T 1390/22 (Treating Hepatitis C/ABBVIE) 22-10-2024

1. Admittance of document D21

1.1 Document D21 was filed by the patent proprietor after the Board had issued its communication under Article 15(1) RPBA. In accordance with Article 13(2) RPBA the admittance of this document in the appeal proceedings is to be denied unless there are exceptional circumstances which have been justified with cogent reasons by the patent proprietor.

1.2 According to the patent proprietor the content of document D21 demonstrated that the assertion in document D5 regarding the pan-genotypic activity of NS5A inhibitors in general was not supported by the data relied upon in document D5.

The patent proprietor justified the filing of document D21 at the late stage of the proceedings in view of the issue of the relevance of document D5 which the Board would have newly raised the communication under Article 15(1) RPBA.

1.3 The Board considers that the patent proprietor raised a complex new issue with the filing of document D21, namely the question whether the mention of the pan-genotypic activity of NS5A inhibitors in document D5 was supported by the data in document D21.

The argument that document D5 indicated pan-genotype activity for NS5A inhibitors in general had already been presented by the opponent during the first instance proceedings (see decision under appeal, page 13, section 5.1.2). Moreover, this argument was maintained by the opponent in its reply to the appeal (see page 13). Contrary to the suggestion by the patent proprietor, the Board did thus not raise a new issue by referring to the possible relevance of document D5 in its communication under Article 15(1) RPBA.

The Board does therefore not recognize any exceptional circumstances that could justify the late introduction of the new issues with the filing of document D21.

Accordingly, the Board has not admitted this document into the appeal proceedings.

2. Novelty - main request

2.1 The assessment of the HCV genotype in treatment of HCV prior to the administration of antiviral therapy was standard practice at the time of the priority date for the patent. Document D19 indicates that such assessment formed part of the standard of care in order to select the appropriate type of antiviral therapy, including the dose of the medication and the duration of the treatment (see D19, page 250, section 4.4.5). Moreover, document D20 explicitly qualified the assessment of the HCV genotype in patients with chronic HCV infection as necessary (see D20, page 3, Table 2). The intentional omission of the HCV genotyping as defined in claim 1 of the main request therefore represents a technically meaningful characteristic of the defined therapeutic treatment.

It follows from the considerations in G 2/08 (see Reasons 5.10.9), which refer to the wording "any specific use" in Article 54(5) EPC and confirm the seamless fit between the exclusion from patentability of methods of treatment by therapy and the special provisions regarding the novelty of a substance or composition for use in such a method, that this technically meaningful characteristic of the defined therapeutic treatment involving the use of pibrentasvir is suitable to characterize the claimed subject-matter in terms of a specific use as intended in Article 54(5) EPC.

Contrary to the opponent's argument the considerations in G 2/08 do not imply any limited framework in terms of the type of technical features of a method of treatment by therapy that may characterize a specific use as intended in Article 54(5) EPC. The opponent's argument regarding such a limited framework does also not find support in T 2056/17. In T 2056/17 (see reasons 2.6) the deciding Board concluded that a pharmaceutical combination for a defined therapeutic use lacked novelty in view of the known use of that combination for the same therapeutic purpose in the same patients by the same route of administration and with the same dosage regimen. In line with the considerations in G 2/08 the deciding Board in T 2056/17 held that the definition of the co-marketing or co-promoting of the individual compositions in the combination was not a technical feature characterizing the defined therapeutic use, because the definition of the co-marketing or co-promoting does not change the clinical situation nor contribute to the therapeutic effect.

2.2 Document D2 describes the non-structural HCV protein NS5A as a critical component of HCV replication which is believed to exert multiple functions at various stages of the viral life cycle which represents a promising target for treating HCV (see D2, paragraph [0004]). In this context document D2 presents compounds of the general formula I and IA-IG for inhibiting HCV replication indicating their activity against NS5A (see D2, paragraph [0005]).

Document D2 describes pibrentasvir (see D2, page 259, example 3.52) as an example of an advantageous halogenated benzimidazole derivative of general formula IB and as a member of a group of four examples (examples 3.48, 3,52, 4.38 and 5.1) which exhibit improved activity relative to the activity of ombitasvir (see D2, page 16, reference example 37 from US 2010/0317568) against the replication of the HCV genotypes 1a, 2a, 3a and 6a as well as NS5A mutants L31V, M28T, M28V, Q30E, Q30R, Y93C, Y93H and Q30H of HCV genotype 1a (see D2, paragraph [0181]):

"For instance, when tested against HCV replicons of different genotypes in stable cell lines (in the presence of 5% FBS), and as compared to Example 37 of U.S. Patent Application Publication No. 2010/0317568, the EC50 values ofthe compounds of Examples 3.48,3.52, 4.38, and 5.1 were at least about 6-fold less than that of Example 37 against genotype la, at least about 3-fold less against genotype 3a, at least about 50-fold less against genotype 6a, and significantly less against genotype 2a. In addition, when tested against HCV genotype la replicons containing certain NS5A mutations in transient transfection assays, and as compared to Example 37 of U.S. Patent Application Publication No. 2010/0317568, the EC50 values of the compounds of Examples 3.48, 3.52, 4.38, and 5.1 were at least about 130-fold less than that of Example 37 against the L31V variant, at least about 7,500 fold less against the M28T variant, at least about 80-fold less against the M28V variant, at least about 500-fold less against the Q30E variant, at least about 300-fold less against the Q30R variant, at least about 800-fold less against the Y93C variant, at least about 1,500-fold less against the Y93H variant, and significantly less against the Q30H variant.

Likewise, when tested against HCV genotype lb replicons containing certain NS5A mutations in transient transfection assays, and as compared to Example 37 of U.S. Patent Application Publication No. 2010/0317568, the EC50 value of the compound of Example 5.1 was at least about 10-fold less than that of Example 37 against the Y93H variant."

Document D2 concludes in this context that accordingly the compounds of formula IB are suitable for treating patients infected with HCV genotype 1a, 1b, 2a, 2b, 3a, 4a, 5a or 6a or one of the described variants (see D2, paragraph [0181]).

2.3 Document D2 does not explicitly disclose the utility of pibrentasvir in treatment of HCV in which the assessment of the HCV genotype is intentionally omitted as defined in claim 1 of the main request.

Moreover, whilst document D2 describes compounds of formula IB to be suitable for treating patients infected with HCV genotype 1a, 1b, 2a, 2b, 3a, 4a, 5a or 6a and identifies pibrentasvir as an advantageous example thereof, document D2 does not describe any absolute activity data for pibrentasvir. The reported activity data for pibrentasvir and the three further examples are only expressed in terms of factors by which the EC50 values of these examples for the different HCV genotypes and mutants thereof are at least reduced with respect to the EC50 values of ombitasvir. Meanwhile, document D2 presents for ombitasvir only limited and partly approximate EC50 values (see D2, page 16):

FORMULA/TABLE/GRAPHIC

Contrary to the opponents argument, document D2 does therefore not disclose any quantitatively consistent activity of pibrentasvir against a spectrum of HCV genotypes and mutants that might imply that in treatment of HCV patients with pibrentasvir the HCV genotyping could be omitted.

2.4 Accordingly, the Board considers that document D2 does not disclose the intentional omission of the HCV genotyping, and that this omission represents a technically meaningful feature of therapeutic use distinguishing the subject-matter of claim 1 of the main request from the teaching of D2.

In view of this distinguishing technical feature of the defined therapeutic use the opponent's argument that according to the criteria applied in point 2.2 of T 1491/14 claim 1 of the main request does not define the treatment of a new patient group remains without consequence. In this context it is noted, however, that in the case of T 1491/14 the deciding Board acknowledged the novelty of the claimed subject-matter in view of criteria proposed by the patent proprietor that were not contested by the opponent, but also explicitly indicated that the jurisprudence of the Boards of Appeal does not seem to provide fixed criteria for the definition of a new patient group (see T 1491/14, reasons 2.2).

2.5 Accordingly, the Board concludes that the subject-matter of claim 1 of the main request is new in view of the prior art (Article 54 EPC).

3. Inventive step - main request

3.1 The starting point in the prior art

It was not in dispute that document D2 represents the closest prior art.

As explained in section 2 above the intentional omission of the genotyping of the patient in the treatment for HCV as defined in claim 1 of the main request distinguishes the claimed subject-matter from the teaching in document D2.

3.2 The objective technical problem

The patent (see paragraph [0069]) reports in Table 2 experimental results concerning the mean IC50 values of pibrentasvir for HCV genotypes 1a, 1b, 2a, 2b, 3a, 4a, 5a and 6a which range from 1.4 to 4.3 pM. Moreover the patent (see paragraph [0071]) presents in Table 3 additional average IC50 values of pibrentasvir for HCV wild type genotypes 2a, 2b, 3a, 4a, 5a and 6a as well as a variety of mutants of each of these wild types, including the Y93H mutant of genotype 3, which are all within the range from 0.8 to 4.3 pM. In addition, Table 3 of the patent provides a comparison of the IC50 values for pibrentasvir with the IC50 values for ombitasvir. The reported IC50 values of ombitasvir range from 0.4 to 80 pM for the HCV wild type genotypes 2-6 and are significantly increased for the mutants thereof showing a greatly increased variability depending on the particular mutation. The reported EC50 value of ombitasvir for the Y93H mutant of genotype 3 even exceeds 100.000 pM.

As pointed out in section 2 above, the assessment of the HCV genotype was conventionally required in therapy of HCV in order to determine the appropriate dose for the antiviral treatment. With the reported quantitatively consistent inhibitory activity of pibrentasvir against HCV genotypes 1-6 and mutants thereof the patent credibly demonstrates that in the treatment of HCV an appropriate dose of pibrentasvir should be effective regardless of the specific genotype of the HCV infection.

The opponent's objection that the patent does not demonstrate the efficacy of pibrentasvir against the more recently discovered HCV genotype 7 and mutants of the more prevalent HCV genotype 1a, including the problematic Y93H mutant, is not considered convincing. In view of the extensive efficacy data in the patent the skilled person had no reason to doubt that pibrentasvir would be similarly effective against HCV genotype 7 and mutants of HCV genotype 1a. Moreover, the post-published document D12 confirms the required efficacy of pibrentasvir against HCV genotype 1a mutants, including the Y93H mutant (see D12, page 4, Table 4) and raises no concern regarding the efficacy of pibrentasvir against the more recently identified HCV genotype 7.

The opponent's further objection that document D3 indicates for the use of pibrentasvir in the treatment of HCV patients in which prior therapy with sofosbuvir had failed a longer duration in case of infection with HCV genotype 3 than in case of infection with HCV genotypes 1-2 and 4-6, and that the treatment of HCV with pibrentasvir therefore still requires genotyping at least for this subgroup of patients, is also not considered convincing. Document D3 recommends for the treatment of patients infected with HCV genotypes 1-6 the same dose of pibrentasvir and in general also the same duration of treatment irrespective of the specific HCV genotype (see D3, page 1, section 4.2, Table 1). Only in the case of patients in which prior therapy with sofosbuvir had failed does document D3 recommend a longer duration of treatment if the patients are infected with HCV genotype 3 (see D3, page 1, Table 2). In these patients the recommended effective dose of pibrentasvir remains according to document D3 unchanged. The mere variation in the recommended duration of treatment with an established effective dose of pibrentasvir does not indicate any necessity for the assessment of the specific HCV genotype, because when the effectiveness of the dose is not in question the effective duration of such treatment follows from the observable effects of the treatment on the HCV infection irrespective of the involved specific HCV genotype.

The intentional omission of the genotyping distinguishing the subject-matter of claim 1 of the main request is therefore associated with the utility of pibrentasvir in treatment of HCV regardless of the HCV genotype. Accordingly, the objective technical problem underlying the subject-matter of claim 1 of the main request may be seen in the provision of an effective treatment of HCV regardless of the HCV genotype, which evidently represents a significant simplification in the conventional treatment of HCV.

3.3 The assessment of the solution

3.3.1 Document D2 itself describes pibrentasvir as an example of compounds of a general formula IB having utility in the treatment of infection by HCV genotypes 1-6 which forms part of a group of four exemplified compounds with enhanced activity against various HCV genotypes and mutants thereof as compared to the activity of ombitasvir (see D2, paragraphs [0181]-[0182]). However, as explained in sections 2.2 and 2.3 above, document D2 does not distinguish the activity of pibrentasvir within this group of examples nor disclose any absolute activity data for pibrentasvir. Document D2 does therefore not provide the skilled person with any information that pibrentasvir exhibits effective inhibitory activity against HCV across a wide spectrum of HCV genotypes and mutants within a narrow concentration range that would allow for the treatment of HCV without the need for genotyping.

From the information in document D2 itself the skilled person could therefore not derive any reasonable expectation that pibrentasvir would be suitable for treatment of patients infected with HCV irrespective of the specific HCV genotype without the need for genotyping.

In this context the Board considers the opponent's argument that if the skilled person could on the basis of the data in the patent conclude that in treatment of HCV with pibrentasvir the assessment of the HCV genotype may be omitted, the omission of this assessment in treatment of HCV with pibrentasvir would already be obvious in view of document D2, not convincing, because document D2 does not describe the quantitatively consistent activity of pibrentasvir against a wide spectrum of HCV genotypes disclosed in the patent.

3.3.2 Documents D1, D4, D6 and D7 describe the specific NS5A inhibitor BMS-790052, also known as daclastavir, to exhibit activity against a broad spectrum of HCV genotypes (see D1, page 91, left column; D4, page 97, left column; D6, page 466, right column; D7, page 3). Document D4 presents for this specific compound EC50 values against HCV genotypes 1-6 ranging from 9-146 pM (see D4, page 97, Table 1).

Documents D8 and D9 describe the specific NS5A inhibitor PPI-461 to exhibit pan-genotypic antiviral against HCV (see D8, under "Results"; D9, title). Document D8 reports for this specific compound EC50 values for the HCV genotypes 1a and 1b of 0.2 and 0.01 nM and for genotypes 2-7 EC50 values ranging from 0.1-19 nM.

Document D5 states that NS5A inhibitors demonstrate pan-genotypic activity against HCV in general (see D5, page 6354, left column, lines 2-3). A similar statement is found in document D10 (see page 3, under "NS5a Inhibitors").

As is evident from the broad ranges of the EC50 values reported for the specific NS5A inhibitors in documents D4 and D8, the qualification of NS5A inhibitors as pan-genotypic does not imply that these specific NS5A inhibitors, let alone NS5A in general, exhibit effective inhibitory activity against HCV across a wide spectrum of HCV genotypes and mutants within a narrow concentration range that would allow their use for the treatment of HCV without the need for genotyping.

Documents D1 and D4-D10 do therefore not provide the skilled person with any additional information allowing for a reasonable expectation that pibrentasvir would be suitable for treatment of patients infected with HCV irrespective of the specific HCV genotype without the need for genotyping.

3.4 Accordingly, the Board concludes that the subject-matter of claim 1 of the main request involves an inventive step (Article 56 EPC).

4. Sufficiency - main request

4.1 As pointed out in section 3.2 above the patent credibly discloses on the basis of the quantitatively consistent inhibitory activity of pibrentasvir against HCV genotypes 1-6 and mutants thereof that in the treatment of HCV a suitable dose of pibrentasvir should be effective regardless of the specific genotype of the HCV infection. The Board therefore considers that the patent sufficiently discloses the claimed utility of pibrentasvir in the treatment of HCV regardless of the specific HCV genotype wherein the patient is not genotyped for the treatment.

4.2 The opponent's objection that the patent does not disclose the efficacy of pibrentasvir against the more recently discovered HCV genotype 7 and mutants of the more prevalent HCV genotype 1a, including the problematic Y93H mutant, is not considered convincing for similar reasons as set out in section 3.2 in the context of the assessment of inventive step. In particular, the Board considers that in view of the extensive efficacy data in the patent the opponent has not raised serious doubts concerning the efficacy against HCV genotype 7 or mutants of HCV genotype 1a.

The opponent's further objection that document D3 indicates for the use of pibrentasvir in the treatment of HCV patients in which prior therapy with sofosbuvir had failed a longer duration in case of infection with HCV genotype 3 than in case of infection with HCV genotypes 1-2 and 4-6, and that the treatment of HCV with pibrentasvir therefore still requires genotyping at least for this subgroup of patients, is also not considered convincing for similar reasons as set out in section 3.2 in the context of the assessment of inventive step. In particular, the Board considers that the mere variation in the recommended duration of treatment with an established effective dose of pibrentasvir does not indicate any necessity for the assessment of the specific HCV genotype, because when the effectiveness of the dose is not in question the effective duration of such treatment follows from the observable effects of the treatment on the HCV infection irrespective of the involved specific HCV genotype.

4.3 Accordingly, the Board concludes that the main request complies with the requirement of Article 83 EPC.