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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 January 14, 2026 has been entered.
DETAILED ACTION
3. Claims 31 – 52 are pending in this application. Applicant’s Amendment and Remarks, filed January 14, 2026, is entered, wherein no claim is amended, claims 36, 38 – 42, and 47 are withdrawn, and claims 1 – 30 are canceled.
Claims 31 – 35, 37, 43 – 46, and 48 – 52 are currently examined.
Priority
4. This application is a continuation application of 17/016,992, filed September 10, 2020, which claims benefit of domestic application 62/898,152, filed September 10, 2019.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62/898,152, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The domestic application 62/898,152 does not provide support for the recitations of “no more than 5% of the nucleotide protected by the 3’-O-NH2 is degraded” recited in claim 43, “no more than 3% of the nucleotide protected by the 3’-O-NH2 is degraded” recited in claim 44, “no more than 2% or no more than 1% of the nucleotide protected by the 3’-O-NH2 is degraded” recited in claim 45, “no more than 3% of the nucleotide protected by the 3’-O-NH2 is degraded when the nucleotide comprises a cytosine nucleobase” recited in claim 46, “at least 95% of the nucleotide” recited in claim 48, “at least 97% or at least 98% of the nucleotide” recited in claim 49, and “the method adds the 3’-O- NH2 moiety in place of the 3’-O-oxime moiety to at least 98% of a population of nucleotides having the 3’-O-oxime moiety in no more than 3 hours” recited in claim 50; and the chemical structures except:
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recited in claim 51. Thus, the priority date of claims 43 – 46 and 48 – 51 is September 10, 2020.
Withdrawn Rejections
5. Claims 31 – 35, 37, 43 – 46, and 48 – 52 are rejected in the previous Office Action, mailed July 14, 2025, on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 4 and 6 of U.S. Patent No. 11180520B2. As terminal disclaimer is filed and approved on January 14, 2026, the rejection has been withdrawn.
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 (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 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:
i. Determining the scope and contents of the prior art.
ii. Ascertaining the differences between the prior art and the claims at issue.
iii. Resolving the level of ordinary skill in the pertinent art.
iv. 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.
Claims 31 – 35, 37, 43 – 46, and 48 – 52 are rejected under 35 U.S.C. 103 as being unpatentable over Benner (US20180265537A1, cited in the previous Office Action) in view of Collins et al. (Polymer Chemistry, 2016, Vol. 7, Issue 23, page 3812 – 3826, cited in the previous Office Action).
a. Regarding claims 31 – 35, 37, 43 – 46, and 48 – 52, Benner teaches a composition comprising an aqueous solution containing a molecule having the structure:
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wherein B is
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wherein R is CH3 (claim 1). Benner also discloses the synthesis of the above molecule as follow (fig 2):
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The product triphosphate is released from the support by elution with an aqueous solution of an alkoxylamine. After preferably 90 minutes, the eluate contained the desired triphosphate as the main component of the total nucleotide material. No side products that have a 3’-OH moiety are present (para. [0035]).
However, Benner does not teach the reagent R2-ONH2, wherein the R2 is alkyl with a molecular weight greater than 36 g/mol.
Collins et al. disclose a dynamic chain termination through the addition of a monofunctional hydroxylamine in oxime-based mimics of naturally occurring mycobacterial arabins as shown below (page 17, Fig. 8):
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The scheme above shows the exchanges of O-methyl and O-N=C with O-tert-butyl and O-NH2, respectively.
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the alkoxylamine in the reaction of modifying nucleotide with O-oxime moiety as taught by Benner with the O-tert-butylhydroxylamine used in the above reaction shown in figure 8 in view of Collins et al. because Collins et al. teach the reaction between O-tert-butylhydroxylamine with arabins, wherein arabins contains O-N=C bonds that reacts with O-tert-butylhydroxylamine to yield -ONH2. One would have been obvious to substitute the alkoxylamine with O-tert-butylhydroxylamine because both Benner and Collins et al. disclose the O-N=C moiety on a sugar. The references do not disclose detectable degradation of the product, the degradation level would be expected to be at most negligible and within the claimed upper limit. For claims 48 – 50, the claims recite the consumption of nucleotide comprising 3’-O-oxime moiety and the specific time for achieving the specified consumption of nucleotide comprising 3’-O-oxime moiety. Benner teaches reacting 3’-O-oxime modified nucleotide with an alkoxyamine to produce the corresponding 3’-ONH2 modified nucleotide, and further teaches that the desired nucleotide is obtained as the main component of the nucleotide material after 90 minutes, which is within the claimed time period of no more than 3 hours. Although Benner does not explicitly disclose the consumption of the 3’-O-oxime modified nucleotide, the consumption of 3’-O-oxime modified nucleotide is a result-effective variable for the claimed method. It would have been obvious for one of ordinary skill in the art to adjust the known reaction parameters, including reaction time, concentration of reagents, temperature, and etc, to increase consumption to the desired levels. One of the ordinary skill in the art would have a reasonable expectation of success by substituting the alkoxylamine in the reaction of modifying nucleotide with O-oxime moiety as taught by Benner with the O-tert-butylhydroxylamine used in view of Collins et al. as Benner teaches the production of triphosphate nucleotide and Collins et al. disclose the possible reagent that would react with O-N=C to yield O-NH2 for a predictable result.
Responses to Applicant’s Remarks:
Applicant’s Remarks, filed January 14, 2026, have been fully considered and are found to be no persuasive.
Regarding Benner and Collins et al., Applicant argues that one skilled in the art would not have had a reasonable expectation of success based on the combined teachings of Benner and Collins et al. to synthesize a reversibly terminated nucleotide without generating unwanted side products using the claimed reagent and method because Benner provides no teaching or suggestion of replacing methoxylamine with the claimed reagent and Collins et al. disclose a reaction that produces a side product with -O-NH2 moiety, a terminated yet degraded polymer with an O-tert-butyl moiety, and a monomer with O-tert-butyl moieties. Therefore, one skilled in the art starting with the teachings of Benner to generate no reaction side products would not turn to Collins et al., which clearly teach the production of side products. However, these arguments are not persuasive. Benner teaches converting a nucleotide comprising a 3’-O-oxime moiety to a nucleotide comprising a 3’-O-NH2 moiety by reaction with an alkoxyamine. The proposed modification merely substitutes one known reagent within the alkoxyamine class for another to accomplish the same type of reaction. A statement of replacing methoxylamine in Benner is not necessary because obviousness does not require an explicit substitution instruction in the primary reference. The combination of Benner and Collins et al. is sufficient to provide a rationale for such substitution with a reasonable expectation of success because Benner teaches the conversion of oxime to -ONH2 using alkoxyamine reagent and Collins et al. teach that alternative R-ONH2 reagents of the same class, such as O-tert-butylhydroxylamine, are suitable for reacting with oxime moiety to form a product with -ONH2. Therefore, substituting alkoxyamine with O-tert-butylhydroxylamine would have been an obvious simple substitution of one known reagent for another within the same class to achieve the same reaction, yielding predictable results. For the reaction side products, Benner discloses “no side product” is limited to the absence of detectable nucleotide species comprising a 3’-OH group. It does not refer to the reaction produces no byproducts. One of ordinary skill in the art would still turn to Collins et al. because the combination of Benner and Collins et al., again, is based on the reaction mechanism, wherein both references teach converting oxime to -ONH2. Moreover, the present claims are drawn to a method and do not recite any limitation requiring a product of a particular purity or absence of side products/byproducts. Again, the rejection is based on simple substitution of one known R-ONH2 reagent for another to perform the same oxime-to-ONH2 reaction, which would have been expected to yield the same product. A person of ordinary skill in the art would have reasonably expected the substitution will lead to the same reaction and yield the same product.
Claims 31 – 34, 43 – 46, and 48 – 52 are rejected under 35 U.S.C. 103 as being unpatentable over Benner (US20180265537A1, cited in the previous Office Action) in view of Polyakov et al. (Journal of Physical Organic Chemistry, 1999, Vol. 12, Issue 5, page 357 – 363, Reference included with PTO-892).
b. Regarding claims 31 – 34, 43 – 46, and 48 – 52, Benner teaches a composition comprising an aqueous solution containing a molecule having the structure:
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wherein B is
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wherein R is CH3 (claim 1). Benner also discloses the synthesis of the above molecule as follow (fig 2):
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The product triphosphate is released from the support by elution with an aqueous solution of an alkoxylamine. After preferably 90 minutes, the eluate contained the desired triphosphate as the main component of the total nucleotide material. No side products that have a 3’-OH moiety are present (para. [0035]).
However, Benner does not teach the reagent R2-ONH2, wherein the R2 is alkyl with a molecular weight greater than 36 g/mol .
Polyakov et al. teach the reaction of an O-aryl oximes with O-aryloxyamines:
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wherein the O-aryloxyamine is O-(p-nitrophenyl)hydroxylamine (page 360, Left Col., para. 1), which yields PhONH2 (page 359, Right Col., Scheme 4). The reaction is monitored by 1H NMR by the disappearance of the signals of oxime 6 (page 359, Right Col., para. 2).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the alkoxylamine in the reaction of modifying nucleotide with O-oxime moiety as taught by Benner with the O-aryloxyamine, such as O-(p-nitrophenyl)hydroxylamine, used in the reaction of O-aryl oximes yielding PhONH2 in view of Polyakov et al. because Polyakov et al. teach the reaction between O-aryl oximes with O-aryloxyamines, wherein O-aryl oximes contains O-N=C bonds that reacts with O-aryloxyamine to yield Ph-ONH2. One would have been motivated to substitute the alkoxylamine with O-aryloxyamine, such as O-(p-nitrophenyl)hydroxylamine, because Benner teaches the production of -ONH2 by reacting O-oxime with alkoxyamine and Polyakov et al. disclose the same reaction mechanism using O-(p-nitrophenyl)hydroxylamine as the reagent. O-(p-nitrophenyl)hydroxylamine meets the limitation “R2 has a molecular weight greater than 36 g/mol” as the R2 moiety in O-(p-nitrophenyl)hydroxylamine has a molecular weight of 124 g/mol. The references do not disclose detectable degradation of the product, the degradation level would be expected to be at most negligible and within the claimed upper limit. For claims 48 – 50, the claims recite the consumption of nucleotide comprising 3’-O-oxime moiety and the specific time for achieving the specified consumption of nucleotide comprising 3’-O-oxime moiety. Benner teaches reacting 3’-O-oxime modified nucleotide with an alkoxyamine to produce the corresponding 3’-ONH2 modified nucleotide, and further teaches that the desired nucleotide is obtained as the main component of the nucleotide material after 90 minutes, which is within the claimed time period of no more than 3 hours. Although Benner does not explicitly disclose the consumption of the 3’-O-oxime modified nucleotide, the consumption of 3’-O-oxime modified nucleotide is a result-effective variable for the claimed method. It would have been obvious for one of ordinary skill in the art to adjust the known reaction parameters, including reaction time, concentration of reagents, temperature, and etc, to increase consumption to the desired levels. Moreover, Polyakov et al. teach that the signal of oxime 6 disappears when being monitored by 1H NMR, thereby proving that the oxime 6 reactant has been consumed completely. One of the ordinary skills in the art would have a reasonable expectation of success by substituting the alkoxylamine in the reaction of modifying nucleotide with O-oxime moiety as taught by Benner with the O-aryloxyamine, such as O-(p-nitrophenyl)hydroxylamine, used in the reaction of O-aryl oximes yielding PhONH2 in view of Polyakov et al. as Benner teaches the production of triphosphate nucleotide and Polyakov et al. discloses the possible reagent that would react with O-N=C to yield O-NH2 for a predictable result.
Conclusion
No claim is found to be allowable.
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/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693