T 0143/15 (Glycopyrrolate / VECTURA) 20-11-2018

Main request (patent as granted)

1. Article 100(a) EPC, Inventive step

The problem underlying the claimed invention is the provision of dry powder formulations comprising glycopyrrolate and exhibiting greater stability on storage. These dry powder formulations are to be administered using dry powder inhalers (see patent in suit, page 2). Known micronized glycopyrrolate comprises surface hygroscopic amorphous material leading to formation of hard agglomerates upon moisture absorption (see [0015]). To address this problem, the claimed invention relies on a conditioning step, whereby exposure to moisture leads to re-crystallisation of the amorphous material (see [0035]), and on the addition of a force control agent (magnesium stearate) which reduces the cohesion between fine particles (see [0047]).

1.1 Both parties agree on the choice of document D7 as the closest prior art. The Board sees no reason to differ.

D7 (see the abstract) generally relates to a method of making composite active particles for inhalation, comprising the steps of milling particles of the active material with particles of an additive material, such as magnesium stearate. In D7, it is recognised that small particles of active material have a tendency to agglomerate and that milling increases the level of amorphous material on the surface of the milled particles, making them more cohesive (see pages 1-2; page 4 lines 13-15). The additive material promotes dispersion of the particles and avoids the formation of agglomerates (e.g. page 4, lines 13-18). The method of D7 will in general produce composite active particles bearing the additive material in the form of a coating on their surface, which coating may be continuous or discontinuous (see page 3, lines 9-19; page 12, lines 5-16; page 6 lines 18-20).

A disclosure of glycopyrrolate as active material can be found in example 5 of D7, where micronised glycopyrrolate and magnesium stearate (in a ratio of 75:25 or 95:5) are milled together in a mechanofusion machine.

1.2 According to the appellant, the process shown in example 5 of D7 leads to a complete and coherent coating of magnesium stearate onto the glycopyrrolate particles, with both ratios of 75:25 and 95:5. A reproduction of example 5 of D7 (i.e. D14) and two declarations (D15 and D16) were submitted as evidence. The Board sees no reason to depart from these conclusions.

1.3 In the process of claim 1, the glycopyrrolate undergoes a conditioning step, "which step includes exposure to humid conditions [...]". According to the appellant, since claim 1 requires the glycopyrrolate to be exposed to these humid conditions, a process in which the conditioning step takes place after complete coating of the glycopyrrolate particle (as in D7) is outside the scope of the claims, because the coating will prevent the exposure of glycopyrrolate.

Even if following arguendo this interpretation, it remains the case that claim 1 requires the glycopyrrolate to be micronised and conditioned, and the final formulation to comprise magnesium stearate, without limitation as to how this magnesium stearate is to be incorporated. Accordingly, the magnesium stearate may be incorporated as a coating after conditioning; indeed, a coating step is explicitly considered in the patent in suit in example 8 (which is not identified as a reference example), where a glycopyrrolate is coated with 5% magnesium stearate in a manner similar to that of D7.

Thus the claims cover embodiments in which glycopyrrolate is milled and then undergoes a conditioning step before being finally coated with magnesium stearate in the conditions of D7. Such an embodiment differs from the method shown in D7 by, and only by, the addition of the conditioning step as an intermediate step before coating.

1.4 It is undebated that the particles resulting from the claimed process do not exhibit any improved stability over those of D7 as a result of the conditioning step. The process of D7 was stated by the appellant (e.g. in D15) to result in an inhalable glycopyrrolate formulation with excellent stability. Neither example 7 of the patent in suit, nor any of D12-D16 allow for any proper comparison between conditioned and unconditioned formulations of magnesium stearate - coated glycopyrrolate. Accordingly no effect is shown to arise as a result of this additional step.

1.5 The Board thus concurs with the appellant's definition of the technical problem as the provision of an alternative method for preparing stable formulations of glycopyrrolate suitable for inhalation. Considering the evidence on file, this technical problem is regarded as solved by the subject-matter of claim 1.

1.6 Turning to the obviousness of the claimed solution, document D8 relates to a process for providing a stable crystalline form of a fine-grained substance or substance mixture which can be produced, stored and used while maintaining the aerodynamic properties required for inhalation (see the abstract). D8 thus belongs to the same technical field and addresses the same problem of stability on storage as D7 or the patent in suit. D8 explains on page 2, lines 10-21 that during micronisation of solids, disruption or activation of the crystalline structures often leads to varying degrees of disorder through the formation of defects or amorphous regions. Such regions are often more sensitive to moisture. D8 further states that it is necessary to convert the amorphous form to the more stable crystalline state. This is achieved using a conditioning step in which the micronised material is treated with a water containing vapour phase in a controlled fashion, under the same conditions as those defined in claim 1 of the patent in suit, namely a temperature between 0 and 100°C, preferably between 10 and 50°C, a relative humidity above 35%, preferably above 50%, for a time ranging from minutes to days (see page 5, line 15 to page 6, line 1). Thus D8 suggests to apply the claimed conditioning step as a solution to the same problem of stability on storage.

Regarding the order of steps, D8 also considers mixing the substances after conditioning (see page 10, lines 9-11) and recommends that the conditioning step be performed directly after micronisation (see paragraph bridging pages 10-11).

Accordingly, the Board considers that, in light of D8, the skilled person would anticipate that the addition of a conditioning step prior to coating as taught in D7 would still lead to stable particles.

1.7 The appellant submits that the stability issue is already solved in D7, such that the skilled person would not subject the already stable glycopyrrolate particles to an unnecessary, long and hence inconvenient extra processing step when there was no expectation of a benefit in doing so. The appellant further argues that the skilled person would not consider recrystallising the amorphous surface of the particles using a conditioning step if this crystalline layer was subsequently to be destroyed by the coating step. In this respect, the appellant, referring to T 439/92, considered the modification to go beyond the limits imposed by the choice of D7 as the closest prior art.

For the Board, the addition of the conditioning step as an intermediate step between milling of glycopyrrolate and coating with magnesium stearate remains within the scope of the potential developments the skilled person would consider starting from D7: it is firstly to be noted that, although the specific conditions of example 5 of D7 lead to a complete coating, the general disclosure of D7 allows for partial, discontinuous or porous coating (see page 6, lines 18-20). Furthermore, the starting material in example 5 of D7 is micronized glycopyrrolate; according to D7 (see page 4, lines 13-15), it is known that milling generates amorphous material on the surface of the particles, making them more cohesive. Thus D7 would prompt the skilled person to address the presence of amorphous material in the starting material of D7 by adding a conditioning step as taught in D8 before coating with magnesium stearate. Thus, contrary to the appellant's position, a combination with the teaching of D8 does not amount to a departure from the disclosure or framework of D7 (as in case T 439/92), but represents a further development which the skilled person would consider based on the information in D7.

It may be possible that a complete coating in the conditions taught in D7 will damage the crystalline state induced by the conditioning step of D8 on the surface of the particles. This however does not mean that the skilled person would, when combining these steps, thereby modify the closest prior art in a manner contrary to its purpose: the addition of the conditioning step does not jeopardize the properties of the (stable, coated) final formulation, is not detrimental to the coating step of D7, nor does it require any modification thereof.

As part of the problem-solution approach, the skilled person is assumed to seek a solution to the objective technical problem. As a consequence, in the context of the present invention, the modification of the known process by addition of the otherwise known conditioning step, without thereby achieving any benefit, cannot derive an inventive step from the very fact that the skilled person would expect no benefit from this modification.

The appellant also argues that the skilled person would not look to stabilise the highly hygroscopic glycopyrrolate by exposure to moisture as taught in D8; the evidence D17, comparing the physical state of micronised drugs after 4 days in vials, is cited to show the increased difficulty of working with glycopyrrolate as compared with other substances. However D17 does not appear relevant, as the skilled person would not wait 4 days between micronisation and conditioning in light of the teaching of D8. Furthermore, if glycopyrrolate is so hygroscopic as to render the conditioning of D8 technically impracticable, then it must be observed that no such special precautions during conditioning are defined in claim 1.

Accordingly the main request does not comply with the requirements of Article 56 EPC.

Auxiliary request 1

2. Article 56 EPC

The more narrowly defined temperature (10-50°C) and relative humidity (50-90%) parameters do not depart from those explicitly mentioned in D8 (namely a temperature preferably between 10 and 50°C and a relative humidity preferably above 50%, see page 5, lines 15-36). Consequently the conclusion of lack of inventive step equally applies to auxiliary request 1.

Auxiliary request 2

3. Article 56 EPC

3.1 Starting from D7 as the closest prior art, the claimed process now differs in that the glycopyrrolate undergoes a conditioning step including exposure to humid conditions of 50-90% RH at temperatures between 10°C to 50°C for at least 48 hours, wherein "the powder is agitated or turned during conditioning to ensure that all of the particles are equally exposed to the humid atmosphere".

3.2 The added feature of agitation or turning of the powder is not shown to be associated with any additional effect on stability. The evidence cited regarding an effect of the conditioning step remains unconvincing, even taking this additional feature into account, for the reasons already given above (see point 1.5).

3.3 The objective technical problem thus remains the provision of an alternative method for preparing stable formulations of glycopyrrolate suitable for inhalation.

3.4 Considering that the way D8 addresses the stability problem is by provoking a phase transition from amorphous to crystalline state by contact with a water containing vapour phase, it follows that the skilled person would naturally seek to guarantee a proper contact when implementing the teaching of D8. An agitation or turning of the particles therefore represent a trivial addition to the teaching of D8, which the skilled person would consider as a matter of evidence. Accordingly, the subject-matter of auxiliary request 2 does not comply with the requirements of Article 56 EPC.

Auxiliary request 3

4. Article 56 EPC

The process disclosed in D7 leads to glycopyrrolate particles bearing a coating of magnesium stearate. The feature introduced in claim 1 of auxiliary request 3, according to which the magnesium stearate is predominantly present on the surface of the glycopyrrolate particles, is consequently fulfilled by the particles produced in the closest prior art D7, and does not modify the above conclusions on inventive step.

Accordingly, the subject-matter of auxiliary request 3 does not comply with the requirements of Article 56 EPC.

Auxiliary requests 4 and 5

5. Article 56 EPC

Claim 1 of each of auxiliary requests 4 and 5 is identical to claim 1 of the main request. These requests thus do not comply with the requirements of Article 56 EPC either.