T 0177/08 (Mediators of hedgehog signaling pathways/CURIS INC.) 08-04-2011

Summary of Facts and Submissions

I. European patent No. 1 216 234 based on application No. 00 963 551.7 was granted on the basis of 32 claims. The independent claims read as follows:

"1. Use of a compound for the preparation of a pharmaceutical composition for inhibiting hyperproliferation of a cell, wherein the compound is an organic molecule represented by the general formula (II):

FORMULA/TABLE/GRAPHIC

wherein, as valence and stability permit,

R1 and R2, independently for each occurrence, represent

H, C1-C10 alkyl, aryl (substituted or unsubstituted), aralkyl (substituted or unsubstituted), heteroaryl (substituted or unsubstituted), or heteroaralkyl (substituted or unsubstituted);

L, independently for each occurrence, is absent or represents -alkenyl-, -alkynyl-, -(CH2)nO(CH2)p,

-(CH2)nNR2(CH2)p-, -(CH2)nS(CH2)p-, -(CH2)nalkenyl(CH2)p-,

-(CH2)alkynyl(CH2)p-, -O(CH2)n-, -NR2(CH2)n-, or -S(CH2)n-;

X is selected from -N(R8)-, -0-, -S-, -Se-, -N=N-,

-ON=CH-, -(R8)N-N(R8)-, -ON(R8)-, a heterocycle, or a direct bond between L and Y;

Y is selected from -C(=0)-, -C(=S)-, -S(02)-, -S(0)-,

-C(=NCN)-, -P(=0)(0R2)-, a heteroaromatic group, or a direct bond between X and Z;

Z is selected from -N(R8)-, -0-, -S-, -Se-, -N=N-,

-ON=CH-, -R8N-NR8-, -0NR8-, a heterocycle, or a direct bond between Y and L;

R8, independently for each occurrence, represents H, C1-C10 alkyl, aryl (substituded or unsubstituted), aralkyl (substituted or unsubstituted), heteroaryl (substituted or unsubstituted), or heteroaralkyl (substituted or unsubstituted), or two R8 taken together form a 4-to 8-membered ring, together with the atoms to which they are attached, which ring may include one or more carbonyls;

W represents a substituted or unsubstituted benzo or pyrido ring fused to the pyrimidone ring;

p represents, independently for each occurrence, an integer from 0 to 10; and n, individually for each occurrence, represents an integer from 0 to 10,

wherein the term "heteroaryl" or "heteroaralkyl" refers to an aryl group having up to 4 heteroatoms and wherein the term "substituted" refers to a substituent selected from halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, or -CN.

21. The use as in any preceding claim, wherein L adjacent to R1 is absent, and L adjacent to X is a substituted or unsubstituted methylene.

27. Use of a compound for the preparation of a pharmaceutical composition for treating cancer, wherein the compound is an organic molecule represented by the general formula (II) as defined in any preceding claim.

31. Use of a compound for the preparation of a pharmaceutical composition for inhibiting unwanted hair growth, wherein the compound is an organic molecule represented by the general formula (II) as defined in any preceding claim."

II. Two oppositions were filed against the patent. The patent was opposed under Article 100(a) EPC for lack of novelty and inventive step, under Article 100(b) EPC for insufficiency of disclosure and under Article 100(c) EPC for amendments that contained subject-matter extending beyond the content of the application as originally filed.

III. The present appeal lies from a decision of the opposition division, pronounced on 11 October 2007, to revoke the patent pursuant to Article 102(1) EPC.

IV. In substance, the opposition division arrived at the conclusion that the main request filed at the oral proceedings did not meet the requirements of Article 123(3) EPC. As regards the defintion "L adjacent to X is a substituted or unsubstituted methylene", a basis therefor could be found in claim 21 as granted. The skilled person, reading the claims, would immediately recognise that claim 21, although referring to any preceding claim, was de facto an independent claim, which, as a consequence, did not meet the requirements of Rule 29 EPC 1973. Instead of interpreting said definition as non-existent as proposed by opponent 02, the opposition division concluded that the reformulation of claim 21 into an independent claim constituted a correction of an obvious error. As a consequence, the above definition was encompassed by the subject-matter of the claims as granted and its introduction into claim 1 of the main request was not objectionable under Article 123(3) EPC.

As regards the introduction of the list of possible substituents for any alkyl group, the opposition division concluded that claim 1 as granted had to be interpreted as it literally stood. In the claims the terms "substituted" or "unsubstituted" were never used in connection with "alkyl" as such, but only in combination with a specific alkyl group in claim 21 as granted. Moreover, the IUPAC definition for alkyl groups was CnH2n+1. As a consequence, the introduction into claim 1 of the list of substituents from paragraph [86] of the patent as granted, with a view to further defining the alkyl group, extended the protection conferred.

V. The appellant (patentee) lodged an appeal against that decision.

VI. With the statement of the grounds of appeal dated 25 March 2008, the appellant filed a main request and three auxiliary requests. The sole independent claims of the main request and of auxiliary request 1, which are identical to the corresponding requests of the decision under appeal, read as follows:

(i) Main request

"1. Use of a compound for the preparation of a pharmaceutical composition for inhibiting hyperproliferation of a cell, wherein the compound is an organic molecule represented by the general formula (II):

FORMULA/TABLE/GRAPHIC

wherein, as valence and stability permit,

R1 represents H, C1-C10 alkyl, aryl (substituted or unsubstituted), aralkyl (substituted or unsubstituted), heteroaryl (substituted or unsubstituted), or heteroaralkyl (substituted or unsubstituted);

R2 represents a substituted or unsubstituted aryl or heteroaryl group;

L adjacent to X is -CH(R10)-, wherein R10 is alkyl, alkenyl, cycloalkyl or aralkyl, and

L adjacent to R2 is absent or represents -alkenyl-,

alkynyl-, -(CH2)nO(CH2)p, -(CH2)nNR2(CH2)p-, -(CH2)nS(CH2)p-, -(CH2)nalkenyl(CH2)p-, -(CH2)nalkynyl(CH2)p-, -O(CH2)n-,

-NR2(CH2)n-, or -S(CH2)n-;

X is -N(R12)-, wherein R12 is a substituted or unsubstituted C1-C10 alkyl;

Y is selected from -C(=0)-, -C(=S)-, -S(02)-, -S(0)-,

-C(=NCN)-, -P(=0)(0R2)-, or a heteroaromatic group;

Z is selected from -N(R8)-, -0-, -S-, -Se-, -N=N-,

-ON=CH-, -R8N-NR8-, -ONR8-, a heterocycle, or a direct bond between Y and L;

R8, independently for each occurrence, represents H, C1-C10 alkyl, aryl (substituded or unsubstituted), aralkyl (substituted or unsubstituted), heteroaryl (substituted or unsubstituted), or heteroaralkyl (substituted or unsubstituted), or two R8 taken together form a 4-to 8-membered ring, together with the atoms to which they are attached, which ring may include one or more carbonyls;

W represents a substituted or unsubstituted benzo or pyrido ring fused to the pyrimidone ring;

p represents, independently for each occurrence, an integer from 0 to 10; and

n, individually for each occurrence, represents an integer from 0 to 10,

wherein the term "heteroaryl" or "heteroaralkyl" refers to an aryl group having up to 4 heteroatoms,

wherein any substituted aromatic ring can be substituted at one or more ring positions with a substituent selected from halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, or -CN

and wherein any alkyl group can be substituted on one or more carbons of the hydrocarbon backbone with a substituent selected from halogen, azide, aralkyl, hydroxyl, alkoxyl, amino, nitro, suiThydryl, imino, amido, phosphate, phosphonate, phosphinate, alkylthio, sulfonyl, sulfonamido, heterocyclyl, aromatic or heteroaromatic moieties, or —CN,

for the treatment of squamous cell carcinoma (e.g. lung squamous carcinoma), carcinosarcoma, adenocystic carcinoma, epidemoid carcinoma, nasopharyngeal carcinoma, renal cell carcinoma, papilloma, epidemoidoma, tumors related to Gorlin’s syndrome (e.g., medulloblastoma, meningioma, etc.), tumors evidenced in pct knock-out mice (e.g., hemangioma, rhabdomyosarcoma, etc.), tumors resulting from gli-I amplification (e.g., glioblastoma, sarcoma, etc.), tumors connected with ptc homolog TRC8 (e.g., renal carcinoma, thyroid carcinoma, etc.), Ext-I-related tumors (e.g., bone cancer, etc.), Shh-induced tumors (e.g., lung cancer, chondrosarcomas, etc.), breast cancer, urogenital cancer (e.g., kidney, bladder, ureter, prostate, etc.), adrenal cancer, primary CNS malignant neuroectodermal tumors (e.g. malignant medulloblastoma), malignant gliomas, meningiomas, neuroectodermal tumors, ependymomas, pineoblastoma, or keratoacanthoma."

(ii) Auxiliary request 1

Claim 1 is identical to claim 1 of the main request except for the following additional feature at the end of the claim: "wherein the cell has a hedgehog-gain of function phenotype".

VII. In its reply to the statement of the grounds of appeal dated 12 August 2008, respondent 02 (opponent 02) raised objections under Articles 84 and 123(2) and (3) EPC.

VIII. In the communication of 23 February 2011, issued pursuant to Article 5(3) RPBA, the board informed the parties that in its provisional opinion none of the requests on file appeared to meet the requirements of Article 123(3) EPC.

IX. With a letter of 8 March 2001, the appellant filed new auxiliary requests 2 and 3. The sole independent claims read as follows:

(i) Auxiliary request 2

"1. Use of a compound for the preparation of a pharmaceutical composition for inhibiting hyperproliferation of a cell, wherein the compound is an organic molecule represented by the general formula (II):

FORMULA/TABLE/GRAPHIC

wherein, as valence and stability permit,

R1 represents H, C1-C10 alkyl, aryl (substituted or unsubstituted), aralkyl (substituted or unsubstituted), heteroaryl (substituted or unsubstituted), or heteroaralkyl (substituted or unsubstituted);

R2 represents a substituted or unsubstituted aryl or heteroaryl group;

L adjacent to X is -CH(R10)-, wherein R10 is alkyl, alkenyl, cycloalkyl or aralkyl, and

L adjacent to R2 is absent or represents -alkenyl-,

alkynyl-, -(CH2)nO(CH2)p, -(CH2)nNR2(CH2)p-, -(CH2)nS(CH2)p-, -(CH2)nalkenyl(CH2)p-, -(CH2)nalkynyl(CH2)p-, -O(CH2)n-,

-NR2(CH2)n-, or -S(CH2)n-;

X is -N(R12)-, wherein R12 is C1-C10 alkyl;

Y is selected from -C(=0)-, -C(=S)-, -S(02)-, -S(0)-,

-C(=NCN)-, -P(=0)(0R2)-, or a heteroaromatic group;

Z is selected from -N(R8)-, -0-, -S-, -Se-, -N=N-,

-ON=CH-, -R8N-NR8-, -ONR8-, a heterocycle, or a direct bond between Y and L;

R8, independently for each occurrence, represents H, C1-C10 alkyl, aryl (substituted or unsubstituted), aralkyl (substituted or unsubstituted), heteroaryl (substituted or unsubstituted), or heteroaralkyl (substituted or unsubstituted), or two R8 taken together form a 4- to 8-membered ring, together with the atoms to which they are attached, which ring may include one or more carbonyls;

W represents a substituted or unsubstituted benzo or pyrido ring fused to the pyrimidone ring;

p represents, independently for each occurrence, an integer from 0 to 10; and

n, individually for each occurrence, represents an integer from 0 to 10,

wherein the term "heteroaryl" or "heteroaralkyl" refers to an aryl group having up to 4 heteroatoms,

wherein any substituted aromatic ring can be substituted at one or more ring positions with a substituent selected from halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, or -CN

for the treatment of squamous cell carcinoma (e.g. lung squamous carcinoma), carcinosarcoma, adenocystic carcinoma, epidemoid carcinoma, nasopharyngeal carcinoma, renal cell carcinoma, papilloma, epidemoidoma, tumors related to Gorlin’s syndrome (e.g., medulloblastoma, meningioma, etc.), tumors evidenced in pct knock-out mice (e.g., hemangioma, rhabdomyosarcoma, etc.), tumors resulting from gli-I amplification (e.g., glioblastoma, sarcoma, etc.), tumors connected with ptc homolog TRC8 (e.g., renal carcinoma, thyroid carcinoma, etc.), Ext-I-related tumors (e.g., bone cancer, etc.), Shh-induced tumors (e.g., lung cancer, chondrosarcomas, etc.), breast cancer, urogenital cancer (e.g., kidney, bladder, ureter, prostate, etc.), adrenal cancer, primary CNS malignant neuroectodermal tumors (e.g. malignant medulloblastoma), malignant gliomas, meningiomas, neuroectodermal tumors, ependymomas, pineoblastoma, or keratoacanthoma."

(ii) Auxiliary request 3

Claim 1 is identical to claim 1 of auxiliary request 2 except for the following additional feature at the end of the claim: "wherein the cell has a hedgehog-gain of function phenotype".

X. Oral proceedings were held before the board on 8 April 2011.

XI. In connection with the requirements of Article 123(3) EPC, the appellant's arguments can be summarised as follows:

The subject-matter of the claims as granted encompassed substituted alkyl groups in the light of the disclosure in paragraph [0086] of the contested patent which stated that the term "alkyl" as used throughout the specification, examples and claims embraced both unsubstituted and substituted alkyls. Moreover, paragraph [0086] pertained to both "alkyl" and "lower alkyl", the latter being defined as having from 1-10 carbon atoms. According to the established case law of the boards of appeal, the patent document could serve as its own dictionary, which meant that definitions provided therein took precedence over definitions commonly used in the technical field under consideration, even in cases where the meaning resulting from such a definition deviated from the meaning commonly held in the art. Decision T 1321/04 (unpublished) was cited in this context. A further indication that "alkyl" included "substituted alkyl" could be seen in the fact that in cases where substitution was to be excluded, the alkyl rests were defined by their chemical formula (CH2)n. The fact that claim 1 as granted specifically mentioned that the aryl rest could be either substituted or unsubstituted did not allow the conclusion that substitution was not foreseen for the alkyl rest, where this indication was missing. This difference was the consequence of different definitions given in paragraphs [0086] and [0092] of the contested patent. According to paragraph [0086], the term "alkyl" encompassed per se substituted and unsubstituted alkyl rests, while paragraph [0092] only said that the aromatic rings of the aryl groups could be substituted, which did not indicate that the term "aryl" taken alone would include substituted species. As a consequence, the option of a substituent being present had to be included in claim 1 in connection with "aryl".

Regarding the feature "L adjacent to X is -CH(R10)", it was held that claim 21 as granted, which was not the result of an obvious error, specifically mentioned substituted methylene groups.

XII. In connection with the requirements of Article 123(3) EPC, the arguments of respondent 02 can be summarised as follows:

Regarding the main request and auxiliary request 1, it was reasoned that the subject-matter of the claims as granted did not include substituted alkyl groups. As claims had to be read literally, paragraph [0086] of the contested patent could not be used to interpret the content of the claims. In view of the fact that formula II as defined in claim 1 of the main request and auxiliary request 1 included substituted alkyl groups, the requirements of Article 123(3) EPC were not met.

The inclusion of the definition "L adjacent to X is -CH(R10)" into claim 1 extended the protection conferred, as compounds wherein L is a substituted methylene group were not included in formula II as defined in claim 1 as granted. L could comprise a substituted methylene group according to claim 21 as granted. Claim 21, however, was erroneous as it did not contain all the features of the preceding claims to which it referred. Claim 21 as granted did not meet the requirements of Rule 43 EPC and should either be deleted or ignored. Reference was made to decision T 0307/05 (unpublished), which in connection with the requirements of Article 123(2) and (3) EPC stated that the slightest doubt that the unamended patent could be construed differently to the patent as amended would preclude the allowability of the amendment. Decision T 681/00 (unpublished) was also cited in this context. Alternatively, it was reasoned that claim 21 as granted contained an obvious error. The feature "L adjacent to X is a substituted or unsubstituted methylene" had not been included in the claims as originally filed but had been added in the course of substantive examination. However, the corresponding passage in the original description had not been correctly cited.

XIII. Respondent 01 (opponent 01) did not make any submissions.

XIV. The appellant requested that the decision under appeal be set aside and a patent be maintained according to the main request submitted during the oral proceedings before the opposition division, or, in the alternative, to auxiliary request 1, filed with the statement of the grounds of appeal, or, in the alternative, to auxiliary requests 2 or 3 filed with letter dated 8 March 2011.

The respondents requested that the appeal be dismissed.