T 1173/03 (Collections/SPIROGEN) of 29.6.2006

European Case Law Identifier: ECLI:EP:BA:2006:T117303.20060629
Date of decision: 29 June 2006
Case number: T 1173/03
Application number: 99941767.8
IPC class: C07D 487/04
Language of proceedings: EN
Download and more information:
Decision text in EN (PDF, 104.358K)
Documentation of the appeal procedure can be found in the Register
Bibliographic information is available in: EN
Versions: Unpublished
Title of application: Collections of compounds
Applicant name: Spirogen Limited
Opponent name: -
Board: 3.3.01

Headnote

-
Relevant legal provisions:
European Patent Convention 1973 Art 56
European Patent Convention 1973 Art 84
European Patent Convention 1973 Art 111(1)
European Patent Convention 1973 R 68(2)
Keywords: Main and first auxiliary request: clarity (no)
Second auxiliary request: decision unreasoned - remittal to first instance
Catchwords:

-

Cited decisions:
T 0022/82
T 0068/85
T 0238/88
T 0939/92
Citing decisions:
-

Summary of Facts and Submissions

I. The appeal lies from the Examining Division's decision to refuse the application 99 941 767.8, since the claimed collections of compounds were considered not to be inventive over the disclosure of document

(11) Chem. Rev. 1994, 94, pages 433 to 465.

In particular, the Examining Division was of the opinion that PBD (pyrrolobenzodiazepine) compounds were known from document (11), that for none of the compounds a surprising effect had been shown and that the provision of a further library for the purpose of screening in order to identify chemical compounds with desired activities is within the routine work of a skilled person.

II. With letter of 16 May 2006 the Appellant filed sets of claims according to a main and three auxiliary requests.

Claims 1 and 2 according to the main request were concerned with a collection of compounds all of which are of formula (II)

FORMULA/TABLE/GRAPHIC

respectively of formula (i)

FORMULA/TABLE/GRAPHIC

wherein R2 is H-(t)n-X'-Y-A- and

where T is a combinatorial unit.

Claims 1 and 2 according to the first auxiliary request were concerned with a collection of at least 1000 compounds all of which are of formula (II) respectively formula (i) as defined in Claims 1 and 2 of the main request.

The second auxiliary request consisted of 19 claims with the independent claims reading:

"1. A collection of compounds all of which are of formula (II):

FORMULA/TABLE/GRAPHIC

wherein

R2 is H-(t)n-X'-Y-A-

where:

X' is CO, NH, S or O;

Y is a divalent group such that HY = R;

A is O, S, NH or a single bond;

T is an amino acid residue;

and n is a positive integer;

R3 is selected from: H, R, OH, OR, =0, =CH-R, =CH2, CH2-CO2R, CH2-CO2H, CH2-SO2R, O-SO2R, CO2R, COR and CN, and there is optionally a double bond between C1 and C2 or C2 and C3;

R6, R7, R8 and R9 are independently selected from H, R, OH, OR, halo, nitro, amino, Me3Sn; or R7 and R8 together form a group -O-(CH2)p-O-, where p is 1 or 2;

where R is a lower alkyl group having 1 to 10 carbon atoms, or an aralkyl group of up to 12 carbon atoms, whereof the alkyl group optionally contains one or more carbon-carbon double or triple bonds, which may form part of a conjugated system, or an aryl group of up to 12 carbon atoms; and is optionally substituted by one or more halo, hydroxy, amino, or nitro groups."

"2. A collection of compounds all of which are of formula (i):

FORMULA/TABLE/GRAPHIC

wherein

one of R2 and R8 is:

H-(t)n-X'-Y-A-

where:

X' is CO, NH, S or O;

Y is a divalent group such that HY = R;

A is O, S, NH or a single bond;

T is an amino acid residue;

and n is a positive integer;

R2 (if not H-(t)n-X'-Y-A-) and R3 are independently selected from: H, R, OH, OR, =0, =CH-R, =CH2, CH2-CO2R, CH2-CO2H, CH2-SO2R, O-SO2R, CO2R, COR and CN, and there is optionally a double bond between C1 and C2 or C2 and C3;

R6, R7, R8 (if not H-(t)n-X'-Y-A-) and R9 are independently selected from H, R, OH, OR, halo, nitro, amino, Me3Sn; or, if R8 is not H-(t)n-X'-Y-A-, R7 and R8 together form a group -O-(CH2)p-O-, where p is 1 or 2;

R11 is either H or R;

Q is S, O or NH;

L is a linking group, or a single bond;

omicron is a solid support;

where R is a lower alkyl group having 1 to 10 carbon atoms, or an aralkyl group of up to 12 carbon atoms, whereof the alkyl group optionally contains one or more carbon-carbon double or triple bonds, which may form part of a conjugated system, or an aryl group of up to 12 carbon atoms; and is optionally substituted by one or more halo, hydroxy, amino, or nitro groups."

"12. A compound of formula (i):

FORMULA/TABLE/GRAPHIC

wherein:

one of R2 and R8 is X-Y-A-, where X is -COZ', NHZ, SH, or OH, where Z is either H or an nitrogen protecting group, Z' is either OH or an acid protecting group, Y is a divalent group such that HY = R, and A is O, S, NH, or a single bond;

R2 (if not X-Y-A-) and R3 are independently selected from: H, R, OH, OR, =0, =CH-R, =CH2, CH2-CO2R, CH2-CO2H, CH2-SO2R, O-SO2R, CO2R, COR and CN, and there is optionally a double bond between C1 and C2 or C2 and C3;

R6, R7, R8 (if not X-Y-A-) and R9 are independently selected from H, R, OH, OR, halo, nitro, amino, Me3Sn; or R7 and R8 together form a group -O-(CH2)p-O-, where p is 1 or 2;

R11 is either H or R;

Q is S, O or NH;

L is a linking group, or a single bond;

omicron is a solid support;

where R is a lower alkyl group having 1 to 10 carbon atoms, or an aralkyl group of up to 12 carbon atoms, whereof the alkyl group optionally contains one or more carbon-carbon double or triple bonds, which may form part of a conjugated system, or an aryl group of up to 12 carbon atoms; and is optionally substituted by one or more halo, hydroxy, amino, or nitro groups."

III. Oral proceedings before the Board took place on 29 June 2006.

IV. The Appellant essentially argued that the term "combinatorial unit", as presented in Claims 1 and 2 according to the main request and the first auxiliary request, is a generally accepted term in the art and, consequently, that the clarity of the claims is not affected thereby. Moreover, in favour of inventive step, the Appellant essentially argued that it was the objective of the claimed invention to reduce the time taken to identify a compound having a specific biological activity. Since it was the first time library technology had been applied to PBD compounds and since the claimed collections combine the protection of the N10-C11 reactive site with attaching the compounds to a solid support, the proposed solution was not obviously derivable from the prior art.

V. The Appellant requested that the decision under appeal be set aside and that a patent be granted on the basis of one of the four sets of claims filed as main and auxiliary request 1, 2 and 3 with letter dated 16 May 2006.

Reasons for the Decision

1. The appeal is admissible.

2. Main request and first auxiliary request

2.1 Article 84 EPC - Clarity

2.1.1 Article 84 EPC requires that the matter for which protection is sought be defined in the claims in a clear manner. Since Claims 1 and 2 in both sets of claims define collections of compounds of formula (II) respectively (i), it must be unambiguously derivable from the wording of Claims 1 and 2, possibly in combination with the teaching of the description, which compounds may be comprised in the claimed collections and, therefore, all substituents in the compounds of formula (i) and (II) must be defined in an unambiguous way.

2.1.2 Whereas no objection arises against the clarity of the substituents R3, R6 to R9, R11, L and ?, due to the definition of the radical T as a "combinatorial unit", the substituent R2 cannot be considered to be defined in an unambiguous way.

Namely, in assessing whether the compounds of formula (i) and (II) meet the requirement of clarity, it is decisive, whether a skilled person, considering the teaching in the description and his common general knowledge, would be able to find out which R2 substituent the compounds comprised in the claimed collections must have and, more particularly, which chemical radical is to be understood as a combinatorial unit T.

2.1.3 The only information about the meaning of the term "combinatorial unit" that can be found in the description is the one on page 11, line 17 to page 13, line 9. In this passage examples of suitable combinatorial units are provided and on page 11, lines 18 to 34, it is stated that a combinatorial unit is

"any monomer unit which can be used to build a chain as shown in a compound of formula I as defined in the second aspect of the present invention, or a compound of formula II, when derived from a compound of formula I as defined in the second aspect of the present invention. ....... Examples of molecules suitable for such chain building are found in Schreiber et al. (JACS, 120, 1998, pp.23-29), which is incorporated herein by reference." (emphasis added)

2.1.4 The Appellant submitted in the last paragraph on page 1 of the letter of 20 October 2003 that the combinatorial unit provides the necessary variation to allow the identification of compounds having highly specific biological activities and thus affects the location at which the PBD moiety binds to DNA. As an explanation, the Appellant further submitted in the second paragraph on page 2 of the letter of 20 October 2003 that the combinatorial unit will lie adjacent the DNA strands, and by its interaction, will enable targeting of the PBD moiety to particular sequences.

However, since nowhere in the description any further information can be found about which monomer, useful to build a chain, may affect the location at which the PBD moiety binds to DNA, a skilled person cannot find out which compounds are embraced within the definition of Claims 1 and 2.

2.1.5 The Appellant further submitted that the article Schreiber et al. (see point 2.1.3) disclosed suitable molecules for such chain building and, thus, provided the necessary information to a skilled person to find out which monomers could be useful as radical T.

The Board does not dispute that the Schreiber et al. article discloses monomers suitable for chain building. However, in deciding whether the term objected to in the claim is clear, it is not relevant whether a skilled person obtains information on monomers qualifying for chain building, but whether he could define which monomers are suitable as a "combinatorial unit" in the sense of the application in suit and which not. Such information is clearly missing in the Schreiber et al. article.

Moreover, the Appellant himself had to admit that the Schreiber et al. article is completely silent about the meaning of the term "combinatorial unit" and he did not refer to any other document which could be considered as representing common general knowledge in the field concerned, wherefrom it could be deduced that chemical radicals are unambiguously defined by that term.

2.1.6 In arguing in favour of clarity, the Appellant referred to the principle set out in decision T 68/85 (OJ EPO 1987, 228), stating in essence that functional features defining a technical result are permissible, if such features cannot otherwise be defined more precisely and if these features provide instructions which are sufficiently clear for the skilled person to reduce them to practice. However, independent thereof whether the term "combinatorial unit" may be considered as a functional feature, for the reasons given above, it does not provide instructions which are sufficiently clear for a skilled person to reduce them to practice. Therefore the principle described in T 68/85 is not applicable in the present case.

2.1.7 In the absence of not only information in the description about which monomers are to be considered as combinatorial units and which not, but also any relevant common general knowledge thereupon, it is the position of the Board that a skilled person is not able to define in an unambiguous way which compound may be comprised in the claimed collections. Therefore, Claims 1 and 2 do not meet the requirement of clarity pursuant to Article 84 EPC.

2.2 Since, thus, the sets of claims according to the main and first auxiliary requests do not meet all requirements of the EPC, these requests are refused.

3. Second auxiliary request

3.1 Article 123(2) EPC

The wording of Claims 1 and 2 differ from the wording in the main request and the first auxiliary request by the fact that the term "combinatorial unit" has been replaced by the term "amino acid residue".

On page 11, line 27, of the application as filed "amino acid residue" is cited as an important example of a combinatorial unit.

Moreover, the remaining features of Claim 1 correspond with the features of original Claims 1, 4, 5 and 23; the remaining features of Claim 2 correspond with the features of original Claims 1, 2, 3 and 4; and the features of Claim 12 are a combination of the features of original Claims 1 and 2.

The requirement of Article 123(2) EPC is thus met.

3.2 Clarity

The Board does not have any reason to doubt that the radical T in substituent R2 is unambiguously defined by the term "amino acid residue", which is generally accepted. The clarity of a claim is not diminished by the mere breadth of a term of art contained in it, if the meaning of such term per se is unambiguous for a person skilled in the art (T 238/88 OJ EPO 1992, 709).

Thus, the requirement of clarity is fulfilled.

3.3 Novelty

Since neither collections of PBD compounds (Claims 1 and 2) nor PBD compounds attached to a solid support (Claim 12) were disclosed in any of the cited prior art documents, the requirement of novelty is fulfilled.

3.4 Inventive step

3.4.1 The Examining Division found that "[A]n inventive step cannot be attributed to the provision of a collection of compounds in analogy to the mere provision of new compounds which themselves do not have any unexpected effects (cf. decision T 22/82)" and that "[A]n inventive solution could only be ascribed to the collection if a specific (e.g. pharmaceutical) effect was shown.

However, the problem underlying the claimed invention is not the provision of compounds having unexpected effects, but rather the reduction of the time it takes to identify a compound having a specific biological activity (see point IV above and page 1, lines 22 ff. of the description).

Since T 22/82 (OJ EPO 1982, 341) is concerned with inventive step for a process for preparing known substances more economically and technologically more simply than in the prior art, which situation differs completely from the one in the present case, the principle described therein is not applicable in the present case.

Moreover, if the problem underlying the claimed invention is that stated above, an inventive step cannot be based on an unexpected effect of a particular compound. The claimed collections of compounds, proposed as a solution to the problem to be solved, are then rather intended to be used for screening the compounds comprised therein on a specific biological activity. Thus, in assessing inventive step, the relevant question seems to be rather whether it was obvious to provide the collections of compounds now claimed in order to speed up the process of identifying a compound having a specific biological activity in comparison with the classical method of synthesizing compounds one by one and separately testing each compound in a specific screening test. In this respect, in the contested decision also reference was made to decision the T 939/92 (OJ EPO 1996, 309). However, the principle described therein, namely that it must be made credible that substantially all claimed compounds possess the alleged activity, is not applicable in the present case, where the facts are significantly different as set out above.

3.4.2 The Applicant (now Appellant) extensively argued in the letter of 1 April 2003 that the solution offered by the present invention was not only obtained by applying library technology to PBD compounds, but also by combining protection of the N10-C11 reactive site with attaching the compounds to a solid support and derivatising the PBD core so that it can be attached to a combinatorial chain. As not a single one of these steps was taught or suggested in the prior art, the claimed collections were not obviously derivable thereof.

Although the Applicant provided those arguments well before the oral proceedings before the Examining Division, namely on 7 May 2003, there is not any trace in the contested decision showing these arguments of the Applicant.

3.4.3 Moreover, in the contested decision it is stated that "the preparation of libraries for the purpose of screening in order to identify chemical compounds with desired activities is considered to be within the routine work of a person skilled in the art."

Nowhere in the decision, however, can any explanation be found in respect of how the Examining Division had arrived at this conclusion, nor could the Board identify any support for it. Consequently, such statement is no more than an unsubstantiated allegation.

3.4.4 In order to comply with Rule 68(2) EPC, however, requiring that decisions before the EPO which are open to appeal shall be reasoned, the reasoning given in a decision open to appeal has to enable the Appellant and, in case of appeal, the Board of Appeal to examine whether the decision was justified or not. Therefore, a decision on inventive step has to contain the logical chain of reasoning used to justify the conclusion that the claimed subject-matter does not involve an inventive step. As this is not the case for the presently contested decision refusing the application for the grant of a patent, the decision is in fact unreasoned and, therefore, contravenes the provisions of Rule 68(2) EPC.

4. The de facto absence of reasoning (see points 3.4.2 and 3.4.3) combined with the application of a wrong principle for assessing inventive step are also fundamental deficiencies pursuant Article 10 of the Rules of Procedure of the Boards of Appeal, which must have the consequence that the decision under appeal is to be set aside and the case to be remitted to the first instance in application of Article 111(1) EPC for further prosecution on the basis of the second auxiliary request filed with letter of 16 May 2006.

4.1.1 For assessing inventive step when resuming the examination of the application in suit, the well established problem-solution approach should be followed. Thereby it is in particular necessary

- to establish the closest state of the art forming the starting point,

- to determine in the light thereof the technical problem which the invention addresses and effectively solves and

- to examine the obviousness of the claimed solution to this problem in view of the state of the art and common general knowledge, as reflected in "Combinatorial Chemistry", 1998 (N. K. Terrett) edited by Oxford University Press and in some overview articles, such as, Angew. Chem. 1996, 108, pages 2436 to 2488.

4.1.2 Moreover, it should be verified whether dependent Claims 7 and 15 meet the requirement of Article 123(2) EPC. In particular, it is questionable whether support can be found in the application as filed, in particular, original Claim 9, for a lower alkyl group optionally substituted by one or more halo, hydroxy, amino or nitro groups.

ORDER

For these reasons it is decided that:

1. The decision under appeal is set aside.

2. The case is remitted to the department of first instance for further prosecution on the basis of the second auxiliary request.

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