T 2209/21 12-12-2023

1. Oral proceedings, absence of opponent 1

1.1 In conformity with Article 15(3) RPBA and Rule 115(2) EPC, the oral proceedings before the board took place in the absence of opponent 1.

1.2 Opponent 1 had been duly summoned and had not presented any requests or arguments in writing (see points VIII. and IX. above). Thus, opponent 1 chose not to avail itself of the opportunity to present its comments on the grounds and evidence in the appeal case (Article 113(1) EPC).

2. Main request - inventive step (Articles 100(a), 52(1) and 56 EPC)

Patent in suit

2.1 Cytisine is a plant alkaloid used in the treatment of pain and nicotine addiction (see paragraphs [0002] and [0003] of the patent in suit). The patent in suit aims to provide stable solid formulations of cytisine, in particular tablet formulations that can be prepared by direct compression (see paragraphs [0001], [0016] and [0018]).

2.2 The patent reports that the presence of lactose was found to impair the stability of cytisine, whereas a number of other excipients showed better compatibility (paragraphs [0014] and [0015]).

2.3 The cytisine tablets according to claim 1 of the main request (see point I. above) are prepared by direct compression. They do not contain lactose, but must contain 20% to 75% by weight of microcrystalline cellulose, a glidant and at least one excipient chosen from mannitol, colloidal silicon dioxide and calcium hydrogen phosphate. Moreover, it is mandatory that at least 60% of the cytisine particles have a size of 10 mym to 200 mym.

Starting point in the prior art

2.4 It was common ground that D1 represented the closest prior art. Like the patent in suit, D1 relates to solid dosage forms, in particular tablets, containing cytisine (see D1: paragraph [0001] and claim 1).

2.5 Document D1 discloses coated tablets containing cytisine, lactose, microcrystalline cellulose, talc and magnesium stearate (see D1: claim 1; Examples 1 and 2 in paragraph [0006]). Lactose and microcrystalline cellulose are present in a defined ratio ranging from 1:2.0 to 1:2.5, at a total content of 87% to 97% of the tablet mass. The formulations shown in Examples 1 and 2 both contain 1.5 mg cytisine per tablet.

Talc is a tablet glidant (see D10: page 3659, Table 3). According to paragraph [0029] of the patent in suit, magnesium stearate is also to be regarded as a glidant within the meaning of claim 1.

2.6 Among the advantages mentioned in D1 are stability and a homogeneous distribution of cytisine in the tablet mass (see D1: paragraph [0007]).

Distinguishing technical features and associated technical effects

2.7 It was not in dispute that the compositions according to claim 1 differ from the compositions in D1 by

(a) the absence of lactose, and

(b) the mandatory presence of at least one excipient selected from mannitol, colloidal silicon dioxide and calcium hydrogen phosphate

2.8 Feature (a): absence of lactose

2.8.1 As pointed out in paragraph [0020] of the patent in suit, a first technical effect of the absence of lactose is the suitability of the claimed tablets for lactose-intolerant patients.

2.8.2 Increased stability of cytisine during storage was mentioned as a further technical effect of the absence of lactose.

According to compatibility testing described in the patent in suit (paragraphs [0010] to [0015]) and in the application as filed (page 3, line 5 to page 4, line 13), storing a mixture of cytisine and lactose at 50°C/75% RH for 28 days resulted in a high impurity content of 77.1%. Mixtures of cytisine with microcrystalline cellulose or with certain other excipients tested (these included mannitol, colloidal silicon dioxide and calcium hydrogen phosphate) resulted in considerably lower impurity contents of between 1.7% and 0.1%.

The appellant did not dispute in its submissions that replacing lactose in the formulations resulted in better stability.

However, the board is of the view that the compatibility experiment described in the patent cannot demonstrate conclusively that the claimed tablets achieve increased stability compared to that of the tablets according to D1. In the experiment described in the patent in suit, two-component-mixtures of cytisine with varying excipients were compared. However, there was no experiment comparing tablet compositions according to claim 1 with tablet compositions taught and disclosed in D1. The tablet compositions are more complex than the mixtures compared in the experiment described as they contain more than two components and are characterised by further properties not considered in the compatibility experiment.

Furthermore, the data in D1 itself ("Stability Test Table" on pages 4 and 5) does not suggest unsatisfactory stability, nor does D1 mention any concerns in this regard, and in fact it states in paragraph [0007] that the test results illustrate the compositions' good stability. Two lots of tablets made according to Example 2 were tested (paragraphs [0007] and [0008]). The tablets of the first lot still contained 98.7% of the active agent cytisine after one year and 96.8% after two years of storage, and the tablets of the second lot still contained 98.0% of the active agent after one year and 96.7% after two years of storage (at 25 ± 2°C and 60 ± 5% RH).

Since the information in D1 does not raise any concerns about stability, an experiment providing a direct comparison of tablets according to claim 1 and those according to D1 would have been required to show that the claimed tablets do indeed have superior stability.

In the absence of such evidence, the alleged but unconfirmed technical effect of superior stability cannot be used in the formulation of the objective technical problem.

2.9 Feature (b): mandatory presence of at least one specified excipient

2.9.1 Claim 1 defines three alternative embodiments for this feature. For the purposes of the present decision, it is sufficient to consider the embodiment according to which the tablets contain mannitol.

2.9.2 According to the results of compatibility testing as reported in the patent in suit (see point 2.8.2 above), mannitol was found to be compatible with cytisine.

2.9.3 Apart from this, there is no evidence on file of any specific technical effect linked to the presence of mannitol beyond its well-known usual function in pharmaceutical tablets as a diluent or filler (see paragraph [0027] of the patent in suit; D8: pages 449 to 452; D10: page 3679, Table 5; D13: 7.4.2).

2.10 According to the respondent, further distinguishing technical features were

(c) the requirement that the cytisine included micronised material (i.e. having particle sizes below 10 mym) in a proportion of up to 40%, as implied by the feature in claim 1 that the size of at least 60% of the cytisine particles was 10 mym to 200 mym, and

(d) product features associated with tablet preparation by direct compression, specifically a lower water content than achievable according to D1

This was contested by the appellant.

2.11 The board reached the conclusion that the respondent's arguments in relation to technical features (c) and (d) and associated technical effects are not convincing, for the following reasons.

2.11.1 Feature (c): particle size

Claim 1 of the main request provides that at least 60% of the cytisine particles have a size from 10 mym to 200 mym (according to the description in paragraph [0021], this is the size requirement for the cytisine material before tableting).

Claim 1 of D1 does not specify a particle size for cytisine. The description mentions, in paragraph [0004], that the average dimension of the cytisine particles is 90 mym. This is also a feature of dependent claim 2 of D1. While particle size is not mentioned in Examples 1 and 2, the examples may arguably be read together with paragraph [0004], which specifies an average dimension of 90 mym.

The feature "average dimension of 90 mym" in D1, while not incompatible with the definition in claim 1 of the main request, does not translate into a defined particle size range and does not amount to a direct and unambiguous disclosure of at least 60% of the particles having a size of 10 mym to 200 mym. Indeed it is readily apparent that the same average value could be reached with fewer than 60% of the particles being in the size range of 10 mym to 200 mym.

As a consequence, the particle size restriction in claim 1 is considered to be a further distinguishing feature. However, the size definition in claim 1 overlaps with the definition of preferred dimensions stated in D1.

Contrary to the respondent's further assertion, the particle size requirement in claim 1 does not necessarily mean that a fraction of the cytisine is present in micronised form with particle sizes below 10 mym. While this is a possible embodiment, the terms of claim 1 are equally met if, for instance, 100% of the cytisine particles have a size of 60 mym to 120 mym, or of 180 mym to 200 mym.

In its reasoning in support of inventive step, the respondent did not rely on any technical effect associated with the size range defined in claim 1, except in relation to the presumed presence of a substantial micronised fraction with particle sizes below 10 mym. Since the presence of a micronised fraction is not mandatory in claim 1, this is not a feature that distinguishes the entire scope of claim 1 from the disclosure of D1. As a consequence, any alleged technical effect associated with this feature (such as tablet hardness, as mentioned by the respondent) cannot be taken into account in the formulation of the objective technical problem.

2.11.2 Feature (d): product-by-process feature(s)

Claim 1 of the current main request is directed to a pharmaceutical composition in the form of a tablet. The claim also specifies that the tablet is manufactured by direct compression.

Document D1 does not disclose any method for tablet preparation. In its reply to the grounds of appeal (see page 3, penultimate paragraph), the respondent stated that it was not possible to know what the preparation method in D1 was. In contrast, at the oral proceedings before the board the respondent argued that the preparation method according to D1 could only be a wet granulation method.

The board is of the view that it cannot be derived from the information in D1 which method was used for preparing, for instance, the two lots of tablets according to Example 2 that underwent testing. The board is not persuaded by the respondent's reasoning that direct compression can be ruled out as being encompassed by the teaching of D1. D1 simply does not discuss tablet preparation and does not teach or disclose any preferred method. Even if one were to assume, in the respondent's favour, that D1 restricts tablet preparation to wet granulation methods, there is no evidence of a specific technical effect linked to this alleged difference in process.

The following considerations apply:

Claim 1 is directed to a product in tablet form. Any method steps relating to its preparation are not technical features of the product. Any distinction of the claimed subject-matter over D1 on account of the direct compression method would have to reside in structural features or properties of the tablets resulting from this manufacturing method. Thus, the question to be answered is whether there is any evidence that the tablets according to claim 1 differ from those taught in D1 as a result of the method of preparation thereof.

According to the established case law of the Boards of Appeal, if a patent proprietor wishes to rely on a "product-by-process" feature as a distinguishing feature, the burden is on the patent proprietor (here: the respondent) to show that the claimed product does indeed differ from products of the prior art by its structural features and/or properties.

In the case at hand, this could only have been shown by means of experiments performed to provide a direct comparison of cytisine tablets prepared by different tableting methods. Such comparative data is not on file. It was not shown how tablets according to claim 1 might differ in their structure or properties from tablets prepared by a wet granulation process, nor how this would result in a technical effect relevant for inventive step.

The respondent submitted that tablets prepared according to D1 were less stable than tablets according to claim 1 obtained by direct compression. However, the available data on tablet stability does not permit this conclusion to be drawn. Firstly, as mentioned above (see point 2.8.2), the data provided in D1 does not confirm the respondent's assertion that the tablets in the example lacked stability. Secondly, no direct comparison with tablets according to claim 1 is available.

In its submissions in relation to tablet stability, the respondent referred in particular to water content.

In fact, claim 1 does not set an upper limit for the tablets' water content. The respondent argued that low water content was nevertheless an inherent feature of the process of preparation by direct compression.

In a process that involves wet granulation (as postulated by the respondent for D1), the granulation liquid is removed by evaporation before the granules are used for tableting. No evidence was provided to show that the hypothesised potential adverse effects of wet granulation will actually materialise in the circumstances of the case at hand, e.g. that wet granulation will impair the stability of cytisine during processing or that the product of a direct compression process will inevitably have a lower water content than the product of a process involving wet granulation. Moreover, the respondent did not provide any evidence for its allegation that only a direct compression process would result in tablets with a low enough water content to ensure storage stability.

Objective technical problem and solution

2.12 In view of these considerations, the objective technical problem starting from the disclosure of document D1 is the provision of a modified pharmaceutical cytisine tablet with better tolerability.

2.13 This problem is solved by the tablet defined in claim 1, which is suitable also for patients suffering from lactose intolerance (see point 2.8.1 above).

Obviousness of the solution

2.14 D1 describes cytisine tablets containing both lactose and microcrystalline cellulose in a specified ratio. The rationale behind these technical features is not explained.

2.15 However, a commonly known drawback of the use of lactose as a tableting excipient is the unsuitability of the resulting tablets for patients with lactose intolerance (see, for instance, D6: Table 2).

2.16 In light of common general knowledge, it would thus have appeared obvious to the person skilled in the art seeking to solve the objective technical problem to consider developing modified lactose-free formulations, in order to provide cytisine tablets that could also be administered to patients with lactose intolerance.

2.17 The function of lactose in tablet formulations is that of a diluent (or filler). If lactose was to be omitted, it would have appeared obvious to replace it with another widely-used diluent, such as mannitol. The mere fact that D1 happens to rely on lactose is not a technical reason why it cannot be replaced by an equivalent diluent if there is an incentive for doing so.

2.18 There was no technical prejudice against combining mannitol with cytisine, and it would not have been surprising that mannitol, which has the advantage of not being a reducing sugar, proved to be compatible with cytisine (see point 2.8.2 above).

2.19 D1 does not teach any particular tableting process. Since direct compression has the advantages of simplicity and economy and avoids exposure of the active agent to heat and moisture, the skilled person would have envisaged and sought formulations that can be tableted by direct compression as the method of choice.

2.20 In this context, it was known that both mannitol and microcrystalline cellulose can be used in both granulated and directly compressed tablet formulations (see D8: page 132, point 7, page 449, point 7; D10: page 3656, Table 1, page 3664, Table 6).

2.21 The optimisation of the ratios and particle sizes of the components of a tablet is part of a pharmaceutical formulator's routine actions. The particle size of cytisine as defined in claim 1 is not unusual, overlaps with particle sizes taught in D1, and has not been associated with any particular technical effect.

2.22 Thus, the incentive for changing the formulation taught in D1 would have been the known problem of lactose intolerance in certain patients. The person skilled in the art would have had no reason to doubt the suitability of mannitol as a diluent and of direct compression as the method for preparing the tablets. They would have implemented these features as a matter of routine, without using inventive skill and without being dissuaded by the teaching of any of the prior-art documents on file.

2.23 As a consequence, the subject-matter of claim 1 of the main request does not involve an inventive step within the meaning of Article 56 EPC.

3. Auxiliary request 1 - admittance (Article 13(2) RPBA)

3.1 Auxiliary request 1 was filed for the first time on the afternoon of the oral proceedings before the board. It constitutes an amendment of the respondent's appeal case because no request had previously been on file with an independent claim containing the feature "the cytisine has average particle size d50 in the range from 10 mym to 30 mym".

3.2 The respondent failed to provide convincing reasons as to why this late amendment to its case would be justified by exceptional circumstances.

3.3 In opposition-appeal proceedings, it is often the case that the board does not arrive at the same conclusions as the opposition division, or that it agrees with arguments made by the opposing party. This is not an exceptional situation.

3.4 If the respondent intended to rely on the feature defining a range of d50 as a fallback position, it should have filed a corresponding set of claims at an earlier stage of the proceedings.

3.5 For these reasons, the board did not admit auxiliary request 1, in accordance with Article 13(2) RPBA.

3.6 Auxiliary request 2 - inventive step (Articles 52(1) and 56 EPC)

3.7 Claim 1 of auxiliary request 2 differs from claim 1 of the main request in that it specifies that the tablet contains 1.5 mg cytisine (see point VII. above).

3.8 This is not a feature distinguishing the claimed tablets from those described in D1 (see D1: Examples 1 and 2 in paragraph [0006]; the formulations disclosed in Examples 1 and 2 of D1 both contain 1.5 mg cytisine in 100 g uncoated tablet).

3.9 Hence, this feature cannot have any impact on the formulation of the objective technical problem and on the assessment of inventive step as set out in section 1 above.

3.10 As a consequence, the subject-matter of auxiliary request 2 does not involve an inventive step within the meaning of Article 56 EPC, for the same reasons as those set out with respect to claim 1 of the main request.