DETAILED ACTION
The present Office Action is responsive to the Amendment received on July 7, 2026.
Preliminary Remark
Claims 3, 5, 6, 12, 17, and 19 are canceled.
Specification
The objection to the disclosure for containing embedded hyperlink and/or other form of browser-executable code, made in the Office Action mailed on April 7, 2026 is withdrawn in view of the Amendment received on July 7, 2026.
Claim Objections
The objection made to claim 11 for reasons discussed in the Office Action mailed on April 7, 2026 is withdrawn in view of the Amendment received on July 7, 2026.
Claim Rejections - 35 USC § 112
The rejection of claims 2-6, 19, and 20 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to particularly point out and distinctly claim the subject matter, made in the Office Action mailed on April 7, 2026 is withdrawn in view of the Amendment received on July 7, 2026.
Rejection – New Grounds, Necessitated by Amendment
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, 4, 7-11, 13-16, 18, and 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 1 and 201 are indefinite for reciting the phrase, “an oligonucleotide primer and/or probe capable of hybridizing with the target nucleic acid and the control nucleic acid” because it is unclear whether a single subject primer and/or probe hybridizes to both the target and the control nucleic acid; or a respective primer and/or probe is present for the target and the control nucleic acid.
Claim 2 is indefinite for reciting the phrase, “a second or more amplification cycle performed in the presence of an amplification mixture” because it is unclear whether this amplification mixture is the same amplification mixture of the preceding limitation where the first amplification cycle is performed, or an entirely different amplification mixture. For the purpose of prosecution, the former interpretation has been assumed.
Claim 20 is indefinite for the same reason as above.
Claims 2, 4, 7-11, 13-16, and 18 are rejected by way of their dependency on claim 1.
In addition, claim 20 is indefinite for reciting the phrase, “the oligonucleotide primer” because there is an insufficient antecedent basis for this limitation in the claim.
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, 4, 7-11, 13-16, 18, and 20 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. This is a New Matter Rejection.
Independent claims 1 and 202 have been amended to recite that the method employs a “primer and/or probe capable of hybridizing with the target nucleic acid and the control nucleic acid”.
There is no support for this limitation. All references made to the primer and/or probe which is cleavable are directed to that which hybridizes to the target nucleic acid. There is no support for any that anneals to target nucleic acid and control nucleic acid (see above rejection) nor that which targets a control nucleic acid.
Claims 2, 4, 7-11, 13-16, and 18 are rejected by way of their dependency on claim 1.
The new matter must be removed.
Claim Rejections - 35 USC § 102
The rejection of claims 1, 3, and 6-20 under 35 U.S.C. 102(a)(1) as being anticipated by So, Austin (US 2013/0310269 A1, published November 2013, IDS ref), made in the Office Action mailed on April 7, 2026 is withdrawn in view of the Amendment received on July 7, 2026.
Specifically, So does not teach the reverse transcription of target nucleic acid and a control nucleic acid with a reverse primer.
Claim Rejections - 35 USC § 103
The rejection of claims 2, 4, and 5 under 35 U.S.C. 103 as being unpatentable over So, Austin (US 2013/0310269 A1, published November 2013, IDS ref) in view of Asada et al. (CN 101629959 A, published January 20, 2010), made in the Office Action mailed on April 7, 2026 is withdrawn in view of the Amendment received on July 7, 2026.
Rejection – New Grounds, Necessitated by Amendment
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, 7-11, 13-16, and 18, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over So, Austin (US 2013/0310269 A1, published November 2013, IDS ref) in view of Chen et al. (Biotechnol Lett, 2006, vol. 28, pages 1787-1792).
With regard to claims 1 and 20, So teaches a method of amplification of a target nucleic acid (“method for amplifying a target polynucleotide”, section [0007]) comprising the steps of:
annealing a target nucleic acid (“contacting a target polynucleotide with a reaction mixture …”, section [0007], also see “probes can be used to detect amplicons … A label … used on a probe (e.g., a Taqman probe) to detect a target nucleic acid sequence or reference nucleic acid3 sequence in the methods described herein”, section [0185]); and
subjecting the target nucleic acid to one or more amplification step in the presence of a mixture comprising a surfactant and an oligonucleotide primer and/or probe capable of hybridizing with the target nucleic acid, wherein the oligonucleotide primer and/or probe comprise a cleavage stie and a cleavable 3’ end (see Fig. 2, the cleavable site “rG”, and the cleavable end generated includes the 3’ end of the primer structure”; “digestive enzyme that is capable of cleaving said first forward primer … and amplifying said target nucleotide in said reaction mixture with a DNA polymerase”, section [0007]; “non-ionic Ethylene Oxide/Propylene Oxide block copolymer is added to the aqueous phase … Common biosurfactants include non-ionic surfactants such as Pluronic F-68, Tetronics, Zonyl FSN … at a concentration of about 0.5% w/v”, section [0209]).
The PCR reaction includes a primer annealing step (“annealing temperature of the primers”, section [0084]), which occurs between denaturation and extension steps.
With regard to claims 8 and 10, the cleavage site is one or more RNA residues (“modified primers can comprise an RNA moiety, which can serve as the RNase H cleavage site”, section [0087]).
With regard to claims 7 and 9, the primer also comprises a non-complementary region at the 3’ end (thus mismatch).
With regard to claim 11, the reference nucleic acid can be used for normalization purposes (see above for reference nucleic acid sequence present in the sample).
The method further comprises a reverse transcription step when target nucleic acid is RNA (“poly-A tail of an mRNA molecule, for example, can be used to initiate reverse transcription. Following conversion to DNA, the methods detailed herein can be used”, section [0162]).
With regard to claim 13, the method is also quantitative (“PCR techniques that can be used include, but are not limited to, quantitative PCR”, section [0183]).
With regard to claims 14-16, the sample is maternal plasma, which contains cell-free nucleic acids (“plasma/urine samples”, section [0056], also “maternal plasma … fetal DNA [from maternal plasma]”, section [0150]; also “RNA can be cell-free RNA”, section [0163]).
With regard to claim 18, the amplification is a real time amplification method (“analyzed using the respective real-time RT-PCR assays”, section [0163]; “[a]mplification of target nucleic acids can be performed by any means known in the art … real time PCR (RT-PCR) …”, section [0183]).
With regard to claim 19, the amplification reaction as discussed would necessarily comprise a mixture comprising: 1) control (or reference) nucleic acid; a surfactant (see above for citation); and an oligonucleotide primer and/or probe that is capable of hybridizing with a target nucleic acid, wherein the oligonucleotide primer and/or probe comprises a cleavage site and a cleavable 3’ end (see above for citation).
So, while explicitly teaching that their method is applicable to target RNA molecules4, the artisans do not explicitly teach that the reverse transcription occurs with a reverse primer for both the target and the control nucleic acid sequence (claim 1 and 20, in-part).
Chen et al. teach that an RNA positive control is included in a reverse transcription-polymerase chain reaction (i.e., RT-PCR), wherein the artisans teach including an RNA control with the target nucleic acid during the reverse transcription reaction with a primer (i.e., reverse primer):
“[p]rior to amplification the RNA was reverse transcribed at 42oC for 30 min …” (page 1788, 2nd column).
“we demonstrated … prepare a stable and differentiable RNA positive controls for RT-PCR assay with a real-time RT-PCR assay for NiV detection … approach to prepare the favorable RNA positive control should be applicable to most other RT-PCR assays” (page 1791)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of So with the teachings of Chen et al., thereby arriving at the invention as claimed for the following reasons.
The practice of co-amplifying an RNA control, as discussed by Chen et al., has been well-established:
“RNA positive controls are important for RT-PCR as they can be used to monitor the quality of concerned RT-PCR assays.” (page 1787, 2nd column, Chen et al.)
Chen et al. identify the two conventionally known types of utilizing an RNA-control and provide a solution which arrives at an RNA control that combines the benefit of both:
“One is homogenous RNA positive controls which are RNA extracted from confirmed positive samples or in vitro transcribed from a sequence homogenous to the target of concerned RT-PCR” (page 1788, 1st column)
“other type of RNA positive controls, i.e., heterogeneous RNA positive controls whose sequences are different from the target of concerned RT-PCR, are widely used …” (page 1788, 1st column)
“we report a simple method to prepare a stable RNA positive control with a demonstration of a real-time RT-PCR assay for the detection of Nipah virus (NiV) … method can indicate the quality of the whole concerned RT-PCR. It is also differentiable, i.e., false positives caused by contamination of the RNA positive control or its amplicons can easily be differentiated from the real positives … the new RNA positive control combine the advantages and avoids the disadvantages of the two types of RNA positive controls stated above”(page 1788, 1st column)
Therefore, one of ordinary skill in the art would have been motivated to combine the teachings of So with the teachings of Chen et al., that is, utilize the RNA control during the expressly suggested step of using RNA and performing cDNA synthesis, utilizing the primer (i.e., reverse primer) which generates a first strand cDNA from both the target and the control nucleic acid, for the advantage of providing confirmed positive and the quality of the RT-PCR reaction performed by So.
Therefore, the invention as claimed is deemed prima facie obvious over the cited references.
Claims 2 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over So, Austin (US 2013/0310269 A1, published November 2013, IDS ref) in view of Chen et al. (Biotechnol Lett, 2006, vol. 28, pages 1787-1792), as applied to claims 1, 7-11, 13-16, and 18, and 20 above, and further in view of Asada et al. (CN 101629959 A, published January 20, 2010).
The teachings of So and Chen et al. have already been discussed above
While So explicitly teaches that the amplification reaction mixture comprises surfactants, the artisan does not disclose all possible amounts of the surfactant that can be employed, nor does the artisan teach that the produced PCR products can be frozen and stored and thawed for subsequent analyses.
Asada et al. teach a well-known practice of freezing a PCR product upon completion (“[a]fter the reaction, freeze the PCR product for storage”, page 20).
However, it would have been prima facie obvious before the effective filing date of the claimed invention to take the generalized teachings of So and Asada et al. and conventional knowledge in the art, thereby arriving at the invention as claimed.
As discussed above, So already teaches an amplification reaction mixture comprising a surfactant and while the artisan did not disclose all possible amounts of the surfactant that can be employed, one of ordinary skill in the art would have been motivated to involve routine optimization so as to arrive at an optimized condition tailored for any specific assay.
MPEP 2144.05(II)(A) discloses that, “differences in concentrations or temperature will not support patentability of subject matter encompassed by prior art unless there is evidence indicating such concentration or temperature is critical,” citing In re Aller, F.2d 454, 456, 105 USPQ 233, 235, (CCPA 1995).
As to freezing the PCR products produced by So et al. for storage and later usage for subsequent analysis such as sequencing reaction (which involves additional cycles of extension during a sequencing reaction) or further assays by thawing, doing so was conventionally performed and therefore, would have been an obvious application of storing/using the PCR products of So.
Therefore, the invention as claimed is deemed prima facie obvious over the cited references.
Double Patenting
The rejection of claims 1-20 on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/294,652 (reference application) in view of Dobosy et al. (WO 2018/031625 A2, published February 2018; IDS ref), made in the Office Action mailed on April 7, 2026 is withdraw in view of reconsideration.
Conclusion
No claims are allowed.
Applicant’s arguments with respect to previous rejections have considered but are moot because the new ground of rejection based on new reference(s).
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.
Inquiries
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Young J. Kim whose telephone number is (571) 272-0785. The Examiner can best be reached from 7:30 a.m. to 4:00 p.m (M-F). The Examiner can also be reached via e-mail to Young.Kim@uspto.gov. However, the office cannot guarantee security through the e-mail system nor should official papers be transmitted through this route.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's supervisor, Gary Benzion, can be reached at (571) 272-0782.
Papers related to this application may be submitted to Art Unit 1681 by facsimile transmission. The faxing of such papers must conform with the notice published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 CFR 1.6(d)). NOTE: If applicant does submit a paper by FAX, the original copy should be retained by applicant or applicant’s representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED, so as to avoid the processing of duplicate papers in the Office. All official documents must be sent to the Official Tech Center Fax number: (571) 273-8300. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-1600.
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/YOUNG J KIM/Primary Examiner
Art Unit 1637 September 26, 2026
/YJK/
1 Claim 20 recites the same phrase except using a generic term in the phrase, “an oligonucleotide capable of hybridizing …”.
2 Claim 20 recites the same phrase while generically reciting “an oligonucleotide capable of hybridizing …”
3 Reference nucleic acids are also commonly known as control nucleic acids in the art.
4 “target polynucleotide can also encompass cDNA generated from RNA … through RT-PCR”, section [0059]; also “nucleic acids can be DNA … RNA (including mRNA and rRNA) …”, section [0060]).
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