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 .
This Office action is responsive to Applicant’s preliminary amendment and remarks, filed 27 Feb 2026, in which claims 5-13 are amended, and new claims 16-18 are added.
This application is a domestic application, filed 29 Aug 2023; claims benefit as a CON of PCT/EP2021/084316, filed 06 Dec 2021; and claims benefit of foreign priority document EP 20212441.8, filed 08 Dec 2020.
Claims 5-18 are pending in the current application. Claims 11-12, drawn to non-elected inventions, are withdrawn. Claims 5-10 and 13-18 are examined on the merits herein.
Priority
Upon reconsideration, the filing date or 371(c) date of the current application is deemed to be 29 Aug 2023. See the Filing Receipt mailed 08 Nov 2023. This effective filing date is more than 30 months from the filing date of foreign priority document EP 20212441.8, which was filed 08 Dec 2020. Therefore the current application does not receive the benefit of the claimed foreign priority document. See MPEP 1895.01.
Further, a certified copy of the foreign priority document EP 20212441.8 is not of record.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 5-10, 13-15, and new claims 16-18, in the reply filed on 27 Feb 2026 is acknowledged.
Claims 11-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 27 Feb 2026.
Applicant’s election of species of locked nucleic acid (LNA) in the reply filed on 27 Feb 2026 is acknowledged.
Search and examination has been expanded to include the species of ribose n modified at the 2’ position of its ring with the protecting group TBDMS.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. MPEP 606 provides a listing of words that are not considered as part of the title of an invention, should not be included at the beginning of the title of the invention and will be deleted when the Office enters the title into the Office’s computer records, and when any patent issues. This listing includes the words “Improved”, “New”, and “Novel”.
In this case the title “Novel Synthesis of Phosphorodithioate Oligonucleotides” begins with the word “novel”, and will be entered as “Synthesis of Phosphorodithioate Oligonucleotides”.
Claim Objections
Claim 13 is objected to because of the following informalities: claim 13 at line 3 appears to recite “2′-0-methoxyethyl (2′-0-MOE), 2′-0-Methyl” (emphasis added), with the number zero in place of the letter O, by comparison with the recited “MOE”. The previously filed claims clearly recited the letter O at these locations.
Appropriate correction or clarification is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 15 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 15 depends from claim 5 and recites the method “for the preparation of an oligonucleotide comprising at least one phosphorodithioate, at least one phosphorothioate and/or at least one phosphodiester internucleoside linkage.” Claim 5 recites the method “for the preparation of an oligonucleotide containing at least one phosphorodithioate internucleoside linkage”. Considering the alternative of claim 15 “for the preparation of an oligonucleotide comprising at least one phosphorodithioate” internucleoside linkage, this claim is identical in scope as claim 5 from which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
For example, if claim 15 recited the method “for the preparation of an oligonucleotide comprising at least one phosphorodithioate internucleoside linkage, and at least one phosphorothioate and/or at least one phosphodiester internucleoside linkage” (emphasis added) then this claim would be proper dependent form.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 5 and 14-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Greef et al. (Tetrahedron Letters, 1996, 37(26), p4451-4454, provided by Applicant in IDS filed 06 Sep 2023).
Greef et al. teaches the synthesis of phosphorodithioate RNA. Deoxynucleoside 3’-H-phosphonothioate monoesters were developed as synthons in the preparation of phosphorothioate and phosphorodithioate DNA on a solid support. These methods were adapted to the synthesis of ribonucleoside 3'-H-phosphonothioates
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. Phosphoramidites (la-d) (Fig. 1) were treated with H2S to generate the H-phosphonothioate diesters (2a-d) which were then deprotected to give the H-phosphonothioate monoesters (page 4451, paragraph 2 and figure 1). These compounds 3a-d are interpreted as species of ribose n modified at the 2’ position of its ring with the protecting group TBDMS and corresponding to claimed formula (I). For the solid phase synthesis of S2RNA, a synthetic cycle was developed that optimized the phosphorodithioate content of the final product, although contamination with phosphorothioate was the major challenge (page 4451, paragraph 3). The H-phosphonothioate is reacted with a solid-support-bound monomer having a 5’-OH group detritylated with TCA in the presence of diphenylchlorophosphate in combination with pyridine as a coupling agent to give the H-phosphonothioate diester compound 4, sulfurized, and which were then deprotected and removed from the support (page 4452, figure 2), meeting limitations of claim 5. Generally, oligomers synthesized by this approach contained 90-96% phosphorodithioate linkages (I 15-118 ppm) with the remainder being phosphorothioate (56-58 ppm) (page 4452, figure 2 and paragraph 1), or an oligonucleotide comprising at least one phosphorodithioate and at least one phosphorothioate internucleoside linkage meeting limitations of claims 14-15.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. 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.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Greef et al. (Tetrahedron Letters, 1996, 37(26), p4451-4454, provided by Applicant in IDS filed 06 Sep 2023) in view of Stawinski et al. (Nucleosides & Nucleotides, 1991, 10(1-3), p511-514, cited in PTO-892).
Greef et al. discloses as above regarding claims 5 and 14-15. Greef et al. further teaches the use of 31P gel phase NMR to monitor nucleic acid chemistry has allowed stepwise analysis of intermediates in the synthesis cycle, and this methodology will prove useful for monitoring solid phase synthesis strategies for other analogs (page 4453, paragraph 2).
Greef et al. does not specifically disclose the method to obtain a compound of formula (V) (claim 9).
Stawinski et al. teaches chemical and stereochemical aspects of condensations of ribonucleoside 3’-H-phosphonates, 3’-H-phosphomonothioates and 3’-H-phosphodithioates into the corresponding diesters 4 and 5, together with oxidation and sulfurization (page 511, abstract). Stawinski et al. teaches the dinucleotide diester 5
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prepared by reaction of 3’-H-phosphomonothioate
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with a coupling agent and protected uridine mononucleotide (page 512, scheme 1; paragraph spanning pages 512-513).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Greef et al. in view of Stawinski et al. in order to isolate the 3’-H-phosphomonothioate diester. One of ordinary skill in the art would have been motivated to combine Greef et al. in view of Stawinski et al. with a reasonable expectation of success because both Greef et al. and Stawinski et al. are drawn to the condensations of ribonucleoside3’-H-phosphomonothioates, and both Greef et al. and Stawinski et al. suggest analysis of intermediates in the synthesis cycle is desired, suggesting it would have been obvious to isolate the 3’-H-phosphomonothioate diester in order to monitor the solid phase synthesis strategy.
Claims 10 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Greef et al. (Tetrahedron Letters, 1996, 37(26), p4451-4454, provided by Applicant in IDS filed 06 Sep 2023) in view of Sobkowski et al. (Tetrahedron: Asymmetry, 2010, 21, p410-419, cited in PTO-892).
Greef et al. discloses as above regarding claims 5 and 14-15.
Greef et al. does not specifically disclose the method wherein the coupling agent is the dialkylchlorophosphate diethylchlorophosphate in combination with pyridine (claims 10 and 16).
Sobkowski et al. teaches stereoselective strategies for the preparation of ribonucleoside 3’-H-phosphonothioate monoesters (page 410, abstract). Ribonucleoside 3’-H-phosphonates and ribonucleoside 3’-H-phosphonothioate are known for use in reaction with nucleosides in the preparation of oligonucleotides (page 410, left column, paragraph 1). Sobkowski et al. teaches diphenyl chlorophosphate (DPCP; a reagent of choice for standard nucleoside 3’-H-phosphonothioate condensations) was subject to rapid hydrolysis, while diethylchlorophosphate (DECP), which is less susceptible to hydrolysis, was able to promote the asymmetric transformation of H-phosphonothioate 5 nearly as efficiently as PvCl and without any desulfurization. The optimal pyridine content for this reaction was established to be ca. 20%. These prevented detritylation of 4 and kept hydrolysis of DECP at a low level (page 413, right column, paragraph 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Greef et al. in view of Sobkowski et al. in order to substitute the DPCP used in the method of Greef et al. for the DECP taught by Sobkowski et al. One of ordinary skill in the art would have been motivated to combine Greef et al. in view of Sobkowski et al. with a reasonable expectation of success because both Greef et al. and Sobkowski et al. are drawn to the field of ribonucleoside 3’-H-phosphonothioates for use in the preparation of oligonucleotides, Greef et al. teaches the method wherein diphenyl chlorophosphate in combination with pyridine is used to activate the nucleoside 3’-H-phosphonothioate for the condensation or coupling, and Sobkowski et al. teaches the method wherein diethylchlorophosphate is used in place of the diphenyl chlorophosphate for the same purpose in the reaction with the additional advantage that DECP is less susceptible to hydrolysis. Therefore it would have been obvious to substitute the DPCP used in the method of Greef et al. for the DECP taught by Sobkowski et al. because they are known equivalents used in the prior art for the same purpose, and additionally one of ordinary skill in the art would have been motivated to substitute the DPCP for the DECP in order to improve similar methods in the same way because DECP is taught by Sobkowski et al. to be less susceptible to hydrolysis.
Claims 5, 13-15, and 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Elmen et al. (US 2009/0176977, published 09 July 2009, cited in PTO-892) in view of Greef et al. (Tetrahedron Letters, 1996, 37(26), p4451-4454, provided by Applicant in IDS filed 06 Sep 2023).
Elmen et al. teaches oligonucleotides which comprise a dinucleotide consisting of a 5' locked nucleic acid (LNA) and a phosphorothioate internucleoside linkage bond to a 3' RNA or RNA analogue (abstract). Elmen et al. teaches LNA has an extraordinary ability to protect oligonucleotides from nuclease degradation and at the same time increase affinity for its complementary target. It has been shown that the RNAi cellular machinery recognizes LNA, and as such LNA based oligonucleotides may be used to down-regulate target molecules via RNAi or similar mechanisms (page 1, paragraphs 2-3). The oligonucleotides of the invention may be produced using the polymerisation techniques of nucleic acid chemistry, which is well known to a person of ordinary skill in the art of organic chemistry. Generally, standard oligomerisation cycles of the phosphoramidite approach may be used, but other chemistries, such as the H-phosphonate chemistry or the phosphortriester chemistry may also be used (paragraph 170 spanning pages 10-11). The internucleoside linkages other than the phosphorothioate may by selected from the group including phosphodiesters -O-P(O)2-O-, and phosphorodithioates -O-P(S)2-O- (page 6, paragraphs 93-94). Elmen et al. teaches a preferred structure of the LNA unit is
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, where Z and Z* are absent or selected from the group consisting of an internucleoside linkage group, a terminal group and a protection group; and B is a nucleobase (page 5, paragraphs 88-89). In the synthesis the nucleobase is optionally protected (page 11, paragraph 172).
Elmen et al. does not specifically disclose the method of synthesizing the oligonucleotide comprising using the H-phosphonate chemistry (claim 5).
Greef et al. teaches the synthesis of phosphorodithioate RNA. Deoxynucleoside 3’-H-phosphonothioate monoesters were developed as synthons in the preparation of phosphorothioate and phosphorodithioate DNA on a solid support. These methods were adapted to the synthesis of ribonucleoside 3'-H-phosphonothioates
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. Phosphoramidites (la-d) (Fig. 1) were treated with H2S to generate the H-phosphonothioate diesters (2a-d) which were then deprotected to give the H-phosphonothioate monoesters (page 4451, paragraph 2 and figure 1). For the solid phase synthesis of S2RNA, a synthetic cycle was developed that optimized the phosphorodithioate content of the final product, although contamination with phosphorothioate was the major challenge (page 4451, paragraph 3). The H-phosphonothioate is reacted with a solid-support-bound monomer having a 5’-OH group detritylated with TCA in the presence of diphenylchlorophosphate as a coupling agent to give the H-phosphonothioate diester compound 4, sulfurized, and which were then deprotected and removed from the support (page 4452, figure 2 and paragraph 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Elmen et al. in view of Greef et al. in order to select the method of synthesizing the oligonucleotide comprising using the H-phosphonate chemistry taught within Elmen et al. to be the chemistry taught by Greef et al. One of ordinary skill in the art would have been motivated to combine Elmen et al. in view of Greef et al. with a reasonable expectation of success because Greef et al. suggests ribonucleoside 3'-H-phosphonothioates to be synthons in the preparation of phosphorothioate and phosphorodithioate RNA on a solid support, and Elmen et al. teaches the oligonucleotides of the invention may be produced using the known polymerisation techniques of nucleic acid chemistry, such as H-phosphonate chemistry. Further, Elmen et al. suggests the use of LNA oligonucleotides in place of RNA oligonucleotides, providing guidance to select the teachings of Greef et al. drawn to the use of H-phosphonate chemistry in the synthesis of RNA oligonucleotides, with a reasonable expectation of success. Regarding the specification structures used in claim 18, Elmen et al. teaches preferred structures of the LNA unit, and Greef et al. teaches the structure of the ribonucleoside 3'-H-phosphonothioates formed during the coupling reaction, and it would have been obvious to one of ordinary skill in the art to expect that the claimed structures would similarly form during the coupling reaction made obvious by the combined teachings of Elmen et al. in view of Greef et al.
Claims 5-8, 13-15, and 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Bleicher et al. (WO 2019/122279 A1, published 27 June 2019, cited in PTO-892) in view of Elmen et al. (US 2009/0176977, published 09 July 2009, cited in PTO-892) and Greef et al. (Tetrahedron Letters, 1996, 37(26), p4451-4454, provided by Applicant in IDS filed 06 Sep 2023).
Bleicher et al. teaches an oligonucleotide comprising at least one phosphorodithioate internucleoside linkage of formula (I) (abstract). Bleicher et al. teaches non-bridging phosphorodithioates can be introduced into oligonucleotide, in particular to oligonucleotide gapmers or mixmers in general and LNA-DNA-LNA gapmers or LNA/DNA mixmers in particular, which retains the activity or efficacy of the identical compound containing phosphodithioate linkages and reduces the diastereoisomeric complexity of the compound compared to the phosphorothioate (page 2, lines 15-35). The chemical synthesis of non-bridging phosphorodithioate linkages in oligonucleotides is best achieved by solid phase oligonucleotide synthesis techniques using appropriate thiophosphoramidite building blocks known in the prior art (page 3, lines 5-15). The phosphorodithioate in the produced oligonucleotide may be of formula IA or IB
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where R is a hydrogen or a phosphate protecting group (page 3, line 25 to page 4, line 5). Bleicher et al. teaches monomers of formula (II) wherein RX can be cyanoalkyl such as cyanoethyl (page 119, line 5 to 20), implying that the phosphate protecting group R in formula IA encompasses the cyanoalkyl group. Bleicher et al. teaches embodiments of the oligonucleotides comprising phosphorodithioate and phosphorothioate internucleotide linkages (table spanning page 134-135), addressing limitations of claims 14-15. Bleicher et al. teaches embodiments of the monomers of formula (II) wherein the nucleobases are protected using amino-protecting groups (page 121, line 10 to page 122), addressing limitations of claim 18. Bleicher et al. teaches the solid phase oligonucleotide synthesis techniques using appropriate thiophosphoramidite building blocks (page 105-107).
Bleicher et al. does not specifically disclose the method of synthesizing the oligonucleotide comprising using the H-phosphonothioate chemistry (claim 5).
Elmen et al. teaches as above. Elmen et al. suggests the standard oligomerisation cycles of the phosphoramidite approach may be used, but other chemistries, such as the H-phosphonate chemistry or the phosphortriester chemistry may also be used to synthesize the oligonucleotide containing LNA units.
Greef et al. teaches as above. Greef et al. teaches the use of H-phosphonothioate chemistry in the synthesis of oligonucleotides containing phosphorothioate and phosphorodithioate internucleoside linkages.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Bleicher et al. in view of Elmen et al. and Greef et al. in order to modify the method of Bleicher et al. in order to substitute the thiophosphoramidite approach for synthesizing the oligonucleotide with the H-phosphonothioate chemistry taught by Greef et al. It would have been obvious to one of ordinary skill in the art to combine Bleicher et al. in view of Elmen et al. and Greef et al. with a reasonable expectation of success to substitute known methods of synthesizing the oligonucleotide to obtain predictable results because Elmen et al. teaches the phosphoramidite approach and H-phosphonate chemistry are known for the same purpose of synthesizing the oligonucleotides including LNA units, and Greef et al. teaches the use of H-phosphonothioate chemistry in the synthesis of oligonucleotides containing phosphorothioate and phosphorodithioate internucleoside linkages, suggesting a reasonable expectation that one of ordinary skill in the art could have substituted one known process step for another and that the results of the substitution would have been the predictable synthesis of the oligonucleotide including LNA units. Regarding the specification structures used in claim 18, both Bleicher et al. and Elmen et al. teaches preferred structures of the LNA unit, and Greef et al. teaches the structure of the ribonucleoside 3'-H-phosphonothioates formed during the coupling reaction, suggesting it would have been obvious to one of ordinary skill in the art to expect that the claimed structures would similarly form during the coupling reaction made obvious by the combined teachings of Bleicher et al. in view of Elmen et al. and Greef et al.
Conclusion
No claim is found to be allowable.
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/JONATHAN S LAU/ Primary Examiner, Art Unit 1693