W 0006/95 (Pyrimidine derivatives) 16-07-1996

I. Following the filing of International Patent Application No. PCT/US.... the EPO, acting as ISA, on 6 February 1995 issued an invitation to pay within 45 days four additional search fees (Article 17(3)(a) and Rule 40.1 PCT).

II. The said International Patent Application contained 30 claims, Claim 1 concerning compounds having the structure

FORMULA

wherein Rl is a binding partner, a linker or H;

a and b independently are O or 1, provided that the total of a and b is O or 1;

A is independently N or C;

X is independently S, O, -C(O)-, NH or NCH2R6;

Y is -C(O)-;

Z is taken together with A to form an aryl or heteroaryl ring structure comprising 5 or 6 ring atoms wherein the heteroaryl ring comprises a single O ring heteroatom, a single N ring heteroatom, a single S ring heteroatom, a single O and a single N ring heteroatom separated by a carbon atom, a single S and a single N ring heteroatom separated by a carbon atom, 2 N ring heteroatoms separated by a carbon atom, or 3 N ring heteroatoms at least two of which are separated by a carbon atom, and wherein the aryl or heteroaryl ring carbon atoms are unsubstituted with other than H or at least 1 nonbridging ring carbon atom is substituted with R6 or =O;

R6 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NO2, N(R3)2, CN or halo, or an R6 is taken together with an adjacent R6 to complete a ring containing 5 or 6 ring atoms; R3 is a protecting group or H; and tautomers, solvates and salts thereof; and provided that where a is 0, b is 1, and Rl is

FORMULA

in which D2 is independently hydroxyl, blocked hydroxyl, mono, di or triphosphate, or an oligodeoxyribonucleotide otherwise containing only the bases A, G ,T and C; and D3 is H or OH;

then Z is not unsubstituted phenyl.

Claims 2 to 16 related to certain sub-groups of compounds of the above formula;

Claims 17 to 21 to chemical compounds useful for preparing the compounds of formula (1) ("intermediates");

Claims 22 to 27 and 29 to oligonucleotides containing at least one base of the structure indicated in Claim 1, bound to the oligonucleotide at the N-atom carrying the substituent R1 in formula (1);

Claim 28 to a method making use of the compound of Claim 22; and

Claim 30 to a method making use of a broad class of compounds, including those of Claim 22.

The ISA cited document

Dl: JP-A-62/059293 (Chem. Abstr. 107 : 7526n)

and held that it disclosed compounds which fell within the scope of the proviso of claim 1, namely 2-(2-deoxy-beta-A-erythro-pentofuranosyl)-pyrimido- (4,5-c)isoquinoline-3,6-(2H,4H)-dione and its mono- di- and tri-phosphate derivatives, which were useful as components of oligo- or poly-nucleosides and could serve as fluorescent probes. In respect of that state of the art, the ISA identified the technical problem underlying the international patent application to be the provision of further compounds serving the same purpose. Three different solutions of this problem were found to be contained in the above Claim 1, namely

1. the compounds of formula (1), where a=0 and b=0 ;

2. the compounds of formula (1) where a=0 and b=1;

3. the compounds of formula (1), where a=1 and b=0;

these sub-classes of compounds having no novel structural or functional technical feature in common and represented therefore three different inventions not so linked as to form a single general inventive concept (hereinafter "invention 1", "invention 2" and "invention 3") (Rules 13.1 to 13.3 EPC).

The ISA further held that the intermediate compounds of Claim 21 (hereinafter "invention 4") could not be fairly said to belong to any one of the above-identified inventions, since they were structurally too different from the compounds of formula (1), and that the method of Claim 30 in so far as it did not make use of an oligonucleotide of claim 22 (hereinafter "invention 5"), did also form a separate invention.

III. On 20 March 1995 the Applicant paid four additional search fees and indicated that three of them were paid under protest (Rule 40.2(c) PCT). He did not protest against the invitation to pay an additional search fee for "invention 5". In respect of the other four "inventions" he submitted that "a priori" these inventions shared a common inventive concept, and that the ISA had found lack of unity of invention only "a posteriori" on the basis of an objection of lack of inventive step. In his opinion, the ISA had not substantiated its finding, since it only alleged that the compounds covered by Claim 1 had properties identical with those excluded from that claim by the proviso contained in it, but failed to take into account that Dl was solely concerned with the problem of introducing base-pairing fluorescent pyrimidine nucleoside analogues into oligonudeotides in order to improve the detection of the oligonudeotides by fluorescence means, and was silent about the affinity of such compounds, so that it expressed no concern or interest about the problem underlying the present application.

In respect of "invention 4" he submitted that Claim 21 related to intermediates used in the preparation of the compounds of "invention 2", which had no disclosed utility other than in the preparation of the compounds of "invention 2" and should therefore be considered to represent embodiments of the same inventive concept.

He therefore requested that three additional search fees be refunded.

IV. On 11 July 1995 the result of the prior review provided for in Rule 40.2(e) PCT was communicated to the Applicant, who was also invited to pay the protest fee. The Review Panel found the protest justified in respect of the intermediate compounds of "invention 4", but maintained the view expressed in the invitation in respect of the other two of the three search fees paid under protest. It considered Part 1 (f)(i) of Annex B of the Administrative Instructions under the PCT. The Rewiew Panel stated that the technical problem defined by the Applicant was already known and solved. The Review Panel held that at most the compounds of "invention 3" solved the problem of increasing the hybrid stability over the known level, whereas the compounds according to "invention 1" and "invention 2" were merely alternatives having the same effect as a compound of the state of the art. The common technical problem solved by all three "inventions" was thus seen in providing further pyrimidine nucleotide analogues suitable for enhancing hybrid stability in respect of the natural pyrimidine. This problem was said to be a well known desideratum which was achieved by quite different inventive concepts, since the three groups of compounds did not share a common novel structural feature.

On 9 July 1993 the Applicant paid the protest fee.