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 .
Status of The Claims
Claim(s) 19-24 and 30-33 is/are pending and are under examination.
Claim(s) 1-7 and 25-29 is/are withdrawn.
Claim(s) 8-18 is/are canceled.
Applicant’s election without traverse of Group IV, which includes Claims 19-33 in the reply filed on 05/18/2026 is acknowledged.
Claim(s) 1-7 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected method for tagging a nucleic acid with an oligonucleotide and method for primer-mediated nucleic acid library generation, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05/18/2026.
Claim(s) 25-29 withdrawn from further consideration as being drawn to non-elected species. Applicant elected the species in which “X is H; Qis H; Z is alkyl; Y is a combination of amide, ether and alkynyl groups; and CXN is a heterocyclic group containing three nitrogen atoms and no substitution.” Applicant further confirms “claims 19-24 and 30-33 read on the elected species”.
Claim Rejections - 35 USC § 112(b)
Claim(s) 19-24 and 30-33 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, 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 19 recites “or heterocyclic group containing from one to four N, 0, S atom(s) or a combination thereof where the heterocyclic group is optionally substituted at carbon, nitrogen or sulfur atom(s).”, where in the claim fails to identify the substituent group(s). The claim only identifies the possible atoms on heterocycle at which substitution may occur, but does not define the scope of the substituent.
Claims 20-24 and 30-33 depend from claim 19 and are therefore similarly rejected.
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.
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.
Becker et al. and Ayer et al.
Claim(s) 19-22, 24, and 30-33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Becker et al. (US20130171631A1) in view of Ayer et al. (WO2017202917A1).
Regarding claim 19-22, Becker discloses an oligonucleotide-tethered nucleotide of Formula (A) (e.g. A Nuc-Macromolecule comprises composition that has structure of (Nuc-Linker)n-Marker. Wherein: Nuc is a nuc-component; Linker is a linker component; Marker is a marker component; and n is a positive integer from 1 to 10000 [¶0086 and Fig. 1-3])
wherein NB is a nucleobase; X is H; Q is H (e.g. Nuc component of Nuc macromolecule is natural substrate for polymerases such as dNTP and their analogues, which may include different variations of the sugar part of the nucleotides such as ribose, 2′-deoxyribose or 2′,3′-dideoxyribose [¶0090 and ¶0100]).
Oligo is an oligonucleotide of 3 to 100 nucleotides; (e.g. marker component can comprise one or several domains, such as a target domain, anchor domain, and/or signal domain[¶0086]. Target domain can be nucleic acid chains of lengths 3 to 6, 6 to 9, 9 to 12, 12 to 14, 14 to 16, 16 to 18, 18 to 20, 20 to 25, 25 to 30, 30 to 40, 40 to 50, 50 to 60, 60 to 70, 70 to 100 nucleobases [¶0177]. Anchor domain can be nucleic acid chains of lengths 8 to 10, 10 to 12, 12 to 14, 14 to 16, 16 to 18, 18 to 20, 20 to 25, 25 to 30, 30 to 40, 40 to 50, 50 to 60, 60 to 70, 70 to 100 nucleotides [¶0221]).
Regarding the claimed Z and Y linker components, Becker discloses the linker components links the nucleotide to marker component. Becker also teaches suitable coupling units include alkyl, alkenyl, , alkynyl, ether, amide, ester, thioether, disulfide, and related linking groups, including structures containing —NH—, —O—,—CO—NH—, —NH—CO—, —CO—O—,—(CH2)n—, —C≡C—, and combination thereof. [¶0538]
Regarding the claimed CXN component, Becker discloses nuc macromolecules can be synthesized using click chemistry and expressly discloses that azide and alkyne reacting groups can be introduced at various positions of a nucleotide (e.g. at the base or sugar) or an oligonucleotide (e.g. at the 3′ end or 5′ end or in the internal positions). The azide-alkyne click reaction yields 1,2,3-triazole ring, i.e. the elected unsubstituted three nitrogen heterocycle [¶1152-1158].
According, Becker teaches using alkyl, ether, amide, and alkynyl containing linker components between a nucleotide and an oligonucleotide/marker. Becker also teaches using alkyne/azide click chemistry to couple such components. However, Becker does not disclose the particular order arrangement of the elected linker as Z-CXN-Y, wherein Z is alkyl, CXN is an unsubstituted three nitrogen heterocycle, and Y is combination of amide, ether, and alkynyl group.
Ayer discloses the tagged multi-nuclei compounds having a linker structure R1-LB-X-LA- R2, wherein R1 and R2 maybe the nucleotide and the tag, X is a chemical linker moiety formed by reaction click reaction of linker forming groups, and LA and LB are chemical linkers/spacers between the nucleotide or the tag and their linker forming groups. Ayer teaches X may be a triazole (e.g. WVc [table 1]) formed by a click reaction between an azide linker forming group (e.g. WVa [table 1]) and an alkyne linker forming group (e.g. XVb [table 1]), shown below. LA and LB spacers/liners on both sides of X may independently include linear (C1-C12) alkyl, amide, ether, and alkyne, moieties etc. [¶0070-0079].
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366
1386
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As of the application’ s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to use Ayer’s triazole containing click linker in Becker’s nucleotide conjugate because Becker already teaches azide/alkyne click coupling for nucleotide and oligonucleotide components, while Ayer provides a known structurally defined linker arrangement for same type of covalent coupling. Ayer’s linker is applicable even though the linker attachment is through phosphate side of the nucleotide because Becker expressly teaches click chemically reactive groups may be introduced at various nucleotide positions and at various oligonucleotide positions. The chemical function of the linker is independent from the attached point since it still provides a covalent connection between nucleotide and oligonucleotide/marker, and the azide-alkyne cycloaddition predictably forms triazole linkage with alkyl, amide, ether, and/or alkyne spacer groups providing distance, flexibility, or other purposes. The combination represents applies a known structural organization of linkers/spacers to Becker’s already disclosed nucleotide to oligonucleotide tethering system for the same covalent tethering purpose. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (MPEP § 2143).
Regarding claim 24, Becker further discloses linker can be introduced into various positions of an oligonucleotide/marker (e.g. at 5′ phosphate end, i.e. (C1)) [¶1158]. marker can comprise one or several domains, such as a target domain, anchor domain, and/or signal domain[¶0086]. Target domain can be nucleic acid chains of lengths 3 to 6, 6 to 9, 9 to 12, 12 to 14, 14 to 16, 16 to 18, 18 to 20, 20 to 25, 25 to 30, 30 to 40, 40 to 50, 50 to 60, 60 to 70, 70 to 100 nucleobases [¶0177]. Anchor domain can be nucleic acid chains of lengths 8 to 10, 10 to 12, 12 to 14, 14 to 16, 16 to 18, 18 to 20, 20 to 25, 25 to 30, 30 to 40, 40 to 50, 50 to 60, 60 to 70, 70 to 100 nucleotides [¶0221])
Regarding claim 30, Becker further discloses the nucleobase is adenine, 7-deaza-adenine, cytosine, guanine, 7-deazaguanine, thymine, uracil, or inosine. [¶0167]
Regarding claim 31, Becker further discloses the nucleobase is a pyrimidine that is tethered to the oligonucleotide at the 5th position of the nucleobase. (e.g. If the coupling position of nuc component is on the base, then the following positions are preferable: position 4 or 5 for pyrimidine bases [¶0107])
Regarding claim 32, Becker further discloses the nucleobase is a purine that is tethered to the oligonucleotide at the 7th position of the nucleobase. (e.g. If the coupling position of nuc component is on the base, then the following positions are preferable: positions 6,7,8 for purine bases. [¶0107])
Regarding claim 33, Applicant’s specification described adapter sequence in NGS context, where the sequence can mediate binding to a sequencing platform (e.g. P5 and P7 in Illumina platforms) [¶0257]. Becker discloses this limitation by teaching anchor domain are nucleic acid chains, such as oligonucleotides, which can hybridize to the complementary partner immobilized on a base/solid phase [0222].
Becker et al., Ayer et al., and Hansen et al.
Claim(s) 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Becker et al. (US20130171631A1) in view of Ayer et al. (WO2017202917A1) and Hansen et al. (US10577388B2).
Regarding claim 23, Becker discloses the oligonucleotide tethered nucleotide can be present as in form of acid or as salts (e,g, sodium, potassium, ammonium or lithium can be used as an ion). However, Becker does not explicitly list quaternary ammonium salt [¶1073].
Hansen discloses oligonucleotides may be solubilized using lipophilic salts comprising lipophilic cations include quaternary ammonium cations having alkyl substituents. Hansen further identifies quaternary ammonium cations (e.g. cetyltrimethylammonium (CTA) and tetrabutylammonium(TEA)), and discloses the molar equivalents of the lipophilic cation used based on phosphorus internucleoside linkage (e.g. phosphodiester, phosphorothioate or phosphorodithioate) present in the oligonucleotide [column 6, line 28-column 7, line 5].
As of the application’ s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to substitute Becker’s salts (e,g, sodium, potassium, ammonium) for Hansen’s quaternary ammonium salt because Hansen teaches lipophilic quaternary ammonium cation can improve solubilization of the oligonucleotide in the organic solvent by forming lipophilic salt with the phosphate containing oligonucleotide [column 6, line 28-column 7, line 5]. Further, In example 3, Hansen performs conjugation using oligonucleotide sodium salt in aqueous and reports that the system need least a two times molar excess of NHS ester to achieve high conversion, meaning inefficient use of reagents. In example 4, Hansen performs similar conjugation using oligonucleotide CTA salt in DFM and states that the conversion correspond to the molar equivalent used and was “a significant improvement compared to example 3” [column 21, line 9-column 22, line 10]. Hence, selecting quaternary ammonium cation for Becker’s anionic phosphate containing nucleotide/oligonucleotide conjugate would have been a predictable modification motivated by improve organic solvent solubility and conjugate performance. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (MPEP § 2143).
Conclusion
No claims are allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Khai Quynh Tien Pham whose telephone number is (571)272-6998. The examiner can normally be reached M-T, 9-4 ET.
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/KHAI QUYNH TIEN PHAM/Examiner, Art Unit 1684
/JEREMY C FLINDERS/Primary Examiner, Art Unit 1684
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