DETAILED ACTION
This Office Action is in response to Applicant’s Amendment and Remarks filed on 05 February 2026 in which claims 2, 4 and 6-14 were canceled, and claims 1, 15, 17 and 23 were amended to change the scope and breadth of the claims.
Claims 1, 3, 5, 15, 17, 18 and 20-23 are pending in the current application and are examined on the merits herein.
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 .
Withdrawn Rejections
Applicant’s amendment, filed 05 February 2026, with respect to the rejections of claims 1 and 4-10 under 35 U.S.C. § 102(a)(1)/(a)(2) as being anticipated by Bleicher et al., has been fully considered and is persuasive because claim 1 has been amended to recite “the thiol is a C2-C20 alkyl thiol, or a C4-C8 cycloalkyl thiol”. The rejection is hereby withdrawn.
Applicant’s amendment, filed 05 February 2026, with respect to the rejection of claim 23 under 35 U.S.C. § 112, second paragraph, for indefiniteness, has been fully considered and is persuasive because claim 23 has been amended to recite “the composition comprises oligonucleotides are N nucleotides in length and oligonucleotides that are N-1 nucleotides in length, wherein the ratio of oligonucleotides that are N-1 nucleotides in length to oligonucleotides that are N nucleotides in length in the composition is less than 5.8%”. The rejection is hereby withdrawn.
New & Modified Rejections
The following are new ground(s) or modified rejections necessitated by Applicant's amendment, filed on 05 February 2026, where the limitations in pending claims 1, 15, 17 and 23 as amended now have been changed. Therefore, rejections from the previous Office Action, dated 05 September 2025, have been modified and are listed below.
Response to Arguments
Applicant's arguments filed 05 February 2026 have been fully considered but they are not persuasive.
Applicant contends the combination of Antia and Bleicher is improper because these two references prepare structurally distinct oligonucleotides.
The above argument is not found persuasive. Antia and Bleicher are both secondary references. Antia was relied upon for teaching the use of 1-dodecanethiol and an acid in the deprotection reaction of 5’-DMTr protected oligonucleotides were known before the effective filing date of the claimed invention. Bleicher was relied upon to show the use of a thiol-containing cation scavengers and an acid in the deprotection reaction of 5’-DMTr protected oligonucleotides in solid-phase synthesis were known before the effective filing date of the claimed invention. These secondary references establish the use of thiol-based scavengers including 1-dodecanthiol and an acid to deprotect a 5’-DMTr protected oligonucleotide was a known technique for preparing oligonucleotides. Furthermore, Bleicher et al. demonstrate one of ordinary skill in the art would have had a reasonable expectation of success in applying the 1-dodecanethiol in deprotection of 5’-DMTr groups in oligonucleotide synthesis using solid phase.
Applicant contends the data in Table 2 show unexpected results.
The data in Table 2 has been carefully considered but is not found persuasive, because the data does not appear to demonstrate a statistically significant difference in the amount of N-1 mer deletion product formed. Furthermore, Antia already expressly teach using 1-dodecanethiol and an acid for deprotection reactions of 5’-DMTr groups in oligonucleotide synthesis. The use of a cation scavenger during the deprotection step was a known technique for preparing oligonucleotides. And one of ordinary skill in the art would have expected the use of a cation scavenger including 1-dodecanethiol would improve the overall purity of the obtained product.
See MPEP 716.02(c)(I), “Evidence of unexpected results must be weighed against evidence supporting prima facie obviousness in making a final determination of the obviousness of the claimed invention. Also see MPEP 716.02(c)(II), “"Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof."
Applicant further argues one having ordinary skill in the art would not have been motivated to use a cation scavenger in solid phase synthesis because the present Specification states “in solid-phase synthesis, since such a cation is discharged to outside of the system without being retained in the system, it is known that the equilibrium reaction proceeds smoothly and the above-mentioned problems for liquid-phase synthesis may not occur (see Non-Patent Literature 1). Therefore, in solid-phase synthesis, there is no need for using the cation scavenger in general”.
The above argument is not found persuasive. As evidenced by Chamorro et al. (Accounts of Chemical Research, 2018, vol. 51, pp. 2918-2925, cited in PTO-892), “maintaining a nonequilibrium condition throughout the reaction by removing products as they are formed (Le Chatelier’s principle) can facilitate the formation of a metastable product, as shown in Figure 1a. The removed product is usually a volatile byproduct, while the desired metastable phase remains. This is in fact driven by thermodynamics as it tilts the energy balance in favor of the products.” (see p.2920, second para).
Furthermore, Bleicher et al. expressly teach the use of a cation scavenger in solid phase synthesis, during the deprotection reaction of a 5’-DMTr group.
Thus, even if detritylation reactions are faster in solid phase organic synthesis (as argued by Applicant), the use of a cation scavenger to remove unwanted byproducts while simultaneously shifting the reaction towards forming the desired product was a known technique before the effective filing date of the claimed reaction. Furthermore, this was a known technique for the removal of the same protecting group at the same position of a protected oligonucleotide in a method for synthesizing an oligonucleotide.
The rejection is hereby maintained.
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.
Claim(s) 1, 3, 5, 15, 17, 18 and 20-23 are rejected under 35 U.S.C. 103 as being unpatentable over Aoki et al. (US Patent No. 9,481,702, cited in previous Office Action) in view of Antia et al. (WO2022/103842, cited in previous Office Action) and further in view of Bleicher et al. (WO2018/019799, cited above).
Aoki et al. teach a method of preparing a ribonucleotide, comprising step A1, deprotecting a compound of formula (201) to form a compound of formula (202), (col.35-36):
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320
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For the compound of formula 201, R1 (reads on present G1) is a hydrogen atom or a protecting group (col.2:34). R1 includes dimethoxytrityl (DMTr), see R1Aa (col.11:30-55). The exemplified nucleotides having a protecting group at the C5’-position all contain a 5’-DMTr group (see examples throughout Specification). R2c (reads on present G2) is a hydrogen atom, an electron-withdrawing group or any substituent (col.6:55-57). At least one of E and T is a substituent represented by formula (204):
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or
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, wherein [S] is a solid phase carrier (reads on present definitions of W1 and X1; col. 36). B is a nucleobase (reads on present Ba; col.2:32-33). R200 (reads on R is a protected hydroxy group) is the same or different and each is a hydrogen atom, an acyloxy group or a substituent represented by the following chemical formula (203) or (204), (col. 36:25-27). Aoki et al. disclose using cyanoethoxymethoxymethyl (i.e. n is 1), (reads on present claims 17 and 18; example 1).
The acid used in step A1 includes trifluoroacetic acid, dichloroacetic acid, trichloroacetic acid and the like (col. 38: 21-25). The acid can be dissolved in a solvent, including dichloromethane and acetonitrile (col.38:25-32).
Aoki et al. further teach step A5 which cleaves the oligonucleotide from a solid support (E or T; reads on present Z), and simultaneously removes the protecting group of formula (204), (e.g. a cyanoethoxy group) from the 2’-position (col.43-44):
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.
R100 is a hydrogen atom or a hydroxyl group (col.6:40-41). Z is a hydrogen atom or a phosphate group (col. 35:39-40). Aoki et al. disclose preparing a 40-mer (i.e. m is 39), (example 6); and a 62-mer (SEQ ID 2, SEQ ID 3).
Aoki et al. do not expressly disclose a thiol (present claims 1-3, 21, 22). Aoki et al. do not expressly disclose wherein the obtained oligonucleotide is 100 mer or more (present claim 20).
Antia et al. disclose preparing a M19-Fragment, a dinucleotide (i.e. an oligonucleotide). The method comprising the steps of deprotecting a 5’-DMT protecting group with 15 eq trifluoroacetic acid, 3 eq 1-dodecanethiol (p.137, para [0312]-[0313]):
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Step 1 results in the formation of the disaccharide. Step 2 results in the formation of the P=S moiety. Thus, the disaccharide after step 2 reads on claim 12 formula (1), where G1a and G2 are protecting groups, Y is a sulfur atom, Ba represents two different nucleobases, R represents a 2-methoxyethyl group, (W1 represents an OZ group, Z is liquid carrier), X1 represents an R group and R is a 2-methoxyethyl group, n is 1. The M19-fragment I-UC reads on formula (2), wherein G2, Ba, R, Y, X1, W1, and n are described above. Antia et al. also disclose detritylation using dichloroacetic acid in DCM and 1-dodecanethiol to convert 5’-DMT protected nucleotide H-1 to 5’-OH nucleotide H-1; K-1 to K-2 and for the preparation of O-3 (para [0385]-[0386]; [0403]-[0404]; [0433]-[0434]). Antia et al. disclose preferable detritylation reagents include trifluoroacetic acid (TFA) or dichloroacetic acid (DCA), (para [0162]). Alternative cation scavengers to 1-dodecanethiol include cyclohexanethiol (CySH), (para 0159]). The above steps are repeated to obtain oligonucleotide fragment A (p.137-139). Antia et al. teach preparing oligomers of 20 monomers in length, or until the desired length is obtained (see for example claim 54; p.89 para [0170]).
Bleicher et al. teach “solid support” refers to supports used for solid phase synthesis, and preferably includes controlled pore glass (p.5:19-22). The term “cation scavenger” preferably includes triethylsilane and methoxy thiophenol (p.6:18-22). Bleicher et al. teach the preparation of an oligonucleotide, wherein the oligonucleotide is bound to a solid support for solid phase synthesis using controlled pore glass modified with an universal linker (col.23:19-31; claim 23).The oligonucleotide is protected at the 5’-terminus with a DMTr group. The DMTr group is removed with an acid and a cation scavenger (claim 44; col.22:20-30). The acid is dichloroacetic acid or trichloroacetic acid (claim 24). The DMT deprotection is preferably done in dichloromethane (col.23:1-18). The scavenger is used at 2-30% (v/v), and the acid is used at 1-10% (v/v), (col.22:23-30 and col.23:1-5). Example 4 describes a method for the synthesis of an oligonucleotide using a controlled pore glass support bearing a universal linker, the DMTr is deprotected with trifluoroacetic acid in the presence of triethylsilane in dichloromethane and/or p-methoxy thiophenol in dichloromethane (p.34).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to remove the DMTr protecting group from the 5’-terminal position with an acid in the presence of 1-dodecanethiol or cyclohexanethiol (CySH).
In the same field of endeavor for preparing oligonucleotides, Aoki et al., Antia et al. and Bleicher et al. teach deprotecting a 5’ terminal DMTr protecting group using an acid. The ordinary artisan would have been motivated to further include a thiol as a cation scavenger because both Antia et al. and Bleicher et al. teach preparing an oligonucleotide by deprotecting the 5’-terminal DMTr protecting group using an acid in the presence of a thiol containing cation scavenger. While Antia et al. is concerned with solution-phase synthesis, Bleicher teaches the use of silane and thiol-based scavengers for solid phase oligonucleotide synthesis. Thus, the ordinary artisan would have known the use of a thiol-based cation scavenger can be used in solid or solution-phase oligonucleotide synthesis during the detritylation reaction with a reasonable expectation of success (removing the DMTr group from the 5’-terminus).
Turning to Antia et al., the ordinary artisan would have been motivated to use 1-dodecanethiol or cyclohexanethiol (CySH) as scavengers for the detritylation reaction, because they are recognized as cation scavengers to be used during the detritylation reaction. The ordinary artisan would have had a reasonable expectation of success because Bleicher teaches detritylation reaction using an acid in the presence of a thiol-containing cation scavengers wherein the oligonucleotide is prepared using solid phase synthesis.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to detritylate a 5’-DMT group in either toluene or DCM, because Antia et al. teach they are suitable alternative solvents, and exemplifies using both solvents in detritylation reactions. The ordinary artisan would have had a reasonable expectation of success because toluene was successfully used to remove a 5’-DMT group in an oligonucleotide using solid phase synthesis.
The recitation “a non-nucleotide linker may be incorporated between nucleotides” in claim 1 is broadly and reasonably interpreted as optional.
With respect to the length of the oligonucleotide, the ordinary artisan would have been motivated to prepare an RNA oligonucleotide of any desired length, including 40-mer or 62-mer, because Antia et al. and Aoki et al. teach repeating the chain elongation to arrive at the desired chain length. This overlaps with the size recited in amended claim 23.
The prior art is silent with respect to the nucleotide deletion product, N-1 mer. As evidenced by the Specification, “by using the production method of the present invention, according to one embodiment, it is possible to produce an oligonucleotide wherein the content of nucleotide deletion product (also referred to as N-1 mer) is reduced (see para [0082] of the present Specification).
Thus, the claimed invention as a whole is prima facie obvious over the combined teaching of the prior art.
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 1, 3, 5, 15, 17, 18 and 20-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 10-21 of copending Application No. 18/691,479 in view of Antia et al. (cited above) and Bleicher et al. (cited above).
The claims of the reference Application are directed towards a method of removing a 5’-DMT protecting group in the presence of dichloroacetic acid, see claim 12 in particular of the reference Application. The variables of the oligonucleotides are the same as the present claims. The solvents include DCM, MeCN and toluene.
The claims do not expressly disclose a thiol.
Antia et al. and Bleicher et al. teach as discussed above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to detritylate a 5’-DMT group with dichloroacetic acid in the presence of dodecanethiol because Antia et al. expressly teach using the thiol as a cation scavenging agent.
The ordinary artisan would have had a reasonable expectation of success because Bleicher teaches detritylation reaction using an acid in the presence of a thiol-containing cation scavengers, wherein the oligonucleotide is prepared using solid phase synthesis.
Thus, the claims are prima facie obvious over the claims of the ‘479 Application in view of Antia et al. and Bleicher et al.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 05 February 2026 have been fully considered but they are not persuasive.
Applicant’s arguments are the same as above.
The response is not found persuasive as discussed above.
The rejection is hereby maintained.
Conclusion
In view of the rejections to the pending claims set forth above, no claim is allowed.
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.
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/BAHAR CRAIGO/
Primary Examiner
Art Unit 1699