T 1256/11 (Tablet preparation/NOVARTIS) 09-05-2017

1. The appeal is admissible.

2. Amendments (Article 123(2) EPC)

2.1 Claim 1 of the main request is directed to a process for the preparation of an enteric coated tablet with mycophenolic acid or mycophenolate salt in an amount of from 20 to 80% by weight based on the total weight of the tablet via direct compression or granulation and compression, i.e. steps (i) to (iv) (see point XIV above). The mycophenolic acid or mycophenolate salt is present in substantially anhydrous form and the coating and the granulation step are carried out applying only non-aqueous solvents.

2.2 The subject-matter of the claim finds support on page 11, lines 4 to 22 of the application as originally filed, which discloses a process for the preparation of a tablet comprising the steps (i) to (iii), which may further comprise a coating step (iv). The use of only non-aqueous solvents in the granulation and coating process, if mycophenolic acid and mycophenolate salt is anhydrous, is also disclosed in this context (see page 11, lines 18 to 24). The disclosure on page 11 does not specifically refer to enteric coating. However, the only type of coating that is explicitly and in detail disclosed in the application as originally filed is an enteric coating (see pages 7 to 10). Hence, the addition of the feature "enteric" does not add any technical information which is not directly and unambiguously derivable from the application as originally filed. The same applies with regard to the amount of mycophenolic acid or mycophenolate salt (i.e. 20 to 80%), which finds a basis on page 2, lines 27 to 31. This passage, which refers to a tablet, discloses an amount of 20 to 90% and a preferred amount of 45 to 80%. According to established jurisprudence a combination of the preferred disclosed narrower range and one of the part-ranges lying within the disclosed overall range on either side of the narrower range is unequivocally derivable from the original disclosure (see e.g. T 2/81, OJ EPO 1982, 394, point 2 of the headnote and point 3 first paragraph of the Reasons; T 925/98, point 2 of the Reasons, T 2001/10, point 10 of the Reasons).

Claims 2 to 5 find a basis on page 3, lines 20 to 24 and page 2, lines 27 to 31 of the application as originally filed.

2.3 The board therefore concludes that the subject-matter of the main request does not extend beyond the content of the application as originally filed. Article 123(2) EPC is therefore complied with.

3. Article 84 EPC

3.1 Claim 1 of the main request contains the expression "substantially anhydrous form". It has been argued by the third party that due to the term "substantially" said expression was unclear.

3.2 In decision G 3/14 (OJ EPO 2015, A102) of the Enlarged Board of Appeal, it was decided that "the claims of the patent may be examined for compliance with the requirements of Article 84 EPC only when, and then only to the extent that the amendment introduces non-compliance with Article 84 EPC" (see order).

3.3 The unclear term and the unclear expression were already present in the claims as granted. It was not argued, and the board has no reason to believe, that the alleged lack of clarity was introduced by any of the amendments made after the grant of the patent in suit. Rather, it was submitted that, in line with decision T 1459/05, an exception to the rule that there is no power to examine the amended claim under Article 84 EPC should be made. The board notes that the Enlarged Board of Appeal in its decision G 3/14 disapproved the line of diverging jurisprudence (see point 87 and points 30 to 43 of the Reasons), including decision T 1459/05.

3.4 In view of the above considerations, the board concurs with the appellants that the board has no power to examine the clarity objection raised in the third party observation.

4. Sufficiency of disclosure and novelty

4.1 In the decision under appeal, the opposition division held that the subject-matter of all requests was sufficiently disclosed. Although the present main request is not identical to any of the requests underlying the decision under appeal, the board has no reason to deviate from the opposition division's findings. The same applies with regard to novelty.

5. Inventive step

5.1 The board, in agreement with the appellants, considers that document (1) represents the closest prior art. This document relates to enteric coated pharmaceutical compositions of mycophenolate salts (see claim 1). Suitable pharmaceutical compositions are tablets, pellets, granules or capsules. The enteric coating may be carried out in conventional manner, e.g. spraying with a solution. The solvents may be an organic solvent or an aqueous solution (see page 5, lines 5 to 13). The examples of document (1) disclose the preparation of enteric coated capsules by mixing mycophenolic mono sodium salt with suitable excipients, filling the mixture into a size 1 capsule and coating the capsule with a solution of the enteric coating ingredients in ethanol/acetone. The specific enteric coated capsules produced in examples 1 and 2 contain 16% mycophenolic acid mono sodium salts based on the total weight of the capsule contents and the enteric coating. A larger capsule with ten times the amount of salt is suggested, with a reduction of the amount of lactose (see page 11, lines 19 to 20). As this amount is not defined, no conclusion as to the relative amount of mycophenolic acid salt can be drawn.

Document (1) does not place any emphasis on the use of anhydrous mycophenolic acid or mycophenolate salts. It does not mention such a form, although, according to a calculation made by the opposition division, which was accepted by the appellant, an anhydrous form has incidentally been used in the preparation of the capsules.

Document (1) also mentions that for mycophenolate salts the production of tablets is particularly interesting (see page 2, lines 21 to 25). However, no such tablet has been prepared and no details as to the preparation of tablets are provided.

5.2 In the light of document (1), the board sees the problem to be solved in the provision of a process for the production of an enteric coated tablet for oral administration of mycophenolic acid or its salts, which is convenient to administer.

The proposed solution is the production of such a tablet via direct compression (step (ii) is optional) or granulation and compression followed by enteric coating, which uses anhydrous mycophenolic acid or mycophenolate salts in an amount of 20 to 80% by weight based on the total weight of the enteric-coated tablet and carries out the granulation and coating step with non-aqueous solvents.

5.3 The board has no reason to doubt that the above formulated problem is solved.

5.4 It then remains to be decided, whether the claimed process was obvious for the person skilled in the art in view of the prior art.

5.5 It is undisputed that direct compression and wet granulation/compression (i.e. steps (i) to (iii)) are per se well-known methods in the preparation of tablets, with which the person skilled in the art is undoubtedly familiar (see document (10), page 1633, right-hand column, last paragraph, page 1634, section entitled "Compressed tablets", document (13), section 9.1, paragraph bridging the right- and left-hand column; document (14), page 70, lines 1 to 3 of first paragraph). The same applies to the coating step (see for example document (10), page 1634, left-hand column, first three paragraphs). The question to be examined is therefore whether the skilled person in an attempt to put the teaching of document (1) into practice and prepare tablets containing mycophenolic acid or mycophenolate salt as suggested in document (1) would have used the presently claimed amount of drug and the non-aqueous solvents in the coating and the granulation step.

5.6 Document (1) is silent as to the relative amount of mycophenolic acid or mycophenolate salts to be used in the pharmaceutical compositions (e.g. capsules, pellets, granules, tablets) disclosed therein. The only reliable information in this respect can be found in examples 1 and 2, in which this amount is 16%. The board also notes that none of documents (10), (13) or (14), which are considered to represent common general knowledge, addresses the issue of what would be a conventional or commonly used or achievable drug load in tablets prepared by direct compression or wet granulation and compression.

On page 8, lines 10 to 11, document (1) discloses that representative unit dosage forms contain from about "50 mg, e.g. 100 mg, to about 1.5 g" mycophenolate salt. There is no disclosure in this context as to the relative amount of the drug in the various unit dosage forms, let alone any reference to tablets.

5.7 It is also undisputed that the preparation of tablets usually requires the presence of excipients/additives to provide the necessary physical (and possibly chemical) characteristics of the material to be formulated into the tablet and of the tablets themselves. In the present case, the board concurs with the appellants that the preparation of an enteric coated tablet requires acceptable mechanical stability, otherwise the tablets are liable to crumble, edge, chip or break during coating. As acknowledged in the patent in suit (see paragraph [0009]), using a drug with e.g. a low bulk density, such as mycophenolic acid or mycophenolate salt, in high amounts has the disadvantage that high amounts of excipients are usually required to ensure sufficient mechanical stability of the tablet, which would result in a tablet with an undesirable or unacceptable size. Decreasing the amount of excipients leads to tablets with inferior mechanical stability which creates problems in the coating step.

In view of these difficulties and faced with the technical problem as formulated in point 5.2 above, the board concurs with the appellants that the skilled person had no incentive to increase the drug load taught in document (1) (i.e. 16%) when preparing the suggested enteric coated tablets by direct compression or wet granulation and compression.

5.8 Furthermore, as already explained in point 5.1 above, document (1) places no emphasis on the use of an anhydrous form of the mycophenolic acid or mycophenolate salt. It also does not teach the skilled person to avoid aqueous solutions in the coating and granulation step. On the contrary, aqueous solutions are mentioned as equally suitable for the coating step (see page 5, lines 7 to 13). No information regarding the granulation solvent can be found anywhere in document (1).

In the absence of any evidence to the contrary, the board accepts the appellants' argument that the anhydrous form was found to be the form best suited for the production of tablets and that it converts to hydrates as already indicated in the patent in suit (see paragraph [0055]), which jeopardises reproducible tablet production. This problem of conversion into hydrates has not been discussed in the available prior art. The skilled person had therefore no reason to avoid the use of aqueous solution during granulation and coating.

5.9 A number of prior art documents appear to suggest the use of high amounts of mycophenolic acid or mycophenolate salt in tablets (documents (2) to (4), (12) and (22)). However, none of them is concerned with the preparation of enteric coated tablets, which as explained in point 5.7 above requires adequate mechanical stability. Moreover, the disclosure in document (3) (see example 3, referring an active ingredient "e.g., mycophenolic acid, mychophenolate [sic] mofetil, or a pharmaceutically acceptable salt or derivative thereof") and document (22) ("up to 99% of the active ingredient", see page 15, lines 28 to 33) is rather general and speculative. It does not prompt the skilled person to increase the drug load in enteric coated tablets as suggested in document (1), in particular taking into account the difficulties associated therewith. Document (4) is concerned with aqueous suspensions and documents (2) and (12) (see examples) disclose a wet granulation process, in which an aqueous maize paste in unknown quantities is used. Accordingly, none of these documents alone or in combination with the disclosure in document (1) would lead the skilled person in an obvious manner to the presently claimed process.

5.10 The same applies with regard to document (7). This document refers to a new enteric coated formulation of mycophenolic acid-sodium (ERL 080A). It states that "[A]n initial human relative bioavailability study (...) allowed the selection of an ERL 080A tablet strength of 360 mg for further development" and mentions in the last line that "Future clinical trials will utilize the enteric coated 360 mg ERL 080A tablet". It also mentions an oral dose of "ERL 080A 720 mg". Whether this oral dose was indeed a tablet is not clear. Document (7) is silent as to the relative amount of the drug in the tablet. However, even if, in view of the common general knowledge with regard to conventional tablet weights and sizes (see document (14), page 71, second paragraph), it were to be accepted that the use of an amount of 360 mg would result in tablet with an amount of mycophenolate salt within the claimed range, the board notes that document (7) is also silent as to how the tablet has been prepared, e.g. by direct compression, dry granulation/compression, wet granulation/compression or injection moulding (see document (5)). In particular, there is no disclosure to avoid aqueous solutions during granulation and coating.

5.11 In view of the above, the board concludes that none of the available prior art documents, either alone or in combination leads the person skilled in the art in an obvious manner to a process according to claim 1 of the main request. The subject-matter of the main request therefore complies with Article 56 EPC.