g (solvent)

6. citronella oil: 0.001g (flavouring improver)

7. ester of p-benzoic acid: 0.0075g (preservative)

The resulting mixture is poured into a mould having a shape adapted to the anatomical site to which it is intended to be applied and divided after cooling. The above working example merely serves as an illustration and is not to be construed as a limitation (see page 6, last two paragraphs).

5.2. The Board does not agree with the submission by the Appellants that the technical problem underlying the patent in suit consisted in the unrecognised problem of poor patient compliance.

In the Board's view, this approach is not realistic because the mere posing of a problem, even if it were new, does not represent a contribution to the inventive merits of a solution to that problem if it could have been posed by the average person skilled in the art. Such is the case where, as here a problem necessarily comes to light when an object or product is used. Consequently, a problem which amounts to no more than noticing an obvious non-compliance with an obvious desiderata in a given situation, namely poor patient compliance using nystatin formulations as a result of the unpleasant taste of the active substance, cannot be retained as the actual problem to be solved, all the more since in accordance with the "problem-and-solution" approach" developed in the jurisprudence of the Boards of Appeal, the problem underlying a patent or patent application must be objectively defined vis-à-vis the closest prior art (see for example T 24/81, OJ EPO 1983, 133, in particular points 4 and 14 of the Reasons and T 13/84, OJ EPO 1986, in particular points 10 and 11 of the Reasons).

Thus, in the light of (1) the Board can only see the technical problem to be solved in the present case as being finding another suitable nystatin containing pharmaceutical formulation of the known type.

The Board is satisfied that the above-stated problem has been solved by the pastille with the features required in accordance with Claim 1 of any of the Appellants' requests.

5.3. As can be seen from point 5.1 above, the teaching of document (1) covers the preparation of a large number of pharmaceutical bodies of different shape and size depending on the body cavity and the mucosal membranes to be treated including those containing sufficient nystatin for the treatment, over a sustained period of time, of the buccal cavity of subjects suffering from mucosal lesions due to Candida albicans and which contain 1.5 to 50% of gelatin as a carrier. These formulations may also contain a softening agent (preferably glycerol) and, if necessary, additional ingredients such as flavouring and colouring agents. The known formulations are thus soft formulations designed to provide a persistent level of medication.

Moreover, from the general statement in (1) that flavouring and colouring agents could be added if necessary, and the working example, the man skilled in the art would certainly have understood that such additives might be required to make a formulation more appealing to the user and that especially in the case of nystatin (known for its unpleasant taste) such a measure indeed makes sense. When trying to find out which flavouring agents would be suitable apart from the expressly mentioned citronella oil, he would inevitably have come across document (9) reflecting a common practice in galenics to use for the preparation of pastilles, i.e. a soft variety of lozenge (cf. page 80 of (12)), an extremely large excess of saccharose in comparison with the gum base. As a matter of fact, for preparing 100 pastilles the following composition can be used: saccharose (finely powdered) 100 g, arabic gum (finely powdered) 7 g, water q.s. Since according to (9) pastilles are moreover known to be small bodies of a pharmaceutical formulation of variable size and shape which deploy their activity in the mouth or throat region by dissolving slowly in the mouth, the skilled man would have readily realised that the closely related formulation described in (1) could not only be very strongly sweetened by incorporating large amounts of sugar, i.e. one of the most famous allround flavouring agents, but also readily presented in the form of a pastille without risk of impairing the softness and sustained release properties characteristic of the formulations described in (1). Furthermore, (9) illustrates well that when using medication by pastilles, the concern of the skilled man to provide efficient medication obviously prevails over a possible risk of caries due to the presence of a high amount of saccharose. This would particularly apply in the case of treatment of a severe disease like candidiasis, as emphasised by the Appellants.

5.4. The Appellants unsupported argument that, apart from masking the unpleasant taste of nystatin, sugar ensured a concentrated application of the active substance to the infected areas of the mouth tends to suggest an unexpected advantage or effect due to the high sugar content of the claimed formulation. As this was contested by the Respondents, the Board is faced with a situation which it is unable to resolve on the strength of its own knowledge. It is however jurisprudence of the Boards of Appeal of the EPO that in such a situation it is the party whose argument rests on the alleged facts who fails in the absence of supporting evidence (see T 219/83 , OJ EPO 1986, 211).

5.5. As can be seen from (15), the use of different sugars in solid and/or syrup form in accordance with Claim 1 of auxiliary request II is an obvious measure when preparing heavily saccharinated soft gum articles containing gelatinous materials such as gelatin and/or pectin. As explained in the patent in suit such mixtures prevent sugar crystallisation.

5.6. In view of the preceding and the fact that the Appellants presented in support of their auxiliary requests I and II the same arguments as those for the main request, the Board has come to the conclusion that Claim 1 of all three requests does not involve an inventive step in the sense of Article 56 EPC.

The dependent claims in each of the three requests must fall with the main claim, since each request can only be considered as a whole.

6. Additional requests at the stage of opposition

As correctly pointed out by the Appellants in their Statement of Grounds of appeal, the Opposition Division did not deal in its decision with Appellants' two auxiliary requests, corresponding to the present main and first auxiliary request. Since the patent was revoked in its entirety solely on the basis of the claims of the main request submitted at that time without mentioning reasons for the non-allowability of the two additional auxiliary requests, the decision of the Opposition Division did not in this respect meet the requirements of Rule 68(2) EPC. This omission constituted a substantial procedural violation which would have justified a reimbursement of the appeal fees if the Board had decided that the appeal were allowable (Rule 67 EPC). However, in view of the conclusion reached in point 5.6 above, the appeal must be dismissed so that the Board has no power to refund the appeal fees.