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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on December 22, 2025 has been entered.
Priority
This application is a 371 of PCT/US2020/061755 11/23/2020, which claims benefit of 62/941,153 11/27/2019.
Claim Status
The claim set and Applicant’s remarks filed December 22, 2025 have been entered. Claims 3, 9 and 22-30 are canceled. Thus, claims 1-2, 4-8 and 10-21 as amended are examined on the merits herein.
Response to Arguments
The rejection of claims 1-2, 4-8 and 10-21 under 35 U.S.C. 103 is maintained.
Applicant argues:
(A) There is no reason, rationale, or motivation that would lead a person of ordinary skill in the art to substitute Seela’s Compound 13 for Compound 14 based solely on the teachings of Seela, see Applicant’s remarks, pg. 7 of 14, paragraph 3.
(B) The Examiner fails to articulate with any rationale underpinnings how and where Seela teaches or suggests synthesizing an oligonucleotide comprising a 2’→5’ internucleotide linkage, Applicant’s remarks, pg. 7 of 14, paragraph 3.
(C) Seela provides no motivation to substitute Compound 13 with Compound 14 in the process taught therein in the manner asserted, Applicant’s remarks, pg. 7 of 14, paragraph 3.
(D) The Examiner’s rationale that “one of ordinary skill in the art would have been motivated to synthesize ribonucleotides incorporating 3-Deazaguanosine as taught by Seela”, does not explain with any rationale underpinnings why the skilled artisan would have been motivated to specifically synthesize a 3’-Deazaguanosine ribonucleotide comprising a triisopropyl group at the 3’-position and a phosphoramidite group at the 2’ position of the sugar moiety, see Applicant’s remarks, pg. 8 of 14, last paragraph of the page – pg. 9, first paragraph of the page.
(E) There is no teaching or suggestion in Seela to prepare an oligonucleotide comprising a 2’→5’ linkage, see Applicant’s arguments, pg. 9 of 14, paragraph 1.
(F) The monomers and synthetic process described in Seela exclusively produce oligonucleotides with a canonical 3’→5’ phosphodiester internucleotide linkage; and Seela does not disclose a 2’-O phosphoramidite or any method that would produce 2’→5’ linkages; and neither does Seela teach or suggest adapting its process to produce oligonucleotides with 2’→5’ phosphodiester internucleotide linkages, see Applicant’s remarks, pg. 9 of 14, paragraph 1.
(G) There is no disclosure of 2’-O-phosphoramidite monomers or any method that would direct 2’→5’ assembly in Gao, see Applicant’s remarks, pg. 10 of 14, paragraph 1.
(H) As seem from the data summarized in Table 5 of Applicant’s Specification, the oligonucleotides prepared with monomers of Formula (I), having a triisopropyl (TIPS) protected 3’-hydroxyl group and a 2’-β-cyanoethyl phosphoramidite moiety are stable against prolonged base treatment at elevated temperature, see Applicant’s remarks, pg. 11 of 14, paragraph 1.
(I) Thus, the data shows that oligonucleotides prepared with monomers having a TIPS 3’-protected hydroxyl group and a 2’-β-cyanoethyl phosphoramidite moiety surprisingly and unexpectedly are much more stable against prolonged based treatment at elevated temperature in comparison to monomers having a TBS, TOM, or PivOM protected 3’-hydroxyl group. This huge difference in stability is not obvious from the prior art of record, see Applicant’s remarks, pg. 11 of 14, last paragraph of the page.
(J) A person having ordinary skill in the art would reasonably believe that oligonucleotides prepared using monomers having a 2’-O-methylphosphoramidite moiety and a 3’-hydroxyl protected within different silyl groups would have similar stability against prolonged base treatment at elevated temperature, see Applicant’s arguments, pg. 11 of 14, last paragraph of the page – pg. 12 of 14, first paragraph of the page.
(K) Beigelman does not cure the above-discussed deficiencies in the combination of Gao and Seela as applied to base claim 1, specifically using a nucleoside monomer of Formula (I) for synthesizing oligonucleotides with 2’→5’ internucleotide linkages, see Applicant’s arguments, pg. 12 of 14, last paragraph of the page – pg. 13 of 14, first paragraph of the page.
With respect to Applicant’s arguments (A)-(G) and (K), the Examiner respectfully notes the new 103 rejections recited below use the combination of Wu and Gao to teach the synthesis of oligonucleotides having at least one nucleoside with a 3’-OH group and a 2’→5’ internucleotide linkage. The Examiner notes particular attention to Scheme III of Wu illustrates the preparation of 2’-5’ dinucleotides as discussed in greater detail in the new 103 rejections below.
With regard to Applicant’s arguments (H)-(J) in particular, the Examiner respectfully notes Table 5, disclosed on pp. 29-30 of the Specification, only demonstrates the stability of silyl protecting groups on the 2’- or 3’-position on the sugar moiety of the nucleoside and does not teach nor suggest the phosphoramidite is protected by a β-cyanoethyl group as argued by Applicant within Arguments (H) and (I) above as evidenced by the Specification in Table 3 on pg. 27, column 7 which recites the structures of 3’-OTBS-U, 3’-OTOM-U, 3’-OTIPS-U, 2’-OTBS-U and 2’-OTOM-U.
Therefore, the Examiner reasonably interprets the prolonged stability of the monomers used to prepare the oligonucleotide as argued by Applicant in view of Table 3 and Table 5 of the Specification supports the argument the TIPS 3’-protected hydroxyl group of the monomer provides increased stability to the nucleoside monomer and not the combination of the TIPS 3’-protected hydroxyl group and the 2’-β-cyanoethyl phosphoramidite moiety as argued by Applicant above.
In addition, the Examiner respectfully notes the Gao reference already discloses increased stability when 2-cyanoethyl is used as a protecting group of phosphates in oligonucleotide synthesis as a known consideration in the prior art, e.g. Gao teaches those skilled in the art will recognize that cyanoethyl moieties are preferred phosphate protecting groups for their stability under oligonucleotide synthesis as discussed in greater detail within the new 103 rejections below.
Additionally, Applicant argues monomers having a 2’-O-methylphosphoramidite moiety and a 3’-hydroxyl group protected with different silyl groups would have similar stability against prolonged base treatment at elevated temperature as disclosed in Applicant’s argument (J) above. The Examiner also respectfully notes Wu teaches a 2’-O-methylphosphoramidite moiety, whereas Gao teaches 2-cyanoethyl phosphoramidites.
Thus, Applicant’s arguments (A)-(K) have been fully considered but are not found persuasive.
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.
(I) Claims 1-2, 4-8, 10-14 and 19-21 are rejected under 35 U.S.C. 103 as being unpatentable over Wu et al. (Published 01 July 1990, The Journal of Organic Chemistry, Vol. 55, Issue 15, pp. 4717-4724, IDS filed 04/30/2024) in view of Gao et al. (Published 03 October 2013, US-20130261026-A1, IDS filed 05/25/2022).
Regarding claims 1-2, 4-8, 10-14 and 19-21, Wu teaches oligoribonucleotide synthesis, see pg. 4717, title.
Wu teaches isomeric dinucleotides with 2’-5’-interlinkages (ApU, CpU, GpU UpU) were prepared with 3’-silylated nucleoside 2’-phosphoramidites (e.g. synthesizing oligonucleotides having one nucleoside with a 3’-OH and a 2’-5’-internucleoside linkage, claim 21, lines 1-2), see abstract.
The Examiner respectfully notes dinucleotides are included within the term oligonucleotide as evidenced by Applicant’s specification which discloses oligonucleotides refers to a nucleic acid molecule (RNA or DNA) for examples of length less than 100, 200, 300, or 400 nucleotides, and as used herein an oligonucleotide also encompasses dinucleotides, see specification, pg. 14, paragraph [0077],
Wu exemplifies a scheme of preparing 2’-5’ dinucleotides depicted as follows,
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605
625
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, see pg. 4720, Scheme III.
Wu teaches in the synthesis of protected dinucleotides 6a-d collidine (250 µL) was added to the solution, followed by the dropwise addition of an aqueous iodine solution (0.1 M, 7/3 water/THF), see pg. 4723, right column, synthesis of protected dinucleotides (5a-d, 6a-d), paragraph 1.
The Examiner respectfully notes compounds 4a-d as discussed above are coupled with the free 5’-hydroxyl group on a silyl protected nucleoside, exemplified as a uridine within Scheme III above, when tetrazole is added as the first reagent and then collidine/I2 (e.g. the weak base and reaction conditions, required in claims 4-6) is added as the second reagent as shown above to produce compounds 6a-d as shown in Scheme III, see Scheme III of Wu above. The Examiner also respectfully notes this step corresponds to the coupling and oxidizing steps as required in claim 1, lines 4-9.
With respect to the limitations of “to form a phosphite triester intermediate”, required in claim 1, lines 6-7 and “to form a protected intermediate”, required in claim 1, lines 8-9; the Examiner reasonably interprets both of these limitations are physical limitations when synthesizing the oligonucleotide as recited in claim 1, line 1.
Since Wu teaches a protected phosphodiester bond within the structure of compounds 6a-d as shown in Scheme III of Wu above, the physical limitations as recited above are met by the teachings of Wu above.
Wu teaches in Scheme I both ribonucleoside 3’-phosphoramidites and 2’-phosphoramidites depicted as,
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494
498
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, see pg. 4717, right column, scheme I.
The Examiner respectfully notes within Scheme I above compound 4c contains a triisopropylsilyl group (TIPS) at the 3’-position of the ribose sugar moiety and a bis(diisopropylamino)methoxyphosphine at the 2’-position of said ribose as shown in Scheme I of Wu above.
The Examiner respectfully notes within Scheme 1 of Wu that compound 4c comprises a N2-phenoxyacetylguanine (e.g. B is a modified nucleobase, required in claim 1, line 15 and claim 21, line 4); R1 is monomethoxytrityl (MMT) (e.g. R1 is a hydroxyl protecting group, required in claim 1, line 16 and claim 21, line 5); R2 is triisopropylsilyl (TIPS), (e.g. R2 is -Si(R4)3, wherein each R4 is isopropyl, required in claim 1, line 17 and line 19 and claim 21, line 6 and line 8); R3 is a methyl diisopropylphosphoramidite (e.g. -P(NR5R6OR7, wherein R5=R6=alkyl, required in claim 1, line 18 and claim 21, line 7 and line 9).
Although, Wu does not teach (a) the nucleoside phosphoramidite monomer has a β-cyanoethyl as R7, required in claim 1, pg. 3 of 14, line 3 and claim 21, line 11; and (b) deprotecting the protected intermediate with a base, wherein said treating with the base is at a temperature of 30°C or higher, see claim 1, lines 10-11.
However, in the same field of endeavor of oligoribonucleotide synthesis, with respect to limitations (a)-(b), Gao teaches oligonucleotide synthesis and purification on solid supports, see title; wherein Figure 7 presents a schematic depiction of the synthesis of an exemplary oligonucleotide, see paragraph [0034] and Sheet 7, Fig. 7. Gao teaches the term “oligonucleotide” as used herein is defined as a molecule comprising two or more deoxyribonucleotides or ribonucleotides (e.g. the number of nucleotides, required in claims 19-20), see paragraph [0050].
Gao teaches phosphate groups are usually protected as 2-cyanoethyl phosphoramidites, see paragraph [0097]; and those skilled in the art will recognize that cyanoethyl moieties are preferred phosphate protecting groups for their stability under oligonucleotide synthesis and their ease of removal with ammonia or methylamine (e.g. methylamine, required in claim 1, line 9 and claim 10), see paragraph [0092].
Gao teaches nucleosides with the 3’-O protecting group of t-butyldimethylsilyl (TBDMS) or other protecting groups used for 3’-O protection of ribonucleotides, see paragraph [0010] and [0011].
Gao teaches protective groups are easily removed after completion of the oligonucleotide synthesis by treatment with a concentrated solution of ammonium hydroxide (e.g. deprotecting with ammonium hydroxide, required in claim 1, line 9 and claim 10), see paragraph [0096].
Gao teaches removal of protective groups from the nucleobases and the phosphate backbone where the process usually takes about 24 hours at room temperature or about 6 hours at 55°C (e.g. the temperature of the base, required in claim 11, line 2; and treating time with the base, required in claims 13-14), see paragraph [0097].
Gao exemplifies a deoxyribonucleotide is linked through thioate phosphate (PS) bonds, where PS bonds form in regular DNA or DNA chemical synthesis when the oxidation step employs 3H-1,2-benzodithiol-3-one 1,1-dioxide (BDTD) for sulfurizing phosphite triesters formed from coupling of phosphoramidites (e.g. the sulfurizing agent required in claim 1, claim 7 and claim 8), see paragraph [0017].
Gao teaches the oligonucleotide synthesis used an automated DNA synthesizer (e.g. the synthesizer, required in claim 2), see paragraph [0118].
With respect to the limitation of “treating with the base is at a temperature of 35°C”, required in claim 12; the Examiner reasonably interprets this limitation to be a physical limitation of the deprotection reaction using the base as recited in claim 1, from which claim 12 depends.
Therefore, since Gao teaches removal of the protecting groups from the nucleobases and phosphate backbone at room temperature for 24 hours or at 55°C for 6 hours it would have been well within the scope of the artisan through routine experimentation to optimize the amount of time required for deprotection by optimizing the temperature at which the deprotection takes place, because the Examiner respectfully notes Gao teaches the amount of time required for deprotection changes as the temperature of the deprotection reaction changes. Therefore, the teachings of Gao in view of the interpretation above make obvious instant claim 12.
Moreover, MPEP 2144.05(II)(A) states “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the invention’s effective filing date to have incorporated the teachings of Gao particularly with respect to limitation (a) in substituting the methyl protected phosphoramidite taught by Wu above for the 2-cyanoethyl protected phosphoramidite taught by Gao above as within the scope of the artisan as a simple substitution of one known element for another in the method of oligonucleotide synthesis to yield predictable results.
One of ordinary skill in the art would have been particularly motivated to make the substitution as discussed above because Gao explicitly teaches phosphate groups are usually protected as 2-cyanoethyl phosphoramidites and that 2-cyanoethyl is a preferred phosphate protecting group because of its stability under oligonucleotide synthesis as discussed above. One of ordinary skill in the art would have had a reasonable expectation of success to have made the substitution as discussed above as both Wu and Gao are drawn to synthesis of oligonucleotides as discussed above.
With respect to limitation (b), it would have been prima facie obvious to one of ordinary skill in the art at the invention’s effective filing date to have incorporated limitation (b) within the method of Wu above as within the scope of the artisan as combining prior art elements according to known methods to yield predictable results.
One of ordinary skill in the art would have been motivated to deprotect the silyl protecting groups from the synthesized oligonucleotide of Wu, exemplified as a dinucleotide in Scheme III of Wu as discussed above. One of ordinary skill in the art would have had a reasonable expectation of success of incorporating limitation (b) as taught by Gao into the method of Wu discussed above, because both Wu and Gao use silyl protecting groups at the 3’-OH position of the sugar moiety of the nucleoside; both particularly teach TMBDS and other silyl protecting groups; and wherein Wu specifically teaches both TMBDS and TIPS protecting groups at the 3’-OH position of the ribose sugar moiety as discussed above.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have included the teachings of Gao into the method of Wu as discussed above for the reasons discussed above. One of ordinary skill in the art would have been motivated to conduct oligoribonucleoside synthesis by synthesizing oligonucleotides as taught by both Wu and Gao above, for example the dinucleotides exemplified and taught by Wu above.
One of ordinary skill in the art would have had a reasonable expectation of success of incorporating the teachings of Gao into the method of Wu, because both Wu and Gao are drawn to using silyl protecting groups and protected phosphoramidites for oligonucleotide synthesis as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the teachings of the prior art.
(II) Claims 15-18 are rejected under 35 U.S.C. 103 as being unpatentable over Wu et al. (Published 01 July 1990, The Journal of Organic Chemistry, Vol. 55, Issue 15, pp. 4717-4724, IDS filed 04/30/2024) and Gao et al. (Published 03 October 2013, US-20130261026-A1, IDS filed 05/25/2022) as applied to claims 1-2, 4-8, 10-14 and 19-21 above, and further in view of Beigelman et al. (Published 29 August 2002, US-20020120129-A1, IDS filed 05/25/2022).
Wu and Gao address claims 1-2, 4-8, 10-14 and 19-21 as written above. Although, Wu and Gao do not teach treating with a deprotecting reagent effective to convert the TIPS-protected hydroxyl group to a free hydroxyl group, required in claims 15-18.
However, in the same field of endeavor of protection/deprotection using triisopropylsilyl groups for synthesizing nucleosides, Beigelman teaches methods for the chemical synthesis of nucleosides and derivatives thereof, see abstract. Beigelman teaches silyl deprotection of the invention for example of the 3' hydroxyl of a nucleoside is performed with an acid, a fluoride source, or a combination thereof, for example HF/pyridine (e.g. the deprotecting reagent, required in claims 16-17), see paragraph [0375]; and defines “silylation” to include tert-butyldimethylsilyl (TBDMS) and triisopropylsilyl (TIPS), see paragraph [0067].
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have substituted the ammonium hydroxide deprotecting reagent as taught by Gao above for the HF/pyridine deprotecting reagent as taught by Beigelman above as within the scope of the artisan as a simple substitution of one known element for another according to known methods of deprotection of silyl groups to yield predictable results.
One of ordinary skill in the art would have been motivated to substitute the ammonium hydroxide deprotecting reagent as taught by Gao for the HF/pyridine deprotecting reagent as taught by Beigelman in order to deprotect the silyl protecting groups from the synthesized oligonucleotide of Wu above.
One of ordinary skill in the art would have had a reasonable expectation of success to have substituted the ammonium hydroxide deprotecting reagent taught by Gao for the HF/pyridine deprotecting reagent taught by Beigelman in the method of Wu above, as both Wu and Beigelman use both tert-butyldimethylsilyl (TBDMS) and triisopropylsilyl (TIPS) as protecting groups of the 3’-hydroxyl of nucleosides as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
Conclusion
No claims are allowed in this action.
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/JARET J CREWS/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691