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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/26/2026 was filed after the mailing date of the Non-final Rejection on 11/26/2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of claims / Response to Amendment
This office action is in response to an amendment filed on February 26, 2026.
Claims 194-213 were previously pending. Applicant amended claims 194, 196, 208 and 212.
Claims 194-213 are currently pending, with claims 198, 200-207 and 209 withdrawn.
Claims 194-197, 199, 208 and 210-213 are under consideration.
All of the amendment and arguments have been thoroughly reviewed and considered. All of the previously presented objections and rejections have been withdrawn as being obviated by the amendment of the claims.
Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
This office action contains new grounds for rejection necessitated by amendment.
Claim Objections
Claim 194 is objected to because of the following informalities:
In Claim 194, part (b), line 4: "- at the first temperature" should read "- at the first temperature: " for consistency.
Priority
For the instant claims 194-197, 199, 208 and 210-213 in this U.S. Application, the applicant claims priority of PCT Application PCT/AU2020/050682, which has a filling date on 06/30/2020.
New Grounds of Rejections - 35 USC § 112(b)
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.
Claims 194-197, 199, 208 and 210-213 are rejected under 35 U.S.C. 112(b), 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.
Regarding claim 194, it recites generating a "first detectable signal" and a "second detectable signal" in the incubating step in part (b). However, it is unclear whether the claim requires these two generated detectable signals to be the same signal or different.
The claim in part (a) recites:
"a first detection moiety capable of generating a first detectable signal";
"a second detection moiety capable of generating a second detectable signal";
"wherein the first and second detection moieties are capable of generating the same detectable signals."
However, “the same detectable signals” lacks antecedent basis, and it is unclear whether “the same detectable signal” refer back to ”first detectable signal” and/or “second detectable signal,” or something else such as wavelength, color, etc.
Claims 195-197, 199, 208 and 210-213 are rejected for depending from claim 194 and not remedying the indefiniteness.
For the purpose of compact prosecution and applying prior art under 35 USC§ 102 and 103, the recited "first detectable signal" and "second detectable signal" are interpreted under BRI as being either the same or different from each other.
New Grounds of Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 194-197, 199, 208 and 210-213 are rejected under 35 U.S.C. 103 as being unpatentable over Mokany (Mokany et al. MNAzyme qPCR with superior multiplexing capacity. Clin Chem. 2013 Feb;59(2):419-26. doi: 10.1373/clinchem.2012.192930. Epub 2012 Dec 11. PMID: 23232065), in view of
Zhang (Zhang et al. Catalytic and molecular beacons for amplified detection of metal ions and organic molecules with high sensitivity. Anal Chem. 2010 Jun 15;82(12):5005-11. doi: 10.1021/ac1009047. PMID: 20481627; PMCID: PMC2917616) and
Fu (US20130267434A1 - Multiplex amplification and detection; Published 2013-10-10); as evidenced by
Diao (Diao et al. Electrochemical DNA biosensor based on MNAzyme-mediated signal amplification. Microchim Acta 183, 2563–2569 (2016)); and
Bone (Bone, Simon. The development of signal amplification detection technology utilising DNAzymes. Diss. UNSW Sydney, 2014).
A) Mokany teaches multiplexing MNAzyme quantitative PCR (qPCR) methods, which utilizes multiple linear MNAzyme reporter probes to detect different targets (Fig. 1, Fig. 2).
Regarding claim 194, Mokany teaches a method for determining the presence or absence of first and second targets in a sample, the method comprising:
preparing a mixture for a reaction by contacting the sample comprising the first and second targets with:
- a first oligonucleotide for detection of the first target, and comprising
a first detection moiety (Fig.2, probe 1 ),
- a second oligonucleotide for detection of the second target (Fig.2, probe 2),
- a first enzyme (Fig.2, MNAzyme),
wherein the first and second targets are capable of inducing a modification via MNAzyme digestion to the oligonucleotides thereby generate detectable signals indicative of different targets (Fig.1-2), the MNAzyme digests the oligonucleotide reporter probes only when the probes bind to their respective targets.
Thus, Mokany teaches a multiplexed target detection method that utilizes multiple linear MNAzyme reporter probes to detect different targets. While Mokany does not explicitly teach stem-loop probes as substrates for MNAzyme cleavage, this gap is filled by Zhang.
Zhang teaches methods and systems for improved target detection using stem-loop probes (e.g., Molecular Beacons) as substrate for DNAzyme 1 (Scheme 1).
While Zhang’s teaching focuses specifically on metal ion detection application, it also notes that “molecular beacons (MBs) that have been widely used in DNA/RNA detections” (page 5006, left-hand col) and that its system using molecular beacon “provides several significant advantages over the linear substrate” and “can be used as a general platform for amplified detection of a number of targets with higher sensitivity than previously reported methods” (page 5007, left-hand col, para 1).
Therefore, a skilled artisan would appreciate that Zhang’s teaching also relates to and can be applicable to detection of nucleic acid targets, such as the targets in Mokany. And a skilled artisan would have been motivated to modify the detection system for multiplexed target detection in Mokany to use molecular beacon probes instead of linear probes, in order to leverage the additional advantages suggested by Zhang.
There is a reasonable expectation of success in using MNAzymes with stem-loop reporter probes for the detection of nucleic acid targets, because such approach is known and has been successfully demonstrated in the art with a variety of probe signal detection schemes, for examples see Diao (see Scheme 1, probe cleavage product detected via electrochemical DNA biosensor) and Bone (Figure 3.14, probe cleavage initiates downstream polymerase reaction). A skilled artisan would reasonably recognize that detection via FRET, as disclosed in Mokany and Zhang is merely another variation of these established methods.
Although the combined teachings of Mokany and Zhang do not explicitly disclose temperature-dependent multiplex detection using probes for a first and second targets, that produce the detection signals at different temperatures, this concept is taught and suggested by Fu.
Fu teaches, in the field of multiplex nucleic acid target detection, methods for assaying a sample for one or more nucleic acid targets in a single reaction at different temperatures based on the distinct melting temperatures or melting profiles of probes (entire document; see Fig. 16 for example). These probes specifically include molecular beacon probes ([0149]; [0180] for examples) as well as double-stranded probe duplexes comprising FRET fluorescent signals (see Fig. 15 for example; Fig. 16 provides representative examples of probes melt curve analysis).
Fu further teaches that, in multiplex reactions, fluorescent probes having indistinguishable emission spectra but distinct melting temperatures can be applied ([0189]; [0250]). And in a reaction comprising multiple probe duplexes with different melting temperatures(Tm), the probe duplex having the lowest Tm will dissociate at the first temperature, while a probe duplex having a higher Tm will dissociate at a second temperature higher than the first, thereby allowing their signals being distinguished:
"In a multiplex assay, when a reaction temperature rises from the hybridising temperature to a denaturing temperature, the probe duplex with the lowest Tm unwinds first, the probe duplex with the next highest Tm separates next, and the probe duplex with the highest Tm denatures last. Concurrently, the fluorescent emission of the label attached to the probe changes in proportion to the rising reaction temperature due to the incremental melting of the probe duplex, hence allowing each probe to be distinguished in the combined melting profile" ([00250])
Thus, Fu teaches measuring a level of detectable signal at a first temperature and a second temperature.
Fu teaches that its method using different probes in a set attached with the same label, provides the advantage of allowing for monitoring at a single emission wavelength and a significant improvement over the current closed-tube multiplex PCR technology, allowing for a 2-4 fold increase in the capacity of targets being analyzed in the current instruments. ([0444]).
Therefore, in view of the above references, a person of ordinary skill in the art before the effective filing date of the claimed invention, would have found it prima facie obvious and motivated to combine the teachings of Fu, using different probes in a set attached with the same label but different melting temperatures, with the teachings of Mokany and Zhang.
In particular, Zhang teaches that the hybridized stem of stem-loop probes exhibits melting temperature characteristics that are distinct from those of cleaved probes (page 5007, left-hand col, lines 34-38):
"It is known that the intramolecularly hybridized MB stem is more stable than the two intermolecularly hybridized DNA strands of the same sequence by up to 20 °C (Tm) or 7.8 kcal/mol (ΔG, calculated by the Mfold program and DINAMelt program, respectively)."
Accordingly, a skilled artisan would recognize that cleaved and intact stem-loop probes would exhibit distinct temperature-dependent dissociation profiles.
Thus, a person of ordinary skill in the art would have appreciated that the cleaved and intact stem-loop probes described in Zhang are suitable for the temperature-dependent dissociation profiling method described in Fu. Because these probes dissociate at different temperatures, their dissociation profiles, detected by assays such as melt curve analysis, provide an indication of target-hybridization-induced cleavage as taught by the combined teachings of Mokany and Zhang.
Accordingly, a person of ordinary skill in the art would have found it obvious and reasonably expected that applying the teaching of Fu to the combined teachings of Mokany and Zhang would meet the limitations recited in part (b) of claim 194, namely, incubating at a first and second temperature, wherein at the first temperature a detectable signal from a first oligo’s modification is generated while the second stem-loop oligo (both cleaved and intact forms) remains hybridized at the stem and does not generate signal, and wherein at the second temperature a detectable signal from dissociation of the cleaved second stem-loop oligo is generated, while the intact second stem-loop oligo remains hybridized at the stem and does not generate signal. These features follow directly from the principles taught in Fu (detecting probe duplex dissociation at different temperatures using probes with different Tm but the same detectable signal) and Zhang (stem-loop probes exhibit distinct melting behaviors in cleaved versus intact states).
To elaborate further, the combined teachings of Mokany and Zhang (as discussed above in detail) disclose a multiplex nucleic acid detection method using stem-loop probes that are cleavable at the loop region. Zhang further teaches incubating the stem-loop probes with target at a temperature that allows dissociation of cleaved probe strands while maintaining intact stem-loop structures in a hybridized and quenched state, thereby generating detectable signal only from cleaved probes after binding to target (Zhang, page 5007, left-hand col, para 1, lines 12-22; page 5008, left-hand col, lines 3-12). Although Zhang does not further teach incubating probes at multiple temperatures such that the dissociation state of different probes can be distinguished. These additional features are obvious in view of Fu. In the context of multiplex target detection, and in view of Fu’s teaching of distinguishing different probe duplexes with identical labels based on their distinct melting temperatures, a skilled artisan would have reasonably arrived at designing at least two stem-loop probes (probe 1 and probe 2) with different Tm values for melt curve analysis 2. Under such conditions, cleavage of all target-binding probes occur simultaneously at a first temperature, as taught in Zhang, but their signal generation is distinguished by applying different temperatures, as suggested by Fu. At a first temperature, the lower-Tm probe (probe 1), at cleaved state, dissociates to generate a detectable signal, while the higher-Tm probes (both cleaved and intact forms of probe 2 and intact probe 1) remain hybridized at the stem and do not generate a signal. At a second, higher temperature, the cleaved higher-Tm probe (probe 2) dissociates and generates a detectable signal. As further taught by Fu, these signals, such as fluorescent signals are continuously measured as temperature increases and plotted as peaks relative to background signal, with temperature as the variable (Fig. 16 of Fu shows representative format of melt curve analysis result comprising distinct peaks) . Accordingly, measurements of probe-derived signals at different temperatures, based on probe structure that influences their stability at these different temperatures (e.g., sequence-dependent Tm and cleaved vs. intact state), serves as indicators of the presence of specific targets in the reaction. For example, when two targets are present in a sample, the dissociation profile produces four peaks at four distinct temperatures corresponding to the melting/dissociation of cleaved and intact hairpin probes associated with each target, wherein the cleaved probe peaks indicate the presence of targets in the sample.
The combined teachings of Mokany, Zhang and Fu render obvious the claimed method for detection of at least two targets comprising two stem-loop probes containing enzyme cleavage sites within the loop region. The probes are labeled with the same detectable label but possess distinct melting temperatures. After target-specific probe cleavage as taught by Mokany and Zhang, continuous fluorescent measurements are performed at different temperatures, such as by performing melting curve analysis with real-time detection as taught by Fu (e.g., [0180]; [0385]; [0409]; Fig. 16). Such measurements correspond to the steps of "measuring a level of detectable signal at the first temperature and the second temperature" and "determining whether" the first and second signal differs from background signal, because melting curve analysis in Fu involves continuous fluorescence measurements during gradual temperature ramping, with the resulting plots identifying peaks corresponding to probe dissociation relative to background signal (see Fig. 16; [0385]; Fig. 20 for examples).
The person of ordinary skill would have had a reasonable expectation of success in combining the teachings because the references are in the same or overlapping field of nucleic acids detection and disclose technically compatible teachings. Mokany and Zhang teach DNAzyme-based probe cleavage for target detection, while Fu teaches temperature-dependent discrimination of probes based on melting profile. All three references teach using and detecting FRET probes. These teachings involve well-understood probe hybridization and melting properties, and their combination would have predictably produced distinguishable signals for different targets based on probe cleavage and melting profiles.
B) Regarding claim 195, Fu teaches determining using a predetermined threshold value to determine if the first detectable signal arising from said modification differs from any said background signal at the first temperature ([0212] baseline value is predetermined prior to probe fluorescent measurement; [0231]).
Regarding claim 196, Zhang teaches the modification to the first oligonucleotide enables the first detection moiety to provide the first detectable signal at the first temperature; and - generation of the first detectable signal is reversible (Zhang, Scheme 1. C, the cleaved molecular beacon probe produces fluorescent signal, this signal is reversible as the stem portion of probe rehybridizes at a lower temperature).
Regarding claim 197, Zhang teaches the first target is a nucleic acid sequence (Zhang, Scheme 1. C); - the first oligonucleotide is a stem-loop oligonucleotide comprising a double- stranded stem portion of hybridised nucleotides on opposing strands of which are linked by an unbroken single-stranded loop portion of unhybridised nucleotides of which all or a portion is/are complementary to the first target;- the modification of the first oligonucleotide is a conformational change arising from hybridisation of the target to the single-stranded loop portion of the first oligonucleotide by complementary base pairing (Zhang, Scheme 1. C); and
- the conformational change is dissociation of strands in the double-stranded stem portion of the first oligonucleotide arising from said hybridisation of the target to the single- stranded loop portion of the first oligonucleotide by complementary base pairing (Zhang, Scheme 1. C).
Regarding claim 199, Zhang teaches the first detection moiety is a fluorophore and the modification increases its distance from a quencher molecule (Zhang, Scheme 1. C). Regarding claim 208, Mokany teaches MNAzyme (Fig. 1, 2). As discussed above, the combined teachings of Mokany and Zhang teach binding of the first MNAzyme to the second target and hybridisation of substrate arms of said first MNAzyme to the loop portion of the intact stem-loop oligonucleotide, to thereby digest the one or more unhybridised nucleotides of the intact stem-loop oligonucleotide and provide the split stem-loop oligonucleotide (Zhang, Scheme 1. C; Mokany, Fig. 2 teaches detecting a 2nd target using MNAzyme), and wherein: - the second target is a nucleic acid sequence(Zhang, Scheme 1. C; Mokany, Fig. 2 ); and
- the second target hybridizes to the sensor arms of the first MNAzyme by complementary base pairing to thereby facilitate assembly of the first MNAzyme (Zhang, Scheme 1. C; Mokany, Fig. 2).
Regarding claim 210, Fu teaches melt curve analysis ([0180]; [0385]; [0409]; Fig. 16).
Regarding claim 211, Fu teaches generating a first target positive control signal using a known concentration of the first target and a known concentration of the first oligonucleotide after said modification (Fig. 16B).
Regarding claim 212, Fu teaches assessing a negative control signal that does not contain the target ([0441] lines 15-21) and normalising detectable signal using said negative control signal ([0441] lines 15-21; [0228])).
Regarding claim 213, Fu teaches the first and second detectable moieties emit in the same colour region of the visible spectrum ([0250]; [0166]).
Double Patenting- Obvious Type -- New Grounds
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 194, 196-197, 199, 208 and 210-213 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9, 15, 17 and 20-21 of U.S. Patent No.12163182B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are obvious over claims of the '182 patent.
Instant claim 194 recites:
A method for determining the presence or absence of first and second targets in a sample, the method comprising:
(a) preparing a mixture for a reaction by contacting the sample or a derivative thereof putatively comprising the first and second targets with:
- a first oligonucleotide for detection of the first target, and comprising
a first detection moiety capable of generating a first detectable signal ,
wherein the first target is capable of inducing a modification to the first oligonucleotide thereby enabling the first detection moiety to generate the first detectable signal;
- an intact stem-loop oligonucleotide for detection of the second target, and comprising
a double-stranded stem portion of hybridised nucleotides, opposing strands of which are linked by an unbroken single-stranded loop portion of unhybridised nucleotides,
wherein the stem portion comprises a second detection moiety capable of generating a second detectable signal,
wherein the first and second detection moieties are capable of generating the same detectable signals; and
- a first enzyme capable of digesting one or more of the unhybridised nucleotides of
the intact stem-loop oligonucleotide only when the second target is present in the sample to thereby break the single-stranded loop portion and provide a split stem-loop oligonucleotide (‘182 Patent, claim 1);
(b) incubating the mixture at a first temperature and a second temperature,
wherein the second temperature is higher than the first temperature and wherein:
- at the first temperature
- the first target, if present, induces a modification to the first oligonucleotide thereby enabling the first detection moiety to generate the first detectable signal, and
- opposing strands of the double-stranded stem portion of the split stem- loop oligonucleotide cannot dissociate thereby preventing the second detectable moiety from providing the second detectable signal; and
- at the second temperature:
- opposing strands of the double-stranded stem portion of the split stem- loop oligonucleotide partially or completely dissociate enabling the second detection moiety to provide the second detectable signal, and
- opposing strands of the double-stranded stem portion of the intact stem- loop oligonucleotide cannot dissociate thereby preventing the second detectable moiety from providing the second detectable signal (‘182 Patent, claim 1);
(c) measuring a level of detectable signal at the first temperature and the second temperature (‘182 Patent, claim 1);
(d) determining whether:
- the first detectable signal arising from said modification differs from a background signal at the first temperature and is indicative of the presence of the first target in the sample;
- the second detectable signal arising from dissociation of opposing strands of the double-stranded stem portion of the split stem-loop oligonucleotide differs from the background signal at the second temperature and is indicative of the presence of the second target in the sample (‘182 Patent, claim 21).
Therefore, instant claims 194, 196-197, 199 and 213 are anticipated by claims 1, 21 of the '182 patent. Instant claims 208; 210; 211; 212 are anticipated by claims9; 15; 17; 20 of the '182 patent, respectively.
Conclusion
Claim 194 is objected to; claims 194-197, 199, 208 and 210-213 are rejected. No claims are allowed.
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.
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/TIAN NMN YU/Examiner , Art Unit 1681 /AARON A PRIEST/Primary Examiner, Art Unit 1681
1 MNAzyme is an engineered version of DNAzyme, with the same function of cleaving a ss site between two ds regions. See Mokany et al. MNAzymes, a versatile new class of nucleic acid enzymes that can function as biosensors and molecular switches. J Am Chem Soc. 2010 Jan 27;132(3):1051-9. doi: 10.1021/ja9076777. PMID: 20038095; PMCID: PMC2808728
2 Approaches of designing oligonucleotide probes with specific Tms is well-known in the art and disclosed in Fu in para. [0140]