Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Detailed Action
This office action is a response to applicant’s communication submitted April 13, 2026, wherein claim 1 is amended and new claim 14 is introduced. This application is a national stage application of PCT/JP2019/018307, filed May 7, 2019, which claims benefit of foreign application JP2018-088911, filed May 2, 2018.
Claims 1-3 and 14 are pending in this application.
Claims 1-3 and 14 as amended are examined on the merits herein.
Withdrawn Rejections
Applicant’s amendment, submitted April 13, 2026, with respect to the rejection of claims 1-3 under 35 USC 112(b) for including the indefinite term “excess diastereomer ratio,” has been fully considered and found to be persuasive to remove the rejection as the claims have been amended so as to refer to the percent of major diastereomer instead. Therefore the rejection is withdrawn.
Applicant’s amendment, submitted April 13, 2026, with respect to the rejection of claims 1-3 under 35 USC 103 for being obvious over Ravikumar et al. in view of Oka et al. in view of Wada et al., has been fully considered and found to be persuasive to remove the rejection as base claim 1 has been amended to define the amount of the major diastereomer present as being at least 99%. Therefore the rejection is withdrawn.
The following rejections of record in the previous action are maintained:
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-3 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Ravikumar et al. (US patent 6294664, of record in previous action) in view of Oka et al. (of record in previous action)
The claimed invention is directed to a modified oligonucleotide having a phosphoramidite group on either the 3’- or 5’- end hydroxyl, comprising 2-6 nucleotide residues, wherein all of the phosphodiester linkages are chiral stereodefined phosphorothioate linkages protected by a chiral auxiliary which is an acylated tetrahydropyrrolylmehylene group.
Ravikumar et al. discloses oligonucleotides having a 3’- phosphoramidite wherein the internucleotide linkages can be phosphorothioate linkages bearing a phosphorus protecting group. (column 5 lines 1-56) Ravikumar et al. further discloses that oligonucleotides including tetramers or higher (e.g., n=2 in the present claims) can be prepared as phosphoramidites in this manner and used in solid phase synthesis methods in place of standard monomer phosphoramidites. (column 4 lines 17-40) Figure 2 of Ravikumar et al. further discloses a tetramer segment (compound 11) wherein all three internucleotide linkages are phosphorothioates furthermore protected by a protecting group. Jung et al. does not specifically disclose a phosphorothioate tetramer or higher phosphoramidite wherein the phosphorothioate linkages are sterodefined and bear a chiral protecting group as described in claim 1.
However, Oka et al. discloses a method for producing stereocontrolled phosphorothioate dinucleotides using chirally controlled cyclic phosphoramidite compounds. (p. 16034 scheme 2) The intermediate before deprotection (compound 11 in scheme 2) bears the same chiral protecting group recited in present claims 1 and 3. Oka et al. further discloses that the protected phosphorothioate can be carried forward into further cycles of solid-phase synthesis, indicating that it is compatible with conditions of phosphoramidite couplings. (p. 16035 scheme 3)
It would have been obvious to one of ordinary skill in the art at the time of the invention to attach a phosphoramidite group to a stereodefined tetranucleotide or higher oligonucleotide produced according to Oka et al., to produce a phosphorothioate containing segment for use as a building block as described by Ravikumar et al. One of ordinary skill in the art would have seen the description of phosphorothioates by Ravikumar et al. as suggesting incorporating prior art phosphorothioate oligonucleotides into the disclosed method. Furthermore the disclosure by Oka that stereoregular phosphorothioate linkages are desired would have motivated one of ordinary skill in the art to use oligonucleotide segments having such linkages in the synthesis method of Ravikumar in order to produce useful products.
Regarding the limitation requiring that the percentage of the major diastereomer is more than 99%, a review of the supporting information for Oka et al. (Reference included with PTO-892) indicates that a linkage between two thymidine nucleosides was obtained in a diastereomeric ratio of >99.5:<0.5. (p. S17 figure S5) If this degree of diastereomeric excess was obtained for a dinucleotide having a single linkage, then if multiple coupling steps were carried out to make an oligonucleotide the diastereomer ratio for a tetranucleotide having three linkages should be >98.5:<1.5, a pentanucleotide having four linkages should be >98.0:<2.0, and a hexanucleotide having five linkages should have a ratio of >97.5:<2.5. While these values are less than the percentage of 99% or greater recited in present clam 1, since Oka discloses the diastereomeric ratio of the internucleotide bond as being significant, one of ordinary skill in the art would have regarded it as a result-effective variable, and would have attempted to obtain the resulting oligonucleotides in higher diastereomeric purity. In particular, the supporting information for Oka discussed above discloses that the Rp and Sp diastereomers of a dinucleotide elute at different times, and additionally discloses using RP-HPLC to purify the resulting oligonucleotides. (p. S17 last paragraph) Therefore one of ordinary skill in the art would have had a reason to attempt to improve the stereochemical purity of the oligonucleotide and a reasonable expectation of success in doing so using HPLC purification.
Regarding claim 14, this claim merely describes a method by which the total diastereomer content could be determined. Because total diastereomer content is an objective structural feature of the composition which is independent of the method by which it is measured, and because the present claims are directed to a composition of matter rather than a method of determining total diastereomer content, this limitation is not seen to further distinguish this claim from the prior art.
Therefore the invention taken as a whole is prima facie obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-3 and 14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 17/051931 (US pre-grant publication 2021/0269470, of record in previous action, herein referred to as ‘931) in view of Ravikumar et al. (US patent 6294664, of record in previous action) in view of Oka et al. (of record in previous action)
Claim 1 of ‘931 claims an oligonucleotide phosphoramidite segment for use in synthesis of an oligonucleotide. However, the segment claimed is not a stereocontrolled segment having the particular stereodefined structure recited in the present claims. However, as discussed previously under 35 USC 103, such a structure is obvious over the disclosures of Ravikumar in view of Oka. Therefore it would have been obvious to one of ordinary skill in the art at the time of the invention to make an optically active segment having this structure for reasons discussed above under 35 USC 103.
This is a provisional nonstatutory double patenting rejection.
Claims 1-3 and 14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 3 of copending Application No. 17/595613 (US pre-grant publication 2022/0235089, of record in previous action, herein referred to as ‘613) in view of Ravikumar et al. (US patent 6294664, of record in previous action) in view of Oka et al. (of record in previous action)
Claim 3 of ‘613 claims an oligonucleotide phosphoramidite segment for use in synthesis of an oligonucleotide. However, the segment claimed is not a stereocontrolled segment having the particular stereodefined structure recited in the present claims. However, as discussed previously under 35 USC 103, such a structure is obvious over the disclosures of Ravikumar in view of Oka. Therefore it would have been obvious to one of ordinary skill in the art at the time of the invention to make an optically active segment having this structure for reasons discussed above under 35 USC 103.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant’s arguments, submitted April 13, 2026, with respect to the above grounds of rejection, have been fully considered and not found to be persuasive to remove the rejection. With respect to the rejections still pending, Applicant argues that it would not be practically possible to purify the prior art protected segments to the claimed major diastereomer content. This argument is based on the assertion that it would not have been possible for one of ordinary skill in the art to purify the protected oligomers described by Oka, due to the hydrophobicity of the protecting groups and the instability of the phosphoramidite.
Regarding the phosphoramidite group, one of ordinary skill in the art, in attempting to purify Oka’s oligomers for use in Ravikumar’s method, would not have purified a phosphoramidite-containing segment. Looking to the actual method used by Ravikumar, (examples 1-19 in columns 22-28) the process involves producing individual dimers, trimers, tetramers, and pentamers, which are purified by flash chromatography, and then subsequently phosphitlylating the purified segments to make the active blocks for use in further synthesis. In carrying out an analogous method using the oligomers described by Oka, one of ordinary skill in the art would have performed any desired stereochemical purification before attaching the final 3’- phosphoramidite.
Regarding the presence the other protecting groups, Applicant’s argument concerns the question of whether the RP-HPLC method used by Oka would be effective at purifying oligomers that still contained the internucleotide chiral auxiliaries. In particular, Applicant argues that such auxiliaries might be too lipophilic or hydrolytically unstable to be purified in this manner. Applicant further submits a declaration under 37 CFR 1.132 by Masanori Kataoka purporting to demonstrate that the high content of the major diastereomer in the product described in the present specification is the result of a high diastereomeric excess in the coupling reaction itself rather than of subsequent purification. This is not entirely accurate. In paragraph 5 of the declaration, the declarant states, “Because the actual starting materials for the final 2+2 coupling (i.e., compounds 10 and 12) already possess fully stereocontrolled linkages and do not contain any diastereomeric impurities, the only stereocenter that needs to be considered is the newly formed phosphorus atom generated during the final 2+2 coupling.” While this may be literally true, the dimers did not spring into existence in a fully diastereomerically pure state. Rather, there is in fact an intermediate purification step carried out during Applicant’s method. For example looking to step 4 on pp. 30-31 of the present specification, the disclosed process involves synthesizing a protected dimer, and then purifying the dimer by column chromatography. In later steps this protected dimer is subject to further deprotection, coupling, and purification processes. By the time the optically active building blocks have been synthesized, they have been subjected to column purification. Furthermore, there is no evidence backing up the assertion that oligomers bearing the claimed chiral auxiliaries are particularly unstable and cannot be subjected to further purification steps.
Additionally, in attempting to improve the diastereomeric purity of oligomers bearing chiral auxiliaries such as those described by Oka, one of ordinary skill in the art would have been reasonably able to adjust the specific conditions used to arrive at appropriate purification conditions for these species, with a reasonable expectations of success. Therefore it is still the case that, for the present claims directed to a composition of matter rather than a process, one of ordinary skill in the art would have had both the motivation and a reasonable expectation of success in improving the amount of the major diastereomer of the oligomer before activating it as a phosphoramidite for use in the block synthesis method described by Ravikumar.
Therefore the rejection is deemed proper and maintained.
Conclusion
No claims are allowed in this action. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDREA OLSON whose telephone number is (571)272-9051. The examiner can normally be reached M-F 6am-3:00pm.
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/ANDREA OLSON/ Primary Examiner, Art Unit 1693 6/4/2026
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