T 0387/21 (Solid dispersion of Rotigotine / UCB BIOPHARMA) 28-10-2022

Main request (patent as granted), inventive step

1. Following appellant O1's withdrawal, at the oral proceedings, of the objections of added subject-matter, insufficiency of disclosure and lack of novelty, the sole issue to be addressed is inventive step. In the following, inventive step is assessed for the subject-matter of claim 4, which is the broadest claim of the main request.

The invention seeks to address the problems of stabilizing a solid dispersion of non-crystalline rotigotine for use in the preparation of a transdermal therapeutic system (TTS) having increased long term storage stability due to the reduced formation of rotigotine crystals (see paragraph [0001] of the patent). To solve these problems, the claimed solid dispersion comprises a dispersed phase comprising PVP and rotigotine free base in defined ratios, and a dispersing agent containing at least one silicone pressure sensitive adhesive and having defined solubility for rotigotine.

Appellant O1 raised objections of lack of inventive step starting alternatively from D1, D2 or D3/D8.

2. Starting from D1

2.1 D1 discloses a solid dispersion transdermal drug delivery system (TTS) including an adhesive layer which comprises an adhesive, a therapeutic agent in amorphous form and a combination polymeric stabilizing and dispersing agent and a protective release liner (see paragraphs [0002] and [0020]). The therapeutic agent is present in a stable amorphous form (i.e. non-crystalline) and forms a solid dispersion with a polymer stabilizer (see paragraph [0051]). The therapeutic agent may, in one of several alternatives, be rotigotine (see paragraphs [0057]-[0068]). The adhesive material is most preferably one or more polysiloxanes (i.e. silicones; see paragraph [0044]). The stabilizer is most preferably polyvinyl-pyrrolidone (i.e. PVP; see paragraph [0049]).

The weight ratio of the stabilizing agent to rotigotine is 0.5 or greater, or, in other words, the weight ratio of rotigotine to stabilizing agent is 9:4.5 or lower (see paragraph [063]).

Thus, D1 discloses a TTS solid dispersion comprising one or more polysiloxanes as adhesive material, PVP as stabilizer, and rotigotine, with a rotigotine : stabilizer weight ratio of 9:4.5 or lower.

2.2 However, for the following reasons, D1 neither discloses this ratio in combination with the use of rotigotine free base, nor that the solubility of rotigotine in the dispersing agent is below 1 wt%.

2.2.1 Firstly, D1 does not explicitly disclose that "the solubility of rotigotine in the dispersing agent is below 1 wt%".

Appellant O1's position is that, if the solubility of rotigotine in a silicone dispersing agent is below 1 wt% according to the contested patent, then the same must be true for the same material (polysiloxane adhesive) in D1.

The Board does not share this position. There is no indication, in the patent or otherwise, that all silicones or polysiloxane adhesives generally stated in paragraph [0044] of D1 are characterized by a solubility for rotigotine free base below 1 wt%. In the patent, the formulation examples (see the examples and table 1) contain specific silicone adhesives as dispersing agent, namely a mixture of the Dow Corning silicone adhesives BIO-PSA Q7-4301 and 4201. In contrast, D1 neither discloses the claimed solubility, nor specific polysiloxane adhesives (such as those exemplified in the patent) leading implicitly to this solubility.

2.2.2 Secondly, paragraph [0063] of D1 does not disclose the rotigotine : PVP ratio of 9:4.5 in the context of rotigotine free base.

D1 generally indicates that the "references to the therapeutic agents also include their salts" (see paragraph [0053]). In light of this general indication, the mention of rotigotine in paragraph [0063] cannot be assumed to refer specifically to the free base, but must be regarded as being unspecific as to which form of rotigotine is meant.

2.2.3 Furthermore, D1 discloses that "if the therapeutic agent has a low glass transition temperature, the weight ratio of the polymeric material to the amorphous form of a therapeutic agent required to disperse the amorphous form of the therapeutic agent is 2 or greater", a low glass transition temperature (Tg) being less than 50° C (see paragraph [0030]). Thus D1 indicates that, if the therapeutic agent (here: rotigotine) has a low Tg, a weight ratio of polymeric stabilizing/dispersing agent (here: PVP) to rotigotine of at least 2 is not just preferable, but mandatory to obtain a dispersion. A weight ratio of PVP to rotigotine of at least 2 corresponds to a rotigotine : PVP ratio below 9:18, which is outside the claimed range of 9:4 to 9:6.

Appellant O1 points out that the weight ratio of polymeric stabilizing/dispersing agent to therapeutic agent in D1 is generally at least 0.5 according to claims 2 and 14 of D1. However, in the Board's view, the broad definition of the invention in claims 2 and 14 of D1 does not lead to a different reading of D1. This broad definition covers both alternatives, namely a polymer : therapeutic agent ratio above 0.5 for high Tg therapeutic agents, and above 2 for low Tg therapeutic agents. However it does not imply that a ratio of 0.5 is possible in the specific case of low Tg therapeutic agents. This is also not derivable from paragraphs [0058]-[0060] of D1, since these passages are limited to different therapeutic agents (namely scopolamine, oxybutynin or naltrexone). On the contrary, paragraph [0057] reiterates that therapeutic agents with lower Tg "require an increased amount of stabilizing agent, by weight, to disperse and stabilize the therapeutic agent" (i.e. in a ratio of 2 or greater).

2.2.4 As shown in D13, rotigotine free base has a low Tg of 9° C (see section 5). Accordingly, the disclosure in paragraph [0063] of D1, relating to a weight ratio of stabilizing agent to rotigotine of 0.5, is not only unspecific as to the form of rotigotine referred to (i.e. salt or free base), but is in fact incompatible with rotigotine free base having a low Tg. This passage is rather consistent with a form of rotigotine with a high Tg (see paragraph [0031] of D1), such as a rotigotine salt. Rotigotine HCl for instance has a Tg=76° C (see D13).

2.3 The Board comes to the conclusion that, even if the problem to be solved is the provision of an alternative solid dispersion of rotigotine, an inventive step is to be acknowledged, because the skilled person, starting from D1, would not consider the use of rotigotine free base in combination with the claimed rotigotine : stabilizer weight ratio.

As explained above (see 2.2.3), in D1 (see paragraph [0030]), a ratio polymeric material : therapeutic agent of 2 or greater, corresponding to a rotigotine : PVP ratio of 9:18 or lower, is "required" for therapeutic agents with low Tg, e.g. less than 50°C. The combination of rotigotine free base (having a low Tg) with the much higher ratio of from 9:4 to 9:6 is thus not compatible with the teaching of D1.

2.4 Accordingly, the skilled person, starting from D1, would not consider a rotigotine : PVP ratio of 9:4-9:6 in combination with the use of rotigotine free base as an obvious solution to the problem.

3. Starting from D2

3.1 D2 is concerned with the provision of a TTS encompassing a rotigotine containing adhesive matrix. TTS Formulation 20011036 of D2 (see page 10, table 1) is a solid dispersion comprising a silicone pressure sensitive adhesive (silicone-based hot melt adhesive containing Bio-PSA 7-4300 Bio adhesive), 10 wt% PVP and 15 wt% free-base rotigotine, hence with a rotigotine : PVP ratio of 9:6.

Considering the similarity of the general purpose (the preparation of rotigotine TTS) and in terms of features, D2 is a suitable starting point for the assessment of inventive step.

3.2 The subject-matter of claim 4 differs from the TTS formulation 20011036 of D2 in that the solubility of rotigotine in the dispersing agent is below 1 wt%.

3.3 Considering that no effect has been shown to be associated with the differentiating feature, the technical problem starting from D2 is the provision of an alternative solid dispersion of rotigotine.

3.4 The Board agrees with appellant O1 that the claims of the main request are not limited to any particular process for the preparation of the dispersion, and cover both solvent-based or hot-melt processes. The relevant question is however whether the skilled person, starting from D2, would consider using a dispersing agent in which rotigotine (free base) has a solubility below 1 wt%.

3.4.1 The crux of D2 is to avoid the drawbacks associated with solvent-based processes, and in particular to allow for larger amounts of rotigotine. To this end, D2 proposes a TTS with a rotigotine-containing adhesive matrix, characterized in that the adhesive matrix is produced in a hot-melting process, whereby the adhesive matrix contains a hot-meltable adhesive in which rotigotine is dispersed and partly or completely dissolved (see paragraphs [0010] and [0018]). In the Board's view, the skilled person, starting from D2, would not realistically take a step back and consider solvent-based processes. Hence the skilled person starting from D2 would consider the use of dispersing agents only to the extent that they are compatible with the hot-melt process of D2.

3.4.2 In this respect, D2 requires the use of specific hot-meltable dispersing agents (see paragraphs [0052]-[0055]) in which rotigotine is partly or completely dissolved. This statement must be read in the context of the purpose of D2, which is to allow for higher charges of rotigotine such as up to over 40%. In particular, the chosen starting point (formulation 20011036 of D2) contains 15 wt% rotigotine. Accordingly, the skilled person is explicitly instructed by the starting point D2 not to choose dispersing agents with a low solubility for rotigotine, and would be deterred from choosing a dispersing agent with a solubility for rotigotine below 1 wt%.

Contrary to appellant O1's opinion, there is no indication that the skilled person could regard a dispersing agent in which rotigotine has a solubility below 1 wt% as compatible with these limitations set in D2. Appellant O1 referred to paragraphs [0139]-[0141] of D2, which allow for the adhesive matrix to contain 50-99 wt% of hot-meltable adhesive and 1-40 wt% rotigotine. However, even if this broad disclosure covers, at one end-point, the presence of rotigotine in an amount of 1 wt% in the adhesive matrix, it does not mean that this low amount of 1 wt% rotigotine could be only partially soluble in the matrix.

Accordingly, the skilled person, starting from D2, would not consider the use of a dispersing agent with a solubility for rotigotine below 1 wt% as an obvious solution to the problem.

4. Starting from D3 or D8

Both D3 (see examples 2 and 4 on pages 15-16 and 20-22) and D8 (see Invention example 1 on page 4) show TTSs containing rotigotine free base, PVP and at least one silicone pressure-sensitive adhesive, wherein the rotigotine : PVP ratio is 9:3 or 9:2. The compositions of D3 and D8 correspond to the (comparative) 9:2 composition of the patent (see table 1) and use the same mixture of BIO-PSA® Q7-4301 and 07-4201 as dispersing agent.

The sole distinguishing feature is the rotigotine to PVP weight ratio of 9:4 to 9:6.

According to the appellants P, the technical effect resulting from this difference is an improvement in stability in combination with an unchanged drug release. In the Board's view, this effect is supported by the experimental data of the patent (see paragraph [0129] and table 3): increasing the amount of PVP to a rotigotine : PVP ratio of 9:4 or 9:6 prevents the crystallization of rotigotine which occurs for a ratio of 9:2. At the same time, the drug release profiles for ratios of 9:4 and 9:6 remain similar to, or better than, those for ratios of 9:2 and 9:3 (see figure 1 and paragraph [0142]).

Accordingly, the objective technical problem is the provision of an improved transdermal therapeutic system containing rotigotine as active ingredient preventing rotigotine from crystallization and providing for a sufficient drug release.

Appellant O1 considers that the claimed solution is obvious in light of D1 or D2, or taking into account the known properties of PVP. The Board does not concur and considers that the skilled person could not expect that the claimed subject-matter would solve the above problem. In D1, a rotigotine : stabilizer ratio within the claimed range of 9:4-9:6 is not considered in the context of rotigotine free base (see 2.2.4 above). In D2, a rotigotine : PVP ratio of 9:6 is shown in the context of hot-meltable dispersing agents, and is not associated with the improvement observed in the patent. Lastly, PVP is known as a crystallization inhibitor for transdermal preparations, but is also known to be detrimental to other properties such as permeation rates for delivery (see D10, paragraphs [0008] and [0017]). Hence, the skilled person would not expect that the release profile would remain satisfactory.

In conclusion, the main request meets the requirement of inventive step.