T 2596/12 (Prasugrel tablets comprising hydroxypropyl cellulose/DAIICHI UBE) 25-05-2018

Reasons for the Decision

1. The appeal is admissible.

Main request

2. Inventive step (Article 56 EPC)

2.1 Claim 1 of the main request is directed to a tablet comprising a compound of formula (I) (hereinafter prasugrel) and hydroxypropyl cellulose (see point IV above).

2.2 The board considers, in agreement with the examining division and the appellants, that document D1 is a suitable starting point for the assessment of inventive step.

This document discloses prasugrel salts and pharmaceutical formulations comprising them. The formulations may be, inter alia, in the form of tablets (see D1, paragraph [0020]). Additives, such as excipients, lubricants, binders, disintegrants, emulsifiers, etc., may be present in the formulations (see D1, paragraph [0021]). Excipients include, inter alia, sugar derivatives, such as lactose, sucrose, starch derivatives, such as corn starch potato starch, cellulose derivatives, such as crystalline cellulose (see D1, paragraph [0022]). Binders to be used include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone or excipients as described in paragraph [0022] (see D1, paragraphs [0024]).

Document D1 also explicitly discloses tablets with prasugrel hydrochloride or maleate, cellulose, lactose and magnesium stearate as ingredients (see page 10, formulation examples 2 and 4).

According to the board's knowledge, cellulose is commonly known to have binding properties. That has been conceded by the appellants at the oral proceedings before the board and confirms the appellants' view expressed in the statement of grounds of appeal (see point 8, last two lines). Lactose, although mainly used as filler, is also known to be useful as a binder. That has been acknowledged by the appellants in the statement of grounds of appeal (see page 4, point 4). Magnesium stearate acts as lubricant.

2.3 In the light of document D1, the appellants defined the problem to be solved as the provision of a tablet with improved storage stability.

2.4 The proposed solution lies in the presence of hydroxypropyl cellulose.

2.5 In order to demonstrate that the technical problem as defined above has effectively been solved, the appellants relied on results provided in the application, in particular the comparison between example 1 and comparative example 1.

2.6 In example 1 of the application prasugrel hydrochloride (3.4 g), hydroxypropyl cellulose (17.5 g), croscarmellose sodium (12.5 g), lactose (215.3 g) and magnesium stearate (1.3 g) had been mixed to give a powder, which was compressed to obtain tablets of approximately 80 mg. Hydroxypropyl cellulose and lactose constitute the binder. In a subsequent step the tablets were coated. In comparative example 1 lactose alone, the amount of which had been increased by 17.5 g, constitutes the binder. Stability tests with example 1 and comparative example 1 showed an improved storage stability for example 1 (73% vs 4%; see application page 15, table 1).

It is immediately apparent that the comparative example of the application does not reflect the closest state of the art, namely the tablets disclosed in document D1, in which cellulose and lactose constitute the binder.

2.7 The appellants argued that the comparison made was a fair comparison. Example 1 and comparative example 1 differed only in the presence of hydroxypropyl cellulose. Therefore, the observed improvement in storage stability could clearly be attributed to the presence of hydroxypropyl cellulose. The effect was highly surprising for a binder, the purpose of which was normally to improve the mechanical strength of a tablet. Moreover, document D1 disclosed that binders might be chosen from a list of known binders (see D1, paragraph [0024]). No specific binder from that list was taught or recommended. Therefore, the comparison made against a tablet which contained "a binder" (i.e. lactose as in comparative example 1) was a valid comparison with the prior art.

2.8 The board does not agree.

It cannot be denied that an improvement in storage stability has been observed for example 1 compared to comparative example 1. However, comparative example 1 does not reflect the closest state of the art (i.e. the tablets according formulation examples 2 and 4). The comparison against this example is therefore not suitable for making the alleged improvement in storage stability plausible, let alone surprising. The board also notes that it is established jurisprudence of the boards of appeal that where comparative tests were relied on as evidence for an alleged effect, there must be the closest possible structural approximation to the subject-matter of the invention (see T 181/82, OJ EPC 1984 401, headnote I). This is not the case here. The selection of lactose as a binder in comparative example 1 does not represent the closest approximation, because other binders, such as cellulose derivatives (e.g. microcrystalline cellulose), which are structurally much closer to the claimed hydroxypropyl cellulose than lactose, are equally suggested in paragraph [0024] of document D1. Moreover, the use of cellulose has been explicitly taught in formulation examples 2 and 4 of document D1. Hence, in the board's judgement, for a proper comparison it would have been necessary to compare the tablet according to example 1 of the application comprising hydroxypropyl cellulose and lactose against a tablet comprising cellulose and lactose as in the formulation examples 2 and 4 of document D1. The board also notes that lactose and cellulose, although both are useful as binders, belong to different classes of compounds with different physico-chemical properties. Any effect that may have been shown against lactose cannot be extrapolated to cellulose.

2.9 It follows from the above that the comparison of example 1 of the application with comparative example 1 cannot properly demonstrate that the purported improvement in storage stability of the claimed tablet has been successfully achieved vis-à-vis the tablets known from document D1. Accordingly, the technical problem as defined by the appellant (see point 2.3 above) needs to be reformulated in a less ambitious way. In the light of document D1, the board considers that the problem to be solved was the provision of a further prasugrel comprising tablet. The board has no doubts that this problem has been solved by the claimed subject-matter.

2.10 It then remains to be decided whether the proposed solution is obvious for the skilled person in view of the prior art.

Document D1 discloses in the general part of the description that the prasugrel salt comprising pharmaceutical formulations can be prepared by well-known methods using additives, such as excipients, lubricants, binders, disintegrants, emulsifiers, etc. (see page 4, paragraph [0021]). Hydroxypropyl cellulose is explicitly disclosed as an example of a suitable binder (see page 4, paragraph [0024]). Its selection has not been shown to result in a particular technical effect and is therefore neither critical nor purposive. It is merely an arbitrary selection of no technical significance, made within the ambit of document D1. Such a selection does not require any inventive ingenuity. The claimed subject-matter is therefore obvious in view of the teaching of document D1 alone.

2.11 The appellants' arguments with regard to obviousness were based on the assumption that the purported improvement in storage stability had been adequately established and was highly surprising (see point VI above).

2.12 However, since the objective technical problem consists merely in the provision of a further tablet, the appellants' arguments cannot succeed. As explained in point 2.10 above, the mere arbitrary selection of a binder, which is a commonly used additive in tablets, does not require inventive skills.

2.13 The argument that document D1 did not place any emphasis on any of the additives mentioned on page 4 and did not single out a particular additive can also not succeed. In the present case, where the technical problem is merely the provision of a further tablet and where the solution merely consists in arbitrarily selecting a feature within the ambit of document D1, no particular incentive for the selection is required.

2.14 For the aforementioned reasons, the board concludes that the subject-matter of claim 1 of the main request does not involve an inventive step (Article 56 EPC).

First auxiliary request

3. Inventive step (Article 56 EPC)

3.1 Claim 1 of the first auxiliary request differs from claim 1 of the main request in that the amount of hydroxypropyl cellulose is specifically defined (i.e. 2.5 to 20% by weight with respect to the total amount of the composition of the tablet).

3.2 This amendment does not alter the above assessment of inventive step regarding the subject-matter of the main request. No advantageous effects or improvements have been shown to be associated with the selected amount. The problem to be solved therefore remains the same as formulated in point 2.9 above.

3.3 The selection of an appropriate amount of binder is a routine task which does not exceed the ordinary skills of the person skilled in the art. Inventive ingenuity is not required. Nor have the appellants provided any arguments - and none are apparent to the board - that the selected amount of hydroxypropyl cellulose would be unusual for a tablet binder.

3.4 For the aforementioned reasons, the board concludes that the subject-matter of claim 1 of the first auxiliary request also lacks an inventive step (Article 56 EPC).

Second auxiliary request

4. Inventive step (Article 56 EPC)

4.1 The sole claim of the second auxiliary request differs from the main request in that the tablet consists of a specific ingredients (i.e. prasugrel hydrochloride, a disintegrant, lactose, magnesium stearate and hydroxypropyl cellulose).

4.2 The tablet disclosed in formulation example 2 of document D1, which consists of prasugrel hydrochloride, lactose, magnesium stearate and cellulose, is considered to represent the closest state of the art.

4.3 At the oral proceedings before the board, the appellants admitted that no causal link existed between the allegedly observed improved storage stability and the presence of a disintegrant. According to the appellants, this effect was associated with the presence of hydroxypropyl cellulose.

4.4 However, as explained in point 2.8 above, the purported improvement in storage stability has not been adequately demonstrated. Therefore, the objective technical problem is still considered to be the same as defined in point 2.9 above.

4.5 The selection of hydroxypropyl cellulose as binder or binder component does not require inventive skills for the reasons set out in point 2.10 above. The use of disintegrants is also explicitly suggested in document D1 (see paragraph [0021]). Its presence has admittedly not been shown to result in a particular technical effect and is therefore neither critical nor purposive. It is merely an arbitrary selection of no technical significance, made within the ambit of document D1, and as such does not require inventive skills.

4.6 For the aforementioned reasons, the second request must also be rejected for lack of inventive step of the claimed subject-matter (Article 56 EPC).