T 2114/13 (Stable polymorphic form of febuxostat/TEIJIN) 12-10-2016

1. The appeal is admissible

2. Observation by a third party (Article 115 EPC)

2.1 Third party observations were filed anonymously at a late stage in the appeal proceedings. Subsequently, third party observations with essentially the same content were filed by a professional representative (see points VI and VIII above).

2.2 Observations by a party which pursuant to Article 115 EPC, second sentence, is not party to the proceedings can be taken into account at the boards' discretion. When exercising their discretion, the boards usually take criteria into account which they consider when deciding on the admission of late filed submissions by any party to the proceedings (cf. Articles 12(4), 13(1) and 13(3) RPBA). One of these criteria is the relevance of the submission filed.

In the present case, the board considers that the observations filed by the third party are not more relevant than what is already on file. Also, none of the parties to the proceedings adopted the arguments and documents provided by the third party as their own. In fact, the opponent withdrew its opposition (see point VII).

2.3 The board therefore decided not to admit the submissions by the third parties.

Main request

3. Amendments, clarity and sufficiency of disclosure (Articles 123(2), (3), 76(1), 84 and 83 EPC)

3.1 In the decision under appeal the opposition division held that the subject-matter of the auxiliary request, that is the pharmaceutical compositions consisting of crystalline Form C and their use in the treatment of hyperuricemia, complied with Articles 123(2) and (3) and 76(1) EPC (see decision under appeal, point 17.2 of the reasons). The board has no reason to deviate from the opposition division's findings in this respect. The present main request differs from the request considered by the opposition division solely in that the crystalline form is further defined by IR data. This amendment finds a basis in claim 2 and page 5, lines 3 to 5 of the application as originally filed and page 5, lines 3 to 5 of the parent application. It does not give rise to an objection under Article 123(2) or 76(1) EPC.

3.2 The board also has no reason to deviate from the opposition division's findings with regard to Articles 84 and 83 EPC (see decision under appeal, points 17.3 and 17.4 of the reasons). The amendment in claim 1 of the main request is of no consequence as regards the opposition division's assessment of clarity and sufficiency of disclosure.

4. Novelty (Article 54 EPC)

4.1 Claim 1 is directed to a pharmaceutical composition comprising 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid (febuxostat) as active principle. This active principle consists of a single specific crystalline form (i.e. Form C) which is defined by a X-ray powder diffraction peaks and IR absorption bands.

Due to the word "comprising" the claimed pharmaceutical compositions may contain other ingredients (additives, excipients, coatings, etc.), but the presence of a crystalline form which is different from the crystalline form claimed is excluded.

4.2 Document (1) discloses a crystalline form, which lacks at least one of the characterising IR-absorption bands. X-ray powder diffraction peak are not disclosed in document (1). Moreover, it has been shown during the examination proceedings (see documents (10) and (11)) that the crystalline form obtained in document (1) is a mixture of two crystalline forms (Forms A and C).

4.3 In view of the above the board concludes that the claimed subject-matter is novel over document (1).

5. Inventive step (Article 56 EPC)

5.1 The board considers, in agreement with the opposition division and the appellant, that document (1) is the closest state of the art. It concerns a one-pot-synthesis of 4-alkoxy-1,3-benzenedicarbonitriles, which are key intermediates in the synthesis of 2-(4-alkoxy-3-cyanophenyl)-4-methylthiazole-5-carboxylic acid derivatives, including TEI-6729 (i.e. febuxostat). TEI-6720, which is described as a promising remedy for hyperuricemia and gouty arthritis (see page 857, lines 1 to 3), was synthesised and obtained in crystalline form, after crystallisation from the reaction mixture containing ethanol and THF and recrystallisation from acetone (see page 863, lines 5 to 20).

As mentioned in point 4.2 above, it has been shown by the appellant during the examination procedure that the crystalline form in document (1) is a mixture of two polymorphic forms, that is polymorphic Forms A and C, in an 80:20 ratio. This was not contested by the opposition division and, in the absence of any conclusive evidence to the contrary, is accepted by the board.

5.2 In the light of document (1), the appellant defined the problem to be solved as the provision of a pharmaceutical composition of febuxostat with improved quality and reliability, that is improved polymorphic stability, in particular during formulation. The proposed solution is the crystalline form of febuxostat with the X-ray diffraction peaks and IR absorption bands according to claim 1 of the main request.

5.3 In order to demonstrate that the aforementioned technical problem was plausibly solved, the appellant relied on experimental evidence provided in document (11) and the disclosure in the patent in suit, in particular paragraphs [0035] and [0036].

5.4 Document (11) describes on page 4 two experiments in which a slurry of the crystalline Form C according to the invention and a slurry of an 80:20 mixture of crystalline forms corresponding to "D4", which is document (1) in the present opposition appeal proceedings, was stirred with acetone water. Samples were taken after 2, 4 and 24 hours and analysed by X-ray diffraction in order to determine the crystalline form. The results are summarised in the table on page 4, which shows that the crystalline form according to the invention remained unchanged, while the mixture of crystalline forms according to document (1) converts into Form C.

Such solvent-mediated conversion is also disclosed in the patent in suit (cf. paragraph [0030]), according to which Form C is produced by solvent-mediated polymorphic transition. Furthermore, in paragraphs [0035] and [0036] it is stated that Form A, which is characterised as a metastable form in methanol, converts into the stable Form C.

5.5 In the decision under appeal, the opposition division did not accept the existence of an improvement, since the active principle of a drug was not stored in acetone and other standard tests were commonly applied for assessing long term stability of pharmaceuticals. Although these assertions are undoubtedly correct, it cannot be denied that polymorphic stability during formulation is also crucial for any drug manufacturer and that solvents, including acetone or alcohols, are frequently used in formulation technology (see for example document (15), page 87, second paragraph, page 88, fourth and last paragraph, page 89, fourth and fifth paragraphs; document (16), page 769, tables 33.6, 33.8. 33.9; document (17); document (20), English translation). The board notes that document (16) is a post-published text-book. However, it confirms the teaching of documents (15) or (17).

A formulation with a polymorphically stable crystalline form compared to a potentially unstable mixture represents an advantage, since it does not require particular efforts to monitor and control the presence of a different crystalline form (see also patent in suit paragraphs [0001], [0003] and [0010]). The board therefore accepts the formulation of the technical problem as defined in point 5.2 above.

5.6 In view of the above and in the absence of any evidence to the contrary, the board considers that the technical problem as formulated in point 5.2 above is plausibly solved.

5.7 It then remains to be decided whether or not the proposed solution was obvious in view of the prior art.

5.7.1 Document (1) neither mentions polymorphs of febuxostat or their potential existence, nor does it address the problem of providing a pharmaceutical composition with improved polymorphic stability. Without knowledge of the invention the skilled person would not even have been aware of the fact that the crystalline form in document (1) is a mixture of crystalline forms with a potential for conversion into a different crystalline form. This document therefore cannot provide the skilled person with any useful information pointing to the presently claimed crystalline form or an incentive to modify the crystalline form according to document (1).

5.7.2 Documents (13) and (14) also cannot help in this respect.

These documents demonstrate that the occurrence of different solid states (polymorphs, hydrates, amorphous forms) is a widespread phenomenon in solid drug substances and that screening for polymorphic forms is advisable and even a regulatory requirement (see document (13), page 945, left-hand column, line 1 to right-hand column, line 15; document (14), page 527, left-hand column, third and fourth paragraphs; page 528, left-hand column, first paragraph). Methods for screening for polymorph are also disclosed (see document (13), page 946, right-hand column, last paragraph; document (14), page 528, left-hand column, first paragraph).

5.7.3 The board notes that the opposition division considered the problem to be solved as the provision of a mere alternative crystalline form, which means any form likely to be found in routine screening methods solves this problem. The board, based on the available evidence, accepts that the problem to be solved is the provision of a polymorphically stable pharmaceutical composition of febuxostat. No guidance can be found in any of the documents (13) or (14) as to how a particular crystalline form with desirable properties can be obtained in a targeted manner.

5.7.4 The board would also like to point out that the facts of the present case differ from those leading to decision T 777/08 (OJ EPO 2011, 633) relied on by both parties during the opposition proceedings (see minutes page 2, penultimate paragraph). In that decision, the specific polymorph claimed was found to be an arbitrary choice from equally suitable candidates, in view of the skilled person's clear expectation that a crystalline form would have improved filterability and drying properties compared to the known amorphous form (see Headnote, point 2). In the present case, the board has no doubt that not all crystalline forms of febuxostat are equally suitable candidates to solve the problem of providing a crystalline form with improved polymorphic stability. Indeed, the patent in suit also mentions crystalline forms, which are not polymorphically stable (see paragraphs [0037] to [0038]).

5.7.5 With regard to the method claim 2 of the main request, the board observes the following:

Starting from document (1), the problem to be solved can be seen in the provision of a consistent and reliable method for the preparation of the crystalline form according to claim 1. The proposed solution was the crystallisation in methanol and water in the presence of seed crystals. The board has no doubt that this problem is solved by the claimed method.

Neither document (1) nor any of the other documents on file provides any guidance that the aforementioned technical problem can be solved by replacing the solvents (THF/ethanol or acetone) used in document (1) with methanol and water. The addition of seed crystals is not essential; it merely helps to accelerate the crystallisation and to improve the reproducibility on an industrial level.

5.8 In view of the above considerations, the board concludes that the subject-matter of the main request involves an inventive step.

6. Having decided that the main request complied with the requirements of the EPC, the board does not need to decide on auxiliary requests 1 and 2.