DETAILED ACTION
Response to Amendment
Applicant’s response to the office action filed on May 20, 2026 has been entered. The claims pending in this application are claims 36-43 and 48-54 wherein claim 43 has been withdrawn due to the restriction requirements mailed on February 15, 2024. Claims 36-42 and 48-54 will be examined.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
New Matter
Claims 53 and 54 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Newly added dependent claim 53 contains a limitation “the concentration of the one or more monovalent cations is greater than 300 mM” while newly added dependent claim 54 contains a limitation “the concentration of the one or more monovalent cations is from 300mM to 650 mM”. Although the specification describes that “[R]esults from trials conducted using Eu3+ as the stabilizing agent confirmed that good discrimination between ternary and binary complex formation was achievable. FIG. 3A shows results from the KCl titration of trials made 2 mM Eu3+ and 80 mM potassium glutamate, indicating maximal fold discrimination was observed when the added KCl concentration was about 500 mM. However, very good results were obtained when the added KCl concentration was greater than 350 mM (e.g., in the range of from 350 mM to 650 mM). FIG. 3B shows results from the KCl titration of trials made 2 mM Eu3+ and 160 mM potassium glutamate, indicating the fold discrimination plateaued when the added KCl concentration was about 550 mM. However, very good results were obtained when the added KCl concentration was greater than 300 mM (e.g., in the range of from 300 mM to 650 mM). FIG. 3C shows results from the KCl titration of trials made 2 mM Eu3+ and 320 mM potassium glutamate, indicating the fold discrimination substantially plateaued when the added KCl concentration was about 500 mM. However, very good results were obtained when the added KCl concentration was greater than 300 mM (e.g., in the range of from 300 mM to 650 mM). Finally, FIG. 3D shows results from the KCl titration of trials made 2 mM Eu3+ and 640 mM potassium glutamate, indicating the fold discrimination plateaued when the added KCl concentration was about 500 mM. However, very good results were obtained when the added KCl concentration was greater than 300 mM (e.g., in the range of from 300 mM to 650 mM)” and “[R]esults from trials conducted using Tb3+ as the stabilizing agent also confirmed good discrimination between ternary and binary complex formation was achievable. FIG. 4A shows results from the KCl titration of trials made 2 mM Tb3+ and 80 mM potassium glutamate, indicating increased fold discrimination was observed when the added KCl concentration was about 350 mM or greater (e.g., in the range of from 350 mM to 650 mM). FIG. 4B shows results from the KCl titration of trials made 2 mM Tb3+ and 160 mM potassium glutamate, indicating increased fold discrimination when the added KCl concentration was 300 mM or greater (e.g., in the range of from 300 mM to 650 mM). FIG. 4C shows results from the KCl titration of trials made 2 mM Tb3+ and 320 mM potassium glutamate, indicating increased fold discrimination when the added KCl concentration was about 300 mM or greater (e.g., in the range of from 300 mM to 650 mM). FIG. 4D shows results from the KCl titration of trials made 2 mM Tb3+ and 640 mM potassium glutamate, indicating increased fold discrimination was obtained when the added KCl concentration was about 350 mM or greater (e.g., in the range of from 350 mM to 650 mM)” (see paragraphs [0229] and [0230] of the specification or [0231] and [0232] of US 2022/0298553 A1, which is US application of this instant application), nowhere in the specification describes such limitations recited in claims 53 and 54 since paragraphs [0229] and [0230] of the specification suggested by applicant only describe the results from KCl titration of trials made 2 mM Eu3+ or Tb3+ and 80 mM potassium glutamate when KCl concentration is greater than 300 mM or in the range of 300 mM to 650 mM and claims 53 and 54 do not limit that one or more monovalent cations is from KCL and the trivalent lanthanide cation are Eu3+ or Tb3+, and the one or more monovalent cations recited in claims 53 and 54 can be any kind of monovalent cations and the trivalent lanthanide cation recited in claims 53 and 54 can be any kind of trivalent lanthanide cation.
MPEP 2163.06 notes “If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112, first paragraph - written description requirement. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981).” MPEP 2163.02 teaches that “Whenever the issue arises, the fundamental factual inquiry is whether a claim defines an invention that is clearly conveyed to those skilled in the art at the time the application was filed...If a claim is amended to include subject matter, limitations, or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application.” MPEP 2163.06 further notes “When an amendment is filed in reply to an objection or rejection based on 35 U.S.C. 112, first paragraph, a study of the entire application is often necessary to determine whether or not “new matter” is involved. Applicant should therefore specifically point out the support for any amendments made to the disclosure” (emphasis added).
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 48 is 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 48 recites the limitation “the catalytic metal ion” in the claim. There is insufficient antecedent basis for this limitation in the claim because there is no phrase “a catalytic metal ion” in claim 36. Please clarify.
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 49-52 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 February 24, 2026.
Regarding claim 36-38, 42, 51, and 52, Vander Horn et al., teach (i) an examination step that comprises detecting a ternary complex in an examination reaction mixture, wherein the examination reaction mixture further comprises one or more monovalent cations (ie., K+ or Na+), wherein the ternary complex comprises polymerase, a primed template nucleic acid, a cation (ie., a concentration of cation at which nucleotide polymerization by the polymerase is inhibited such as Ca2+), 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 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, repeating the examination step prior to the incorporation step as recited in claim 51 and repeating the examination and incorporation steps for a number of cycles as recited in claim 52 (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 the ternary complex comprises a 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 one non-catalytic cation such as Ca2+ taught by Vander Horn et al., from another non-catalytic cation, 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 Vander Horn et al., have shown that substituting Ca2+ for Mg2+, a catalytic cation, permits a nucleotide binding to a wild-type or mutant polymerase but inhibits nucleotide incorporation (Gangurde et al., Biochemistry, 41, 14552-14559, 2002) (see column 12, second paragraph) while 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 another catalytic cation, 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 6, first to last paragraphs of applicant’s remarks, applicant argues that “[A]pplicant respectfully disagrees with the Examiner's allegation that the skilled person
would modify the cited art as proposed in the Office Action. In addition, Vander Horn and Frey,
when considered alone or in combination, do not teach or suggest an examination mixture that
includes either (i) one or more monovalent cations and a ternary complex, or (ii) one or more
monovalent cations and a ternary complex that includes a trivalent lanthanide cation. Because the
cited art do not teach or suggest each and every element of independent claim 36 as amended
herein, the modification of the cited art as proposed in the Office Action cannot render the claims
obvious”.
The above arguments have been fully considered but they are not persuasive toward the withdrawal of the rejection.
First, Vander Horn et al., teach that an examination mixture that includes one or more monovalent cations (ie., K+ or Na+)and a ternary complex (ie., a ternary complex comprising a polymerase, a primed template nucleic acid molecule, Ca2+, and a nucleotide) (see column 15, sixth paragraph and column 106, last paragraph).
Second, although applicant argues that “Vander Horn and Frey, when considered alone or in combination, do not teach or suggest an examination mixture that includes” “a ternary complex that includes a trivalent lanthanide cation”, since Vander Horn et al., have shown that substituting Ca2+ for Mg2+ permits a nucleotide binding to a wild-type or mutant polymerase but inhibits nucleotide incorporation (Gangurde et al., Biochemistry, 41, 14552-14559, 2002) (see column 12, second paragraph), 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 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.
Claims 53 and 54 are rejected under 35 U.S.C. 103 as being unpatentable over Vander Horn et al., in view of Frey et al., as applied to claims 36-42 and 49-52 above, and further in view of Gangurde et al., (Biochemistry, 41, 14552-14559, 2002).
The teachings of Vander Horn et al., and Frey et al., have been summarized previously, supra.
Vander Horn et al., in view of Frey et al., do not disclose that the concentration of the one or more monovalent cations is greater than 300 mM as recited in claim 53 and the concentration of the one or more monovalent cations is from 300mM to 650 mM as recited in claim 54. However, Vander Horn et al., teach that substituting Ca2+ for Mg2+ permits a nucleotide binding to a wild-type or mutant polymerase but inhibits nucleotide incorporation (Gangurde et al., Biochemistry, 41, 14552-14559, 2002) (see column 12, second paragraph) and a ternary complex comprising a polymerase, a primed template nucleic acid molecule, Ca2+, and a nucleotide is formed in the presence of 50 mM NaCl (see column 106, last paragraph)
Gangurde et al., teach a ternary complex comprising a polymerase, a primed template nucleic acid molecule, Ca2+, and a nucleotide is formed in the presence of 500 mM NaCl (see page 14556, right column).
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 53 and 54 wherein the concentration of the one or more monovalent cations is greater than 300 mM and the concentration of the one or more monovalent cations is from 300mM to 650 mM in view of the prior arts of Vander Horn et al., Frey et al., and Gangurde et al.. One having ordinary skill in the art would have been motivated to do so because Vander Horn et al., have shown that substituting Ca2+ for Mg2+ permits a nucleotide binding to a wild-type or mutant polymerase but inhibits nucleotide incorporation (Gangurde et al., Biochemistry, 41, 14552-14559, 2002) and a ternary complex comprising a polymerase, a primed template nucleic acid molecule, Ca2+, and a nucleotide is formed in the presence of 50 mM NaCl (see column 12, second paragraph and column 106, last paragraph) while Gangurde et al., teach a ternary complex comprising a polymerase, a primed template nucleic acid molecule, Ca2+, and a nucleotide is formed in the presence of 500 mM NaCl (see page 14556, right column), and optimization of the concentration of the one or more monovalent cations in the examination reaction mixture during the process for performing step (i) of claim 36, in the absence of convincing evidence to the contrary, would have been obvious to one having ordinary skill in the art at the time the invention was made. One having ordinary skill in the art at the time the invention was made would have a reasonable expectation of success to adjust the concentration of the one or more monovalent cations in the examination mixture comprising the ternary complex comprising a polymerase, a primed template nucleic acid molecule, a trivalent lanthanide ion such as Eu3+, and a next correct nucleotide recited in claim 36 in view of Vander Horn et al., Frey et al., and Gangurde et al., such that the concentration of the one or more monovalent cations such as Na+ in the examination mixture is 500 mM as recited in claims 53 and 54. More particularly, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Where the general conditions of a claim are disclosed in the prior art, it is not inventive, in the absence of an unexpected result, to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Frank Lu, Ph. D., whose telephone number is (571)272-0746. The examiner can normally be reached Monday to Friday, 9 AM to 5 PM.
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/FRANK W LU/
Primary Examiner, Art Unit 1683
July 9, 2026
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