DETAILED ACTION
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 .
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.
Response to Amendment
The amendment filed May 15, 2026 has been entered. Claims 1-6 and 8-10 have been amended. Applicant’s amendments to the claims have overcome the 112(a), 112(b), and 112(d) rejections as well as objections to the claims and specification previously set forth in the Non-Final Office Action mailed February 19, 2026. As such, these rejections and objections are hereby withdrawn.
Applicant’s arguments filed May 15, 2026 were fully considered but they were not persuasive. Maintained rejections and response to arguments addressed below.
Claims 1-11 are pending in this application.
Priority
This application is a 371 of PCT/JP2022/019139 filed April 27, 2022 and claims foreign priority to JP 2021-076609 filed April 28, 2021. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been received. The Examiner notes that no English translation was provided.
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 1-2, and 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over Kotobuki (CA 3099778, IDS filed March 28, 2025) in view of Bhadra (Tetrahedron Letters, 2015, IDS filed March 28, 2025) and Powles (Org. Biomol. Chem., 2012, cited in previous action). The supplementary material for Bhadra was also provided in the IDS filed March, 28, 2025.
Regarding claims 1-2 and 6-7: Kotobuki teaches the following synthesis
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(pg. 31, top of page) Kotobuki teaches the compound C-1 can be treated with an acid to remove the Q1 group and generate compound E-1
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(pg. 36, para. 0066-0067). Kotobuki teaches the specific examples of A-1:
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(pgs. 83-84, table 3). Kotobuki teaches the specific examples of B-1
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(pgs. 20-21, para. 0034, table 1). This compounds react as shown above to form corresponding compounds of C-1. Kotobuki teaches the n values can range from 1 to 25 for A-1 (pg. 13, top half of page). Kotobuki teaches the p values can range from 1 to 5 for B-1 (pg. 19, chem. 22, bottom half of page). Kotobuki teaches “The "optionally protected nucleic acid base" refers to an unprotected "nucleic acid base" and/or a protected nucleic acid base, and examples thereof include adenine, guanine, hypoxanthine, cytosine, thymine, uracil, adenine (Anz) having an amino group protected by benzoyl, cytosine (CBz) having an amino group protected by benzoyl, and guanine (GCE,Pac) having a hydroxyl group protected by 2-cyanoethyl and an amino group protected by phenoxyacetyl.” (pg. 26, middle of page).
The method of Kotobuki differ from the instantly claimed method utilizes a chlorophosphoramidate instead of an H-phosphonate triethylammonium salt. To clarify, Kotobuki teaches this group:
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, while the instantly claimed compounds in the method possess this group:
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. The method does not teach following condensation A-1 and B-1 are treated with an oxidizing agent and an organic amine to obtain C-1.
However, Bhadra teaches the synthesis of T-containing phosphorodiamidate morpholino oligomers by H-phosphate methods on solid support (abstract). Bhadra teaches the following synthesis of an H-phosphonate T monomer:
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(pg. 4566, col. 1, scheme 2). Bhadra teaches this monomer is utilized in the solid phase synthesis of PMO via H-phosphonate chemistry (pg. 4566, col. 2, para. 1, scheme 3). Bhadra teaches 5’-chlorophosphoramidate morpholino monomers are unstable in solution (pg. 4565, col. 1, para. 2). Bhadra teaches the H-phosphonate method with a T morpholino monomer is unique in comparison to chlorophosphoramidate method as it can be transferred to a DNA synthesizer and is stable in solution (pgs. 4567-4568, bridging para.).
Taken together it would have been prima facie obvious to a person of ordinary skill in the art to modify the compound of Kotobuki such that the chlorophosphoramidate (
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) is replaced with an H-phosphonate triethylammonium salt(
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) as taught by Bhadra which is subsequently oxidized in the presence of an oxidizing agent and an organic amine. A person of ordinary skill in the art would have had the motivation to do with a reasonable expectation of success as the H-phosphonate triethylammonium salts are known in the art for the synthesis of PMO oligomers which are subsequently oxidized and reacted with an organic amine to form a PMO and H-phosphonate triethylammonium salts are stable in solution compared to chlorophosphoramidate reagents. Bhadra teaches that following activation and coupling steps the oligomer is subsequently subjected to an oxidizing agent (iodine) and an organic amine (Me2NH)
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(Supporting information, pg. 4, scheme).
The method further differs in the Kotobuki and Bhadra do not teach wherein the condensation between A-1 and B-2 is in performed in the presence of phosphorus reagent 1, phosphorus reagent 2, or an onium reagent in the presence of a base prior to oxidation. According to the instant specification diphenyl chlorophosphite is an example of these reagents (pgs. 31-32, para. 0029).
However, Bhadra establishes that H-phosphonate triethylammonium salts are viable compounds in both PMO (
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) and DNA syntheses (
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) of oligomers (pg. 4566, col. 1, scheme 2, pg. 4567, scheme 4). Additionally Powles teaches that coupling reactions for the synthesis of most oligonucleotides utilize phosphate esters, phosphoramidites, or H-phosphonates (pg. 5940, col. 2, para. 1). Powles teaches that H-phosphonates are a simple and efficient way to produce dinucleoside, which can be activated with diphenylchlorophosphate and pyridine (i.e. a base) (pg. 5940, col. 2, para. 1, scheme 1).
Taken together it would have been prima facie obvious to modify the method such that A-1 and B-1 are reacted in the presence of an activator and base, such as diphenylchlorophosphate and pyridine as taught by Powles. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as activator systems, such as those taught by Powles, are a known technique in the art for forming oligonucleotides with H-phosphonate chemistry.
Claims 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Kotobuki (CA 3099778, IDS filed March 28, 2025) in view of over Bhadra (Tetrahedron Letters, 2015, IDS filed March 28, 2025). The supplementary material for Bhadra was also provided in the IDS filed March, 28, 2025.
Regarding claims 8-9: Kotobuki teaches the preparation of PMO using the following synthesis
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(pg. 31, top of page). Kotobuki teaches the specific examples of A-1:
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(pgs. 83-84, table 3). Kotobuki teaches the specific examples of B-1
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(pgs. 20-21, para. 0034, table 1). This compounds react as shown above to form corresponding compounds of C-1 via the chlorophosphoramidate method. Kotobuki teaches that the p value in [B-1] is suitably an integer from 1 to 10 (pg. 19, chem. 22). Kotobuki teaches the amino group or hydroxyl group of the nucleic acid base for BP may be protected (pg. 26, top paragraph).
The compounds of Kotobuki differ from the instantly claimed compounds in that a chlorophosphoramidate is present instead of an H-phosphonate triethylammonium salt. To clarify, Kotobuki teaches this group:
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, while the instantly claimed compounds possess this group:
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.
However, Bhadra teaches the synthesis of T-containing phosphorodiamidate morpholino oligomers by H-phosphate methods on solid support (abstract). Bhadra teaches the following synthesis of an H-phosphonate T monomer:
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(pg. 4566, col. 1, scheme 2). Bhadra teaches this monomer is utilized in the solid phase synthesis of PMO via H-phosphonate chemistry (pg. 4566, col. 2, para. 1, scheme 3). Bhadra teaches 5’-chlorophosphoramidate morpholino monomers are unstable in solution (pg. 4565, col. 1, para. 2). Bhadra teaches the H-phosphonate method with a T morpholino monomer is unique in comparison to chlorophosphoramidate method as it can be transferred to a DNA synthesizer and is stable in solution (pgs. 4567-4568, bridging para.).
Taken together it would have been prima facie obvious to a person of ordinary skill in the art to modify the compound of Kotobuki such that the chlorophosphoramidate (
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) is replaced with an H-phosphonate triethylammonium salt(
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) as taught by Bhadra. A person of ordinary skill in the art would have had the motivation to do with a reasonable expectation of success as the H-phosphonate triethylammonium salts are known in the art for the synthesis of PMO oligomers and are stable in solution compared to chlorophosphoramidate. Kotobuki teaches “The "optionally protected nucleic acid base" refers to an unprotected "nucleic acid base" and/or a protected nucleic acid base, and examples thereof include adenine, guanine, hypoxanthine, cytosine, thymine, uracil, adenine (Anz) having an amino group protected by benzoyl, cytosine (CBz) having an amino group protected by benzoyl, and guanine (GCE,Pac) having a hydroxyl group protected by 2-cyanoethyl and an amino group protected by phenoxyacetyl.” (pg. 26, middle of page). Kotobuki demonstrates the particular protected B-1 compound with the following structure:
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(pgs. 19-20, table 1, morG). Given that Kotobuki teaches a large amount of known protected bases and the H-phosphonate TEA reagent is encompassed by the prior art, so too are the specific compounds recited by claim 9.
Claims 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over Kotobuki (CA 3099778, IDS filed March 28, 2025) and Bhadra (Tetrahedron Letters, 2015, IDS filed March 28, 2025) as applied to claims 8-9 above in view of Link (Link Technologies, Guidebook for the synthesis of Oligonucleotides, 2015, cited in previous action) and Sinha (US 2021/0130379, cited in previous action, filed October 30, 2020). The supplementary material for Bhadra was also provided in the IDS filed March, 28, 2025.
Regarding claims 10-11: As discussed above the prior art render obvious the compounds of claims 8-9. Bhadra establishes that H-phosphonate triethylammonium salts are viable compounds in both PMO (
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) and DNA syntheses (
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) of oligomers (pg. 4566, col. 1, scheme 2, pg. 4567, scheme 4).
They do not teach wherein the compound is an H-phosphonate DBU salt.
However, Link teaches known reagents for solid-phase oligonucleotide assembly by using H-phosphonates (pg. 61, para. 2). Link teaches the following reagents which differ in their salt form:
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(pg. 60, bottom of page, compounds 2005 and 2035). Additionally Sinha contemplates morpholino H-phosphonate monomer DBU salts to be used in the synthesis of PMOs
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(abstract, pg. 6, bottom right of page).
Taken together, it would have been prima facie obvious to modify the compound such that a DBU salt is utilized instead of a TEA salt as taught by Link and Sinha. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as both these salts are known in the art for H-phosphonate chemistry and the art establishes H-phosphonate chemistry is compatible with PMO and DNA synthesis. Wherein the salts are established equivalents, it is prima facie obvious to substitute equivalents known for the same purpose (See MPEP 2144.03 (II)). As discussed above, Kotobuki teaches the amino group or hydroxyl group of the nucleic acid base for BP may be protected (pg. 26, top paragraph). Kotobuki teaches “The "optionally protected nucleic acid base" refers to an unprotected "nucleic acid base" and/or a protected nucleic acid base, and examples thereof include adenine, guanine, hypoxanthine, cytosine, thymine, uracil, adenine (Anz) having an amino group protected by benzoyl, cytosine (CBz) having an amino group protected by benzoyl, and guanine (GCE,Pac) having a hydroxyl group protected by 2-cyanoethyl and an amino group protected by phenoxyacetyl.” (pg. 26, middle of page). Kotobuki demonstrates the particular protected B-1 compound with the following structure:
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(pgs. 19-20, table 1, morG). Given that Kotobuki teaches a large amount of known protected bases and the H-phosphonate DBU reagent is encompassed by the prior art, so too are the specific compounds recited by claim 11.
Response to Arguments
Applicant’s arguments filed May 15, 2026 with respect to the claims have been fully considered but they are not persuasive.
On pages 37-38 of Applicant’s response, Applicant argues Bhadra only teaches a method for synthesis of monomer-type PMO compounds as H-phosphonate reagents (bridging para.). On page 38 of Applicant’s response, Applicant argues the present specification describes a morpholino nucleic acid having phosphorodiamidate linkages which can be elongated one unit at a time by carrying out a series of steps (para. 2). Applicant argues Example 5 demonstrates a long-chain morpholino nucleic acid oligomer can be efficiently synthesized by so-called block synthesis using PMOs of a certain chain length (para. 2). Applicant argues none of the features are suggested by the prior art references cited.
However, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references (See MPEP 2145 (IV)). Kotobuki is relied upon for teaching oligomer PMO compounds, and a person of ordinary skill in the art would have the requisite motivation to incorporate the conditions employed by Bhadra in the syntheses of the compounds of Kotobuki.
On page 39 of Applicant’s response, Applicant argues the compounds recited by claims 8 and 9 are morpholino nucleic acid compounds having an H-phosphonate group at the 5’-position of a dimer or higher oligomer (para. 2). Applicant argues the specification demonstrates use of the DBU salt of H-phosphonate allows the condensation reaction to proceed more efficiently compared to the triethylamine salt of H-phosphonate (para. 3). On pages 39-40 of Applicant’s response, Applicant argues a person of ordinary skill in the art would recognize that the DBU salts of morpholino nucleic acid monomers recited by instant claims 10 and 11 which are not suggested by the cited references, having an H-phosphonate at the 5’position would enable the condensation reaction to proceed more efficiently than the corresponding triethylamine salt monomer compounds (bridging para.).
However, claims 8-11 are drawn to compound claims. The Examiner notes that, "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process" In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (See MPEP 2113 (I)). Additionally, as discussed above, Sinha contemplates morpholino H-phosphonate monomer DBU salts to be used in the synthesis of PMOs
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(abstract, pg. 6, bottom right of page).Given that the art establishes DBU and Et3N salts can be made for H-phosphonate compounds, it is prima facie obvious to substitute equivalents known for the same purpose (See MPEP 2144.03 (II)).
Applicant’s reply is considered to be a bona fide attempt at a response and is being accepted as a complete response. The 35 USC § 103 rejections are maintained for reason of record and foregoing discussion.
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.
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/S.L.G./Examiner, Art Unit 1693
/ANDREA OLSON/Primary Examiner, Art Unit 1693
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