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
2. This Office Action is responsive to Applicant’s Amendment and Remarks, filed November 13, 2025. The amendment, filed November 13, 2025, is entered, wherein claims 21 – 22, 27, and 32 – 34 are amended, claims 1 – 20, 24 – 25, and 35 – 36 are canceled, and claim 26 is withdrawn.
Priority
This application is a national stage application of PCT/JP2021/000273, filed January 7, 2021, which claims benefit of domestic application 62/958,351, filed January 8, 2020.
Withdrawn Objections
4. The objection of claims 22, 24 – 25, 27, 32, and 34 in the previous Office Action, mailed August 14, 2025, is withdrawn in view of the amended claims and canceled claims.
The followings are maintained / modified grounds of rejection necessitated by Applicant’s Amendment and Remarks, filed November 13, 2025, wherein claims 21 – 22, 27, and 32 – 34 are amended and claims 1 – 20, 24 – 25, and 35 – 36 are canceled. Previously cited references have been used to establish the maintained / modified grounds of rejection.
Maintained / Modified Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
i. Determining the scope and contents of the prior art.
ii. Ascertaining the differences between the prior art and the claims at issue.
iii. Resolving the level of ordinary skill in the pertinent art.
iv. Considering objective evidence present in the application indicating obviousness or
nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 21 – 23 and 27 – 34 are rejected under 35 U.S.C. 103 as being unpatentable over Kataoka (Machine Translation of WO2019/212061A) in view of Glen Research (The Glen Report, 2010, Vol. 22, Issue 1, Reference included with PTO-892).
Regarding claims 21 – 23 and 27 – 34, Kataoka teaches a segment for oligonucleotide synthesis (Abstract). Kataoka teaches the following formula:
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wherein B is an unprotected nucleoside base; R1 is a protecting group; R2, R3, and R4 are OCH2CH2CN; R5 is a substituted or unsubstituted aliphatic group; X is an unshared electron pair; Y is H; Z is H; and the value of (m + n) is an integer of 2 – 23 (page 2, lines 2 – 10). R1 is a protecting group that can be removed under acidic conditions (page 4, line 7). The segment for oligonucleotide synthesis comprises (1) a nucleoside wherein the 5’ hydroxyl group and the nucleoside base, if necessary, are protected with a protecting group and the 3’ hydroxyl group is unprotected 3’ phosphoramidite is obtained as an intermediate in the reaction system by phosphorylating the 3’ hydroxyl group, starting from “protected 3’ unprotected nucleoside” as a starting material; and (2) the obtained intermediate and a nucleoside in which both the 3’ hydroxyl group and the 5’ hydroxyl group are unprotected. The unprotected 3’ hydroxyl group remaining at the 3’ terminal is reacted with a trivalent phosphorylating agent to form a phosphoramidite. By repeating (2) the required number of time as (n +1), and the product is synthesized (page 12, lines 2 – 7). In step (1), an activator that activates the amidite moiety is added after the reaction of unprotected 3’ hydroxyl group remaining at the 3’ terminal is reacted with a trivalent phosphorylating agent (page 12, lines 31 – 32). Kataoka explicitly teaches the following synthesis (page 13 – 14):
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However, Kataoka does not teach the activator that is a saccharin derivative.
Glen Research teaches a number of activators for oligonucleotide synthesis and teaches that saccharin 1-methylimidazole (SMI) is a new activator for said synthesis (page 8, Left Col., para. 1). Data provided illustrates that SMI perform very well for DNA and RNA synthesis (page 8, Center Col., para. 1). Glen Research concludes that saccharin 1-methylimidazole is a useful general purpose activator for DNA and RNA synthesis with excellent performance characteristics.
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the general activator as taught by Kataoka with SMI in view of Glen Research because Glen Research demonstrates the excellent performance of SMI in the study. One would have been motivated to substitute the general activator as taught by Kataoka with SMI in view of Glen Research because SMI has an excellent performance in synthesizing DNA and RNA, thereby, yielding predictable results. One of the ordinary skill in the art would have had a reasonable expectation of success to substitute the general activator as taught by Kataoka with SMI in view of Glen Research because both references are directed to synthesis of oligonucleotide and Glen Research explicitly teaches a novel activator in said synthesis, which provides excellent performance characteristics.
Responses to Applicant’s Remarks:
Applicant’s Remarks, filed November 13, 2025, have been fully considered and are found to be not persuasive.
Regarding Kataoka, Applicant argues that Kataoka does not teach the feature “wherein in at least the last one of the coupling steps performed two or more times, the nucleoside phosphoramidite is a nucleoside phosphoramidite having three nucleoside moieties”, as set forth in amended claims 21 and 33. In response to Applicant’s argument, the examiner would like to point to the modified rejection above, wherein the disclosure of Kataoka recites the segment for use in synthesis of an oligonucleotide having the formula:
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Wherein (m+n) is an integer of 2 – 23. Although Kataoka does not exemplified the coupling step in the disclosure, Kataoka teaches that (m+n) is an integer of 2 – 23 is sufficient to address the feature “in at least the last one of the coupling steps performed two or more times, the nucleoside phosphoramidite is a nucleoside phosphoramidite having three nucleoside moieties”. Based on the disclosure of Kataoka, one of the ordinary skill in the art would know that the coupling steps do not stop at the point where nucleoside phosphoramidite having four nucleoside moieties is obtained.
Regarding Glen Research, Applicant argues that Glen Research also discloses the use of many other activators other than SMI and the publication is a brochure for “click chemistry”. Therefore, there is no motivation within Glen Research to specifically select SMI. Applicant also argues that the data provided by Glen Research shows that SMI does not offer superior coupling efficiency or purity compared to other disclosed alternatives and Glen Research notes that SMI may induce undesirable branching reaction. In response to Applicant’s argument regarding Glen Research is a brochure for “click chemistry”, the examiner does not agree. In fact, Glen Research discloses various chemical compounds for different uses. The examiner also does not agree that SMI does not offer superior coupling efficiency. Glen Research specifically indicates that a 6 minute coupling time for SMI outperforms ETT at 6 minute coupling time. (page 8, Center Col., para. 1). When comparing SMI and TET with the coupling time of 30 second, SMI also perform better than TET (page 8, Center Col., Table). For the undesirable branching reaction, Glen Research discloses that branching occurs with all activators and branching occurs at a level similar or slight less than 4,5-DCl for SMI (page 8, Left Col., para. 5). Based on the data and disclosure of Glen Research, one of the ordinary skill in the art would have motivated to select SMI as an activator because of the better performance. Moreover, Applicant argues that Glen Research teaches SMI causes undesirable branching and provides unpredictable results, thereby discouraging its use in the method disclosed by Kataoka. However, Glen Research provides empirical data directly contradicting this assertion. Specifically, Glen Research teaches that SMI perform very well for both DNA and RNA synthesis, showing high coupling efficiencies of 97.3 – 97.8 % for RNA and 99.6% for DNA with 30 second coupling time (page 8, Center Col., Table). These coupling efficiency values indicate highly reliable and predictable reaction performance, even under varied coupling times and substrate conditions.
Maintained / Modified 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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 21 – 23 and 27 – 34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4 of copending Application No. 18/835,699 in view of Kataoka (Machine Translation of WO2019/212061A).
a. Regarding claims 21 – 23 and 27 – 34, ‘699 teaches a method for producing an oligonucleotide, comprising (a) removing a protecting group from a protected nucleoside which is directly or indirectly attached to supports and in which the protecting group is bonded to a hydroxy group, a thiol group, or the amino group at the 3’ position or the 5’ position; (b) binding a nucleoside phosphoramidite to the hydroxy group, the thiol group, or the amino group at the 3’ position or the 5’ position of the nucleoside from which the protecting group has been removed and which is directly or indirectly attached to the supports in the presence of an activator (claim 1). The activator used in the method is saccharin 1-methylimidazole (claim 4).
However, ‘699 does not teach that the nucleoside phosphoramidite is a nucleoside phosphoramidite having two or more nucleoside moieties.
Kataoka teaches a segment for oligonucleotide synthesis (Abstract). Kataoka teaches the following formula:
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wherein B is an unprotected nucleoside base; R1 is a protecting group; R2, R3, and R4 are OCH2CH2CN; R5 is a substituted or unsubstituted aliphatic group; X is an unshared electron pair; Y is H; Z is H; and the value of (m + n) is an integer of 2 – 23 (page 2, lines 2 – 10). R1 is a protecting group that can be removed under acidic conditions (page 4, line 7). The segment for oligonucleotide synthesis comprises (1) a nucleoside wherein the 5’ hydroxyl group and the nucleoside base, if necessary, are protected with a protecting group and the 3’ hydroxyl group is unprotected 3’ phosphoramidite is obtained as an intermediate in the reaction system by phosphorylating the 3’ hydroxyl group, starting from “protected 3’ unprotected nucleoside” as a starting material; and (2) the obtained intermediate and a nucleoside in which both the 3’ hydroxyl group and the 5’ hydroxyl group are unprotected. The unprotected 3’ hydroxyl group remaining at the 3’ terminal is reacted with a trivalent phosphorylating agent to form a phosphoramidite. By repeating (2) the required number of time as (n +1), and the product is synthesized (page 12, lines 2 – 7). In step (1), an activator that activates the amidite moiety is added after the reaction of unprotected 3’ hydroxyl group remaining at the 3’ terminal is reacted with a trivalent phosphorylating agent (page 12, lines 31 – 32). Kataoka explicitly teaches the following synthesis (page 13 – 14):
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It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the production method of oligonucleotide using a nucleoside phosphoramidite as taught by ‘699 into the production method of oligonucleotide using a nucleoside phosphoramidite having two or more nucleoside moieties in view of Kataoka because both references teach the method of producing oligonucleotide and the methods taught involve similar reagent. It would have been obvious for a person of ordinary skill in the art to modify because such modification will yield predictable results. Therefore, one skilled in the art would have had a reasonable expectation of success to modify the production method of oligonucleotide using a nucleoside phosphoramidite as taught by ‘699 into the production method of oligonucleotide using a nucleoside phosphoramidite having two or more nucleoside moieties in view of Kataoka because the references teach the same method and Kataoka explicitly teaches the type of nucleoside phosphoramidite.
This is a provisional nonstatutory double patenting rejection.
Claims 21 – 23 and 27 – 34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4 of copending Application No. 18/835,547 in view of Kataoka (Machine Translation of WO2019/212061A).
b. Regarding claims 21 – 23 and 27 – 34, ‘547 teaches a method for producing an oligonucleotide, comprising binding a nucleoside phosphoramidite to the hydroxy group, the thiol group, or the amino group at the 3’ position or the 5’ position of the nucleoside which is directly or indirectly attached to the supports in the presence of an activator (claim 1). The activator used in the method is saccharin 1-methylimidazole (claim 4).
However, ‘547 does not teach that the nucleoside phosphoramidite is a nucleoside phosphoramidite having two or more nucleoside moieties.
Kataoka teaches a segment for oligonucleotide synthesis (Abstract). Kataoka teaches the following formula:
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wherein B is an unprotected nucleoside base; R1 is a protecting group; R2, R3, and R4 are OCH2CH2CN; R5 is a substituted or unsubstituted aliphatic group; X is an unshared electron pair; Y is H; Z is H; and the value of (m + n) is an integer of 2 – 23 (page 2, lines 2 – 10). R1 is a protecting group that can be removed under acidic conditions (page 4, line 7). The segment for oligonucleotide synthesis comprises (1) a nucleoside wherein the 5’ hydroxyl group and the nucleoside base, if necessary, are protected with a protecting group and the 3’ hydroxyl group is unprotected 3’ phosphoramidite is obtained as an intermediate in the reaction system by phosphorylating the 3’ hydroxyl group, starting from “protected 3’ unprotected nucleoside” as a starting material; and (2) the obtained intermediate and a nucleoside in which both the 3’ hydroxyl group and the 5’ hydroxyl group are unprotected. The unprotected 3’ hydroxyl group remaining at the 3’ terminal is reacted with a trivalent phosphorylating agent to form a phosphoramidite. By repeating (2) the required number of time as (n +1), and the product is synthesized (page 12, lines 2 – 7). In step (1), an activator that activates the amidite moiety is added after the reaction of unprotected 3’ hydroxyl group remaining at the 3’ terminal is reacted with a trivalent phosphorylating agent (page 12, lines 31 – 32). Kataoka explicitly teaches the following synthesis (page 13 – 14):
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It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the production method of oligonucleotide using a nucleoside phosphoramidite as taught by ‘547 into the production method of oligonucleotide using a nucleoside phosphoramidite having two or more nucleoside moieties in view of Kataoka because both references teach the method of producing oligonucleotide and the methods taught involve similar reagent. It would have been obvious for a person of ordinary skill in the art to modify because such modification will yield predictable results. Therefore, one skilled in the art would have had a reasonable expectation of success to modify the production method of oligonucleotide using a nucleoside phosphoramidite as taught by ‘547 into the production method of oligonucleotide using a nucleoside phosphoramidite having two or more nucleoside moieties in view of Kataoka because the references teach the same method and Kataoka explicitly teaches the type of nucleoside phosphoramidite.
This is a provisional nonstatutory double patenting rejection.
Response to Applicant’s Remarks:
Applicant’s Remarks, filed November 13, 2025, have been fully considered and are found to be not persuasive.
Regarding ‘699 and ‘547, Applicant argues that each are later-filed and published after the present application. Therefore, they are not proper references for obviousness-type double patenting rejections. However, the rejection is consistent with established practice for addressing nonstatutory double patenting. As explained in MPEP 804(II)(B)(5), a later-expiring patent may serve as a proper reference in one-way obviousness-type double patenting rejection unless the applicant can show that the claims could not have been filed in a single application and that the Office was solely responsible for any delay that caused the reference patent to issue first. In the present case, Applicant does not provide evidence that the Office, rather than Applicant, is solely responsible for any prosecution delay, nor that the claims could not have been presented together. Courts have consistently held that applicant-driven prosecution choices, such as filing multiple applications or continuations, do not warrant application for the two-way test. Therefore, the one-way test applies, and the double patenting rejection over ‘699 and ‘547.
Conclusion
No claim is found to be allowable.
Applicant's amendment necessitated the maintained / modified ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693