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 .
Election/Restrictions
Applicant’s election of group IV, claims 12-18 in the reply filed on 10/22/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-11 and 19-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/22/2025.
Priority
The instant application was filed 01/12/2023 and claims priority from provisional application 63/298867 , filed 01/12/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 6/7/2023 is being considered by the examiner.
Claim Objections
Claim 15 objected to because of the following informalities:
Claim 15 is objected to as it recites “LAMP” but does not recite the full terminology for the acronym (or abbreviation). Claims are more concise when the first time an acronym (or abbreviation) is presented the full terminology is also presented. Finally an acronym (or abbreviation) may have alternative meanings to an artisan.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 12-18 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.
Claim 12 recites, “method for producing dual-labeled detection products, the method comprising: (a) performing an isothermal amplification reaction to amplify a target nucleic acid in the presence of: (i) a first hemi-duplex polynucleotide comprising a first polynucleotide strand hybridized to a second polynucleotide strand to form a duplex portion, each polynucleotide strand having a 5' end and a 3' end, the 5' end of the first polynucleotide forming a target nucleic acid sequence-specific single stranded portion that extends past the 3' end of the second polynucleotide strand, and the 3' end of the second polynucleotide strand comprising a first label; (ii) a second hemi-duplex polynucleotide comprising a third polynucleotide strand hybridized to a fourth polynucleotide strand to form a duplex portion, each polynucleotide strand having a 5' end and a 3' end, the 3' end of the third polynucleotide strand forming a single stranded portion having a region of complementarity to the duplex portion of the second polynucleotide strand of the first hemi-duplex polynucleotide and comprising a second label.” Thus the metes and bounds of the claim are unclear what is required as the recitation of “in the presence” requires as it is not an art accepted term and does not specifically require the (i) –(vi) are in a single tube or solution. Further the context of the independent claim suggests the first and second hemiduplex polynucleotides are required substrates of the amplification reaction. However, claims 16 and 17 recite, “wherein the first hemi-duplex polynucleotide is a first hemi- duplex polynucleotide of an amplification reaction probe set” and “wherein the second hemi-duplex polynucleotide is a second hemi-duplex polynucleotide of an amplification reaction probe set.” Further it is unclear how the limitations of claims 16 and 17 limit the structure or active steps of the claims. Thus the metes and bounds of the claim are unclear.
Claim 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.
Claim(s) 12-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (US 20130274135), Becherer (Anal. Methods, 2020, 12, 717-746), Phillips (Anal. Chem. 2018, 90, 6580−6586).
The claims are drawn to producing a dual labeled detection products. The claims recite limitations with respect to first and second hemiduplex polynucleotides, additional probimers, dNTP and polymerase. The specification does not define or limit a first label or second label. Further the requirements of claims 16 and 17 bring into question what is required of (i) and (ii) of the independent claim. Thus the claims are broad.
With regards to claim 12, Zhang teaches in figure 1A and 1B hemiduplexes as encompassed by the claims.
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Zhang teaches, “[0191] The primer systems described herein are able to discriminate a specific target from spurious targets either through a thermodynamic mechanism or through a kinetic mechanism. In distinguishing the target from spurious targets using a thermodynamic mechanism (described below), the strand displacement reaction is run to completion and the target is distinguished from the spurious targets based on differences in equilibrium binding affinity. To distinguish the target from spurious targets using a kinetic mechanism (described below), the strand displacement reaction is stopped before reaching equilibrium, and the differential rate in reaction completion is used to distinguish the targets from spurious targets.” Zhang teaches, “[0074] For example, at 37.degree. C. and 1 M Na.sup.+, the concentration-adjusted standard free energy for hybridization of a primer to a perfectly complementary (correct or specific) target (i.e., 100% nucleotide match) is between 1.9 kcal/mol and 6.6 kcal/mol more favorable than the concentration-adjusted standard free energy for hybridization of the same primer to a spurious target for every nucleotide that the spurious target differs from the intended target. In certain embodiments, the present primer duplexes use toehold exchange strand displacement reactions to translate this 1.9 to 6.6 kcal/mol difference in concentration-adjusted standard free energy to an optimal discrimination between the target and spurious targets. An example of the thermodynamics/kinetics of primer duplex binding to a target nucleic acid is described as follows in reference to FIGS. 3A and 3B.”
Zhang teaches, “[0240] Any one of the methods described herein may further comprise providing or combining in a single reaction one or more of the following reagents: buffer (e.g., KCl, MgCl.sub.2, Tris-HCl), dNTPs (e.g., dATP, dCTP, dGTP, dTTP at concentrations of, e.g., about 50 to about 100 .mu.M), polymerase (e.g., at concentrations of about 0.5-2.0 units per 50 .mu.l reaction), and/or water. The concentration of each strand of a primer duplex in a single reaction varies depending on, for example, the concentration of target nucleic acid. In some embodiments, about 5 to about 50 pg of plasmid or viral target may be used, or about 50 ng to about 500 ng of genomic target may be used. In such instances, the concentration each primer (the first strand and the second strand) may be, for example, about 0.05 .mu.M to about 1 .mu.M. In particular embodiments, the concentration of each primer is about 1 nM to about 1 .mu.M.” Zhang teaches “A polynucleotide may be further modified, such as by conjugation with a labeling component.” [0183]
Thus Zhang teaches the structure of (i), (ii), (iii), (iv), (v) and teaches labeling of nucleic acids.
Zhang does not specifically teach isothermal or LAMP.
However, Becherer provides a review of LAMP mediated isothermal amplification.
Becherer teaches
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Phillips teaches, “
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Thus it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing of the claims to produce a dual labeled detection products by isothermal LAMP amplification. The artisan would be motivated as Zhang teaches first and second hemiduplex polynucleotides which are labeled, additional primers, dNTPA and polymerase to amplify via strand displacement. The artisan would be further be motivated as Becherer teaches, “In the course of the last 20 years, isothermal nucleic acid amplification tests have emerged as an important diagnostic tool, not only for clinical applications, but also for food quality control and environmental monitoring. Loop-mediated isothermal amplification (LAMP) is well known for its robust and highly sensitive and specific amplification of target DNA “ (abstract). Phillips teaches “Until now, the utility of LAMP isothermal amplification outside of a laboratory has been restricted by the lack of signal transduction that is easy-to-use, low-cost, and specific. Strand displacement probes are a simple improvement to LAMP and provide instrument-free nucleic acid detection on low-cost LFIAs without requiring additional user steps. Future research will explore the combination of strand displacement probes with other isothermal amplification assays for instrument-free detection.” (6585, 1st column, bottom) The artisan would have a reasonable expectation of success as the artisan is merely using known LAMP primer, probes and conditions to provide for dual labeled detection products.
With regards to claims 13, Phillips teaches, “Isothermal nucleic acid amplification techniques, such as loop mediated amplification (LAMP), are promising methods for point-of-need pathogen identification because they can efficiently amplify targets without the expensive thermal cycling equipment of conventional PCR.” (page 6580, 1st column, top). Becherer teaches, “LAMP was first described by Notomi et al. in 200019 and was optimized with additional primers for accelerated amplification by Nagamine et al.20 It has proven itself through its high sensitivity and specificity and its tolerance to PCR inhibiting substances.21,22 The outstanding specificity is accomplished by using four to six specific primers, which recognize six to eight different regions in the target DNA sequence.” (717, 2nd column bottom, to 719).
With regards to claim 14-15, Becherer teaches, “LAMP was first described by Notomi et al. in 200019 and was optimized with additional primers for accelerated amplification by Nagamine et al.20 It has proven itself through its high sensitivity and specificity and its tolerance to PCR inhibiting substances.21,22 The outstanding specificity is accomplished by using four to six specific primers, which recognize six to eight different regions in the target DNA sequence.” (717, 2nd column bottom, to 719).
With regards to claim 16-17, the teachings of Phillips figure 1 B with respect to forward loop primer, backward loop primer and labeled probe meet these limitations.
With regards to claim 18, Zhang teaches, “[0186] A target nucleic acids utilized herein can be any nucleic acid, for example, human nucleic acids, bacterial nucleic acids, or viral nucleic acids. A target nucleic acid sample can be, for example, a nucleic acid sample from one or more cells, tissues, or bodily fluids. Target samples can be derived from any source including, but not limited to, eukaryotes, plants, animals, vertebrates, fish, mammals, humans, non-humans, bacteria, microbes, viruses, biological sources, serum, plasma, blood, urine, semen, lymphatic fluid, cerebrospinal fluid, amniotic fluid, biopsies, needle aspiration biopsies, cancers, tumors, tissues, cells, cell lysates, crude cell lysates, tissue lysates, tissue culture cells, buccal swabs, mouthwashes, stool, mummified tissue, forensic sources, autopsies, archeological sources, infections, nosocomial infections, production sources, drug preparations, biological molecule productions, protein preparations, lipid preparations, carbohydrate preparations, inanimate objects, air, soil, sap, metal, fossils, excavated materials, and/or other terrestrial or extra-terrestrial materials and sources. The sample may also contain mixtures of material from one source or different sources. For example, nucleic acids of an infecting bacterium or virus can be amplified along with human nucleic acids when nucleic acids from such infected cells or tissues are amplified using the disclosed methods. Types of useful target samples include eukaryotic samples, plant samples, animal samples, vertebrate samples, fish samples, mammalian samples, human samples, non-human samples, bacterial samples, microbial samples, viral samples, biological samples, serum samples, plasma samples, blood samples, urine samples, semen samples, lymphatic fluid samples, cerebrospinal fluid samples, amniotic fluid samples, biopsy samples, needle aspiration biopsy samples, cancer samples, tumor samples, tissue samples, cell samples, cell lysate samples, crude cell lysate samples, tissue lysate samples, tissue culture cell samples, buccal swab samples, mouthwash samples, stool samples, mummified tissue samples, autopsy samples, archeological samples, infection samples, nosocomial infection samples, production samples, drug preparation samples, biological molecule production samples, protein preparation samples, lipid preparation samples, carbohydrate preparation samples, inanimate object samples, air samples, soil samples, sap samples, metal samples, fossil samples, excavated material samples, and/or other terrestrial or extra-terrestrial samples.”
Double Patenting
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 12-18 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-19 of copending Application No. 18/15617.
This is a provisional nonstatutory double patenting rejection.
The instant claims are drawn to A method for producing dual-labeled detection products, the method comprising: (a) performing an isothermal amplification reaction to amplify a target nucleic acid in the presence of: (i) a first hemi-duplex polynucleotide comprising a first polynucleotide strand hybridized to a second polynucleotide strand to form a duplex portion, each polynucleotide strand having a 5' end and a 3' end, the 5' end of the first polynucleotide forming a target nucleic acid sequence-specific single stranded portion that extends past the 3' end of the second polynucleotide strand, and the 3' end of the second polynucleotide strand comprising a first label; (ii) a second hemi-duplex polynucleotide comprising a third polynucleotide strand hybridized to a fourth polynucleotide strand to form a duplex portion, each polynucleotide strand having a 5' end and a 3' end, the 3' end of the third polynucleotide strand forming a single stranded portion having a region of complementarity to the duplex portion of the second polynucleotide strand of the first hemi-duplex polynucleotide and comprising a second label; (iii) one or more additional primers that bind to the target nucleic acid; (iv) a deoxynucleoside triphosphate (dNTP) mixture; (v) a polymerase; and, optionally, (vi) a reverse transcriptase; and (b) producing dual-labeled detection products by using an oligonucleotide strand displacement reaction to form a duplex molecule comprising the second polynucleotide strand of (i) and the third polynucleotide strand of (ii).
The claims of 617 are drawn to . A method for producing dual-labeled detection products, the method comprising: (1) performing an isothermal amplification reaction to amplify a target nucleic acid in the presence of: a mediator displacement probe comprising (a) a first single stranded polynucleotide having a 5' end and a 3' end, comprising a target sequence-specific portion contiguously linked to a mediator complement (MedC) portion; and (b) a second single stranded polynucleotide having a 5' end and a 3' end, comprising a mediator (Med) polynucleotide sequence, a first label attached to the 5' end of the Med polynucleotide sequence, and an extension blocking agent attached to the 3' end of the Med polynucleotide sequence, wherein the MedC portion of the first single stranded polynucleotide and the Med polynucleotide sequence of the second single stranded polynucleotide are annealed together to form a first hemi-duplex molecule, wherein the target sequence-specific portion of the first single stranded polynucleotide forms the single stranded portion of the hemi-duplex molecule; and, a second hemi-duplex molecule comprising a third polynucleotide strand hybridized to a fourth polynucleotide strand to form a duplex portion, each polynucleotide strand having a 5' end and a 3' end, the 3' end of the third polynucleotide strand forming a single stranded portion having a region of complementarity to the Med polynucleotide sequence of the second single stranded polynucleotide strand of the first hemi-duplex molecule and comprising a second label, wherein the second hemi-duplex molecule does not form a hairpin; one or more additional primers that bind to the target nucleic acid; a deoxynucleoside triphosphate (dNTP) mixture; a polymerase; and optionally, a reverse transcriptase; and, (2) producing dual-labeled detection products by using an oligonucleotide strand displacement reaction to form a duplex molecule comprising the second polynucleotide strand of the mediator probe of (a) and the third polynucleotide strand of the second hemi-duplex molecule.
Thus it would have been prima facie obvious to one of skill in the art the claims of 617 are a species that anticipate or render obvious the instant claims.
The dependent claims are commensurate in scope with those of 617.
Summary
No claims are allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEVEN C POHNERT PhD whose telephone number is (571)272-3803. The examiner can normally be reached Monday- Friday about 6:00 AM-5:00 PM, every second Friday off.
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/Steven Pohnert/ Primary Examiner, Art Unit 1683
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