DETAILED ACTION
CONTINUED EXAMINATION UNDER 37 CFR 1.114 AFTER FINAL REJECTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 of RCE and amendment filed on October 9, 2025 have been entered. The claims pending in this application are claims 36-43 and 48-52 wherein claim 43 has been withdrawn due to the restriction requirement mailed on February 15, 2024. Claims 36-42 and 48-52 will be examined.
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.
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 36-42 and 48-52 are rejected under 35 U.S.C. 103 as being unpatentable over Vander Horn et al., (US 8,632,975 B2, published on January 21, 2014) in view of Frey et al., (Chemistry & Biology, 3, 393-403, 1996).
This rejection is modified from the rejection under 35 U.S.C. 103 mailed on April 9, 2025.
Regarding claim 36-38, 42, 48, 51, and 52, Vander Horn et al., teach (i) an examination step that comprises detecting a ternary complex stabilized by a cation (ie., a concentration of cation at which nucleotide polymerization by the polymerase is inhibited such as Ca2+) in an examination reaction mixture, wherein the examination reaction mixture further comprises unlabeled reversible terminator nucleotides, wherein the ternary complex comprises polymerase, a primed template nucleic acid, and a next correct nucleotide (ie., a first type of nucleotide), wherein the examination step does not comprise a chemical incorporation of the next correct nucleotide molecule into a primer of the primed template nucleic acid molecule (ie., transiently binding the first type of nucleotide to the polymerase in a template-dependent manner without polymerizing the transiently bound nucleotide at the polymerization initiation site by the polymerase), and wherein the cation is non-catalytic; and (ii) a subsequent incorporation step that comprises replacing the next correct nucleotide from the examination step and incorporating another nucleotide into the 3’-end of the primer of the primed template nucleic acid molecule, wherein the incorporation step comprises replacing the examination reaction mixture with an incorporation reaction mixture comprising a catalytic metal ion (eg., Mg2+) as recited in claim 36 wherein the next correct nucleotide of the ternary complex detected in the examination step is a labeled nucleotide as recited in claim 37, the labeled nucleotide comprises a fluorescent label as recited in claim 38, only the next correct nucleotide of the ternary complex comprises a detectable label as recited in claim 42, the catalytic metal ion is magnesium as recited in claim 48, repeating the examination step prior to the incorporation step as recited in claim 49, and repeating the examination and incorporation steps for a number of cycles as recited in claim 50 (see columns 3, 9-11, 30, 31, 52, and 53, and Example 9 in columns 106 and 107).
Regrading claims 39-41, since Vander Horn et al., teach to incorporate a terminator nucleotide onto a primer of a primed template nucleic acid molecule in a template-dependent manner wherein the terminator nucleotide is a chain terminator nucleotide or reversible terminator nucleotide (see columns 43, 44, and 62) and claims 32, 34, and 47 from Vander Horn et al., teach that the first type and the second type of nucleotide are different types and the first type of nucleotide includes an extrinsic fluorescent label and the second type does not, in view of above teachings from Vander Horn et al.,, one having ordinary skill in the art would have been motivated to use a reversible terminator nucleotide taught by Vander Horn et al., as the nucleotide incorporated in the incorporation step as recited in claim 39 wherein the reversible terminator nucleotide is an unlabeled reversible terminator nucleotide that does not include a detectable fluorophore as recited in claim 40 and the next correct nucleotide of the ternary complex detected in the examination step is a labeled nucleotide as recited in claim 41.
Vander Horn et al., do not disclose that a cation is trivalent lanthanide cation as recited in claim 36 wherein the trivalent lanthanide cation inhibits polymerization as recited in claim 49 and the trivalent lanthanide cation is Europium cation as recited in claim 50.
Frey et al., teach that Eu3+ serves as a competitive inhibitor of Mg2+-induced polymerase and exonuclease activity (see abstract) and is considered as a non-catalytic cation.
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made to have performed the methods recited in claims 36, 49, and 50 by substituting the non-catalytic cation such as Ca2+ taught by Vander Horn et al., from a trivalent lanthanide cation such as Eu3+ in view of the prior arts of Vander Horn et al., and Frey et al.. One having ordinary skill in the art would have been motivated to do so because Frey et al., have shown that Eu3+ serves as a competitive inhibitor of Mg2+-induced polymerase and exonuclease activity (see abstract) and is considered as a non-catalytic cation, and the simple substitution of one kind of non-catalytic cation (ie., the non-catalytic cation taught by Vander Horn et al., such as Ca2+) from another kind of non-catalytic cation (ie., the non-catalytic cation taught by Frey et al., such as Eu3+) during the process of performing the methods recited in claims 36, 49, and 50, in the absence of convincing evidence to the contrary, would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made since the non-catalytic cation taught by Vander Horn et al., such as Ca2+ and the non-catalytic cation taught by Frey et al., such as Eu3+ are used for the same purpose (ie., inhibiting Mg2+-induced polymerase activity) and are exchangeable. One having ordinary skill in the art at the time the invention was made would have a reasonable expectation of success to perform the methods recited in claims 36, 49, and 50 by substituting the non-catalytic cation taught by Vander Horn et al., such as Ca2+ from a trivalent lanthanide cation such as Eu3+ in view of the prior arts of Vander Horn et al., and Frey et al., in order to substitute a catalytic metal ion with a trivalent lanthanide cation in step (i) of claim 36 and inhibit polymerization of a primed template nucleic acid in step (i) of claim 36 using the trivalent lanthanide cation.
Furthermore, the motivation to make the substitution cited above arises from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose. Support for making the obviousness rejection comes from the M.P.E.P. at 2144.06, 2144.07 and 2144.09.
Also note that there is no invention involved in combining old elements is such a manner that these elements perform in combination the same function as set forth in the prior art without giving unobvious or unexpected results. In re Rose 220 F.2d. 459, 105 USPQ 237 (CCPA 1955)
Response to Arguments
In page 5, second paragraph bridging to page 6, first paragraph of applicant’s remarks, applicant argues that “[A]s amended, claim 36 recites ‘(i) an examination step that comprises detecting a ternary complex stabilized by a trivalent lanthanide cation in an examination reaction mixture, wherein the examination reaction mixture further comprises unlabeled reversible terminator nucleotides.’ Neither Vander Horn nor Frey discloses an examination reaction mixture comprising a trivalent lanthanide cation and unlabeled reversible terminator nucleotides to stabilize a ternary complex. As such, neither reference alone or in combination would disclose or suggest to one of skill in the art to provide these two components in the same reaction mixture. For at least the reasons described above, claim 36 as amended is non-obvious over the cited art, thus Applicant respectfully submits that claims 35-43 and 48-52 are also non-obvious by virtue of their dependencies from claim 36”.
The above arguments have been fully considered but they are not persuasive toward the withdrawal of the rejection. Although applicant argues that “[N]either Vander Horn nor Frey discloses an examination reaction mixture comprising a trivalent lanthanide cation and unlabeled reversible terminator nucleotides to stabilize a ternary complex”, since Vander Horn et al., teach an examination step that comprises detecting a ternary complex stabilized by a cation (ie., a concentration of cation at which nucleotide polymerization by the polymerase is inhibited such as Ca2+) in an examination reaction mixture (see columns 9-11), the trivalent lanthanide cation recited in claim 36 can be Eu3+ (see claim 50 of this instant application), Frey et al., teach that Eu3+ serves as a competitive inhibitor of Mg2+-induced polymerase and exonuclease activity (see abstract), and the same trivalent lanthanide cation must have the same function, after Ca2+ taught by Vander Horn et al., is substituted from Eu3+ taught by Frey et al., by one having ordinary skill in the art at the time the invention was made, Eu3+ from Frey et al., should have the same function of Eu3+ in claims 36 and 50 and has an ability to work in the stabilization of a ternary complex. Furthermore, since Vander Horn et al., teach that “[P]rovided herein are systems, comprising various compositions useful for practicing the nucleotide transient-binding methods. The compositions include: labeled nucleotides, non-incorporatable nucleotides, terminator nucleotides, different polymerases suitable for transient binding of the nucleotide or for incorporating nucleotides, template molecules (i.e., template molecules), polymerization initiation sites, nanoparticles, reporter moieties, and solid surfaces” and “[T]he nucleotides can be operably linked to a reporter moiety (e.g., labeled nucleotides) or can be un-labeled nucleotides. The nucleotides also include non-incorporatable nucleotides, and terminator nucleotides (e.g., chain terminating nucleotides and reversible terminator nucleotides)” (see columns 52 and 53), the examination reaction mixture taught by Vander Horn et al., further comprises unlabeled reversible terminator nucleotides as recited in claim 36.
Conclusion
No claim is allowed.
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/FRANK W LU/
Primary Examiner, Art Unit 1683
February 23, 2026