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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 21 Aug. 2026 has been entered.
Claims 1-5 and 11-28 are currently pending. Claims 12, 16-18 and 22-25 are withdrawn.
Claims 1-5, 11, 13-15, 19-21 and 26-28 are considered here with respect to the elected species of a base protecting moiety on the 3’O-blocked nucleoside as the elongation condition that prevents hydrogen bonding or base stacking; deoxyguanosine with an acetyl group on the 2’-nitrogen as the 3’O-blocked nucleoside; and DMSO as the denaturation agent.
Any rejection not reiterated herein has been withdrawn.
Response to Arguments
Applicant's arguments filed 21 Aug. 2026 have been fully considered but they are moot in view of the new grounds of rejection below.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 2-5, 11, 13, 15 and 19-21 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 recites “a base protecting moiety attached to its base to prevent hydrogen bonding”. It is unclear whether the base protecting moiety being referred to is the same as or distinct from the one recited in claim 1 (it appears that claim 2 was not amended in accordance with claim 1 after limitations reciting a base protecting moiety were added to claim 1). The rejection can be overcome be amending claim 2 to recite “the base protecting moiety”. It is also noted that in the event that claim 2 is amended to recite “the base protecting moiety”, claims 3-5 would be inconsistent with the limitations in the current version of claim 1 indicating the sites of attachment for the base-protecting moiety.
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.
Claims 1-5, 11, 13-15 and 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of US20190078126 to Baiga et al. in view of US20190112627 to Arlow et al. (previously cited), as evidenced by (in the case of claims 26-27) Kankia, Origins of Life and Evolution of Biospheres 51.3 (2021): 273-286.
Regarding claim 1, Baiga teaches a method for synthesis of a polynucleotide having a predetermined/desired sequence, comprising: (a) providing an initiator oligonucleotide having a free 3'-hydroxyl; and (b) repeating until the polynucleotide is synthesized cycles of (i) under elongation conditions, contacting the initiator or an elongated fragment thereof with a 3'-O-blocked nucleoside triphosphate (3’O-NTP) and, separately, a terminal deoxynucleotidyl transferase (TdT) so that the initiator or fragment thereof is elongated by incorporation of the 3'-O-NTP, and (ii) deblocking the 3'-O-blocked elongated fragment to form an elongated fragment having free 3'-hydroxyls, until the polynucleotide is formed (entire doc, including [0013]-[0039]; [0045]-[0065]; [0072]-[0118]; Examples). Baiga teaches that the 3’O-NTPs can comprise a modified base, e.g. guanosine, and that such modified bases can be modified at the 2-nitrogen and can be modified with an acetyl group ([0033]; [0129]).
Regarding claim 14, Baiga teaches that the initiator can be attached to a solid support ([0005]; [0015]-[0020]; [0024]-[0025]; [0047]; [0076]; claims 1-4, 21).
Regarding claims 19-21, Baiga teaches that the 3’O blocking group can be an azidomethyl (CH2-N3) group or an amino (NH2) group ([0030]; [0055]).
Claims 1-5, 11, 13-15 and 26-28 differ from Baiga in that: the 3’O-NTPs comprise a base-protecting group which is guanosine with an acetyl on the 2-nitrogen (claims 1, 28); the base-protecting moiety prevents H-bonding (claim 2); the base-protecting moiety is base labile (claim 11); the method comprises removing the base-protecting moiety from the 3’O-NTP (claim 13); initiator comprises a base-cleavable nucleoside and the base protecting moiety is base labile, and wherein said removing comprises treating said polynucleotide with base so that the base protecting moiety and the base- cleavable nucleoside are cleaved in the same reaction (claim 15); the predetermined sequence comprises a tract of guanosine that may form a G-quadruplex secondary structure (claim 26); and the base protecting moiety disrupts the formation of the G-quadruplex secondary structure (claim 27).
Regarding claims 1, 2 and 28, Arlow teaches a method for synthesis of a polynucleotide that is substantially similar to that of Baiga, comprising: (a) providing an initiator oligonucleotide having a free 3'-hydroxyl; and (b) repeating until the polynucleotide is synthesized cycles of (i) under elongation conditions, contacting the initiator or an elongated fragment thereof with a 3'-O-blocked nucleoside triphosphate (3’O-NTP) and a terminal deoxynucleotidyl transferase (TdT) so that the initiator or fragment thereof is elongated by incorporation of the 3'-O-NTP, and (ii) deblocking the 3'-O-blocked elongated fragment to form an elongated fragment having free 3'-hydroxyls, until the polynucleotide is formed (entire doc, including [0053]-[0054]; [0061]-[0067]; [0071]-[0077]; [0129]-[0130]; [0142]). Arlow teaches that the 3’O-NTPs can further comprise a removable moiety that inhibits base-pairing and 3'-secondary structure formation (i.e. hydrogen bonding) ([0142]). The moiety can be an acetyl group attached to the exocyclic amine N2 position of guanosine ([0142]).
Regarding claim 11, Arlow teaches that the N2-acetyl base-protecting group can be removed via ammonia treatment (i.e. is base labile) ([0135], [0138], [0142])
Regarding claim 13, Arlow teaches that the method can comprise a step of removing the N2-acetyl base-protecting group ([0135], [0138], [0142]).
Regarding claim 15, the recitation that the initiator comprises a “base-cleavable nucleoside” is construed herein to mean that the initiator comprises a nucleoside having a base-cleavable group at any point in the structure, e.g. on the base. It would have been obvious to one of ordinary skill in the art to use an initiator comprising the same base-protecting group used in the 3’O-NTPs for the same purpose taught by Arlow of inhibiting unwanted base-pairing and 3'-secondary structure formation (i.e. hydrogen bonding) during polynucleotide extension. It would have further been obvious that the step of removing the base-protecting groups that resided on the 3’O-NTPs would also remove the same groups on the initiator sequence, and one would have been motivated to remove the base protecting groups from the entire polynucleotide to give a polynucleotide having a consistent/homogeneous structure.
Regarding claim 26-27, Arlow teaches that modified guanosine with the N2-acetyl base-protecting group can "prevent base pairing or the formation of undesirable secondary structure during synthesis" and that "[s]imilar modifications were shown to significantly enhance the rate of dGTP homopolymer synthesis using TdT" ([0142]). It would have thus been obvious to carry out the method of Arlow to synthesize a polynucleotide having a polyG tract (e.g., a polyG homopolymer) using the modified guanosine to inhibit any secondary structure formation (which would include G-quadruplex formation). Kankia evidences that polyG homopolymers can form G-quadruplex secondary structures that have H-bonding involving the exocyclic (N2) nitrogen of guanosine (Kankia, under Properties of G3N Quadruplex; Fig. 1), and thus the modified guanosine of Arlow would disrupt any such quadruplex secondary structure.
It would have been obvious to one of ordinary skill in the art at the time the invention was made to use the method of Baiga to for template-independent synthesis of a polynucleotide using modified 3’O-NTPs wherein the modified 3’O-NTP comprise a base-protecting group comprising an guanosine N2-acetyl group as taught by Arlow because it would have been obvious to combine prior art elements according to known methods to yield predictable results. One of ordinary skill would have been motivated to use a modified 3’O-NTP comprise a base-protecting group comprising an guanosine N2-acetyl group in the method of Baiga because Arlow teaches that such a protecting group prevents formation of undesirable secondary structure during synthesis. Using a modified 3’O-NTP with a base-protecting group comprising an guanosine N2-acetyl group in the method of Baiga would have led to predictable results with a reasonable expectation of success because Arlow teaches that such a protecting group can be used in a substantially similar template-independent TdT-catalyzed polynucleotide synthesis method. Moreover, while the method of Arlow is distinguishable from that of Baiga in that Arlow utilizes a tethered TdT/3’O-NTP construct, one of ordinary skill would have recognized that the base protecting group on the growing polynucleotide functions independently of the TdT to prevent unwanted secondary structure in the growing polynucleotide chain.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ROBERT J YAMASAKI whose telephone number is (571)270-5467. The examiner can normally be reached M-F 930-6 PST.
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/ROBERT J YAMASAKI/Primary Examiner, Art Unit 1657
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