T 2658/16 (ALPHA AMINOACID ESTER-DRUG CONJUGATES HYDROLYSABLE BY CARBOXYLESTERASE/GlaxoSmithKline Intellectual Property Development Limited) 11-02-2019

Reasons for the Decision

1. Main Request - Article 84 EPC

Claim 1 of the main request relates mainly to "a covalent conjugate of an alpha amino acid ester and a modulator of the activity of a target intracellular enzyme or receptor", wherein inter alia "the alpha amino acid ester is conjugated via the amino group of the alpha amino acid ester" and "the nitrogen of the amino group of the amino acid ester is not linked directly to a carbonyl moiety".

Said conjugate is further defined by the following features:

- "the ester of the conjugate is hydrolysable by one or

more intracellular carboxylesterase enzymes to the

corresponding acid, wherein the corresponding acid is

capable of selectively accumulating in hCE-1 expressing

cells", and

- "the alpha amino acid is conjugated to the modulator...at a position remote from the binding interface between the modulator and the target intracellular enzyme or receptor and wherein the position of conjugation is remote when the conjugate has a potency in a cellular activity assay at least as high as that of the unconjugated modulator in the same assay, which cellular activity assay is a cell proliferation inhibition assay carried out in U937 cancer cells".

1.1 One of the components of the claimed conjugate is thus "a modulator of the activity of a target intracellular enzyme or receptor", and is defined in the form of a functional feature.

Although functional features are generally allowable, a functional feature must remain clear in the sense that the person skilled in the art with his common general knowledge in reading the claim, must be able to understand what is meant by the claim without ambiguity and without complicated, time-consuming investigations, i.e. without undue burden, and must be able to derive a clear definition of what is intended to be claimed. Said features must provide instructions which are sufficiently clear for the skilled person to reduce them to practice without undue burden. This is not the case with the functional feature "a modulator of the activity of a target intracellular enzyme or receptor".

Said feature is indeed vague and unclear and comprises potentially an undefined and great number of possible variables. The claimed modulator does not contain any restriction as to the activity and target, and does not help in identifying which compounds are intended to be used as modulators and a skilled person does not know to which structural feature or features it corresponds. This feature as such is so vague and ambiguous that it relates to a vast catalogue of possible derivatives of unspecified structure. |Since the technical feature "a modulator of the activity of a target intracellular enzyme or receptor" is unclear for the reasons given above, it prevents the skilled person from identifying the exact meaning thereof, and the public is left in doubts as to the distinction of which "modulators" are covered by claim 1 and which are not, which is at variance with the principle of legal certainty.| | | |For this reason, the area covered by the claim is not clearly defined. |

1.2 The appellant argued that said feature "a modulator of the activity of a target intracellular enzyme or receptor" was not an essential element of the invention, which was instead the modulator delivery system, i.e. the amino acid ester and the conjugation link, or even the conjugation link between the amino acid ester and the modulator. Moreover, three different compounds were disclosed in the description, which showed that the skilled person could identify potential modulators.

The Board could not follow the appellant's arguments for the following reasons.

1.2.1 First of all, the assessment of clarity of a claim cannot be limited to some of its features, presented objectively or subjectively as the essential elements of the claimed invention. All features present in a claim must meet the requirements of Article 84 EPC.

1.2.2 In the present case, claim 1 of the main request is furthermore not restricted to the delivery system or the conjugation link and comprises further features relating inter alia to the conjugated modulator. The remaining features considered as non-essential by the appellant must also be taken in account for the assessment of the further requirements of the EPC, such as novelty or inventive step. If the core of the invention was indeed the modulator delivery system or the conjugation link, the applicant had the possibility of limiting the subject matter of the claim to that particular subject matter, with the consequence that said limited subject-matter has also to be assessed as such as regards the remaining requirements of the EPC, such as inter alia novelty and inventive step.

1.2.3 Moreover, the disclosure of three compounds in the description of the patent application, namely compounds (5), (8) and (24), having a different structure and a different activity is irrelevant to the question of clarity of the claimed feature.

Claim 1 relates mainly very broadly to a conjugate between an alpha amino ester and a modulator, wherein the nitrogen of the amino group of the amino acid ester is not directly linked to a carbonyl moiety; this combination encompasses potentially a great number of possible compounds. The question as regards the clarity of the feature relating to the modulator does not boil down to whether some compounds disclosed in the description fall under the claimed definition, but rather to determine whether an existing compound would fall under said claimed definition. This amounts to forcing a person skilled in the art to check whether any compound conjugated to an amino acid ester could have any kind of modulation activity on any kind of intracellular enzyme or receptor. In the absence of any specification of structure or activity in the claim, this amounts to undue burden, which is contrary to the requirements of clarity.

1.3 The subject-matter of claim 1 is therefore unclear in view of the feature "a modulator of the activity of a target intracellular enzyme or receptor". In view of this conclusion, the Board does not see any need in analyzing the clarity of the further remaining functional features in claim 1 of the main request.

Consequently, the main request does not meet the requirements of Article 84 EPC.

2. Auxiliary request 1 - Article 84 EPC

The feature "a modulator of the activity of a target intracellular enzyme or receptor" is also present in claim 1 of auxiliary request 1, which leads to the same conclusions as for the main request and thus auxiliary request 1 does not meet the requirements of Article 84 EPC.

3. Auxiliary request 2 - Article 84 EPC

The feature "a modulator of the activity of a target intracellular enzyme or receptor" is present in claim 1 of auxiliary request 2, and the conclusions as to lack of clarity reached for the main request apply also to this request.

The fact that claim 1 has been reformulated as "a method of selectively increasing or prolonging, in macrophage and monocyte cells relative to other cell types, the intracellular potency and/or residence time of a modulator of the activity of a target intracellular enzyme or receptor" cannot have any incidence on the lack of clarity stated above. The skilled person is still in a position not enabling him to identify which compounds are intended to be used as modulators and a skilled person does not know to which structural feature or features it corresponds.

4. Auxiliary request 3 - Article 84 EPC

As in auxiliary request 2, claim 1 has been reformulated as "a method of selectively increasing or prolonging, in macrophage and monocyte cells relative to other cell types, the intracellular potency and/or residence time of a modulator of the activity of a target intracellular enzyme or receptor".

The conclusions stated above for auxiliary request 2 and the main request apply mutatis mutandis to this request, in view of the feature "a modulator of the activity of a target intracellular enzyme or receptor" in claim 1 and auxiliary request 3 does not meet the requirements of Article 84 EPC.

5. Auxiliary request 4 - Article 84 EPC

As in auxiliary requests 2 and 3, claim 1 of auxiliary request 4 has been reformulated as "a method of selectively increasing or prolonging, in macrophage and monocyte cells relative to other cell types, the intracellular potency and/or residence time of a modulator of the activity of a target intracellular enzyme or receptor". The same conclusions apply mutatis mutandis to this request, in view of the feature of the feature "a modulator of the activity of a target intracellular enzyme or receptor" in claim 1.

Consequently, auxiliary request 4 does not meet the requirements of Article 84 EPC.

6. Auxiliary request 5 - Article 84 EPC

Claim 1 relates to a conjugate comprising "an inhibitor of the activity of a target intracellular enzyme or receptor for use in a method of treating rheumatoid arthritis".

The restriction to an "inhibitor" instead of a more general "modulator" claimed modulator does still not allow to identify which compounds are intended to be used as inhibitors or which enzyme or receptor has to be inhibited, and a skilled person does not know to which structural feature or features it corresponds. This feature remains so vague and ambiguous that it relates to a vast catalogue of possible derivatives of unspecified structure.

Moreover, the further restriction to the "use in a method of treating rheumatoid arthritis" necessitates a further identification and research work as to the medical use of the claimed unidentified inhibitor.

The skilled person is therefore still unable to establish without undue burden which compounds might fall under the double limitation "an inhibitor of the activity of a target intracellular enzyme or receptor for use in a method of treating rheumatoid arthritis".

Consequently, auxiliary request 5 does not meet the requirements of Article 84 EPC.

7. Auxiliary requests 6 and 7 - Article 84 EPC

Claim 1 of auxiliary requests 6 and 7 relate to "a modulator of the activity of a target intracellular enzyme or receptor" and lacks clarity for the same reason as the main request.

Consequently, they do not meet the requirements of Article 84 EPC.

8. Auxiliary request 8 - Article 84 EPC

As in auxiliary request 5, claim 1 of this request relates to a conjugate comprising "an inhibitor of the activity of a target intracellular enzyme or receptor for use in a method of treating rheumatoid arthritis".

The conclusions reached for auxiliary request 5 apply mutatis mutandis to auxiliary request 8, which does not meet the requirements of Article 84 EPC.