T 0795/21 (Chemical compounds / NUCANA) 24-03-2023

1. Admittance of submissions

In its communication under Article 15(1) RPBA (see section 2.3.4) the Board explained that it was of the preliminary opinion that the submission by the appellant-patent proprietor, that compounds such as sofosbuvir prevent hepatocellular carcinoma as a result of their efficacy in treatment of HCV infection and thereby present a solution to the problem of preventing cancer, was not to be admitted into the appeal proceedings in view of Articles 12(4) and 12(6) RPBA.

This submission represented in the Board's preliminary opinion an amendment to the appellant-patent proprietor's case with respect to the proceedings before the opposition division. The Board indicated that it was not convinced that this amendment was justified considering that the addressed objection regarding the suitability of sofosbuvir as anti-cancer agent had already been raised in the notice of opposition (see pages 44-46, sections 6.20-6.23). Moreover, the Board indicated that it was not convinced that the technical effect of prevention of hepatocellular carcinoma as a result of activity against HCV could be relied upon for the formulation of the problem to be solved, because the patent did not provide any pointer regarding this effect.

During the oral proceedings the appellant-patent proprietor relied with respect to this issue on its arguments presented in writing, which preceded the Board's communication.

The Board therefore confirmed its preliminary opinion and did not admit the submission concerning the prevention of cancer by compounds as claimed on the basis of their efficacy in treatment of HCV infection into the appeal proceedings in view of Articles 12(4) and 12(6) RPBA.

2. Main request (filed as auxiliary request 1 with the statement of grounds of appeal) - inventive step

2.1 Starting point in the prior art

The patent describes the defined compounds as useful in treatment and prophylaxis of cancer (see e.g. paragraphs [0001] and [0059]).

In support of this utility the patent (see pages 63-65, Table entries) reports the results from in vitro experiments indicating cytotoxicity of the tested compounds in terms of their EC50 values in a breast cancer cell line (MDA MB231), a human colon cancer cell line (HT115) and a human prostrate cancer cell line (PC-3). The tested compounds are nucleosides and phosphoramidates thereof carrying a substituted vinyl group at the 5-position of the pyrimidine moiety without further substitution at the 2-position of the sugar moiety (see Examples A and 1-95) as well as gemcitabine (see Example G), which are presented as comparative examples, and phosphoramidates of gemcitabine (see Examples 31, 40 and 41), which represent examples of the compounds of claim 1 of the main request in which X and Y are both F. In addition, the patent presents results from experiments in a mouse model involving xenografts of human cancer (colon HT115 and prostrate PC-3) indicating the effectiveness of Example 31 ("CPF31") in reducing tumour volume.

Document D36 describes phosphoramidate nucleosides of the general formula:

FORMULA/TABLE/GRAPHIC

wherein R1 is selected from the group consisting of H,

alkyl, alkenyl, alkynyl, vinyl, propargyl and substituted derivatives thereof;

wherein R2 and R3 are independently the same or different and are selected from the group consisting of Br, Cl, F, I, H, OH, OC(=O)CH3 , -0-and -0-Rg, wherein

Rg is a hydroxyl protecting group other than acetyl;

wherein R8 is a side chain of any naturally occurring

amino acid, its analogue or its isomer;

and wherein R9 is selected from the group consisting of

hydrogen, an aliphatic group, an alicyclic group, an

aromatic group, a heterocyclic group and an adamantly

group and derivatives and analogs thereof.

Document D36 teaches that these compounds have utility in the treatment of hyperproliferative disease, including treatment of cancer (see D36, claims 1 and 29, see also paragraphs [0002], [0014]-[0017]). This teaching in document D36 is supported with experimental results for the exemplified compound NB1011 whose structure is shown in Table 2 of paragraph [0123]. NB1011 carries a bromovinyl group at the 5-position of the pyrimidine moiety and has no substitution at the 2-position of the sugar moiety (compare R1 and R3 in the general formula). These results include cytotoxicity data for NB1011 in a variety of normal and tumor cell strains (see D36, paragraph [0374], Table 5).

As pointed out in the decision under appeal (see pages 33-35, section 5.2), document D36 thus describes compounds of a similar structure with a similar purpose as described in the patent for the compounds of claim 1 of the main request and therefore represents a suitable starting point in the prior art.

As further indicated in the decision under appeal (see page 35-36, section 5.4) and as argued by the appellant-opponent, the bromovinyl substituted benzyl-ester of the phosphoramidate nucleoside defined in claim 12 of document D36, which corresponds to the comparative example 2 ("CPF-2") described in the patent (see paragraph [0108]), represents a suitable reference point within document D36 with respect to the examples 31, 40 and 41 ("CPF-31", "CPF-40", and "CPF-41") of the patent, because these exemplified compounds are the benzyl-esters of related phosphoramidate nucleosides (see the patent paragraphs [0193], [0195] and [0197]).

2.2 Difference with the prior art

2.2.1 The difference between the compounds of claim 1 of the main request and the compound of claim 12 from document D36 concerns in the first place the substitution at the 2-position of the sugar moiety (X/F in the patent vs H/H in the compound of claim 12 in D36). This difference was not in dispute.

The compounds of claim 1 of the main request may further, at least partially, be distinguished from the compound of claim 12 of document D36 in view of the substitution at the 5-position of the pyrimidine base. The compound from document D36 carries at this position a bromovinyl substitution whereas claim 1 of the main request defines at this position "Z", which is selected from the group H, alkyl and halogen.

2.3 Problem to be solved

As pointed out in the decision under appeal (see pages 36-37, section 5.5) the cytotoxicity in terms of the EC50 values reported in the patent (see page 63-65, Table entries) for Examples 31, 40 and 41 do not indicate any particular advantage for the compounds of claim 1 of the main request over comparative Example 2, which corresponds to the compound of claim 12 in document D36.

In the absence of evidence that the compounds defined in claim 1 of the main request are associated with an advantage over the closest prior art the Board concludes that starting from document D36 the problem to be solved could, at best, be seen in the provision of alternative agents with utility against cancer.

2.4 Assessment of the solution

2.4.1 The definition of compounds in claim 1 of the main request overlaps with the definition of the phosphoramidate nucleosides according to the general formula in document D36 (represented in section 2.1 above) when in the definition of claim 1 of the main request X represents H and Z represents H or alkyl.

In view of the teaching in document D36 that the phosphoramidate nucleosides according to the general formula in D36 are useful in the treatment of hyperproliferative disease, including treatment of cancer, the skilled person would as a matter of obviousness expect that the compounds of claim 1 of the main request which fall within the overlap with the general formula of the phosphoramidate nucleosides in document D36 represent alternative agents with utility against cancer.

2.4.2 The appellant-patent proprietor argued that the utility of the compounds covered by the general formula in treating hyperproliferative disease as described in document D36 would not suggest that all of these compounds would be useful against cancer, because in accordance with document D36 the term hyperproliferative disease includes a variety of hyperproliferative diseases other than cancer.

The Board does not consider this argument convincing, because document D36 explicitly teaches the utility of the described compounds in the treatment of hyperproliferative disorders in general and mentions cancer as prominent example of such disorders (see D36, paragraphs [0014] to [0017]).

2.4.3 The appellant-patent proprietor further argued that the skilled person would have serious doubts as to the credibility of the teaching in document D36 regarding the utility of the compounds as broadly defined by the general formula in the treatment of hyperproliferative diseases in general, in particular in as far as the treatment of cancer is concerned.

As contended by the appellant-patent proprietor, document D36 indeed refers in its abstract and paragraphs [0013], [0016] and [0080] to 5-substituted pyrimidine compounds ("5'-phosphoramidatyl, 1,5-substituted pyrimidine compounds") as the therapeutically active agents of its disclosure. However, in the same passages document D36 refers to "derivatives, analogs and pharmaceutically acceptable salts thereof". Moreover, in paragraph [0080] document D36 points out that the intended compounds are "nucleoside analogs comprising a substituted or unsubstituted uracil base covalently joined to a sugar modified by at least the addition of a 5'-phosphoramidate containing an amino acid residue." Accordingly, the teaching of document D36 regarding the therapeutic utility of the disclosed compounds is not limited to the 5-substituted pyrimidine compounds and the cited references to these 5-substituted pyrimidine compounds in document D36 do not contradict or cast doubt on the therapeutic utility of compounds of the general formula described in document D36.

As further argued by the appellant-patent proprietor, document D36 also mentions that the compounds carrying a substitution at the 5-position may interact with an endogenous intracellular enzyme such as thymidylate synthetase (TS) (see paragraphs [0080] and [0089]) and reports in this context that the tested compound NB1011 carrying a bromovinyl substitution at the 5-position acts as a TS ECTA compound (see paragraphs [0336] and [0341]). However, document D36 explicitly states that the interaction with an endogenous intracellular enzyme such as TS via a 5-substitution to the pyrimidine moiety only represents one aspect of the disclosure (see paragraphs [0015], [0046], [0080] and [0089]). The information in document D36 regarding a mechanism of action of the described 5-substituted pyrimidine compounds, including the tested compound NB1011, can therefore also not be considered to contradict or otherwise cast doubt on the therapeutic utility of compounds of the general formula described in document D36.

At the same time the patent only provides experimental results for nucleosides carrying a substituted vinyl group at the 5-position of the pyrimidine moiety having no substitution at the 2-position of the sugar and nucleosides carrying a di-fluoro substitution at the 2-position of the sugar moiety, which do not fall within the overlap of the definition in claim 1 of the main request and the definition of the general formula in document D36. Accordingly, the patent itself provides no more concrete basis for assuming the relevant utility of these compounds than document D36.

The Board therefore considers that the arguments of the appellant-patent proprietor against the credibility of the teaching in document D36 regarding the therapeutic utility of the compounds covered by the described general formula, in particular the compounds within the overlap with the definition of compounds in claim 1 of the main request, remain speculative and are thus not convincing.

2.4.4 Accordingly, the Board concludes that the main request does not comply with the requirement of inventive step.

3. Auxiliary requests including H for X

Auxiliary requests 1-3, 10-13, 24-27, 34-37, 48-49, 52-53, 60-61, 64-65, 72-75, 84-87, 96-97 and 102-103 maintain the overlap in the definition of the compounds of formula I with the definition of the compounds by the general formula in document D36 due to the definition of X including H. The considerations presented in section 2 above with respect to the main request therefore equally apply to these auxiliary requests.

Accordingly, the Board concludes that auxiliary requests 1-3, 10-13, 24-27, 34-37, 48-49, 52-53, 60-61, 64-65, 72-75, 84-87, 96-97 and 102-103 (filed as auxiliary requests 2-4, 11-14, 25-28, 35-38, 49-50, 53-54, 61-62, 65-66, 73-76, 85-88, 97-98 and 103-104) do not comply with the requirement of inventive step.

4. Auxiliary requests excluding H for X

4.1 Auxiliary request 4 (filed as auxiliary request 5)

4.1.1 The parent application as originally filed (see page 3, line 12 to page 4, line 14, see also claim 1) defined the variables X and Y for the compounds of formula I as follows:

"X and Y are independently selected from the group comprising H, F, Cl, Br, I, OH and methyl (-CH3)".

It was not in dispute that the amendments in accordance with claim 1 of auxiliary request 4 include with respect to the definition of the compounds of formula I in the parent application as filed the limitation of the meaning of Y to F in combination with the deletion of H from the list of options for X.

4.1.2 As confirmed in G 2/10 (see inter alia section 4.5.4), the assessment of amendments is to be based on what a skilled person would derive directly and unambiguously, using common general knowledge, from the (parent) application as originally filed (the "gold standard").

The Board observes that in accordance with the established jurisprudence regarding the deletion of meanings from multiple lists defining variables in a generic formula (see Case Law of the Boards of Appeal, 10th Edition, II.E.1.6.3 with reference to T 615/95, T 859/94, T 50/97, T 783/09, T 948/02 and T 801/02) it is not sufficient that the remaining subject-matter still relates to a generically defined group of compounds. In order to comply with Article 123(2) the deletion must not result in a particular combination of specific meanings which was not originally disclosed and which thereby generates another invention. In other words the amendment may not lead to a particular combination which is not derivable from the original application and is therefore potentially suitable to provide a technical contribution to the originally disclosed subject-matter as opposed to a mere restriction of the required protection which does not result in the definition of a new sub-class of compounds and is therefore not potentially suitable to provide a technical contribution to the original subject-matter.

4.1.3 In the patent as granted the definition of the compounds of formula I had already been limited with respect to the originally disclosed group of compounds by restriction of Y to a single meaning. Whilst such limitation is not objectionable as sole amendment, the combination of this limitation of Y with the further deletion of H in the meaning of X as defined in claim 1 of auxiliary request 4 singles out those compounds which are characterized by the combination of the features that the 2-position of the sugar moiety carries a dual substitution and that at least one of these substitutions is a fluoro-substitution. The Board considers this combination of features to define a specific sub-group of compounds within the originally disclosed generic group of compounds, which is well suitable to provide for a technical contribution generating another invention.

The original disclosure does not provide any pointer to this sub-group of compounds. On the contrary, the parent application as filed (see page 9, line 16) explicitly includes in the defined preferred list of meanings for X and Y the option of H: "Preferably, X and Y are, independently, selected from the group consisting of F, H and OH". These preferred meanings for X and Y are also reflected by the examples in the original disclosure, which relate to compounds in which X and Y represent either both H or both F.

4.1.4 The appellant-patent proprietor argued that no technical contribution was associated with the amendments in auxiliary request 4, which would merely remove the overlap with the definition of compounds from document D36 without giving rise to improvements or effects for which the original disclosure provided no basis.

The appellant-patent proprietor does thereby not address the suitability of the sub-group of compounds resulting from the amendments to provide for a technical contribution that was not embodied by the originally described generic group of compounds, which to a substantial extent overlapped with the teaching in document D36.

4.1.5 The appellant-patent proprietor further argued with reference to G 2/10 and T 1937/17 that the notion of a technical contribution should actually not be taken into account at all.

The Board notes that in G 2/10 (see section 4.3) the Enlarged Board of Appeal explained that the notion of a "technical contribution", as referred to in G 1/93 (see section 16) in the context of conflicting requirements under Article 123(2) and (3) EPC and in G 1/03 (see sections 2.6 and 4) in the context of disclaimers for undisclosed subject-matter, was not intended to modify the "gold standard" for the assessment of amendments.

The Board agrees with the considerations in T 1937/17 (see sections 4.3 and 4.3.1) that, accordingly, in the context of an amendment which is found to be allowable or not allowable under the "gold standard" any investigation as to the potential for a technical contribution is without relevance.

However, amendments by the deletion of options from multiple lists of separate characteristics inherently include an aspect of combination and potentially involve an aspect of arbitrariness, which may complicate the assessment of whether such amendments remain within the limits of what the skilled person would directly and unambiguously derive from the original disclosure.

Following the explicit reference in G 2/10 to the applicability of the existing jurisprudence regarding the singling out of compounds or sub-classes of compounds or other so-called intermediate generalisations not specifically mentioned nor implicitly disclosed in the application as filed (see G 2/10, section 4.5.4), the Board understands in this context the notion of

"the remaining generic group of compounds differing from the original group only by its smaller size" versus "singling out an hitherto not specifically mentioned sub-class of compounds"

and the notion of

"mere restriction of the required protection" versus "generating another invention" or "suitable to provide a technical contribution to the originally disclosed subject-matter"

as developed in the jurisprudence (see in section Case Law of the Boards of Appeal, supra, section II.E.1.6.3) not as modifications of the "gold standard" for the assessment of amendments in the form of additional or alternative criteria, but rather as considerations which may arise from the application of this standard when assessing amendments by deletion of options from multiple lists and which may affirm the result of such assessment.

Accordingly, the Board considers that the observation that the deletion of options for X and Y in accordance with claim 1 of auxiliary request 4 is suitable to provide a technical contribution to the originally disclosed subject-matter supports the assessment that this amendment is not in compliance with the "gold standard".

4.1.6 The Board therefore concludes that auxiliary requests 4 does not comply with the requirement of Article 76(1) EPC.

4.2 The claims according to auxiliary requests 5-9, 14-23, 28-33, 38-47, 50-51, 54-59, 62-63, 66-71, 76-83, 88-95, 98-101 and 104-107 include the same limitation in the definition of X by the deletion of H as claim 1 of auxiliary request 4.

The same considerations as presented in section 4.1 above therefore apply with respect to these auxiliary requests.

Accordingly, the Board concludes that auxiliary requests 5-9, 14-23, 28-33, 38-47, 50-51, 54-59, 62-63, 66-71, 76-83, 88-95, 98-101 and 104-107 (filed as auxiliary requests 5-10, 15-24, 29-34, 39-48, 51-52, 55-60, 63-64, 67-72, 77-84, 89-96, 99-102 and 105-108) do not comply with the requirement of Article 76(1) EPC.