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 Final Office Action and the Request for Continued Examination, each filed August 26, 2025, are acknowledged.
Claims 1-2, 4-5 and 7-8 were pending. Claims 1-2 and 4-5 are being examined on the merits. Claims 7-8 are canceled.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 August 26, 2025 has been entered.
Response to Arguments
Applicant’s arguments filed August 26, 2025 have been fully considered.
All of the previously made rejections are WITHDRAWN in view of Applicant’s arguments and amendments to the claims.
Response to arguments regarding prior art rejections
As noted, the prior art rejections directed to the now-canceled product claims are withdrawn. New prior art rejections are added below as to the currently pending method claims. To the extent that Applicant’s arguments relate to the newly added prior art rejections below, the Examiner notes the following.
Applicant argues that the prior art rejections should be withdrawn because the cited prior art does not teach or suggest the limitation in the independent claims reciting that the fluoropolyphosphate cleavage product of the modified nucleoside polyphosphate is an efficient substrate for the pyrophosphatase enzyme (Remarks, pp. 7-8).
As noted below, this limitation is both indefinite and lacks written description support, however, optimizing nucleic acid methods to choose an enzyme that works well with the other assay components is an obvious modification.
Applicant argues that it would not have been obvious to modify the prior art method to incorporate the Park thermostable inorganic pyrophosphatase enzyme, nor would there have been a reasonable expectation of success in doing so (Remarks, pp. 7-8).
These arguments are addressed below in the prior art rejections.
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.
Claims 1-2 and 4-5 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.
Claims 1 and 4 each recite the limitations “wherein the polymerase accepts the
modified nucleoside polyphosphate with equal or better efficiency compared to an unmodified … dNTP” and “wherein the fluoropolyphosphate cleavage product is an efficient substrate for the thermostable inorganic pyrophosphatase enzyme”. As noted below, the meaning of these limitation is unclear. Further, the instant specification has not described the (structural?) features required for the polymerase to accept modified nucleotides with equal or better efficiency, and for the pyrophosphatase to efficiently act on the fluoropolyphosphate cleavage product. Further, to the extent that “the polymerase” and “the … pyrophosphatase” are each referring to a genus of enzymes, the specification has not described any particular species of either enzyme, much less “a representative number” of such species. Thus, the ordinary artisan would not recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. Consequently, these limitations lack written description support.
Claims 2 and 5 depend from claims 1 and 4 respectively, and consequently incorporate the lack of written description issues of claims 1 and 4.
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 1-2 and 4-5 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 1 and 4 each recite the limitations “wherein the polymerase accepts the modified nucleoside polyphosphate with equal or better efficiency compared to an unmodified … dNTP” and “wherein the fluoropolyphosphate cleavage product is an efficient substrate for the thermostable inorganic pyrophosphatase enzyme”. The meaning of these limitations is unclear. Specifically, the limitations are functional as they characterize the polymerase and pyrophosphatase by what they do, rather than what they are. MPEP 2173.05(g). However, these limitations recite only a result that is obtained without also reciting what corresponding structures or steps are encompassed by the limitation. The instant specification also does not describe what features of polymerases or pyrophosphatases would result in the stated outcomes, nor are such features generally known in the art. Further, regarding the limitation “wherein the fluoropolyphosphate cleavage product is an efficient substrate for the thermostable inorganic pyrophosphatase enzyme”, it is not even clear if this is intending to state an inherent property of the fluoropolyphosphate cleavage product, or if this is intended to impose some structural or functional limitation on the cleavage product and/or the pyrophosphatase. Since the ordinary artisan would not be able to determine the metes and bounds of the claims, they are indefinite.
Claims 2 and 5 depend from claims 1 and 4 respectively, and consequently incorporate the indefiniteness issues of claims 1 and 4.
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 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Hirao1 (EP 1 970 445 A1) in view of Ermert2 (Phosphate-Modified Nucleotides for Monitoring Enzyme Activity, Top Curr Chem (Z), 375: 28, 1-25, 2017), Park3 (Facilitation of polymerase chain reaction with thermostable inorganic pyrophosphatase from hyperthermophilic archaeon Pyrococcus horikoshii, Appl Microbiol Biotechnol, 85: 807-812, 2009) and Josse (Constitutive Inorganic Pyrophosphatase of Escherichia coli, Journal of Biological Chemistry, 241(9): 1948-1955, 1966).
Regarding independent claim 1, Hirao teaches …
A method of detecting the presence or absence of a target nucleic acid sequence in a sample comprising, in order: a) performing an amplifying step comprising contacting the sample with amplification reagents comprising a nucleic acid polymerase and a modified nucleoside polyphosphate (para. 10: “a method for replicating [i.e., amplifying] a nucleic acid wherein a deoxyribonucleoside 5’-triphosphate, in which the … [γ] phosphoric acid … is substituted with a fluoro group”; para. 12: “a DNA polymerase … is used during the replication reaction”; para. 94: “[r]eplication reaction is not limited in any way except for using the above substrates”; para. 146: “nucleic acid of the present invention encompasses single-stranded or double-stranded RNA or DNA”; para. 191: “Figure 12 shows the amplification efficiency of PCR products from [target] DNA1, DNA3 to DNA10 …”).
and c) detecting the amplification product (para. 133: “nucleoside or nucleotide … which … is substituted with a fluorescent molecule allows nucleic acid detection”; “Figure 12 shows the amplification efficiency of PCR products from DNA1, DNA3 to DNA10 …”);
wherein the modified nucleoside polyphosphate has the recited structure where R = purine or pyrimidine base or an analog, and n = 1 (para. 10: “a deoxyribonucleoside 5’-triphosphate, in which the … [γ] phosphoric acid … is substituted with a fluoro group”);
Regarding the limitation in the preamble reciting “detecting the … absence of a target nucleic acid”, Hirao does not explicitly teach this limitation. However, Hirao does teach the use of PCR to amplify target DNAs (as noted above). The ordinary artisan understands that if a target DNA is not present in a sample, it would also not be amplified during the PCR, and, consequently would not be detectable after the reaction, or stated differently, the PCR would detect the absence of target nucleic acid. It is also an inherent property of PCR that this would be the case.
Ermert teaches the claim 1 limitation that n=2 in the recited structure (p. 3, paras. 2-3: “[m]any terminally phosphate-modified nucleotides have a length of the phosphate chain of three phosphoanhydride units as found in the most common NTPs … For several applications ... it has been shown that longer phosphate chains are beneficial … a nucleoside tetraphosphate … [or] even longer phosphate chains”).
Park teaches b) hydrolyzing the cleavage product with a thermostable inorganic pyrophosphatase (p. 810, right col., para. 3).
The limitation “to produce an amplification product and a fluoropolyphosphate cleavage
product if the target nucleic acid sequence is present in the sample” is not an active method step. Since the active method steps are all taught in the art, the prior art method inherently meets these limitations as well (MPEP 2112 III). If there is some step or element or structure that is required to achieve this result, then the claim would be unpatentable due to the omission of essential elements or steps (MPEP 2172.01).
As noted above, the meaning of the limitations “wherein the polymerase accepts the modified nucleoside polyphosphate with equal or better efficiency compared to an unmodified dNTP”, and “wherein the fluoropolyphosphate cleavage product is an efficient substrate for the thermostable inorganic pyrophosphatase enzyme” is unclear, and they lack written description support. However, to the extent that these limitations relate to the properties of the polymerase and pyrophosphatase enzymes, it is noted that optimizing nucleic acid methods to choose enzymes that work well with the other assay components is an obvious modification.
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious to practice the method of Hirao and incorporate the longer phosphate chains of Ermert. Hirao teaches the need to increase the efficiency and selectivity of PCR reactions (para. 7). Ermert teaches that nucleotides with additional phosphate groups, include tetraphosphates, have superior enzyme turnover (p. 3, para. 3). Therefore, the ordinary artisan would have been motivated to include the n=2 phosphate chain of Ermert in the Hirao substituted deoxyribonucleoside 5’-triphosphate in order to increase the enzyme turnover, and hence efficiency, of the Hirao method, and would have had an expectation of success, as Hirao teaches the nucleosides can be modified in a number of different ways.
It would have been additionally obvious to further incorporate the pyrophosphatase enzyme of Park into the Hirao method. Hirao teaches the need to increase the efficiency and selectivity of PCR reactions (para. 7). Park teaches that the presence of pyrophosphate in a reaction inhibits PCR, and that adding pyrophosphatase to the reaction mixture enhances the yield of PCR products (p. 810, right col., para. 3). Therefore, the ordinary artisan would have been motivated to include the Park pyrophosphatase enzyme in the Hirao method in order to increase the reaction yield, and hence efficiency, of the Hirao method. The ordinary artisan would have had an expectation of success because Josse teaches the inorganic pyrophosphatase enzyme has multiple substrates, including tri- and tetra-polyphosphates (p. 1948, right col., para. 3).
Finally, it would have been obvious to optimize the choice of the polymerase and pyrophosphatase through routine experimentation to customize the assay as needed. The ordinary artisan would have had an expectation of success, as Hirao does not limit the enzymes that can be used in the amplification reaction.
Claims 2 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Hirao (EP 1 970 445 A1) in view of Ermert (Phosphate-Modified Nucleotides for Monitoring Enzyme Activity, Top Curr Chem (Z), 375: 28, 1-25, 2017), Park (Facilitation of polymerase chain reaction with thermostable inorganic pyrophosphatase from hyperthermophilic archaeon Pyrococcus horikoshii, Appl Microbiol Biotechnol, 85: 807-812, 2009) and Josse (Constitutive Inorganic Pyrophosphatase of Escherichia coli, Journal of Biological Chemistry, 241(9): 1948-1955, 1966), as applied to claims 1 and 4 above, and further in view of Abramson4 (US Patent No. 5,455,170).
Regarding dependent claims 2 and 5, Abramson teaches wherein the nucleic acid polymerase possesses reverse transcriptase activity (abstract; col. 4, ll. 52-55: describes use of enzyme TZ05 in PCR).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious to practice either method of modified Hirao, discussed above, and incorporate the TZ05 enzyme of Abramson. Hirao teaches the need to increase the efficiency and selectivity of PCR reactions (para. 7). Abramson teaches that TZ05 enzyme has both reverse transcriptase and polymerase activity. The ordinary artisan would have been motivated to include the Abramson TZ05 enzyme in the Hirao method in order to complete the transcribing and amplifying steps in a single step, which would increase the throughput and efficiency of the Hirao method, and would have had an expectation of success, as Hirao does not limit the enzymes that can be used in the amplification reaction.
Conclusion
Claims 1-2 and 4-5 are being examined, and are rejected. No claims are allowed.
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/CAROLYN L GREENE/Examiner, Art Unit 1681
1 Hirao was cited in the PTO-892 Notice of References Cited mailed May 23, 2024.
2 Ermert was cited in the PTO-892 Notice of References Cited mailed May 23, 2024.
3 Park was cited in the PTO-892 Notice of References Cited mailed May 23, 2024.
4 Abramson was cited in the PTO-892 Notice of References Cited mailed May 23, 2024.