DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 January 30, 2026 has been entered.
Preliminary Remark
Claims 2, 14, and 16 are canceled.
Claims 6-8 remain withdrawn as being drawn to a non-elected invention.
The practice of rejoinder as discussed in the Office Action mailed on December 10, 2025 remains in effect.
Claim Interpretation
The term “base substitution” has been construed to that which, “refers to a structure that contains no base, and connects the upstream and downstream of the nucleic acid strand to maintain the integrity of the probe as a whole, without interfering with the hybridization of the nucleic acid strand. (section [0024])
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.
Claims 10, 13, and 15 are 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.
Claims 10 and 13 broaden the breadth of their parent claim.
Claim 1 (i.e., parent claim) requires that the probe comprises “at least two RNA bases.” Claims 10 and 13 (and 15 by its dependency on claim 13) broaden this breadth by reciting that the probe has “one RNA base.”
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claim 5 is 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.
Claim 1 has been amended to recite that the combination comprises an additional reagent, DNA polymerase and its dependent claim 5 recites that the probe has an end fixed on a surface of a solid phase carrier or bound to the solid phase carrier upon reaction, and the other end coupled with a signal substance.
The Office is unable to find support for a combination of products wherein DNA polymerase exist together with the probe (of claim 1), and RNAse H2, wherein the probe has an end fixed on a surface of a solid phase carrier.
Applicants are requested to provide a line and page of the specification or drawings where this specific combination is supported.
Claim Rejections - 35 USC § 103
The rejection of claims 1, 3-5, 9-13, and 15 under 35 U.S.C. 103 as being unpatentable over Xiao et al. (CN 1928118, published March 14, 2007; IDS ref) in view of Kurn et al. (WO 01/20035 A2, published March 2001) and Licheng et al. (CN 109750091, published May 2019; IDS ref), made in the Office Action mailed on September 30, 2025 is withdrawn in view of the Amendment received on January 30, 2026.
Specifically, Xiao et al. do not teach the use of a DNA polymerase in conjunction with the disclosed probe. While the artisans do teach amplification reaction prior to the detection utilizing the disclosed probe, thus inherently requiring a DNA polymerase, the produced PCR product is purified and there is no conclusive evidence to suggest that the purified PCR product used to load onto the disclosed probe contains DNA polymerases.
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, 3, 4, 9-13, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Harvey et al. (Analytical Biochemistry, 2004, pages 246-255) in view of Kurn et al. (WO 01/20035 A2, published March 2001), and Licheng et al. (CN 109750091, published May 2019; IDS ref).
With regard to claim 1, Harvey et al. teach a method which employs a composition comprising:
ribonuclease H (“[i]n the presence of RNase H”, page 247, 2nd column),
a probe (“catalytically cleavable fluorescence probe (CataCleave probe)”, page 247, 2nd column, 2nd paragraph), and
DNA polymerase (“2.5 U of Taq DNA polymerase”, page 248, 2nd column)1,
wherein the probe is a single-stranded probe and has a sequence which is partially or entirely complementary to a target DNA molecule to be detected (see Fig 1), and at least two RNA bases are embedded in the complementary region of the probe and divide the complementary region of the probe into at least two segments (see page 248, 1st column, “24-mer chimeric oligonucleotide, 5’-TATGCCATTT-r(GAGA)-TTTTTGAATT-3’”), each of which independently has DNA bases and base substitutions that do not interfere with the hybridization of a nucleic acid strand in total, and wherein the at least two RNA bases are distributed discretely in the probe.
With regard to claims 3 and 4, the at least two segments are labeled with different identification elements (see Fig. 1, “F” and “T”).
With regard to claim 10, the probe comprises (i.e., has) one RNA base, and the complementary region of the probe has a length of less than 25 (see page 248, “[a] 24-mer chimeric oligonucleotide … was synthesized”]).
While Harvey et al. teach that any RNAse H enzyme can be employed for the cleavage of their probe, the artisans do not explicitly teach that RNase H2 enzyme should be utilized.
While Harvey et al. teach a probe comprising multiple contiguous RNA bases within which is cleaved for generating a signal, the artisans do not explicitly teach that multiple RNA bases are embedded into the probe and divide the region of the probe into at least three segments each of which comprising 1-6 DNA bases or base substitutions; or that the probe has a blocking moiety (claim 9).
Harvey et al. while teaching that various amplification reactions can be employed, such as RCA and PCR2, do not explicitly teach that their probe can be utilized in generating detection signals from other types of amplification reactions, such as LAMP, NEAR, or RPA (claims 11 and 15), or that their reagents be packaged into a kit (claim 12).
Harvey et al. do not explicitly teach that their probe comprises a single RNA base (claim 13).
Kurn et al. teach a method of digesting a composite oligonucleotide containing DNA/RNA bases that anneals by complementary to a DNA molecule forming a heteroduplex, wherein the heteroduplex is cleaved at the RNA bases of the probe by RNase H (“hybridizing a single stranded DNA template comprising a target sequence with a composite primer, said composite primer comprising an RNA portion and a 3’ DNA portion … cleaving the RNA portion of the annealed composite primer with an enzyme that cleaves RNA from an RNA/DNA hybrid”, page 6, 2nd paragraph).
In considering various types of such composite primers, Kurn et al. explicitly teach that primers which comprises multiple RNA bases which are separated by DNA bases, there creating at least three segments:
“length of an intervening RNA portion in a composite primer comprising 5’- and 3’- DNA portion with at least one intervening RNA portion can be preferably about 1 to about 7 nucleotides” (page 27, 3rd paragraph)
“Composite primer IA005 is a 20-mer primer with the sequence of: ACGGAUGCGGUCUCCAGTGT” (page 64, underline added for the RNA base, and bolded-italicized for at least 3 segments)
“length of an RNA portion in the composite primer … can be preferably from about 1 to 25 … any of 1, 3, 4, 5 nucleotides” (page 26, 2nd paragraph)
Licheng et al. teach a well-known property of RNAse H2 which also cleaves a DNA/RNA duplex at a location comprising an RNA base (“RNaseH can specifically degrade the phosphodiester bond of RNA in the hybrid strand between DNA and RNA”, section [0006]; probe containing RNA bases is added to the reaction system RNase H2, a high-temperature resistant RNaseH … the probe binds to the target DNA to form a partial DNA-RNA hybrid double-strand, then RNaseH2 Cleavage can be performed so that the reporter group is separated from the quencher group and fluoresces …”, section [0006]).
Licheng et al. also teach that their probe which relies on this cleavage reaction by RNase H2 is employed to detect an isothermal amplification reaction product (“present invention introduces an RNA-base containing probe (RNHP) and high temperature-resistant RNaseH2 on the basis of isothermal amplification, and utilizes the property that RNaseH can digest the phosphodiester bond of RNA in the hybridized chain of DNA and RNA”, section [0009]), with an explicit teaching of RPA (“recombinase polymerase isothermal amplification”, section [0013]).
Licheng et al. also teach that the probe may comprise as little as one RNA (“[t]he fluorescent probe RNHP contains at least 1 RNA base … the at least one RNA base is preferably at least one continuous RNA base, more preferably one RNA base”, section [0014]).
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 Harvey et al. with the teachings of Kurn et al., and Licheng et al., thereby arriving at the invention as claimed for the following reasons.
In KSR, the Supreme Court particularly emphasized “the need for caution in granting a patent based on the combination of elements found in the prior art,” Id. at 415, 82 USPQ2d at 1395, and discussed circumstances in which a patent might be determined to be obvious. Importantly, the Supreme Court reaffirmed principles based on its precedent that “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” Id. at 415-16, 82 USPQ2d at 1395. The Supreme Court stated that there are “[t]hree cases decided after Graham [that] illustrate this doctrine.” Id. at 416, 82 USPQ2d at 1395. (1) “In United States v. Adams, . . . [t]he Court recognized that when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.”
The rationale to include additional RNA bases which may be localized into a single region, as taught by Harvey et al., or interspersed between DNA bases of Harvey et al.’s probe is based on the predictable outcome based on the knowledge available in the art, that is, to produce a probe that is cleaved at the RNA bases so as to generate a FRET signal in an amplification reaction, when the probe is bound to its DNA target molecule.
As demonstrated by Kurn et al., the artisans show that a composite oligonucleotide comprising DNA/RNA bases, wherein the RNA bases are interspersed throughout the region of the probe, when bound to its DNA target, are also cleaved at the location of the RNA bases.
Since cleavage occurred at the RNA bases, regardless of their location, one of ordinary skill in the art before the effective filing date of the claimed invention would have recognized that the probe of Harvey et al. having multiple RNA bases interspersed with DNA bases therebetween (thus forming at least three segments, as shown by Kurn et al.) would have also yielded predictable outcome, that is, a probe which becomes cleaved to generate the same FRET signal.
In addition, as discussed above, Harvey et al. already teach a method of generating a detectable signal utilizing a single-stranded nucleic acid probe comprising at least one RNA bases therein and labeled with a FRET dye pair, wherein during an amplification reaction, its target-specific hybridization with a target DNA, when combined with an RNAs H, results in the cleavage of the single-stranded nucleic acid probe at the site of at least one RNA base.
One of ordinary skill in the art would have recognized that any such RNAse H enzymes could be utilized in the method of Harvey et al.
Indeed, Licheng et al. also teach a method which utilizes a labeled single-stranded nucleic acid probe comprising at least one RNA base therein, when hybridized with its DNA target nucleic acid, results in the cleavage of said single-stranded nucleic acid probe by an RNAse H, wherein the RNAse H employed is RNase H2.
Therefore, one of ordinary skill in the art would have recognized that the cleaving property of the RNAse H2 employed by Licheng et al. would have yielded the same predictable outcome as expressed by Harvey et al., rendering the invention as claimed obvious.
As to the blocking of the 3’ end of the single-stranded nucleic acid employed by Harvey et al., doing so would have been obvious so as to prevent the single-stranded probe of Harvey et al. from participating in the amplification reaction, diverting reagents away from the amplification reaction, as the probe was solely being utilized for its hybridization to the target DNA and its cleavage, not in an extension reaction.
As to the combining the CataCleave probe of Harvey et al. with primers for LAMP, NEAR, or RPA, such combination would have been obvious as the Harvey et al. already demonstrate that their probe can be utilized together in an amplification reaction including PCR as well as an isothermal amplification reaction (RCA), and considering other amplification means already known and established in the art would have yielded no more than a predictable outcome.
Lastly, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to package the reagents of Harvey et al., Kurn et al., and Licheng et al. into a kit in view of the conventionality of kits in the analytical arts for the advantages of convenience, cost-effectiveness, matched and/or pre-weighed components, etc.
For these reasons, the invention as claimed is deemed prima facie obvious over the cited references.
Conclusion
No claims are allowed.
Applicant’s arguments with respect to the previous rejection of recored have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
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 February 7, 2026
/YJK/
1 The RNAse H, the probe, and the DNA polymerase are present together in a combination, see page 248, 2nd column, 4th paragraph: “[r]eal-time reactions were carried out in Taq polymerase buffer … containing 6 mM MgCl2 … 2.5 U of Taq DNA polymerase, 2.5 U of thermostable RNase H, and 10 pmol of CataCleave probe in a total volume of 50 ml”.
2 “CataCleave probe is also ideal for detecting DNA amplification processes, such as polymerase chain reaction (PCR) and isothermal rolling circle amplification (RCA)”, Abstract