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 Application
The Response to Non-Final Office Action filed April 6, 2026 is acknowledged.
Claims 1-2, 4-5 and new claims 9-20 are pending and are being examined on the merits.
Response to Arguments
Applicant’s arguments filed April 6, 2026 have been fully considered.
The following rejections are WITHDRAWN in view of Applicant’s arguments and amendments to the claims.
Rejection of claims 1-2 and 4-5 under 35 USC § 112(a), written description
Rejection of claims 1-2 and 4-5 under 35 USC § 112(b)
Prior art rejections
Response to arguments regarding prior art rejections and response to Nierth Declaration
The Examiner agrees with the following arguments:
Applicant argues that the prior art rejections should be withdrawn because the ordinary artisan would not modify Hirao with the teachings of Ermert because the ordinary artisan would understand that modifying a triphosphate chain to a tetraphosphate chain increases the total negative charge of the molecule, and that this would inhibit polymerase activity (Remarks, p. 5; Declaration, para. 9).
The Examiner agrees.
Applicant additionally argues that the instantly claimed method using fluorinated tetraphosphate analogs provide unexpected results in amplification reactions, as compared to unmodified dNTPs and prior art analogs in an amplification reaction (Remarks, pp. 7-9; Declaration, paras. 6-8). Specifically, Applicant provides evidence that dN4P analogs are worse substrates than both unmodified nucleotides and their F-dN4P counterparts. Applicant also provides evidence that F-dN4P is significantly more efficient than F-dN3P in the context of PCR. Applicant concludes that “this data demonstrates that lengthening the polyphosphate chain in the nucleic acid analog per se can be detrimental to performance in the context of PCR. Thus, the skilled artisan would have no reasonable expectation of success in lengthening the polyphosphate chain for terminal modifications consisting of small chemical groups such as fluorine (Remarks, pp. 7-8; Declaration, paras. 6-8).
The Examiner agrees. For an unexpected results showing, the MPEP requires that the instantly claimed subject matter, which is F-dN4P, be compared with the closest prior art subject matter. MPEP 716.02(e). Here, the closest prior art subject matter is that of Hirao, which is F-dN3P. Applicant has provided comparison data of F-dN3P to F-dN4P in the amplification curve data (Declaration, Fig. 2)1. Although Applicant does not recite specific data points, the amplification curve shows that the prior art F-dN3Ps perform worse than standard nucleotides (through most of the dynamic range of the assay), while the instantly claimed F-dN4Ps perform better than standard nucleotides. MPEP 716.02(a) states that the absence of an expected property is evidence of nonobviousness. Here, the expected property of the instantly claimed F-dN4P modified nucleoside polyphosphate is that it would perform worse than standard nucleotides, based on the data provided in the amplification curve for the prior at F-dN3P modified nucleoside polyphosphate. Since the instantly claimed subject matter lacks the expected property of poorer performance compared to standard nucleotides, the data establishes unexpected results with the claimed subject matter.
Applicant argues that the prior art rejections should be withdrawn because it was not obvious that a thermostable inorganic pyrophosphatase would hydrolyze the instant fluoropolyphosphate cleavage products (Remarks, p. 10).
The Examiner agrees with Applicant’s arguments and their underlying reasoning.
Applicant argues that the secondary references do not remedy the deficiencies of the teachings of Hirao and Emert (Remarks, pp. 11). Applicant additionally argues that new claims 9-20 are free of the art for the reasons already discussed (Remarks, p. 11).
In view of Applicant’s arguments and evidence discussed above, the Examiner agrees.
Applicant’s arguments and evidence are persuasive. The prior art rejections are withdrawn.
Merely for the sake of completeness, the Examiner also notes the following:
The Examiner disagrees with the following arguments:
Applicant argues that the prior art rejections should be withdrawn because Hirao does not teach or suggest performing an amplifying step with modified nucleoside polyphosphates. Specifically, Applicant argues that while Hirao teaches “a deoxyribonucleoside 5’-triphosphate, in which the hydroxyl group of phosphoric acid at the ɣ-position is substituted with […] a fluoro group”, Hirao does not provide an explanation of what is meant by a “fluoro group” nor any specific embodiments of dNTPs comprising a fluoro group (Remarks, p. 3).
The Examiner disagrees. The ordinary artisan would certainly understand that “a fluoro group” would at least comprise fluorine itself, and Hirao teaches where the substitution is to be made. Even if “a fluoro group” refers to a genus of chemical groups, the ordinary artisan would recognize that fluorine would be comprised within the genus.
Applicant argues that even if the ordinary artisan would understand Hirao to teach F-dN3P for use in an amplification reaction, there is no data provided in support of whether it is a functional substrate for a nucleic acid polymerase (Remarks, p. 3).
The Examiner disagrees. The ordinary artisan would understand that most nucleic acid amplification reactions require a polymerase of some kind, and thus even if “amplification reaction” refers to a genus of nucleic acid assays, the ordinary artisan would understand that amplification reaction that require a nucleic acid polymerase would be comprised within that genus.
Applicant argues that the ordinary artisan would not modify Hirao with the teachings of Ermert. Specifically, Applicant argues that the Ermert oligonucleotides incorporate reporter molecules, such as fluorophores, which are large and bulky, and that consequently the teachings of Ermert as to large and bulky molecules, are not relevant to the instant non-bulky fluorine atom (Remarks, pp. 3-5; Declaration, paras. 7-8). Applicant additionally argues that Ermert relies on Baranowski, which is directed to compounds that are useful for NMR spectroscopy studies, and does not address improving a PCR reaction (Remarks, pp. 6-7; Declaration paras. 9-10).
The Examiner disagrees that the teachings of Ermert as to the length of the phosphate chains should be read so narrowly as to be limited to oligonucleotides that incorporate bulky reporter molecules. Further, Baranwoski was not cited in the Non-Final Office Action mailed November 5, 2025, and Ermert does not discuss NMR spectroscopy studies.
Information Disclosure Statement
The Information Disclosure Statement submitted April 10, 2026 has been considered.
Claim Rejections - 35 USC § 112
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.
Claims 16-20 are 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.
Claims 16 recites the limitation “regular deoxyribonucleotide triphosphate mixture”, the meaning of which is unclear. Specifically, the term “regular” is not defined in the specification and does not have any particular or fixed meaning in the art as to deoxyribonucleotide triphosphate mixtures. It is also not clear if “regular” is intended to modify “mixture” (i.e., a regular mixture of deoxyribonucleotide triphosphates”), or if it is intended to modify deoxyribonucleotide triphosphate (i.e., a mixture of regular deoxyribonucleotide triphosphates). Since the ordinary artisan would not be able to determine the metes and bounds of the claim, it is indefinite.
Claims 17-20 depend directly or indirectly from claim 16, and consequently incorporate the indefiniteness issue of claim 16.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 19 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 19 recites the limitation “wherein the amplification reagents further comprise a
thermostable inorganic pyrophosphatase enzyme”. Claim 16, from which claim 19 depends already recites a thermostable inorganic pyrophosphatase enzyme. Thus, claim 19 does not further limit claim 16 and is in improper dependent form.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Prior Art and Allowable Subject Matter
Claims 1-2, 4-5 and 9-20 are free of the art for the reasons noted above.
Claims 1-2, 4-5 and 9-15 are allowed.
Conclusion
Claims 1-2, 4-5 and 9-20 are being examined. Claims 1-2, 4-5 and 9-15 are allowed. Claims 16-20 are rejected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAROLYN GREENE whose telephone number is (571)272-3240. The examiner can normally be reached M-Th 7:30-5:30 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gary Benzion can be reached at 571-272-0782. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CAROLYN L GREENE/Primary Examiner, Art Unit 1681
1 Applicant also provides data comparing standard dNTPs with dN4Ps and F-dN4Ps. Since dN4Ps are not the closest prior art compound, that data is not addressed here.
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