W 0010/99 (Antisense/BIOGNOSTIK) 19-06-2000

Summary of Facts and Submissions

I. International patent application PCT/EP 98/00497 was filed on 30 January 1998 with seventeen claims.

Claims 1 and 7 read as follows:

"1. A method for the preparation of an antisense oligonucleotide or derivative thereof comprising the steps of

- selecting a target nucleic acid, if necessary elucidating its sequence

- generating the antisense oligonucleotide with the proviso that

- the oligonucleotide comprises at least 8 residues,

- the oligonucleotide comprises at maximum twelve elements, which are capable of forming three hydrogen bonds each to cytosine bases,

- the oligonucleotide does not contain four or more consecutive elements, capable of forming three hydrogen bonds each with four consecutive cytosine bases (CCCC) within the target molecule or alternatively four or more consecutive elements of GGGG,

- the oligonucleotide does also not contain 2 or more series of three consecutive elements, capable of forming three hydrogen bonds each with three consecutive cytosine bases (CCC) within the target molecule, or alternatively 2 or more series of three consecutive elements of GGG, and

- the ratio between residues forming two hydrogen bonds per residue (2H-bond-R) with the target molecule and those residues forming three hydrogen bonds per residue (3H-bond-R) with the target molecule, is ruled by the following specifications:

3H-bond-R

_____________________ >= 0.29

3H-bond-R + 2H-bond-R

- and synthesizing the oligonucleotide thus generated in a per se known manner."

"7. An antisense oligonucleotide or derivative thereof obtainable according to the method according to any one of the claims 1 to 6 except oligonucleotides represented in Fig. 4."

Claims 2 to 6 were directed to particular embodiments of the method of claim 1; claims 8 to 13 concerned embodiments of the oligonucleotide according to claim 7. Claims 14 and 15 concerned, respectively, a composition and a medicament comprising the said oligonucleotides, while claims 16 and 17 were directed to the use of the said oligonucleotides.

II. On 14 July 1998 the European Patent Office (EPO), acting as an International Search Authority (ISA), invited the Applicant to pay within a time limit of 30 days 88 additional search fees pursuant to Article 17(3)(a), Rule 40.1 and 40.3 PCT and issued a partial search report on claims 1 to 17 (all partially) relating to the invention first mentioned, ie group 1. The invitation stated the 89 groups of inventions of which the following are of relevance for the purposes of the present decision:

1. Claims 1 to 17 (all partially): A method for preparing antisense oligonucleotides and antisenses obtained. Antisense oligonucleotide against the TGF-beta 1 gene and having SEQ ID 41, modified forms thereof, composition containing it and its therapeutic or diagnostic uses.

39. Claims 1 to 17 (all partially): Antisense oligonucleotides against the TGF-beta 2 gene.

III. The invitation stated that there was no single inventive concept underlying the plurality of claimed inventions. Reference was made in particular to the following prior art documents:

(1) WO-A-94/25588

(2) Biochem. Pharmacol., 1996, vol. 51. pages 173 to 182

(3) WO-A-96/39415

It was found that, due to the fact that the preparation and use of modified antisense oligonucleotides meeting the criteria specified in the first claim for inhibiting TGF-beta 1 nucleic acids as well as their modifications were known in the art, there was no special technical feature which could link the inventions of the different groups together, also in consideration of the fact that there were essential differences in the primary structure of the different targets.

The Applicant's attention was furthermore drawn to the fact that if any of the inventions of groups 34 to 89 was to be chosen as subject-matter for a subsequent search, further objections of non-unity of invention could be raised depending on the results of the search.

IV. On 13 August 1998 the Applicant paid one additional fee for the invention of group 39. The additional fee was paid under protest pursuant to Rule 40.2(c) PCT. The Applicant submitted that the common inventive concept was represented by the method of claim 1 which provided rules for selecting suitable antisense oligonucleotide sequences. None of the cited prior art documents provided a similar method, although they disclosed compounds that could also be synthesised by the method now claimed. The method allowed the synthesis of oligonucleotides which had surprisingly increased effectivity and/or reduced toxicity and/or reduced non-selective effects.

V. On 20 November 1998 the European Patent Office (EPO), acting as an International Search Authority (ISA), invited the Applicant to pay within a time limit of 30 days 129 additional search fees pursuant to Article 17(3)(a), Rule 40.1 and 40.3 PCT and issued the International Search Report on claims 1 to 17 (all partially) relating to the inventions of groups 1 and 39.01. The invitation stated the 131 groups of inventions of which the following are of relevance for the purposes of the present decision:

1. same as No. 1 referred to in Section II above.

39.01. Claims 1 to 17 (all partially): Antisenses oligonucleotides against the TGF-beta 2 gene and having SEQ ID 519.

Groups of inventions 2 to 38 and 40 to 89 were the same as identified in the previous invitation (cf Section II above), the remaining groups 39.02 to 39.43 resulted from a lack of unity objection within the previous group 39.

VI. Apart from repeating the previous reasons for the finding of non-unity (cf Section III above), the invitation stated that, due to the fact that the use of modified antisense oligonucleotides for inhibiting TGF-beta 2 nucleic acids was known in the prior art, and that the adverse biological effects of oligonucleotides containing runs of guanosines was well documented in the prior art, there was no single inventive concept underlying the plurality of inventions also within the group 39, which related to 43. different inventions, namely groups 39.01 to 39.43. Reference was made to document (1) as well as to the following additional documents:

(4) Int. J. Cancer, 1996, vol. 65, pages 332 to 337;

(5) TIBTECH, 1996, vol. 14, pages 376 to 387;

(6) Mol. Biol. Reports, 1993, vol. 18, pages 217 to 221.

VII. On 24 March 1999 the ISA communicated to the Applicant the result of its review under Rule 40.2(e) PCT. The finding of lack of unity was confirmed because it was held that, since, as also admitted by the Applicant, oligonucleotides which satisfied all the necessary criteria stated in claim 1 and which could be prepared also by the claimed method were known from the prior art (cf document (1)), the method of claims 1 to 6 was not specifically necessary for the preparation of the said compounds, being only an alternative method to other known methods of synthesis. Therefore, the method itself could not be seen as the special technical feature which would form an unifying concept between all the claimed compounds. Under these circumstances, each single compound related to separate inventive concepts.

Therefore, the Applicant was invited to pay within one month the protest fee.

VIII. The protest fee was paid by the Applicant on 23 April 1999.