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 .
Status of the Claims
It is acknowledged that the Applicant amended claims 1, 2, 4, 10, 12, and 13 and cancelled claim 5 in the reply filed June 9, 2026.
Claims 1-4, 7-10, 12, 13, 15, 18-21 are currently pending; claims 19-21 were withdrawn as being directed to unelected inventions in the office action mailed March 10, 2026.
Claims 1-4, 7-10, 12, 13, 15, and 18 have herein been examined. Claims 8-10 have been examined to the extent that they read on the elected species.
Summary of Response to Applicant’s Arguments
This action is in response to the papers filed June 9, 2026. Applicant’s remarks and amendments have been fully and carefully considered but are not found to be persuasive. Detailed responses are documented on pages 9-13 of this office action. Any new grounds of rejection presented in this Office Action are necessitated by Applicant’s amendments. Any rejections or objections not reiterated herein have been withdrawn. This action is made FINAL.
In response to the amendments to the claims, claim objections and rejections under 35 U.S.C. 112(b) have been withdrawn.
As a result of amendments to the claims, rejections under 35 U.S.C. 103 have been modified, as set forth below.
Priority
It is acknowledged that the instant application is a 371 of international PCT Application No. PCT/US2022/019086, filed 3/7/22, and that it claims benefit of provisional 63/160,141, filed 3/12/21. The effective filing date is considered to be 3/12/21.
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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1, 2, 4, 7-9, 12, 15, and 18 are rejected under 35 U.S.C. 103 as unpatentable over the combination of Kellner et al. (published January 20, 2021; Kellner et al. medRxiv 2021.01.19.21250079), Dey et al. (published Sept 20, 2019; Dey et al. ACS Omega; 4(14):16191-16200), and Thi et al. (published July 27, 2020; Thi et al. Sci Transl Med. 2020 Aug 12;12(556):eabc7075.). This rejection is further evidenced by Vienna BioCenter (published 2020; accessed from: https://www.rtlamp.org/get-started/rt-lamp-open-access/) and Bearinger et al. (published December 1, 2011; Patent Publication No. US 2011/0294199).
Kellner teaches methods of diagnosing SARS-CoV-2 using assays such as RT-LAMP (pg. 3: Summary).
Regarding claims 1 and 12, Kellner teaches a method for detecting the presence or absence of a target nucleic acid, wherein the target nucleic acids are SARS CoV-2 nucleic acids (pg. 3: Summary). Kellner teaches the method comprising contacting a sample suspected of containing the target nucleic acid (pg. 3, col. 1) with an amplification mixture comprising one or more primer sets to amplify a portion of the target nucleic acid, divalent ions, dNTPs, a dye (pg. 9: RT-LAMP), and a buffer (pg. 3, col. 1). In this case, the buffer is retained in the lysate which is added to the RT-LAMP reaction (pg. 6: RT-LAMP; pg. 10, col 1, 1st par). Although Kellner teaches a Master Mix and not polymerases explicitly, polymerases are used in RT-LAMP, as evidenced by Vienna BioCenter (RT-LAMP Reaction Assembly, see below). In this case, BstLF is the polymerase.
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Kellner teaches incubating the amplification mixture under conditions to perform an isothermal amplification reaction, wherein contacting and incubating are performed at a temperature of less than 65ºC (pg. 10, col. 1, 1st par.). Kellner teaches providing amplified target nucleic acid (in the form of the RT-LAMP product from which colorimetric signal was read: pg. 10, col. 1, 1st par.). Keller does not explicitly teach providing pyrophosphate, but pyrophosphate would be present a natural byproduct of DNA amplification, as evidenced by Bearinger (par. 114).
Kellner teaches a dye which indicates the productions of a metal-pyrophosphate complex and the presence of target nucleic acid in the sample (pg. 6: RT-LAMP). This dye – HNB – demonstrates colorimetric changes as free Mg2+ binds to pyrophosphate generated as a byproduct of amplification, as evidenced by Bearinger (par. 114).
Kellner does not teach an amino-acid functionalized perylene- 3,4:9,10-tetracarboxylic dianhydride (PDI) dye complexed with copper (X-PDI-Cu), wherein amino acid X is selected from aspartic acid, glycyl-l-aspartic acid, and glutamic acid. Kellner does not teach detecting un-complexed X-PDI in in the reaction mixture, wherein un-complexed X- PDI indicates the production of Cu-pyrophosphate and the presence of the target nucleic acid in the sample.
Dey et al. teaches a water-soluble compound suitable for biosensing applications (Abstract).
Regarding claims 1 and 12, Dey teaches an amino-acid functionalized perylene- 3,4:9,10-tetracarboxylic dianhydride (PDI) dye complexed with copper (X-PDI-Cu), wherein amino acid X is selected from aspartic acid, glycyl-l-aspartic acid, and glutamic acid (pg. 16198). Dey teaches detecting un-complexed X-PDI in in the reaction mixture, wherein un-complexed X- PDI indicates the production of Cu-pyrophosphate (pg. 16192, col. 2).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the invention to combine the teachings of Kellner and Dey, in order to utilize a dye effective at a wide range of pH (pH 4-9), with a very low limit of detection (Dey: pg. 16196-8: Conclusions).
Kellner does not explicitly teach an embodiment wherein the sample is a salivary sample, but does teach that the method is compatible with salivary samples (pg. 3, col. 1; pg. 6: RT-LAMP). Given that there are a finite number of solutions (i.e. specimen types) and there is no evidence of unexpected results, it would have been obvious to a person with ordinary skill in the art to try using saliva, in order to analyze a commonly used specimen type (pg. 6: RT-LAMP). This would be desirable as it would allow samples to be collected in a simple, non-invasive manner (pg. 7, 2nd par.).
Regarding claims 1 and 12, Kellner and Dey do not teach that the method does not include a step of heating to 950C.
Thi et al. teaches methods of diagnosing SARS-CoV-2 using assays such as RT-LAMP (Abstract).
Regarding claims 1 and 12, Thi teaches an isothermal amplification method which does not include a step of heating to 95ºC (pg. 10: Swab-to-RT-LAMP assay).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the invention to combine the teachings of Kellner and Dey with the teachings of Thi, in order to assay specimens without a prior RNA processing step (Thi: pg. 5, col. 2). This would be desirable for simpler point-of-care testing.
Regarding claims 2, 4, and 15, Kellner teaches that the amplification reaction is RT-LAMP (pg. 6: RT-LAMP). Although Kellner does not explicitly discuss the amplification mixture comprising a reverse transcriptase, RT-LAMP (or “Reverse Transcription” LAMP) requires the use of reverse transcriptase, as evidenced by Vienna BioCenter (RT-LAMP Reaction Assembly, see above).
Regarding claims 7 and 18, Kellner teaches colorimetric detection and fluorescence detection (pg. 10: 1st par.; pg. 6: RT-LAMP).
Regarding claims 8 and 9, Kellner teaches detecting target nucleic acid from a virus, where the virus is SARS CoV-2 (Summary).
Claim 3 is rejected under 35 U.S.C. 103 as unpatentable over Kellner et al. (published January 20, 2021; Kellner et al. medRxiv 2021.01.19.21250079), Dey et al. (published Sept 20, 2019; Dey et al. ACS Omega; 4(14):16191-16200), and Thi et al. (published July 27, 2020; Thi et al. Sci Transl Med. 2020 Aug 12;12(556):eabc7075), as applied to claim 1 above, and in view of Garafutdinov et al. (published August 9, 2020; Int J Biol Macromol. 2020 Oct 15;161:1447-1455). It is noted that the rejection of claim 1 was further evidenced by Vienna BioCenter and Bearinger et al.
Kellner, Dey, Thi, Vienna BioCenter, and Bearinger teach the limitations of claim 1, as discussed above.
Regarding claim 3, Kellner, Dey, Thi, Vienna BioCenter, and Bearinger do not explicitly teach the amplification mixture further comprising manganese.
Garafutdinov et al. teaches conditions favorable for polymerases used in isothermal amplification methods (Abstract).
Garafutdinov teaches an amplification mixture comprising manganese (pg. 1454: Conclusion).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the invention to combine the teachings of Kellner and Dey with the teachings of Garafutdinov, in order to increase the specificity of isothermal amplification in combination with magnesium (Garafutdinov: pg. 1451), or to enhance reverse transcriptase activity (Garafutdinov: pg. 1448, col. 1, 1st par.)
Claims 10 and 13 are rejected under 35 U.S.C. 103 as unpatentable over Kellner et al. (published January 20, 2021; Kellner et al. medRxiv 2021.01.19.21250079), Dey et al. (published Sept 20, 2019; Dey et al. ACS Omega; 4(14):16191-16200) and Thi et al. (published July 27, 2020; Thi et al. Sci Transl Med. 2020 Aug 12;12(556):eabc7075), as applied to claims 1, 8, 9 and 12 above, and in view of Zhang et al. (published April 8, 2020; Zhang et al. medRxiv 2020.04.08.20056986). It is noted that the rejections of claims 1 and 12 were further evidenced by Vienna BioCenter and Bearinger et al.
Kellner, Dey, Thi, Vienna BioCenter, and Bearinger teach the limitations of claims 1, 8, 9, and 12, as discussed above.
Regarding claims 10 and 13, Kellner teaches a primer set to amplify a portion of a gene encoding an ORF1a of SARS CoV-2 (pg. 6: RT-LAMP), which can be classified as encoding a replication protein. Kellner also teaches primers targeting the envelope/E gene (pg. 3, col. 1) and the nucleocapsid/N gene (pg. 9: Directed RT-PCR) in RT-qPCR applications.
Kellner, Dey, Thi, Vienna BioCenter, and Bearinger do not teach explicitly teach primer sets to amplify a portion of a gene encoding a replication protein, an envelope protein, and a nucleocapsid protein in a single reaction mixture.
Zhang teaches isothermal amplification methods for viral pathogens (Abstract).
Regarding claims 10 and 13, Zhang teaches incorporating primers for multiple SARS CoV-2 gene targets into a single isothermal amplification mixture (Introduction, 2nd par).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the invention to combine the teachings of Kellner and Dey with the teachings of Zhang, in order to increase confidence of sample positivity (Zhang: Introduction, 2nd par.).
Response to Arguments
In the reply, Applicant amended the claims. As a result of the amendments, the rejections under 35 U.S.C. 103 were modified as set forth above.
In the reply, Applicant argued that Kellner and Vienna BioCenter teach a method distinct from the amended claims because they each recite a step of heat-inactivation requiring heating the sample to a temperature of 95ºC.
These arguments have been fully and carefully considered. However, as a result of the amendments to the claims, the modified rejection of claims 1 and 12 relies upon the teachings of Thi (which was previously used to reject the now-cancelled claim 5) to address the relevant limitation. The relied-upon combination of references as a whole teaches the methods of claims 1 and 12. Arguments regarding Thi as applied to claim 5 from the previous office action are addressed more fully below.
In the response, Applicant argued that the substitution of salivary samples for the types of samples utilized in Kellner’s embodiments would not be an option because of the high variability of salivary samples. In the response, Applicant argued that Thi does not cure the deficiencies of Kellner and Dey because Thi describes a method for detection in pharyngeal samples. Applicant argued that these types of samples are less problematic than saliva samples and that methods applicable to pharyngeal samples are not amenable or enabling for detection of nucleic acids from saliva samples.
These arguments have been fully and carefully considered, but are not found persuasive. MPEP 2145(I) states that “Arguments presented by applicant cannot take the place of evidence in the record.” In this case, Applicant has not sufficiently supported the argument that the combination of references relied upon to teach the claimed method would be inoperable due to the variable characteristics of saliva. Furthermore, Kellner and Bearinger describe various sample types (including pharyngeal samples and salivary samples) to be functional equivalents (Kellner: pg. 3, col. 1, last par.; Bearinger: par. 70 – ‘nasal mucus’) and Thi describes the compatibility of RT-LAMP assays with direct saliva specimens (pg. 7, col. 2, 2nd to last par.). Therefore, Applicant has also not sufficiently supported arguments that methods applicable to pharyngeal samples are not amenable or enabling for detection of nucleic acids from saliva samples. The rejections are maintained.
In the response, Applicant argued that Thi teaches drawbacks of the use of crude pharyngeal samples without heat treatment (i.e. ‘the heat treatment rendered the RT-LAMP assay more stringent as it reduced false positives’) which render Thi incapable of providing motivation for the limitation of claim 1 (“wherein the method does not include a step of heating to 95ºC”) because there would be no expectation of success.
These arguments have been fully and carefully considered, but are not found persuasive. MPEP 2141.02(VI) teaches: “A prior art reference must be considered in its entirety, i.e., as a whole, including portions that would lead away from the claimed invention…‘[a] given course of action often has simultaneous advantages and disadvantages, and this does not necessarily obviate motivation to combine.’" (quoting Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165, 77 USPQ2d 1865, 1870 (Fed Cir. 2006).” In this case, there is a tradeoff between simplicity in a constrained diagnostic environment (Abstract; pg. 1, col. 2, 3rd par) and stringency. This tradeoff does not necessarily obviate a motivation to combine because a person with ordinary skill in the art may have reason to prioritize a simplified diagnostic test over a more stringent diagnostic. For example, the diagnostic test may be intended for a resource- or time-poor context. As a further example, Thi recognizes that direct testing of samples did show high sensitivity in certain subsets samples (Fig. 5); an artisan may be motivated to conduct direct testing if they have reason to screen subjects which they believe may have lower CT values. The Applicant has not sufficiently demonstrated that a person with ordinary skill in the art would not be motivated to combine. The rejections are maintained.
In the response, Applicant argued that Kellner does not teach the claimed dye system and that Dey does not teach discuss or suggest a method for isothermal amplification. Applicant further argues that it would not be obvious to exchange the HNB dye of Kellner for the PDI dye of Dey because a person with ordinary skill in the art would not automatically substitute dyes which detect different reaction products.
These arguments have been fully and carefully considered but are not found to be persuasive. The limitations of the claims are based on what the combination of references as a whole would teach or suggest to a person with ordinary skill in the art. In this case, it would be conventional to substitute one dye or detectable moiety for another, even if they were based on different modes of action. For example, Bearinger teaches colorimetric dyes generally, and that colorimetric dyes or fluorescent dyes would both be appropriate in an isothermal amplification assay (Bearinger: par. 80). These dyes detect different reaction products (Bearinger: par. 114), and therefore Bearinger supports the obviousness of interchanging dyes with different modes of action (including Kellner’s HNB dye and Dey’s PDI dye). The rejections are maintained.
In the response, Applicant argued that Garafutdinov “clearly shows that the combination of manganese with copper did not work for the isothermal amplification system they tested,” and that given this negative teaching, there is no motivation for a person with ordinary skill in the art to use manganese as in the claimed method.
This argument has been fully and carefully considered but is not found to be persuasive. The Applicant did not indicate where the negative teaching is found in Garafutdinov, and it is not clear that Garafutdinov actually teaches that manganese in combination with copper is inoperable for the purposes of isothermal amplification. Garafutdinov teaches that magnesium and copper (individually) are effective alternative cofactors (pg. 1454, col. 1; pg. 1450, col. 1), and that the presence of multiple cations has varying effects on amplification efficiency (pg. 1450, col. 2, 2nd par; Table 1). However, Garafutdinov demonstrates amplification efficiencies for combinations of cation pairs where one of the cations is magnesium (pg. 1450, col. 2, 2nd par; Table 1), including magnesium + manganese and magnesium + copper. It is not clear where or if Garafutdinov teaches that the combination of manganese and copper does not to work for isothermal amplification. Clarification is requested. The rejection is maintained.
In the response, Applicant argued that Zhang does not cure the deficiencies of Kellner, Dell, Thi, Garafutdinov, Vienna BioCenter, and/or Bearinger because Zhang teaches a multiplexed LAMP assay that detects four targets, but does not teach or suggest a set of primers for multiple SARS-CoV-2 targets.
This argument has been fully and carefully considered, but is not found to be persuasive. The specific embodiment taught by Zhang uses sets of primers which detect four targets from different targets/organisms, but Zhang contemplates the use of such multiplex assays for multiple genes from a single organism. Zhang explicitly teaches that “Detecting multiple targets from the same pathogen of interest (e.g. Gene N and Gene E from SARS-CoV-2) increases confidence when calling a sample positive…” (pg. 2, last par. ). This provides explicit motivation to utilize sets of primers for multiple SARS-CoV-targets together, as in the claimed method. A person with ordinary skill in the art would have had reasonable expectation of success because multiplex assays (including LAMP assays) are conventional (pg. 3, 1st par.) and because Zhang demonstrates a multiplex LAMP assay with >3 targets. The rejections are maintained.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Christine M Jones whose telephone number is (571)272-2585. The examiner can normally be reached Monday - Friday, 8AM - 4PM.
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/C.M.J./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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