T 0414/18 (Compositions comprising rilpiverin/GILEAD) 21-05-2021

Reasons for the Decision

1. Admittance of documents D44-D46

The decision under appeal acknowledged bioequivalence of a combination tablet comprising rilpiverine HCl, emtricitabine, and tenofovir disoproxyl fumarate as defined in the patent with respect to separate tablets of the individual active agents on the basis of experimental results reported in the patent and document D6. This bioequivalence was an essential ground for opposition division's decision regarding the requirement of inventive step.

Documents D44-D46 were submitted by the appellant-opponent 1 with its grounds of appeal to support the argument that the evidence in the patent and document D6 was not sufficient to establish any bioequivalence and to contest in this respect the decision under appeal. Documents D44 and D45 describe criteria for establishing bioequivalence in the context of market authorisation applications for human medicinal products. Document D46 is from the same authors as document D6 and describes details of the bioequivalence study concerning a single tablet comprising emtricitabine, rilpiverine and tenofovir disoproxyl fumarate, which were not reported in document D6.

Taking account of the mentioned ground for the decision under appeal and the mentioned argument contesting this ground the Board considers the filing of D44-D46 to be part of a fair response to the decision under appeal and has therefore not exercised its discretion not to admit these documents into the proceedings.

2. Main request

2.1 Clarity

Amended claim 1 of the main request defines a tablet in line with the second embodiment of claim 15 of the patent as granted with additional definition of the amounts of the ingredients in terms of %w/w in line with paragraph [0063] of the patent.

Claim 1 of the main request specifically defines the tablet in an open manner as comprising two layers and thereby allows for further components to be present in the tablet, such as a third separating layer or a film coating as defined in dependent claims 2 and 3 of the main request. The introduced definition of the ingredients in terms of %w/w does not explicitly specify the basis for the percentage. However, the open definition of the tablet claim 1 evidently implies that the amounts of the ingredients defined in %w/w, which add up to a total of 100%, are to be calculated on the basis of the combined total weight of the two layers and not the weight of the entire tablet.

Contrary to the decision under appeal the Board therefore considers that the amendments in accordance with the main request comply with the requirement of clarity.

2.2 Inventive step

2.2.1 The patent relates to a single formulation comprising rilpiverine HCl, emtricitabine and tenofovir disoproxyl fumarate which is aimed at achieving chemical stability as well as equivalent plasma concentrations with respect to separate reference products containing the single active agents (see paragraph [0007]).

Document D6 already describes a study investigating the bioequivalence of a tablet containing the triple combination of 25 mg rilpiverine, 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate with respect to separate formulations of the individual active agents. The tablet defined in claim 1 of the main request differs from this prior art in the defined structure separating the rilpiverine HCl from the emtricitabine together with the tenofovir disoproxil fumarate in two different layers and the definition of the excipients with their specific amounts.

Document D1, which also describes a triple combination of rilpiverine HCl, emtricitabine and tenofovir disoproxil fumarate in a single tablet (see page 20, table 2 and page 25, example 4), additionally differs from the subject-matter of claim 1 of the main request in the defined amount of rilpiverine HCl. The Board therefore agrees with the decision under appeal, that document D6 represents the closest prior art.

2.2.2 The Board observes that the patent presents experimental results indicating that a tablet consisting of two layers as defined in claim 1 of the main request and a specific film coat (see formulation 3 in paragraph [0105])

- shows stability of the active ingredients (see example 6, paragraph [0113]),

- allows for a specific pharmacokinetic profile in terms of AUC and Cmax for the defined three active ingredients in healthy adults under fed conditions, which resembles the profile resulting from administration of separate reference dosage forms of these active ingredients indicative for bioequivalence (see example 5, paragraphs [0107] to [0112]) and

- preserves similar AUC values for rilpiverine HCl under fasted conditions (see example 8, paragraphs [0115]to [0118]).

The Board further notes that the patent also presents experimental results indicating that tablets with lower amounts of microcrystalline cellulose, lactose monohydrate and croscarmellose sodium in the rilpivirine HCl layer do not show the pharmacokinetic profile indicative for bioequivalence. (see formulation 4 in paragraph [0105] and the results discussed in paragraph [0111]).

2.2.3 The Board agrees with the appellant-opponent 1, that the subject-matter defined in claim 1 of the main request would be obvious to the skilled person, in as far as the problem solved is merely to be seen in the provision of a stable alternative co-formulation for the defined active agents. Having regard to the known incompatibility of tenofovir disoproxil fumarate with surfactants described in document D3 (see page 1-2 bridging paragraph) and in view of the analogue bilayer tablet described in document D33, in which efavirenz in association with a surfactant is formulated separately from tenofovir disoproxil fumarate and the emtricitabine (see D33, page 5/48 third full paragraph), the skilled person would be motivated to formulate rilpivirine HCl, which also requires a surfactant, in a layer separate from tenofovir disoproxil fumarate and the emtricitabine. Moreover, having regard to the known formulation of rilpivirine HCl as described in document D37 (see paragraph [0121]) and the known co-formulation of emtricitabine and tenofovir disoproxyl fumarate as described in document D43 (see Table 1 in paragraph [0121]), the skilled person would consider the choice of excipients as defined in claim 1 of the main request obvious as alternative.

2.2.4 According to the appellant-patent proprietors the problem underlying the subject-matter of claim 1 would not concern the provision of merely a stable alternative formulation, but should be seen in the provision of a formulation that is also bioequivalent with specific separate formulations of the active ingredients.

The Board observes in this context that claim 1 of the main request defines the tablet as comprising the two layers with the specific amounts of ingredients and thus allows for further components to be included in the tablet. This is confirmed by dependent claims 2 and 3 which define the tablet as further comprising a separating layer or a film coating. According to paragraph [0111] of the patent the difference in plasma concentrations of the active agents following administration of the bioequivalent formulation 3 and the non-bioequivalent formulation 4 reported in paragraph [0110] could have resulted from the influence of the higher amounts of diluents in the rilpivirine layer of formulation 3 on the interactions between rilpiverine and the other active agents. In view of the variation in pharmacokinetics from formulations 3 and 4, which only differ in the amounts of diluents in the rilpivirine layer, and the explanation for this variation postulated in the patent itself the Board is of the opinion that it is reasonable to assume that the pharmacokinetic profile from the tablet is likewise influenced by the further inclusion of a third separating layer or the provision of a different coating or the inclusion or any further component. The Board therefore concludes that the subject-matter of claim 1 of the main request may not be presumed to generally represent within the entire scope of the claim a solution to the problem of providing a co-formulation of the defined active agents which shows the bioequivalence with respect to specific separate formulations of the active ingredients as reported in the patent for formulation 3.

In this context the Board is not convinced by the appellant-patent proprietors' arguments, that claim 1 of the main request completely defines the layers of the tablet essential for achieving the reported bioavailability of the active agents and that the term "comprising" as regularly used in the field of pharmacy should not be interpreted to allow inclusion of components that are incompatible with the teaching of the patent. As is evident from claims 2 and 3 of the main request, tablets including a separating layer or an alternative coating are embodiments covered by claim 1 of the main request and fully in line with the teaching of the patent. In view of the evidence on file as discussed above, such tablets including a separating layer or an alternative coating may not be presumed to generally represent a solution to the problem of providing a co-formulation of the defined active agents with the desired bioequivalence. In the Board's view the definition of the constitution of the tablets beyond the inclusion of the specific layers is thus essential for achieving the desired pharmacokinetic profile.

The problem underlying the subject-matter of claim 1 of the main request is therefore to be seen in the provision of a stable alternative co-formulation for the defined active agents. For the reasons explained in section 2.2.3 above the Board concludes that the subject-matter of claim 1 of the main request would be obvious to the skilled person as solution to such a problem in view of the prior art and therefore does not involve an inventive step. Accordingly, the main request is not allowed.

3. Auxiliary requests 1-11

3.1 Auxiliary request 1

Independent claim 1 of auxiliary requests 1 defines the tablet to consist of the two specifically defined layers and excludes thereby the inclusion of further components of the defined tablet. At the same time dependent claims 2 and 3 of auxiliary request define the tablet of claim 1 to further comprise a third separating layer or a film coating. Dependent claims 2 and 3 are therefore inconsistent with claim 1, which contrary to the requirements of Article 84 EPC gives rise to ambiguity as to what is intended to be covered by the claims. As this ambiguity is introduced by the amendments of the claims as granted auxiliary request 1 is not allowed.

3.2 Auxiliary requests 2-11

3.2.1 In auxiliary requests 2, 4, 6, 8 and 10 the independent claim 1 of the main request is maintained. These auxiliary request are therefore not allowed for the same reasons as explained in section 2.2 for the main request.

3.2.2 In claim 1 of each of auxiliary requests 3, 5 and 9 the tablet is defined as consisting of the two specific layers. At the same time dependent claim 2 of auxiliary request 3 defines such tablet to further comprise a film coating, whilst the dependent claims 2 in each of auxiliary requests 5 and 9 define such tablet to further comprise a separating third layer. Auxiliary requests 3, 5 and 9 thereby introduce the same ambiguity as identified in section 3.1 above with respect to auxiliary request 1. Auxiliary requests 3, 5 and 9 are therefore not allowed for the same reason as explained for auxiliary request 1.

3.2.3 Auxiliary request 7 defines in its claim 1 the tablet as consisting of the two specific layers and seeks to avoid the inconsistency occurring in auxiliary request 3 by formulating its claim 2 in an independent manner as directed to a film coated tablet comprising the tablet as defined in claim 1 and a film coating that covers a portion or all of the tablet. This formulation includes, however, the open terminology "comprising", in view of which the defined film coated tablet may include additional components that influence the pharmacokinetic profile of the active ingredients. Moreover, claim 2 of auxiliary request 7 does not define any restriction as to the composition of the coating and thus includes coatings that influence the bioavailability of the active agents. The Board is therefore of the opinion that the subject-matter of this claim may not be presumed to generally solve the the problem of providing a formulation with the desired pharmacokinetic profile equivalent to that of the specific separate formulations for the individual active agents. Accordingly, the subject-matter of claim 2 of auxiliary request 7 lacks an inventive step for same reason as explained for claim 1 of the main request. Hence auxiliary request 7 is not allowed.

3.2.4 Auxiliary request 11 (previous auxiliary request 13) defines in its claim 1 the tablet as consisting of the two specific layers and optionally a film coating. In a similar manner as claim 2 of auxiliary request 7 this claim fails to define any restriction as to the composition of the coating and thus includes coatings that influence the bioavailability of the active agents as claim 2 of auxiliary request 7. The Board therefore concludes that this claim may also not be presumed to generally solve the problem of providing a formulation with the desired pharmacokinetic profile equivalent to that of the specific formulations with the single agents. Accordingly, claim 1 of auxiliary request 11 lacks an inventive step for same reason as explained for claim 1 of the main request. Hence auxiliary request 11 is not allowed.

In view of the Board's conclusions regarding the allowability of auxiliary requests 2-11 the request of appellant-opponent 1 not to admit auxiliary requests 2, 4, 5, 6, 10 and 11 remains without consequence.

4. Auxiliary requests 12 (previous auxiliary request 11)

4.1 The claims of auxiliary request 12 (as renumbered) correspond to the claims of auxiliary request 6 which was held allowable in the decision under appeal. Regarding this request the appellant-opponent 1 contested upon appeal only the findings of the opposition division with respect to the requirements of novelty and inventive step. The Board finds no grounds for reviewing any of the further findings in the decision under appeal regarding this request.

4.2 Novelty / Priority entitlement

Novelty of the defined subject-matter was contested by the appellant-opponent 1 in view of the alleged prior public use of the COMPLERA / EVIPLERA product as reported in document D23.

According to the decision under appeal no evidence of any public use of the COMPLERA / EVIPLERA product prior to the claimed priority date of 19 November 2010 resulted from the documents on file. This finding was not contested by the appellant-opponent 1.

The relevant priority document, US415600P, presents in its claim 23 a definition of a tablet in the same terms as claim 1 of auxiliary request 12. The priority document also discloses the composition of formulation 3 (see page 21), which corresponds to the coated tablet defined in claim 2 of auxiliary request 12. The priority document further indicates that the described tablets are for treatment of HIV infection and allow for achieving a similar level of rilpivirine AUC or Cmax in the patient when fasted or fed (see Summary of the invention on pages 3-4 and claims 26 and 27) in line with the definitions of claims 3 and 4 of the main request. The formal priority entitlement was not disputed during the appeal procedure. The Board is therefore of the opinion that the subject-matter of auxiliary request 12 is entitled to the priority of 19 November 2010.

Having regard to this effective date the Board concludes that the subject-matter defined in accordance with auxiliary request 12 meets the requirement of novelty.

4.3 Inventive step

4.3.1 Having regard to the experimental data presented in the patent as mentioned in section 2.2.2 above and in view of the limitation to tablets consisting of the quantitatively defined ingredients the Board is satisfied that claimed tablets provide the specific desired pharmacokinetic profile, which is equivalent to the profile from separate reference products of the individual agents.

In view of document D6 as closest prior art the problem solved may therefore be seen the provision of a co-formulation of the defined three active agents which is bioequivalent to specific separate reference products of the individual active agents. The Board agrees with the finding in the decision under appeal that the subject-matter defined in accordance with auxiliary request 12 was not obvious to the skilled person having regard to the influence of even small variations in the amounts of the excipients on the pharmacokinetics as confirmed in the patent for formulation 3 and formulation 4 (see paragraph [0110]).

4.3.2 With reference to the criteria for bioequivalence in the context of applications for market authorisations indicated in documents D44 and D45 the appellant-opponent 1 contested that the data in the patent allow for a conclusion as to bioequivalence of the claimed tablets. At the priority date no approved formulation for rilpiverine HCl was commercially available, that could have served as the reference formulation. Pharmacokinetic data would further vary considerably depending on the exact experimental conditions. The data in document D6 could not be used as a basis for any meaningful comparison to establish bioequivalence, because the details of the experimental conditions, including the methods for determining the plasma levels and the definition of the study population, were not mentioned in document D6. Notably, such details were revealed in the post-published document D46.

The Board observes, however, that the experimental results presented in the patent still indicate the specific desired pharmacokinetic profile for the tested combination tablet, which resembles the profile from separate specific reference products of the individual agents. The data in the patent thereby substantiate that the identified problem is effectively solved. This relevance of the data in the context of the requirements for patentability is not affected by the applicable criteria for bioequivalence in the context of applications for market authorisation or by the argument that at the priority date no approved commercial product for rilpiverine HCl had been available.

4.4 Accordingly the Board confirms the conclusion in the decision under appeal that the patent as amended in accordance with auxiliary request 12 meets the requirements of the EPC.