DETAILED ACTION
The present Office Action is responsive to the Amendment received on May 11, 2026.
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 .
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Claims 6-8 remain withdrawn as being drawn to a non-elected invention.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 rejection of claims 10, 13, and 15 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form for failing to further limit the subject matter, made in the Office Action mailed on February 11, 2026 is withdrawn in view of the Amendment received on May 11, 2026.
The rejection of claim 5 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as failing to comply with the written description requirement, made in the Office Action mailed on February 11, 2026 is withdrawn in view of the Amendment received on May 11, 2026.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.
Claim 5 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 5 recites the phrase, “bound to the solid phase carrier” but lacks a proper antecedent basis. In addition, the limitation appears to be active when the claimed product is in use and therefore, it is indefinite how the claimed limitation further limits the claimed compositions. No further interpretation could be made for the purpose of prosecution.
Claim Rejections - 35 USC § 103
The rejection of claims 1, 3, 4, 9-13, and 15 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) made in the Office Action mailed on February 11, 2026 is withdrawn in view of the Amendment received on May 11, 2026 and the arguments presented in therein.
Specifically, the probe disclosed by Harvey et al. contains segments of DNA that are separated by an intervening RNA base region, but the segments of DNA are 10 bases in length, and in view of Applicants’ argument that the number of DNA bases in such segments matter in yielding a detectable signal (see page 8, Response) has been found persuasive.
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 Duck et al. (U.S. Patent No. 5,660,988, issued August 26, 1997) in view of Harvey et al. (Analytical Biochemistry, 2004, pages 246-255) and Licheng et al. (CN 109750091, published May 2019; IDS ref).
With regard to claims 1, 10, and 13 Duck et al. teach a method that employ a composition comprising:
a ribonucleases H (“exciding agent to bind to single-stranded nucleic acid probe … the excising agent is RNase H”, column 7, lines 54-58);
a probe (“nucleic acid probe”, column 8, lines 14-15), 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, step II), 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 three segments, each of which independently has 1, 2, 3, 4, or 5 DNA base and base substitutions that do not interfere with hybridization of a nucleic acid strand in total (“nucleic acid probe of the this invention comprises the structure (NA1-SL-NA2)n”, column 8, lines 14-16; “NA1 and NA2 are nucleic acid sequences (which may include peptide nucleic acids), wherein SL is the scissile linkage (typically comprising a nucleic acid sequence that is able to hybridize to or bind to the desired nucleic acid sequence and is able to be excited by an excising agent upon such hybridization or binding, thereby cleaving NA1 from NA2, and wherein n is an integer from about 1 to about 10 … SL is between 3 to about 5 nucleotides in length … NA1 and NA2 in the nucleic acid probe independently comprises from about 0 to about 20 nucleotides … NA1 and NA2 in the nucleic acid probe are DNA sequences and SL is an RNA sequence”, column 8, lines 18-48).
Therefore, the probe contemplated by Duck et al. comprise NA1 and NA2, each of which being DNA having lengths of 1, 2, 3, 4, or 4; and that flank SL that is an RNA base, that is 3-5 bases in length, and repeating this unit. For example, (NA12-SL3-NA22)3 would result in a probe having multiple DNA segments of 2-4 bases that are separated by RNA regions of 3 bases.
Duck et al. do not explicitly teach that DNA polymerase is included in the composition (claim 1, in-part).
While Duck et al. teach that 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 (claim 1, in-part).
While Duck et al. do teach the detection of the cleavage of their probe, the artisans do not teach that the detection is produced by labels that produce signals based on FRET pair (claims 3 and 4).
While Duck et al. teach a probe comprising multiple contiguous RNA bases within which is cleaved for detection, the artisans do not explicitly teach that the probe has a blocking moiety (claim 9).
Duck et al. 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. 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.
Havey et al. teach that the detection of the cleavage is detected via at least two segments being labeled with different identification elements (i.e., FRET dye pair, see Fig. 1, “F” and “T”).
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 Duck et al. with the teachings of Harvey 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.”
As discussed above, Duck et al. already teach a method of detecting the presence of a target nucleic acid in a sample by use of a cleavable probe that comprise DNA segments that are separated by intervening RNA regions, with explicit contemplation of the number of DNA bases comprised by the DNA segments intervened via RNA bases as presently claimed.
While Duck et al. relied upon a dated means of detection, based on the teachings of Harvey et al. which also provided a means of detecting the cleavage of DNA/RNA probe utilizing FRET dye pair, one of ordinary skill in the art would have been motivated to adopt the detection means of Harvey et al., allowing for a real time detection of cleavage of Duck et al.’s probes, with a reasonable expectation of success.
In addition, as discussed above, Harvey et al. also 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 Duck et al. and Harvey et al., doing so would have been obvious so as to prevent the single-stranded probe of the artisans 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 cleavable probe of Duck et al. and 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 Duck et al., Harvey 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 record 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.
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 July 18, 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”.
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