DETAILED ACTION
This Office Action is in response to Applicant’s Amendment and Remarks filed on 22 April 2026 in which claims 22 and 44 were amended to correct typographical errors.
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 Claims 32 and 43 remain withdrawn as being drawn to a non-elected species.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 .
Response to Arguments
Applicant's arguments filed 22 April 2026 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. One of ordinary skill in the art would have been motivated to optimize reaction conditions and/or purification methods to increase yield, purity and efficiency, because these are commonly sought goals in organic synthetic chemistry.
Note, Butler et al. teach “A person of ordinary skill in the art would appreciate that the saved steps/transformation could improve the overall efficiency of synthesis, for instance, with respect to yield and product purity” (see para [00564]). Thus, even if Butler et al. did not criticize their own methodology, those skilled in the art of organic chemical synthesis, including oligonucleotide synthesis, would have been motivated to optimize yield, purity and/or overall efficiency. Even small improvements in the yield and purity obtained for each reagent/intermediate is critical since these steps/reagents may be used repeatedly to make a long chain, resulting in larger overall improvements in the synthesis of the oligonucleotide.
Applicant also argues Butler discloses the use of aqueous washes during the isolation and purification of phosphoramidites (Applicant has pointed to para [00130] p.424 of Butler et al.).
The above argument has been considered, but is not found persuasive because aqueous extractions are performed quickly to remove water soluble impurities, wherein the desired compound is soluble in the organic solvent phase.
A compound purified on a silica gel column is in direct contact with the acidic silica gel, and all the solvents present, including water if it were present. In an extraction, the desired compound is soluble/miscible in the organic solvent (not the aqueous phase), which in this case is chloroform, while water soluble impurities are miscible in the aqueous phase, and easily removed.
After performing the solvent extraction, Butler et al. teach drying the chloroform extracts, redissolving it in DCM containing a few drops of triethylamine, then subjecting it to column chromatography with a hexane/EtOAc gradient containing a steady concentration of 2% triethylamine to give pure compound 208 as a white solid foam. The use of a base, triethylamine in the purification method is evidence Butler et al. considered compound 208 to be acid sensitive, since triethylamine is commonly used to prevent degradation from the acidic silica gel (Bickler, cited in PTO-892). It should be noted, water is not present in the purification column described by Butler et al. Thus, while water may be used in an extraction method, it is avoided in silica gel chromatography.
To summarize, Butler et al. teach optimizing reaction conditions and/or purification methods to increase yield, purity and efficiency; and uses a water-free silica gel purification column having triethylamine, which suggests the phosphoramidite is acid sensitive.
With respect to Ellington, Applicant contends the reference discussed the stability of phosphoramidites in the context of oligonucleotide synthesis. Furthermore, Applicant argues Ellington does not teach phosphoramidite instability during purification.
The above argument is not found persuasive. One of ordinary skill in the art would understand that if a compound is susceptible to hydrolysis in the presence of water, such that it must be excluded in the synthetic preparation, it will also need to be excluded in the purification process.
While Applicant has noted Butler and Wang et al. teach performing an extraction with aqueous NaHCO-3, it is not evidence that the compound is stable in water. Water is commonly used in a work-up/extraction with an organic solvent. The desired organic compound has a higher affinity for the organic solvent, while water-soluble impurities are removed. Thus, the organic compound (i.e. the phosphoramidite) is not in contact with the water. And, as noted by Butler et al., purification on silica gel is performed in the absence of water.
Applicant argues Wang does not teach avoiding water, or the benefits of the claimed invention.
Wang et al. was cited for teaching the use of silica gel that had been pre-conditioned with 10% triethylamine in acetonitrile for the express purpose of purifying phosphoramidites.
While the chemical structure of the compounds prepared/purified in Ellington and Wang are different than Butler, they share a phosphoramidite functional group. Furthermore, Ellington expressly teaches phosphoramidites are easily hydrolyzed by water. Thus, one of ordinary skill in the art would have known the phosphoramidite functional group is an important consideration when determining how the compound should be purified. Furthermore, both Butler et al. and Wang et al. teach the use of triethylamine in the solvent system. Thus, they both suggest phosphoramidites are sensitive to the acidic silica gel.
Applicant argues Wang et al. teach the purified phosphoramidites were analyzed by reverse-phase HPLC using a mobile phase consisting of 0.1 M aqueous triethylammonium acetate and acetonitrile.
The above argument is not found persuasive, because the use of water in a post-purification step does not teach away from purifying in the absence of water, as taught by Ellington. Furthermore, this does not teach away from using a pre-conditioned column, as taught by Wang et al., which suggests a column wherein water has been expressly excluded from the silica gel by initially passing 10% TEA-acetonitrile through the column.
Applicant has reiterated that they have shown the yield of the purified compound is improved from 56% to 83% using the claimed composition for purifying compounds falling within formula I. Applicant argues one of ordinary skill in the art could extrapolate the results obtained from methanol to acetonitrile.
The above argument is not found persuasive because the results are directed towards a purification method which requires additional steps to be performed which are not claimed.
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."
Furthermore, the closest prior art expressly teach using acetonitrile during silica gel purification.
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 stable 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.
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
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