T 1698/21 (ANTIVIRAL THERAPY/VIIV Healthcare Company) 02-10-2024

1. Main request - Added Subject-matter

1.1 According to appellant 02, there was no basis in the original application for combinations of dolutegravir, i.e. the compound of Formula I, with salts of the second agent, namely abacavir.

1.2 Claim 1 of the patent application EP 16 187 411.0 discloses directly the combination of dolutegravir and "abacavir or a pharmaceutically acceptable salt thereof".

The requirements of Article 123(2) EPC are therefore met.

1.3 A combination of dolutegravir and abacavir is derivable directly and unambiguously from the subject-matter of claims 1 and 2 of the parent application published as WO 2011/094150 (application EP 11 737 484.3) or from page 6, lines 16 to 18.

With regard to the salts of abacavir, the description of the parent application published as WO2011/094150 makes an explicit reference to the salts of abacavir on page 9, lines 22-26, namely that "the present invention features combinations, methods of treatment, and pharmaceutical compositions as described above wherein one or more therapeutic agents are a pharmaceutically acceptable salt of said therapeutic agents, for example, abacavir hemisulfate,...". This passage constitutes an explicit and valid basis for the presence of salts of abacavir in the claimed combination. The same passage is also included in the other earlier application EP 15 164 931.6 and in the patent application (see paragraph [0043]).

Consequently, the main request meets also the requirements of Article 76(1) EPC.

2. Main request - Sufficiency of disclosure

2.1 The sufficiency of disclosure of the claimed invention has been objected to by appellant 02 in view of claim 4 of the main request, since the patent does not disclose the suitability of the combination for any therapy.

Claim 4 of the main request reads:

"4. A combination according to any of claims 1-3 for use in medical therapy".

2.2 This claim has been drafted in the form of a first medical use type claim (Article 54(4) EPC). The EPC allows a purpose-limited substance claim stating a general therapeutic purpose, in particular when a known compound is for the first time proposed and claimed for use in therapy. Hence, the scope of this claim is not the product for use in any specific medical therapy but for a generic use in medical therapy as defined in Article 54(4) EPC.

Since both products are known in the field of therapy, their combination is obviously suitable for such use and the requirements of sufficiency of disclosure are met.

3. Validity of the priority

3.1 Appellant 04 challenged the validity of the priority, and submitted that D20, which was published after the priority date of the contested patent, would consequently become relevant for novelty under Article 54(2) EPC.

3.2 Documents D18, D19, D53 and D62 were mentioned in this context by the parties.

3.2.1 D53 is a signed assignment from Mark Richard Underwood wherein the whole rights relating to the application US 61/298589 were assigned and transferred to Glaxosmithkline LLC. The assignment was signed on 20 January 2011, hence before the filing date of 24 January 2011 of the PCT application corresponding to the contested patent.

3.2.2 D18 is identical to D19 and is an assignment document comprising the same assignment as in D53 but signed on 31 January 2011, hence after the filing date of the PCT application on 24 January 2011. The document makes reference to the priority application US 61/298,589 and to the further PCT international application PCT/US2011/022219 corresponding to the published application WO 2011/0894150.

3.2.3 D62 is a declaration signed by Arlene Cannon, who was employed by GSK as a US Patent Formalities Manager in 2011, and provides her account of the relevant GSK standard operating procedures at the time. It explains in particular that the standard practice at that time was to execute two assignment documents, a first assignment document which was executed to ensure that the right to claim priority was properly transferred before the filing date of the PCT application. To that end, it was necessary to have that first assignment document prepared and executed before the PCT application number was available, and then to arrange for a second assignment document to be executed by the inventor shortly after the PCT application was filed, which made reference to the PCT application number.

3.3 The Board notes indeed an inconsistency between the information provided by documents D18/D19 and D53. According to documents D18 and D19, the transfer of the priority right was conducted on 31 January 2011, after the filing date of the patent while, according to the assignment D53, the transfer of the priority right was already effected on 20 January 2011. The question is whether this could result in a finding that the priority has not been validly transferred.

According to G 1/22, there is a rebuttable presumption under the autonomous law of the EPC that the applicant claiming priority in accordance with Article 88(1) EPC and the corresponding Implementing Regulations is entitled to claim priority (cf. Headnotes of G 1/22). Such a presumption implies a reversal of the burden of proof and it is therefore up to the opponents to prove that the applicant cannot validly claim priority, and doubts, even serious ones, cannot suffice. In the present case, the mere inconsistency between two documents, for which D62 provides a credible explanation, is no proof that the priority has not been validly claimed nor does it cause serious doubts concerning the transfer.

In the Board's view, it in fact appears convincing that the priority has been validly transferred on 20 January 2011 in view of document D53 and the evidence provided in D62. Document D62 gives a credible explanation for the existence of the two assignments, as disclosed in its points 4-8.

Hence, the Board does not see any reason to question the validity of the priority and document D20 is not relevant under Article 54(2) EPC for the assessment of novelty.

4. Main request - Inventive step

4.1 The claimed invention relates to a combination of a HIV integrase inhibitor, i.e the compound of formula(I) also known as GSK1349572 or dolutegravir, with abacavir, a reverse transcriptase inhibitor.

4.2 The opposition division considered D11, D14 and D15 as equally possible starting points for the assessment of inventive step, since they all relate to the synergistic combination of abacavir with an integrase inhibitor. Appellants 02, 03 and 04 also rely on document D36 as possible closest prior art.

4.2.1 D11 discloses the synergistic combination of an inhibitor of HIV integrase having a bicyclic pyrimidone structure with inter alia abacavir. Example 19 of D11 (column 185) was cited by the opposition division in its decision and discloses a compound having a close structure to dolutegravir:

FORMULA/TABLE/GRAPHIC

In columns 75-76 (see in particular col.75 lines 40-53 and Table 4), D11 states that abacavir shows synergistic effects in combination with the compound of example 19 at all effective levels and molar ratios; Tables 4-8 show a great number of possible combinations with the compound of example 19. The following is an extract from Table 4 regarding the combination with abacavir:

FORMULA/TABLE/GRAPHIC

FORMULA/TABLE/GRAPHIC

D11 does not disclose the claimed compound of formula I, i.e dolutegravir.

4.2.2 D14 relates to a synergistic combination of GSK364735, an HIV Type 1 integrase inhibitor different from dolutegravir, with abacavir (see Fig.1, Table 3, Figure 5).

FORMULA/TABLE/GRAPHIC

The synergistic effect of the combination abacavir/ GSK364735 disclosed in D14 is shown by the following isobologram (see Figure 5 of D14 on page 907):

FORMULA/TABLE/GRAPHIC

4.2.3 D15 relates to Insentress , a medicament based on raltegravir as integrase inhibitor. This document mentions further on page 12 that "additive to synergistic antiretroviral activity was observed when human T-lymphoid cells infected with the H9IIIB variant of HIV-1 were incubated with raltegravir in combination with non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, or nevirapine); nucleoside analog reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, tenofovir, zalcitabine, or zidovudine); protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, or saquinavir); or the entry inhibitor enfuvirtide" (cf. par. "Antiviral Activity in Cell Culture").

This document does not specify whether the association of raltegravir and abacavir provides a synergistic effect, and does not relate to dolutegravir. For this reason, D15 appears to be less relevant compared to the other documents considered as possible starting point for the assessment of inventive step.

4.2.4 D36 is a pilot study of a tri-therapy combination of abacavir/ lamivudine (ABC/3TC) and raltegravir (RAL, integrase inhibitor) in naive HIV-1 infected subjects. The study mentions that the combination achieved a rapid virologic suppression and merits further study (see Conclusions on page 2). The document relates to a tri-therapy and does not mention any synergistic effect, or a possible combination with dolutegravir or replacement therewith in the disclosed combination.

4.2.5 The Board notes that the distinguishing feature between the claimed subject-matter and any of the cited documents is always the presence of the integrase inhibitor dolutegravir. In the Board's view, the closest documents appear to be documents D11 and D14; the assessment of inventive step will neverthless be performed over all four documents.

4.3 D11 as closest state of the art

4.3.1 The opposition division considered that the problem to be solved over D11 was the provision of an alternative synergistic combination of abacavir with an integrase inhibitor. Similar definitions were proposed by appellants 03 and 04 whereas appellants 01 and 02 defined the problem over D11 as the provision of an alternative combination.

During the oral proceedings, the respondent defined the problem over D11 as the provision of an alternative synergistic combination having an improved activity or potency on the integrase enzyme.

4.3.2 The patent presents in Figure 1 an isobologram showing the effect of the claimed combination of abacavir and dolutegravir (see also par. [0077] and [0082] of the specification). The data points fall under the diagonal line which indicates the existence of a strong synergistic action between the two drugs, as shown below:

FORMULA/TABLE/GRAPHIC

According to D57, synergy is indeed expressed when the points fall under the diagonal line as shown below by the line A, in contrast to line B which expresses the additivity of the drug effect and line C which expresses a drug antagonism (see pages 129-130 of D57):

FORMULA/TABLE/GRAPHIC

The relevance of Figure 1 as evidence for a synergistic effect was initially objected to by the appellants, since it would not allow to draw any conclusions regarding an actual synergistic effect of the claimed combination in humans, and also in view of the low number of points tested and the absence of any points for abacavir between 0.5 and 1.0 on the abscissa.

In this regard the Board observes that isobolograms represent a standard and well recognised method for determining the presence of synergy between two drugs (see for instance D57). Moreover, paragraph [0077] of the patent explains how the isobologram of Figure 1 and of the patent was generated and there is no reason to consider that a similar synergistic interaction between the two drugs will not occur in vivo. There is furthermore no reason to doubt that the synergistic effect is present at lower as well as at higher concentrations of abacavir, since Figure 1 shows credibly that the two drugs have an overall synergistic activity rather than an additive activity. During the oral proceedings the appellants eventually acknowledged that Figure 1 of the patent was evidence of a synergistic effect of compound (I) with abacavir.

Hence, a synergic effect has been credibly shown for the combination of dolutegravir and abcavir, but it is not possible to conclude that a better or improved synergistic effect has been demonstrated over the combination disclosed in D11.

4.3.3 With regard to the improved activity or potency on the integrase enzyme alleged by the respondent, the Board considers that this technical effect is based on data relating to the use of dolutegravir as monotherapy whereas the invention disclosed in the original application and claimed in the granted patent relates to a combination of compounds. Thus, this effect is not relevant to the double combination claimed. Moreover, it is also not encompassed by the teaching of the application as filed in the sense of G 2/21.

It follows that the improved potency on the integrase enzyme cannot be taken into account in the definition of the technical problem.

4.3.4 The problem is therefore the provision of an alternative synergistic combination of abacavir with an integrase inhibitor for the treatment of HIV. In view of Figure 1, it appears that this problem has been credibly solved.

4.3.5 With regard to obviousness, it must be determined whether it is obvious to replace the compound of example 19 of D11 in its synergistic combination with abacavir by dolutegravir to obtain an alternative synergistic anti-HIV combination.

In this context, documents D11, D14, D15, D17, D40, and D61 were cited and discussed.

(a) D11 shows in columns 75-76 and Table 4 two-drug combinations of the compound of example 19 with eight different nucleoside reverse transcriptase inhibitors, at a range of concentrations near the EC50 value of each compound. Table 4 shows that four nucleoside RT inhibitors (didanosine, stavudine, abacavir and emtricitibine) show synergistic antiviral effects in combination with example 19 at all effective levels and all molar ratios. For the other four RT inhibitors (zidovudine, lamivudine, tenofovir and zalcitabine) the overall effects of the combinations with example 19 are classified as synergistic to additive.

(b) Document D17 relates to polycyclic carbamoylpyridone derivatives possessing an inhibitory activity against HIV integrase. It discloses dolutegravir in example Y-3 on page 116 or in dependent claim 32, among numerous other possible compounds. D17 recommends the combination of a compound as disclosed therein with another anti HIV compound having a different mechanism of action such as a reverse transcriptase inhibitor and/or a protease inhibiting agent but does not disclose any specific combination (see D17, page 78, lines 5 to 10).

(c) JP4295353B2 (D40) is the patent granted on the Japanese national phase application derived from D17. D40 discloses explicitly in claims 34-36 the compounds of formula (I), (II) and (III) of the contested patent and dolutegravir is the subject of claim 36.

(d) D14 reports in Table 3 how the compound GSK364735 interacts with known anti-HIV drugs. Of the nineteen compounds tested, nine were synergistic with GSK364735, inter alia with abacavir.

(e) D15 states on page 12 that "additive to synergistic antiretroviral activity was observed" when raltegravir was combined with each of several known anti-HIV drugs, including abacavir. This document does however not provide any further detail regarding the specific drugs with which raltegravir was synergistic and with which it was merely additive. It is also unclear from the document how many drugs interacted synergistically with raltegravir.

(f) D61 is an extract from the EMA's scientific discussion document concerning raltegravir. This document evaluates the antiviral activity of raltegravir with 18 licensed antiviral agents from all 4 classes (protease inhibitors, nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and entry inhibitor; cf. page 6 of D61). The results show that when both tested compounds were present at lower concentrations, the effect of adding raltegravir to the other drug was null or additive. At higher compound concentrations, typically in excess of their IC50 values, raltegravir displayed synergistic activity with all other antiviral compounds tested.

Having regard to this state of the art, the Board is of the view that the skilled person, starting from the disclosed combination in D11 of the compound of example 19 as a HIV integrase inhibitor with abacavir as reverse transcriptase inhibitor, would not have expected that the replacement of the compound of example 19 by dolutegravir provided a synergistic effect. In the Board's view, it is not correct to assert that a skilled person would simply assume that any new antiretroviral drug such as dolutegravir would even be compatible with, let alone synergistic with a known anti-HIV drug, since it is even not possible to exclude a possible drug antagonism. The reasons are the following:

- first, none of the documents suggests explicitly a combination of dolutegravir with abacavir. D11 exemplifies a high number of integrase inhibitors, i.e. over 280, and identifies as only integrase inhibitor to be synergistic with abacavir the compound of example 19. Moreover, D11 mentions a clear synergistic effect with only four reverse transcriptase compounds among the eight tested compounds, which indicates that a synergistic effect is neither automatic nor predictable within the same pharmacological class of compounds.

- the data provided in D14 confirms the conclusion that synergy is not predictable. Table 3 on page 906 provides data on the interaction of compound GSK364735 with known anti-HIV drugs. The table shows that of the nineteen compounds tested, only nine were synergistic with GSK364735, the remaining providing an additive effect, and no strong correlation between drug mechanism and synergy was observed, since not all combinations with a revertase transcriptase show a synergistic effect. The authors of D14 also underline on page 905 that it is critical, prior to initiating combination studies in clinical trials, to demonstrate that a particular combination has no or low potential for being antagonistic, at least at the level of antiviral activity;

- D17 and D40 are the only cited documents that have singled out dolutegravir among other possible integrase inhibitors, but these documents do not disclose any therapeutic combination and suggest a possible combination with either a reverse transcriptase inhibitor and/or a protease inhibitor without any indication of preference and with no further specification. In view of D17, the skilled person has still the choice between several possible types of combination without expectation of a synergistic effect;

- With regard to D15, the absence of any indication as to which combination of drugs with raltregravir has a synergistic effect makes the teaching of this document irrelevant. The same conclusion applies to the teaching of D61.

Consequently, the Board considers that none of the cited documents provides evidence or even a suggestion that the claimed combination might provide a synergistic anti-HIV action.

4.3.6 The argument of the appellants that D11, D14 and D15 each provides, at least, a reasonable expectation that a combination of abacavir and any integrase inhibitor is always synergistic also fails. These documents provide indeed the results for some integrase inhibitors, and according to the appellants the skilled person would have a reasonable expectation that these results would also apply to dolutegravir.

The Board disagrees with this position and notes that only D11 and D14 disclose specific synergistic combinations with abacavir, and that it does not appear possible to draw a general conclusion or a general technical concept from such limited disclosure.

It is also not credible that abacavir would provide a systematic synergistic effect with any integrase inhibitor, in the absence of any evidence. Having regard to the documents on file, the skilled person would not have had any reasonable expectation that a drug that is found to be synergistic with one integrase inhibitor would show a similar synergistic interaction with another integrase inhibitor. For example, as argued by the respondent (see point 9.27 of its reply), there are seven drugs that are synergistic both with the compound of formula (I) of the present patent (dolutegarvir) and with the compound of Example 19 of D11 (see results for stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir and enfuvirtide). Each of these seven compounds were also tested for synergy with the compound GSK364735 of D14, and only three of them were synergistic with GSK364735. The other four compounds, which did not interact synergistically with GSK364735, belong to three different mechanistic categories, including the nucleoside reverse transcriptase inhibitor (NRTI) category.

4.3.7 Consequently, the replacement of the compound of example 19 of D11 by dolutegarvir is not obvious and the subject-matter of claim 1 of the main request is inventive over D11 (Article 56 EPC).

4.4 D14 as closest prior art

4.4.1 The opposition division considered that the problem to be solved over D14 was the provision of an alternative synergistic combination of abacavir with an integrase inhibitor.

In the written proceedings, appellant 01 defined the problem over D14 as the provision of an alternative combination, while appellants 02 and 03 defined it as the provision of an alternative synergistic combination of abacavir with an integrase inhibitor for the treatment of HIV.

In its letter dated 16 October 2023 the respondent argued that the drug combination defined in claim 1

represented an improved synergistic combination for treating HIV compared to the combination disclosed in D14. The respondent referred also to a number of additional technical effects which are however not relevant to the outcome of the present decision.

4.4.2 Figure 1 of the contested patent shows credibly a synergistic effect. Said synergic effect also appears to be stronger than the synergic effect shown by the combination disclosed in D14, since the points shown in the isobologramm are located closer to the abscissa in Figure 1 (see point 4.3.2 above and Figure 5 of D14 on page 907).

4.4.3 The problem over D14 is therefore the provision of an improved synergistic combination of abacavir with an integrase inhibitor for the treatment of HIV.

4.4.4 The claimed solution is not obvious for the same reasons as discussed previously over D11.

The conclusions would have been the same if the problem had been the provision of an alternative synergistic combination for treating HIV, instead of an improved synergistic combination, with the same arguments as when starting from D11 as closest state of the art.

4.5 D15 or D36 as closest prior art

4.5.1 The opposition division considered that the problem to be solved over D15 was the provision of an alternative synergistic combination of abacavir with an integrase inhibitor, and over D36 the provision of a combination of abacavir with an integrase inhibitor having a synergistic effect.

In the written proceedings, the problem was defined as follows by the parties:

- appellant 02 defined the problem over D15 as the provision of an alternative synergistic combination of abacavir with an integrase inhibitor for the treatment of HIV, and over D36 as the provision of a synergistic combination of abacavir with an INSTI (HIV integrase inhibitor);

- appellant 03 defined the problem over D15 or D36 as the provision of an alternative synergistic combination of abacavir with an integrase inhibitor for the treatment of HIV;

- appellant 04 defined on page 7 of its statement of grounds of appeal the problem as the selection of an alternative integrase inhibitor for the Kivexa OBT (lamivudine);

- the respondent defined the problem when D15 or D36 is taken as the closest prior art document as the provision of a new drug combination with synergistic activity.

4.5.2 The Board agrees with the definition of the problem as given by the respondent. Since the claimed combination shows a synergistic effect, while the compositions disclosed in D15 or D36 do not specify or prove any synergistic effect linked with the combination therapies disclosed therein, the problem can indeed only be the provision of a synergistic combination for treating HIV.

Appellant 04 observed that synergy of the claimed combination was not proven in clinical trials and that no improvement was shown over the disclosure of D36. The Board does not see any reason to question in vitro tests for showing a synergistic anti-HIV effect, based on drugs which were already known and used for this therapeutic application. Such tests and isobologramm appear to be the usual way to prove a synergistic effect (see point 4.3.2 above). The presence of synergism indicates that the drugs work together to produce an effect greater than the sum of their individual effects. In the Board's view this is a valuable property of the drug combination which needs to be considered in the assessment of inventive step. There is no requirement to demonstrate a pharmacological effect through clinical data.

Consequently, the claimed solution is inventive since none of the cited documents provides an incentive to combine dolutegravir with abacavir in order to obtain a synergistic anti-HIV effect (see also point 4.3 above).

4.6 Consequently, the main request meets the requirements of Article 56 EPC.