T 0570/12 (PRE-METERED DRY POWDER INHALER FOR MOISTURE-SENSITIVE MEDICAMENTS/Boehringer Ingelheim International GmbH) 24-09-2015

Reasons for the Decision

1. Admission of documents and experimental data into the proceedings

1.1 Admission of documents (30)-(32) into the proceedings

Document (31) is the decision T 2/83 from the Boards of Appeal, and as such may be cited at any time during the appeal proceedings. There is thus no need to discuss its admission into the proceedings.

Documents (30) and (32) were filed by the appellant with the statement of grounds of appeal, thus at the earliest stage of the appeal proceedings:

- Document (30) is a general document relating to aerosol powders cited to show that several factors in addition to the moisture content of the powder affect its aerodynamic properties, and can be seen, for this reason, as a reaction to the decision under appeal.

- Document (32) is an experimental report cited to show the effect of the operating conditions of the loading step and can therefore also be considered as a reaction to the arguments of the decision of the opposition division.

Consequently, documents (30) and (32) are admitted into the proceedings (Article 12(4) RPBA).

1.2 Admission of documents (33) and (34)

The documents were filed by opponent 02, in response to the statement of grounds of appeal of the appellant, in particular to the filing of the auxiliary request, which corresponds to the auxiliary request which was submitted for the first time during the oral proceedings before the opposition division. They can therefore be seen as a legitimate reaction to new submissions.

Consequently, documents (33) and (34) are admitted into the proceedings (Article 12(4) RPBA).

1.3 Admission of document (35)

This document constitutes an addendum to the experiments of document (32) in the form of supplementary experiments. These supplementary data are also a direct response to the points raised for the first time by the Board in its preliminary opinion. As such, they could not have been filed earlier. As the experimental data are a complement to the data given in document (32) and not a new document, their content does not change the case.

Consequently, document (35) is admitted into the proceedings (Article 13(1) RPBA).

2. Main request - Inventive step

2.1 The invention relates to the preservation and delivery of a high fine particle dose (FPD) of tiotropium by a dry powder inhaler (DPI) product comprising a metered dose of tiotropium medicament, adapted for inhalation, packaged in a dry and tight container, such that the FPD when delivered is unaffected for the shelf life of the medical product by normal variations in ambient conditions during handling, storage and delivery using the DPI product (see the specification par. [0001] and [0015]).

2.2 The first step is the choice of the closest prior art.

2.2.1 Document (15) was considered by the opposition division to constitute the closest prior art. Not only the choice of this document was contested by the appellant, which considered in its written submission that document (8) was the only document directed to the same purpose as the patent in suit and as such should be the closest prior art, but also the relevant parts of said document (15) were contested by the appellant during oral proceedings.

2.2.2 Document (8) discloses capsules for inhalation made from hydrophobic plastics polymer and not from aluminium (see claims). This document does not relate to tiotropium.

2.2.3 Document (15) discloses an inhalation kit comprising an inhalable powder of tiotropium and a physiologically acceptable excipient (see page 2, lines 10-14 and 21-26). The examples show several powder compositions made from lactose and tiotropium bromide. As to the administration of said powder, document (15) proposes four alternative inhalers which can be used:

(a) A first alternative is represented by the inhaler described in Figure 1 of document (15) (see also the description pages 5, line 15 - page 7, line 18). This inhaler corresponds to the inhaler system used in the commercial product Spiriva®, wherein the medicament dose is usually loaded with a distinct hard gelatin capsule containing the tiotropium powder which has to be inserted within a capsule chamber before use of the inhaler (see for instance document (2), first page). This specific embodiment does therefore not show an inhaler directly loaded with a container and the composition of the container is not given in document (15).

(b) Another alternative is represented by an inhaler comprising a medicament pack having a plurality of containers for containing a medicament in powder form wherein the containers are spaced along the length of and defined between two peelable sheets secured to each other, and said containers are engaged within the inhaler through an opening station, as in the claimed invention (see the description of document (15) on page 9, line 31 - page 11, line 21). This specific embodiment of document (15) shows thus a pre-metered inhaler device identical to the claimed pre-metered inhaler device, without the specification of the material composition of the barrier seal of the container. In relationship with the disclosure of this specific inhaler, a reference is made in the description of the contested patent to the type of inhaler devices disclosed in document (22), which disclosure is "incorporated by reference in its entirety" in the teaching of document (15) (see document (15), page 9, line 32). The teaching of said cross-reference document (22) shows several pre-metered inhalation devices in all of which is indeed mounted a flexible strip in the form of a lid sheet hermetically sealed to a base sheet and defining a plurality of pockets each of which containing a dose of medicament.

(c) Two other alternative inhalers were described in document (15) on page 7, line 20 - page 9, line 29 and on page 11, line 22-page 13, line 36, making reference to two further documents.

2.2.4 The argument of the appellant regarding the relevance of the different alternatives, namely that only the alternative corresponding to figure 1 of document (15) was a credible existing inhaler, and that the three other inhalers described in document (15) were "paper inhalers", cannot be followed.

First, in view of the disclosure of document (15), none of these alternatives can be distinguished as a preferred one, since they are all explicitly referred to as preferred embodiments.

Then, the disclosure of document (15) does not give any indication that one of the alternatives constituted by document (22) might constitute a theoretical or paper alternative, since all these alternatives are disclosed in the description of document (15) with explicit technical informations.

2.2.5 As to the choice of the closest prior art, document (15) thus not only relates to the claimed invention in the sense that it discloses subject-matter conceived for the same purpose or aiming at the same objective, corresponding to a similar use, or relating to the same or a similar technical problem or, at least to the same or a closely related technical field, but also, in comparison to the disclosure of document (8), discloses the greatest number of relevant technical features in common with the claimed invention, i.e. requiring the minimum of structural and functional modifications.

Document (15) does therefore explicitly refer to a pre-metered inhalation device comprising a dry powder medicament dose loaded in a container , but without specific reference to the specific detailed material composition of the container. Hence, document (15), especially its embodiment described on pages page 9, line 31 - page 11, line 21, corresponding to document (22) is seen as the closest prior art.

2.3 According to the appellant, the problem is the provision of a pre-metered dry powder inhaler comprising a metered dose of tiotropium and a container allowing the delivery of a high fine particle dose (FPD) of tiotropium, which remains unaffected/preserved during the shelf life of the dry powder inhaler by normal variations in ambient conditions.

2.4 As a solution to this alleged problem, claim 1 of the main request proposes a pre-metered dry powder inhaler wherein in particular the container comprising the dry powder medicament dose made from tiotropium and particles of at least one dry excipient comprises aluminium.

2.5 It has to be investigated whether there is sufficient evidence supporting the problem as formulated.

The description of the contested patent provides a comparison made by using the Spiriva® inhaler system using the corresponding commercial gelatin capsule and a capsule made from aluminium foils. The test carried out shows that the moisture content of the gelatin capsule reduces the FDP with approximately 50% from the time of loading the dose into a capsule until the point in time when the product reaches the market, and shows a significant difference in favour of a container comprising aluminium since no changes in the FDP are detected even after long periods of time (See Table 1 and par. [0046]-[0047]). Although not using a inhaler with a container directly engaged therein, but a capsule system, this comparison of the contested patent show undoubtedly a satisfactory performance of a container comprising aluminium.

In view of the information found in the description of the contested patent, the board is convinced that the problem has been plausibly solved. In this respect, it is relevant to note that the problem refers to the achievement of satisfactory stability properties, but does not mention an improvement, as the comparative inhaler in the patent is not according to the closest prior art.

2.6 It remains to determine whether the solution was obvious to the person skilled in the art.

Document (15) proposes four explicit alternative inhalers which can be used, two of them being inhalers with a container system loaded within the inhaler device and one of the inhaler with a container system being an inhaler device as shown in document (22). While the reference to document (22) is given in document (15) only in relationship with the type of inhaler device to be used, said document (22) contains further information which could not be regarded as directly incorporated in document (15). Thus, the first inhaler embodiment shown in Figures 1 and 2 of document (22) gives the material composition of the strip, the further embodiments merely referring to said first embodiment (see Fig. 5-9, 10-12 13-16, 17-20, 32-34 and the corresponding texts in the description). In said first embodiment, the unique alternative given is that the strip is in the form of a lid sheet hermetically sealed to a base sheet, both sheet being preferably formed of a plastics/aluminium laminate. By way of unique example, the lid material may be made from kraftpaper/PETP/aluminium and the base material may be a laminate of PVC/aluminium/poylamide (see col. 2, lines 46-66 and Figures 1 and 2). Thus, the use of containers comprising aluminium is disclosed as only possibility in document (22).

In view of the teaching in the prior art, the skilled person implementing the pre-metered inhaler device with the container system of document (15) would have consulted the supplementary technical information contained in document (22) and would have used the same kind of container. It follows that the skilled person would have used the container system disclosed in document (22) in the form of a lid sheet hermetically sealed to a base sheet comprising aluminium as explicitly taught in document (22).

The claimed solution results thus inevitably from a sequence of interconnected technical information originating from the main teaching of the closest prior art document (15) and a supplementary teaching originating from its cross-reference document (22). As a matter of fact, this interconnected technical information differs from a direct disclosure relevant for the question of novelty of the claimed invention only by the fact that document (15) did not contain a direct cross-reference to the materials used in the inhalers of document (22), but only on the type of pre-metered inhaler devices. Hence, the skilled person would have applied one of the possible solutions offered by document (15), which inevitably leads to the claimed solution. Applying this solution requires no particular skills and hence does not involve an inventive step.

As to the existence of the proven stability property which is not explicitly mentioned in document (15), this effect is considered as inevitable when following the alternative chosen as closest prior art and is regarded as a mere additional effect. An additional bonus effect cannot point towards an invention, if the skilled person would inevitably arrive at the invention by simply following the teaching of the prior art document.

2.7 Further arguments from the appellant

The appellant considered that the technical contribution of the patent in suit resides in identifying a problem, which was a hitherto unrecognized problem (cf decision T 2/83). The problem was dealing with the fact that the persistence of very small amounts of water was detrimental for the stability of the powder compositions and that this problem was connected with the influence on the reduction of the fine particle dose (FDP) of tiotropium delivered by the inhaler.

The Board could not follow this argument. The problem raised by the contested patent was indeed a known problem and therefore is not a hitherto unrecognized problem. As mentioned in paragraph [0029] of the description of the contested patent and in document (21) cited therein, tiotropium was known to be extremely sensitive to moisture and document (21) insists on the importance of mastering the water content of the capsules (see pages 6-7). The problem was also identified in document (33), which relates to capsules comprising tiotropium for inhalation having a reduced moisture content, to achieve a high degree of stability and to ensure a high metering accuracy (see document (33), par. [0002], [0007] and [0008]).

As to the possible contribution of the contested patent as regards the influence of "very small quantities of water" over the prior art teaching, the description of the contested patent mentions indeed that the FPD of tiotropium becomes less over time when affected by "very small quantities of water" (see par. [0049]), but said "very small quantities" are not quantified anywhere in the description of the contested patent and therefore cannot be differentiated from the moisture level mentioned in documents (21) or (33). The identification of a smaller quantity of water than the moisture level of the prior cannot thus serve as the identification of a new technical problem.

2.7.1 The main request does not meet the requirements of Article 56 EPC.

3. Auxiliary request 1 - Admission into the proceedings

This request has been filed with the letter dated 12 June 2015 at a late stage in the proceedings. The subject-matter of claim 1 of auxiliary request 1 differs from the subject-matter of claim 1 of the main request by the addition of the feature "directly loaded". According to the appellant, this amendment has no incidence on the discussion on inventive step and has been made to overcome possible objections against the main request on novelty over documents (2) and (21) and objections under Article 123(2) EPC.

Given that the only respondent's objections on the main request related to inventive step and that the amendment made has no incidence on said reasoning on inventive step and was not made to overcome a lack of inventive step, the Board considers that it is appropriate to exercise its discretionary power by not admitting auxiliary request 1 into the procedure in accordance with Article 13(1) of the Rules of Procedure of the Boards of Appeal.

4. Auxiliary request 2 - Inventive step

The subject-matter of claim 1 of auxiliary request 2 differs from claim 1 of the main request by the addition of the feature "the dry powder medicament is loaded into said container at a temperature below 25°C and a relative humidity below 15% Rh".

As the added feature is a product-by-process feature, the first question to be answered is whether the conditions of loading defined therein imply a difference in the loaded powder, which can be acknowledged as a further feature of the claimed dry powder inhaler with respect to the one of the main request. In this respect, it is appropriate to analyse the experimental evidence filed by the appellant.

4.1 Document (32) studies the influence of different environmental conditions during packaging on the fine particle fraction of dry powder formulations of tiotropium packed in aluminium blisters. Two environmental conditions were tested, to be specific at a temperature T of 25°C and relative humidity Rh of 15% and a temperature T of 30°C and relative humidity Rh of 50%. The experimental procedure (part 4) consists in letting the blister strips and the powder blend to equilibrate for 90 minutes under the desired environmental conditions (at T=25°C/Rh=15% and T=30°C/Rh=50%), limiting the time to blister cavity forming and filling to 90 minutes, and performing the filing in rooms with adjusted and controlled room temperatures and relative humidity set again to T=25°C/Rh=15% and T=30°C/Rh=50% respectively. The results obtained were an initial fine particle fraction of 35,2% and 27,0% under the respective conditions of T=25°C/Rh=15% and T=30°C/Rh=50%, and a fine particle fraction after 4 weeks of storage of 33,4% and 12,4% under the respective conditions of T=25°C/Rh=15% and T=30°C/Rh=50%.

The results show clearly that a tiotropium dry powder formulation filled under the conditions of 25°C and Rh of 15% exhibits a higher initial and final fine particle fraction compared to the same formulation filled under the conditions of 30°C and Rh of 50%.

Document (35) provides an addendum to the study performed in document (32), that is at the packaging environmental conditions of 25°C and Rh of 50%. The initial fine particle fraction was 34,3%, very close to the result obtained at T=25°C/Rh=15%, while the fine particle fraction was 21,8% after a 4 week storage period, thus much less than the 33,4% obtained at under the respective conditions of T=25°C/Rh=15%.

4.2 The experiments of documents (32) and (35) are however irrelevant for establishing a difference in the product directly implied by the claimed conditions expressed by the feature that "the dry powder medicament is loaded into said container at a temperature below 25°C and a relative humidity below 15% Rh". The specific packaging environmental conditions used in the experiments (32) and (35) are indeed not representative of the claimed subject-matter and cannot be extrapolated thereto.

The claimed subject-matter refers only to a loading step, while the experimental procedure used in documents (32) and (35) is more complex and includes an equilibration step, a limited filling time, a loading or filling step, and an immediate sealing step. None of those steps, apart from the filling step are part of the claimed subject-matter, nor of the corresponding part of the description where the feature "the dry powder medicament is loaded into said container at a temperature below 25°C and a relative humidity below 15% Rh" originates from paragraph [0057] of the specification. In particular, the blister strips and the powder were let to equilibrate for 90 minutes, an obviously crucial condition which does not appear to be part of the claimed feature or even of the description of the contested patent. The description indeed refers only to the steps of "dose forming, loading and container sealing" that should be closely controlled, with a temperature preferably below 25°C and relative humidity preferably below 15 % Rh.

The results of experiments (32) and (35) cannot therefore be extrapolated to the claimed subject-matter, and there is thus no evidence that a loading step into said container at a temperature below 25°C and a relative humidity below 15% Rh inevitably confers to the powder a different structure or property.

None of the further experiments (32) or (35) offer thus sufficient evidence to support the assumptions that the feature "the dry powder medicament is loaded into said container at a temperature below 25°C and a relative humidity below 15% Rh" provides a difference in the claimed subject-matter.

4.3 As there is no difference related to the added feature in the claimed dry powder inhaler, the analysis of inventive step remains the same as for the main request with the result that the subject-matter of claim 1 of auxiliary request 2 does not involve an inventive step for the same reasons as outlined for the main request (see point 2 above).

Auxiliary request 2 does not meet the requirements of Article 56 EPC.

5. Auxiliary request 3-5 - Admission into the proceedings

5.1 Auxiliary request 3

This request has been filed with the letter dated 12 June 2015 at a late stage in the proceedings. The subject-matter of claim 1 of auxiliary request 3 differs from the subject-mater of claim 1 of the main request by the additional feature "the dry powder medicament dose is formed, loaded and sealed into said container at a temperature below 25°C and a relative humidity below 15% Rh". According to the appellant, this feature was introduced in order to overcome a possible objections under Article 123(2) EPC raised against the subject-matter of auxiliary request 2 during the oral proceedings before the opposition division.

The introduction of this feature, originating from the description, gives a considerable weight to the conditions under which the product is processed. Said processing conditions are however not exhaustively described in the description of the contested patent as regards their exact course and the control of "ambient conditions during dose forming, loading and container sealing" as mentioned in the description (par. [0057]) and do not correspond to the experimental procedure shown in documents (32) or (35). The introduction of this feature in claim 1 of auxiliary request 3 opens thus a new discussion, is not of clear and simple nature, and does not seem likely to prima facie overcome the lack of inventive step observed for the subject-matter of auxiliary request 2 (see point 4.4.3 above).

Consequently, the Board fids it appropriate to exercise its discretion by not admitting auxiliary request 3 into the proceedings (Article 13(1) RPBA).

5.2 Auxiliary request 4

This auxiliary request has been filed with letter dated 28 August 2015, after the issue of the Board's preliminary opinion, at a late stage of the proceedings. The subject-matter of claim 1 of auxiliary requests 4 has been amended by the feature "characterized in that the dry powder medicament dose is directly loaded into said container at a temperature below 25°C and a relative humidity below 15%Rh". Since the term "directly loaded" has no incidence on the discussion on inventive step, the subject-matter of claim 1 as regards inventive step of this request corresponds to the subject-matter of claim 1 of auxiliary requests 2.

The Board sees thus no reason to admit this request into the proceedings (Article 13(1) RPBA).

5.3 Auxiliary request 5

This auxiliary request has been filed with letter dated 28 August 2015, at a late stage of the proceedings. The subject-matter of claim 1 of auxiliary request 5 has been amended by the feature "characterized in that the dry powder medicament dose is formed, directly loaded and sealed into said container at a temperature below 25°C and a relative humidity below 15%Rh".

As for auxiliary request 3, the introduction of this feature in claim 1 of auxiliary request 5, is not of clear and simple nature, opens a new discussion and does not seem likely to prima facie overcome the lack of inventive step observed for the subject-matter of auxiliary request 2 (see point 4.4.3 above).

Accordingly, auxiliary request 5 is not admitted into the proceedings (Article 13(1) RPBA).