DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 23 September 2025 has been entered.
This Office Action is in response to Applicant’s Amendment and Remarks filed on 23 September 2025 in which claim 16 was amended to change the scope and breadth of the claims.
Claims 16, 21-27, 32 and 34-45 are pending in the current application. Claims 32 and 43 remain withdrawn as being drawn to a non-elected species. Claims 16, 21-27, 34-42, 44 and 45 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 .
New Rejections
Upon further consideration, and in view of the amendment to claim 16, the rejection of claims 16, 21-27, 34-42, 44 and 45 over Butler et al. in view of Krotz et al. and Reddy et al. is withdrawn in favor of the new/modified rejections below.
Therefore, rejections from the previous Office Action, dated 23 June 2025, have been modified and are listed below.
Response to Arguments
Applicant's arguments filed 23 September 2025 have been fully considered but they are not persuasive.
Applicant contends one of ordinary skill in the art would not have been motivated to modify the teachings of Butler et al. because Butler et al. did not identify any issues during synthesis or purification.
The above argument is not found persuasive. In the modified rejection, one of ordinary skill in the art would have been motivated to optimize the purification method of Butler in view of the teachings of Ellington et al.
Both references identify the need to purify phosphoramidite using dry conditions. As noted in the previous Office Action, Butler et al. teach the preparation of chirally controlled oligonucleotides, wherein the chiral reagent, which was repeatedly co-evaporated with dry toluene and then dissolved in dry acetonitrile (100%), was added dropwise to the reaction mixture (para [00691]).
Furthermore, one of ordinary skill in the art looking to optimize the purification conditions would have been motivated to use dry conditions, since phosphoramidites were well known to be unstable in the presence of water.
Applicants arguments with respect to Krotz and Reddy are moot, as they are no longer relied upon.
Applicant has also pointed to their Specification for showing the yield of the purified compound is improved from 56% to 83% using the claimed composition for purifying compounds falling within formula I.
The above argument is not found persuasive because the results are not commensurate in scope with the present claims. The results are based on using 100% of methanol with 5% TEA. Furthermore, the present claims are directed towards a composition comprising a silica gel pre-treated with a hygroscopic solvent system and phosphoramidite, whereas the alleged unexpected results are based on a method of purification. The method requires pre-treating the silica gel column with 5 column volumes of methanol (not claimed), followed by equilibrating with 5 column volumes of 20% ethyl acetate/hexanes containing 5% TEA.
See MPEP 716.02(d), “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support."
Additionally, the difference between the teachings of Butler et al. and the present claims is not vast. As noted in the OA, Butler et al. teach the claimed phosphoramidite can be purified on a silica gel column. Butler et al. teach a solution of chiral phosphoramidite in dry MeCN. Thus, Butler et al. teach a composition comprising a) silica gel; and b) a phosphoramidite; and Butler et al. also teach a) a hygroscopic solvent system; and b) a phosphoramidite. Butler et al. simply do not teach pre-treating the silica gel with said hygroscopic solvent system.
The practice of pre-treating a purification medium with acetonitrile for the purification of phosphoramidites was a known technique before the effective filing date of the claimed invention, as demonstrated by Wang et al.
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 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.
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 16, 21-27, 34-42, 44 and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Butler et al. (WO 2014/012081, cited in previous Office Action) in view of Ellington et al. (Current Protocols in Nucleic Acid Chemistry, 2000, vol. 1, pp.A-3C, cited in IDS submitted 20 January 2023) and Wang et al. (US Patent Application Publication No. 2003/0017451, cited in IDS submitted 20 January 2023).
Butler et al. teach synthesizing a phosphoramidite compound having a phosphoramidite group at the C3’-OH position; a –DMTr group at the C5’-OH position (reads on R5s is -ODMTr, present claim 23), and a protected nucleobase
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274
198
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(p.422-423, paragraph [00130]). The compound was subjected to column chromatography (i.e. a purification medium) and with a hexane/ethyl acetate (EtOAc) gradient containing a steady concentration of 2% TEA to give the pure compound 208 as a white solid foam. Butler et al. teach repeating the aforementioned purification procedure for the synthesis of compound 219:
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217
182
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(p.428, paragraph [00137]). Butler et al. teach the preparation of monomer 15a:
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293
251
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(p.183), (i.e. the elected species; reads on first compound recited in original claim 28).
Butler et al. teach compound 15a was prepared in a similar manner as 12a (p.233-234, paragraph [00841]-[00842]). With respect to compound 12a, Butler et al. teach purifying the compound on silica gel (p.214, paragraph [00752]). Butler et al. also teach the synthesis of 2’-deoxy derivatives, wherein alternatives to 2’-deoxy include 2’-halogen; 2’-OMe; 2’-CH2CH2OMe (for example, p.244, compound 35A; also see paragraph [00453], [00477]).
Butler et al. teach the purification technique of compound 208 can be applied to other similar phosphoramidite nucleosides having a different functional group at the C2’-position. Butler et al. teach purifying compound 222 having a –OMe at C2’ (p.429, compound 222), compound 234 having a –F at C2’ (p. 434, compound 234), and compound 258 having a -OCH2OCH2CH2CN at C2’ (p.441, compound 258). Butler et al. teach the preparation of chirally controlled oligonucleotides, wherein the chiral reagent, which was repeatedly co-evaporated with dry toluene and then dissolved in dry acetonitrile (100%), was added dropwise to the reaction mixture (para [00691]).
While Butler et al. teach the claimed phosphoramidite can be purified on silica gel, Butler et al. do not expressly disclose wherein purification medium or silica gel are pre-treated with 50% v/v acetonitrile or methanol (present claim 16). Furthermore, while Butler et al. teach a solution of chiral phosphoramidite in dry MeCN, Butler et al. do not expressly disclose them together on a purification medium or with 5-10% triethylamine (present claims 37-39).
Ellington teaches phosphoramidites are sensitive to water contamination, because they are easily hydrolyzed (p.A.3C.19, first col.). Very dry acetonitrile should be used to dissolve the phosphoramidites.
Wang et al. teach purifying crude phosphoramidites by flash chromatography on silica gel columns, pre-conditioned and packed in 10% TEA-acetonitrile (para [0124]). Wang et al. teach these columns were purchased from Merck. The columns were eluted with DCM/EtOAc (dA derivative); hexane/EtOAc (dC derivative); hexane/EtOAc (dT derivative); and EtOAc (dG), (para [0124]-[0128]). The solvents used to elute the columns additionally contained 0.5% TEA.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to pre-treat silica gel with acetonitrile, pack the silica gel into a chromatography column, and load the phosphoramidite on the silica gel.
From the teachings of Ellington et al., one having ordinary skill in the art would have known to avoid contacting phosphoramidites with water to avoid hydrolyzing/degrading the phosphoramidite, and one solution involves using dry acetonitrile.
Both Butler et al. and Wang et al. are concerned with the preparation and purification of nucleoside phosphoramidite derivatives, wherein both methods rely on the use of silica gel loaded into a chromatography column to purify the desired nucleoside phosphoramidite derivatives.
The ordinary artisan would have been motivated to modify the purification method of Butler et al., such that the silica gel column has been pre-conditioned and packed in acetonitrile containing up to 10% TEA as taught by Wang et al., because this was a known technique for purifying nucleoside phosphoramidite derivatives. A silica gel column pre-conditioned with acetonitrile and TEA would further ensure a dry environment for the purification of the phosphoramidite derivatives of Butler et al.
One having ordinary skill in the would have had a reasonable expectation of success because the compounds of Butler et al. are of the same class as those of Ellington and Wang et al., nucleoside phosphoramidite, and the compounds of Butler et al. and Wang et al. are both subjected to purification by silica gel chromatography.
Thus, the claimed invention as a whole is prima facie obvious over the combined teaching of the prior art.
Conclusion
In view of the rejections to the pending claims set forth above, no claim is allowed.
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/BAHAR CRAIGO/
Primary Examiner
Art Unit 1699