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 .
Claim Status
This Office Action is in response to Applicant’s Response to Election/Restriction
Requirement. Applicant’s election without traverse of Group l (claims 1-18) drawn to a method for performing a molecular diagnostic test in the reply on 04/13/2026 is acknowledged.
Applicant’s election without traverse of the following species in the reply filed on 04/13/2026 is acknowledged.
For claim 3, a lower nasal swab sample
For claim 5, the sample processing buffer functions to enable sample lysis
For claim 6, Tween 20 as surfactant, urea as reducing/denaturing reagent. RNasin Plus as ribonuclease inhibitor, and TBE as buffering salt.
For claim 12, RT-LAMP as the amplification method
For claim 13, pH as readout indicator function
For claim 14, phenol red as pH indicator, 5-Bromo-PAPS as metal indicator, and malachite green as the fluorescent/colorimetric DNA binding dye.
For claim 15, F3 primer as the primer for specific amplification, betaine as reaction enhancer, and trehalose as excipient.
Claims 1-20 are pending.
Claims 19 and 20 are withdrawn.
Claims 1-18 are currently under examination.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10/20/2023, 01/30/2024, and 09/04/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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.
Claim 6 contains the trademark/trade names Tween 20, Tween 80, Triton X-100, Triton X-114, Igepal CA-630 ,RNasin Ribonuclease Inhibitor, RNasin Plus Ribonuclease Inhibitor, RiboLock RNase Inhibitor, SUPERase, RNaseOUT, and RNAsecure.
Claim 14 contains the trademark/trade names SYBR Gold, SYBR Safe, EvaGreen, and SYTO 9.
Claim 15 contains the trademark/trade names Tween 20, Triton-100, Bst 2.0 WarmStart DNA Polymerase, and Antarctic Thermolabile Uracil-DNA-glycosylase (UDG).
Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe surfactants, nuclease inhibitors, fluorescent/colorimetric DNA binding dyes, and DNA polymerase. and, accordingly, the identification/description is indefinite.
Claim Rejections - 35 USC § 103
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) 1-5 and 8-13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Joung (Joung et. al., 2020, NPL) in view of Li (Li et. al., 2021, IDS Ref).
Joung teaches a protocol for a One-Pot Testing method for detection of SARS-CoV-2 RNA in a clinical sample. Joung recites in step 3 “Dip dry NP or AN swab in 400 µL of extraction buffer in a 1.5 mL tube. Swirl swab against the side of the tube to dislodge material.” Step 7 teaches the addition of STOPCovid reaction beads to the sample mixture (pg. 19; Protocol). Joung further teaches the ideal incubation parameters for the experiment were 60 ℃ for at least 50 minutes for lateral flow, though longer incubation times do not affect the results. In addition to lateral flow readout, STOPCovid.v1 is also compatible with fluorescence readout, which allows for simultaneous detection of an internal control using orthogonal fluorescent dyes (instant claim 1, pg. 3/par. 2 and 3).
Joung teaches in step 3 of the protocol, dipping a dry AN swab sample into extraction buffer within a tube, with no requirement of heating the sample prior to mixing with the processing buffer, teaching the limitations of instant claim 2 (pg. 19; Protocol).
Joung teaches the collection of dry anterior (AN) nasal swabs for evaluation of STOPCovid.v2, teaching the limitations of instant claim 3 (pg. 10/ par. 1, pg.12/par. 3, pg. 15/par. 1).
Joung teaches that SARS-CoV-2 was detected by a laboratory-developed RT-qPCR test using CDC distributed N1 and N2 gene primer/probe sets or tests from Hologic (Panther Fusion) and Roche (cobas) for clinical sample collection, teaching the limitations of instant claim 4 (pg.10/ par. 3).
Joung teaches STOPCovid mastermix was directly added to beads, teaching the limitations of instant claim 11 (pg. 11/par. 4).
Joung teaches a method in which the nucleic acid amplification method is RT-LAMP (instant claim 12, pg.2/par.2).
Li teaches a One-Pot RT-LAMP reaction using mild surfactants as reagents for simultaneous viral lysis and disruption of protein-protein, protein-lipid, and lipid-lipid interactions, teaching the limitations of instant claim 5 (pg.5, left col./par. 1).
Li teaches a One-Pot RT-LAMP method for analyses of nasopharyngeal swabs for SARS-CoV-2 detection in a single reaction tube, teaching the limitations of instant claim 8 (pg.2, left col./par.3-right col./par.1; pg.6, right col./par.1)
Li teaches a method of 45 clinical NP swab samples, of which 30 and 15 had been found to be COVID-19 negative and positive by RT-qPCR, respectively, were analyzed in a double-blind manner using the One-Pot RT-LAMP approach, teaching the limitations of instant claim 9 (pg.6, left col./par.1).
Li teaches all RT-LAMP assays were conducted in a designated room with
RNase-free pipettes and tubes, teaching the limitations of instant claim 10 (pg.2, right col./par. 5).
Li teaches that LAMP reaction generates a large amount of DNA and by-product that can be visually observed with color change using pH sensitive indicator dye (instant claim 13, pg. 2, left col./par. 2).
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to take the teachings of Joung with the teachings of Li to create a unified one-pot molecular diagnostic test for detecting the presence of nucleic acids in a sample. The One-pot diagnostic technique provides the benefit of simplicity and sensitivity for visual diagnosis that does not require an RNA extraction step when compared with other detection methods.
Claim(s) 6 and 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Joung (Joung et. al., 2020, NPL) in view of Li (Li et. al., 2021, IDS Ref) as applied to claims 1-5 and 8-13 above, and further in view of Hoffmeier et. al. (WO2022031992A1, Filed 8/5/2021).
The teachings of Juong and Li are discussed above.
Juong teaches a 1X Isothermal amplification buffer for LAMP comprising 0.1% Tween 20, reading the limitations of instant claim 6 (pg.7, par. 5).
Juong and Li fail to teach a sample processing buffer that comprises Urea as a reducing/denaturing agent, however this is commonly known within the art and is taught by Hoffmeier.
Hoffmeier teaches Lysis buffer compositions and methods for preparing a viral biological sample for Covid-19 testing. Paragraph [00184] recites “a protein denaturing agent may comprise a high concentration amount of an aqueous chaotropic salt(s) or an organic compound base or organic compound salt such as urea and/or an alkylated urea(s)…”, teaching the limitations of instant claims 6 and 7.
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Juong and Li with the teachings of Hoffmeier to incorporate Urea as the reducing/denaturing agent of the sample processing buffer for a unified one-pot molecular diagnostic test method. The addition of urea as a protein denaturing agent inactivates proteins in the mixture, prevents degradation of nucleic acids, sterilizes the biological sample without the need for refrigeration.
Claim(s) 14 and 16-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Joung (Joung et. al., 2020, NPL) in view of Li (Li et. al., 2021, IDS Ref) as applied to claims 1-5 and 8-13 above, and further in view of Peltzer (Peltzer et. al., 2020, NPL), Inoue (Inoue et. al., 2018, NPL), and Hoffmeier et. al. (WO2022031992A1, Filed 8/5/2021) as evidenced by New England Biolabs (Getting started with loop-mediated isothermal amplification (LAMP)).
The teachings of Juong and Li are discussed above.
Li teaches that LAMP reaction generates a large amount of DNA and by-product that can be visually observed with color change of a metal sensitive indicator such as malachite green (instant claim 14, pg. 2, left col./par. 2).
Juong and Li fail to teach a readout indicator containing phenol red and 5-Bromo-PAPS (limitations of instant claim 14), however, this was commonly known within the art and taught by Peltzer and Inoue.
Peltzer teaches a LAMP method for detection of Bovine alphaherpesvirus 1 (BoHV-1), with simpler readout using Phenol red, which is included in the Colorimetric WarmStart® LAMP 2x Master Mix used for experimentation as a visual indicator dye. (instant claims 14 and 17, pg. 3, left col./par. 2; right col./par.6). As evidenced by New England Biolab, other non-pH-based colorimetric indicators like hydroxynaphthol blue or calcein can be used with our standard LAMP mixes if samples are likely to be strongly buffered or highly variable in pH, supporting the limitation of instant claim 18 “the sample processing buffer is fully buffered” (pg. 3, section (4)).
Inoue teaches the usage of HEPES buffer adjusted to a pH of 7.0, teaching the limitations of instant claim 16.
Inoue teaches the development of a colorimetric chemosensor for Co2+ in a pure aqueous solution under physiological pH conditions with a mixture of 5-Br-PAPS and PDADMAC. Fig. 3(d) shows 5-Br-PAPS as a function of Co2+ concentration in 10 mmol L−1 HEPES buffer containing PDADMAC (100 µmol L−1) at pH 7.0, resulting in color changes of the solution that were clearly observed by the naked eye from yellow to green and blue with increasing Co2+ concentration (instant claims 14 and 18, pg.1, left col./ par.2; pg.4, right col./par.2).
Hoffmeier teaches usage of a buffer with an alkaline pH 8-8.5 that gives the SARS-CoV-2 sample less infectivity immediately after collection from a patient, teaching the limitation of instant claim 17 ([00263]).
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Juong and Li with the teachings of Peltzer, Inoue, and Hoffmeier to incorporate a basic pH of the sample processing buffer and phenol red and 5-Bromo-PAPS as pH and metal readout indicators with in a unified one-pot molecular diagnostic test method. A method using phenol red as the pH sensitive readout indicator allows for a clear color change from pink to yellow; and 5-Bromo-PAPS allows for sensitive detection of heavy metal ions that can be clearly assessed by the naked eye to distinguish a positive test result. The addition of an alkaline sample processing buffer reduces infectivity immediately after sample collection.
Claim(s) 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Joung (Joung et. al., 2020, NPL) in view of Li (Li et. al., 2021, IDS Ref) as applied to claims 1-5 and 8-13 above, and further in view of Moore (Moore et. al., 2021, NPL).
The teachings of Juong and Li are discussed above.
Li teaches that individual 25 mL RT-LAMP reactions were conducted in tubes
containing 5 mL of RNA template, 0.8 mM F3/B3 primers, 0.4 mM LF/LB primers, 1.6 mM FIP/BIP primers, 6 mM MgSO4, 1.6 mM dNTPs, 2.5 mL 10 _ Buffer (200mMTris-HCl,100mM (NH4)2SO4,100 mM KCl, 20 mM MgSO4, 1% Triton-100, pH8.8), 0.8 M Betaine, 8 U of Bst DNA polymerase mix (Optimized internally [40]), 5 U Reverse Transcriptase AMV, 0.12 mM HNB for optimizing visualization, teaching the limitations of instant claim 15 (pg.2, right col./par. 5).
Juong and Li fail to teach a mastermix comprising GuHCl, UDG, and dUTP, however, these reagents are commonly known within the art and are taught by Moore.
Moore teaches a review of LAMP based testing and best practices for SARS-CoV-2 detection. Moore recites that maintaining a heightened awareness of the potential for contamination is essential in all LAMP laboratories and further teaches an “experiment N” that incorporates the deoxyuridine triphosphate (dUTP)/uracil DNA glycosylase (UDG) (or uracil-DNA N-glycosylase [UNG]) system into LAMP amplicons (pg.244, right col./par. 4). For viral inactivation, many SARS-CoV-2 RNA purification procedures employ an initial lysis step using guanidine or TriZol, which reduces or eliminate viral infectivity without affecting RNA yields or integrity. Such steps include the use of guanidinium chloride (GnHCl), teaching the limitations of instant claim 15 (pg. 234, right col./ par. 4 – pg.235, left col./par.1)
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Juong and Li with the teachings of Moore to incorporate GuHCl, UDG, and dUTP in a mastermix in a unified one-pot molecular diagnostic test method. The skilled artisan would be motivated to add GuHCl to a mastermix to reduce or eliminate viral infectivity without affecting RNA yields or integrity, and the addition of dUTP and UDG would provide the benefit of removing carryover DNA contamination from one experiment to subsequent ones.
Conclusion
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/AVANDA E. HARVEY-BUTLER/ Examiner, Art Unit 1683
/ANNE M. GUSSOW/ Supervisory Patent Examiner, Art Unit 1683
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