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 .
Claims 23 and 25-30 are pending and under examination. Claims 1-22 and 24 are canceled. Claim 23 is amended. Claims 25-30 are new.
Response to Amendment
The Amendment filed 3/31/26 has been entered. Claims 23 and 25-30 are pending.
Response to Arguments
Applicant’s arguments, see pages 4-7, filed 3/31/26, with respect to the rejection of claim 23 under 35 USC 103 have been fully considered and are found persuasive. Therefore, the rejections documented in the Non-Final mailed 1/22/26 have been withdrawn. However, upon further consideration, new grounds of rejections necessitated by claim amendments and new claims 25-30 are made in this Final Office Action.
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.
Claims 23, 25-26, and 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over Wu et al. (2016; NPL citation U in PTO-892 filed 11/3/25; "Screening and development of DNA aptamers as capture probes for colorimetric detection of patulin"; Analytical Biochemistry 508 (2016) 58-64; http://dx.doi.org/10.1016/j.ab.2016.05.024) in view of Schmitz et al. (2020; NPL citation U in PTO-892, page 2, filed 5/14/25; "A SARS-CoV-2 spike binding DNA aptamer that inhibits pseudovirus infection in vitro by an RBD independent mechanism". bioRxiv preprint. https://doi.org/10.1101/2020.12.23.424171) and Juang et al. (2018; NPL citation 1 on IDS filed on 4/15/22; “Proton-ELISA: Electrochemical immunoassay on a dual-gated ISFET array”; Biosensors and Bioelectronics 117 (2018) 175–182. https://doi.org/10.1016/j.bios.2018.06.012).
This new 103 rejection is necessitated by claim amendments and new claims filed 3/31/26.
(i) Wu et al. teaches limitations relevant to claims 23, 25-26, and 30.
Relevant to claim 23, Wu et al. Abstract teaches "Patulin (PAT) is a kind of mycotoxin that has serious harmful impacts on both food quality and human health. A high-affinity ssDNA aptamer that specifically binds to patulin was generated using systemic evolution of ligands by exponential enrichment (SELEX) assisted by graphene oxide (GO)… the sequence PAT-11 bound to patulin with high affinity and excellent selectivity…"
This teaching provides for the Wu et al. detection of a target substance (patulin (PAT)) via a binding substance of a nucleic acid aptamer (ssDNA aptamer PAT-11).
Further relevant to claim 23, Wu et al. teaches that "In first stage, the capture probes (aptamer and glucose oxidase immobilized on AuNPs) hybridized with the separation probes (cDNA immobilized on MNPs) and formed the sandwich complex. In the second stage, glucose oxidase-catalyzed oxidization of glucose led to the formation of gluconic acid and hydrogen peroxide (H2O2). The latter can catalytically oxidize iron (II) to iron (III), which can rapidly coordinate with squaric acid (SQA). Formation of the iron squarate complex causes the color of the solution to change to brownish red accompanying the increasing absorbance (l ¼ 469 nm) of the generated SQA-iron (III) chelate [citation]. In the presence of patulin, the aptamer preferentially bonds with the target and causes the partial capture of probes and the dissociation of separation probes. With an external magnetic field, the remaining capture probes were resuspended in buffer after separation. Accompanying the capture probes, the carried glucose oxidase can trigger the enzymatic catalytic reaction to produce the colored product. The change in the color/absorbance indirectly depends on the concentration of target patulin in the sample. By monitoring the shift in absorbance, we can quantitatively determine the concentration of target patulin in the sample" (page 62, column 1 continued to first paragraph of column 2).
The Wu et al. magnetic field reads on the instant removing a remainder of the plurality of conjugates that is not bound to the target substance in a state where the target substance is not immobilized on the solid phase.
Further relevant to claim 23, Wu et al. teaches "the capture probes were assembled by aptamer PAT-11 and glucose oxidase immobilized on gold nanoparticles (AuNPs)" (page 60, first paragraph of Section "Aptamer-based colorimetric bioassay"). The Wu et al. capture probes with an aptamer (binding substance) and enzyme (label) read on the instant conjugates. Notably, the label is conjugated with the binding substance via the AuNPs.
Further relevant to claim 23, Wu et al. Table 1 teaches that the PAT-11 DNA aptamer contains 40 nucleic acid bases.
The Wu et al. PAT-11 aptamer has an activity to bind to the target substance, a molecular weight less than a molecular weight of an immunoglobulin, and is a nucleic acid aptamer.
Further relevant to claim 23 and relevant to claim 30, Wu et al. teaches that the capture probes and patulin were incubated together in solution, without the patulin target substance immobilized on a solid phase (page 60, second paragraph of Section "Aptamer-based colorimetric bioassay"). As noted, the capture probes contain both the binding substance (aptamer) and label (glucose oxidase). Thus, binding the target substance enables binding the label with the target substance, as both components are brought into proximity via capture probe. The Wu et al. methodology enables allowing the plurality of conjugates and the target substance to coexist in a solution while not immobilizing the target substance on a solid phase (claim 23); and the plurality of conjugates and the target substance coexist in solution prior to detection (claim 30).
Further relevant to claim 23, Wu et al. Figure 1 teaches that the glucose acid catalyzes a detectable phenomenon of a change in hydrogen ion concentrations when the target-aptamer-capture probes come into contact, reading on detecting the target substance by detecting… the hydrogen ions generated by the label conjugated to the nucleic acid aptamer.
Relevant to claim 25, Wu et al. teaches "the capture probes were assembled by aptamer PAT-11 and glucose oxidase immobilized on gold nanoparticles (AuNPs)" (page 60, first paragraph of Section "Aptamer-based colorimetric bioassay").
Relevant to claim 26, Wu et al. Figure 1 teaches that glucose oxidase (label) catalyzes enzymatic metabolism of glucose (substrate) to generate hydrogen ions.
(ii) Wu et al. is silent to specifics regarding the target substance being a spike protein (claim 23) and novel coronavirus SARS-CoV-2 (claims 23 and 30). However, these limitations are known in the prior art and taught by Schmitz et al.
Schmitz et al. teaches "A SARS-CoV-2 spike binding DNA aptamer that inhibits pseudovirus infection in vitro by an RBD independent mechanism" (Title).
The receptor binding domain (RBD) of the spike glycoprotein of the coronavirus SARS-CoV-2 (CoV2-S) is a component viral envelope protein.
Relevant to claims 23 and 30, Schmitz et al. teaches "Having shown SP6 [DNA aptamer] interacts with CoV2-S without interfering with complex formation with its cellular receptor ACE2, we next studied the impact of SP6 on viral infection. To address this question, we used the established VSV-ΔG*-based pseudotype system [citations] and generated Cov2-S and VSV-G pseudotyped virus particles. The interaction of SP6 with the CoV2-S pseudotyped virus was verified by an enzyme-linked oligonucleotide assay (ELONA) [citation]. In this experiment, the CoV2-S protein or the CoV2-S pseudotyped virus were captured by a nanobody binding to the RBD of CoV2-S and after washing the bound protein or pseudovirus particles were detected by adding biotinylated SP6, streptavidin-horse radish peroxidase (HRP) conjugates and its substrate 2,2′-Azino-di(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) (Supporting Fig. 4). We observed a concentration dependent increase in signal when SP6 and SP6.34 were used for detection, but not when employing SP6C and SP6.34C (Supporting Fig. 4a). Likewise, SP6 but not SPC6C detected the CoV2-S pseudotyped virus" (page 7-8).
The Schmitz et al. aptamer SP6 detects the claim 23 the target substance being a spike protein of a novel coronavirus SARS-CoV-2 that is detectable without the spike protein being separated from the novel coronavirus SARS-CoV-2; and claim 30 novel coronavirus SARS-CoV-2.
(iii) Although Wu et al. and Schmitz et al. are silent to specifics regarding detection via ion-sensitive field effect transistor (claims 23 and 29), this limitation is known in the prior art and taught by Juang et al.
Relevant to claims 23 and 29, Juang et al. Abstract teaches “an electrochemical immunoassay platform called Proton-ELISA (H-ELISA) for the detection of bioanalytes. H-ELISA uniquely utilizes protons as an immunoassay detection medium, generated by the enzyme glucose oxidase… A proton-sensitive dual-gated ion-sensitive field effect transistor (DG-ISFET) sensor was also developed for sensitive and accurate detection of the proton signal in H-ELISA.”
This teaching reads on claim 23 detecting the target substance by detecting, with an ion-sensitive field effect transistor, the hydrogen ions generated by the label; and claim 29 the ion-sensitive field effect transistor is a dual-gated ion-sensitive field effect transistor.
(iv) Although Wu et al. does not include the Schmitz et al. limitations (SARS-CoV-2 spike protein target substance) or the Juang et al. limitation (ion-sensitive field effect transistor), they would have been prima facie obvious to the skilled artisan. It is noted that Wu et al., Schmitz et al., and Juang et al. are analogous disclosures to the instant method for detecting target substances.
The skilled artisan would have been motivated to combine the analogous disclosures. Schmitz et al. Abstract teaches “The receptor binding domain (RBD) of the spike glycoprotein of the coronavirus SARS-CoV-2 (CoV2-S) binds to the human angiotensin converting enzyme 2 (ACE2) representing the initial contact point for leveraging the infection cascade. We used an automated selection process and identified an aptamer that specifically interacts with CoV2-S. The aptamer does not bind to the RBD of CoV2-S and does not block the interaction of CoV2-S with ACE2. Notwithstanding, infection studies revealed potent and specific inhibition of pseudoviral infection by the aptamer. The present study opens up new vistas in developing SARS-CoV2 infection inhibitors, independent of blocking the ACE2 interaction of the virus and harnesses aptamers as potential drug candidates and tools to disentangle hitherto inaccessible infection modalities, which is of particular interest in light of the increasing number of escape mutants that are currently being reported.” Schmitz et al. teaches “SP6 revealed binding to CoV2-S” (page 7). Schmitz et al. teaches “The coronavirus SARS-CoV-2 binds via its spike protein (CoV2-S) to the extracellular domain of the human angiotensin-converting enzyme 2 (ACE2) initiating the entry process into target cells” (page 1 of Introduction).
Thus, the skilled artisan would have been motivated to include the Schmitz et al. SARS-CoV-2 spike protein target substance limitations within the Wu et al. detection methodology because Schmitz et al. teaches that the viral envelope protein is critical to the virus’s entry into target cells, and would thus be critical in the viral pathogenesis and disease progression. Additionally, the skilled artisan would be motivated to examine SARS-CoV-2 within the Wu et al. detection methodology because Schmitz et al. teaches that escape mutants are increasingly being reported and that there is “particular interest” amongst other skilled artisans.
The skilled artisan would have been motivated to use the Juang et al. ion-sensitive field effect transistor within the Wu et al. methodology because Juang et al. teaches that it is capable of providing a separate, non-colorimetric measurement of the GOx-mediated ionic changes that the Wu et al. methodology generates. The skilled artisan would be further motivated by the Juang et al. Abstract teaching that “the platform is compatible with complex biological sample conditions such as human serum, suggesting that the platform is sufficiently robust for potential diagnostic applications.”
The skilled artisan would have a reasonable expectation of success based on the disclosures of Wu et al. in view of Schmitz et al. and Juang et al., as discussed in the preceding paragraphs.
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Wu et al. (2016; NPL citation U in PTO-892 filed 11/3/25; "Screening and development of DNA aptamers as capture probes for colorimetric detection of patulin"; Analytical Biochemistry 508 (2016) 58-64; http://dx.doi.org/10.1016/j.ab.2016.05.024) in view of Schmitz et al. (2020; NPL citation U in PTO-892, page 2, filed 5/14/25; "A SARS-CoV-2 spike binding DNA aptamer that inhibits pseudovirus infection in vitro by an RBD independent mechanism". bioRxiv preprint. https://doi.org/10.1101/2020.12.23.424171) and Juang et al. (2018; NPL citation 1 on IDS filed on 4/15/22; “Proton-ELISA: Electrochemical immunoassay on a dual-gated ISFET array”; Biosensors and Bioelectronics 117 (2018) 175–182. https://doi.org/10.1016/j.bios.2018.06.012), as applied to claims 23, 25-26, and 29-30 above, and further in view of Odeh et al. (2020; NPL citation X in PTO-892, page 1, filed 5/14/25; "Aptamers Chemistry: Chemical Modifications and Conjugation Strategies". Molecules 2020, 25, 3; doi:10.3390/molecules25010003).
The teachings of Wu et al. in view of Schmitz et al. and Juang et al. are applied to instantly rejected claim 27 as they were applied to claims 23, 25-26, and 29-30 as rendering obvious a method for detecting a target substance. Wu et al. in view of Schmitz et al. and Juang et al. is silent to specifics regarding fusing the binding substance and label together with a chemical substituent (claim 27). However, these limitations were known in the prior art and taught by Odeh et al.
Odeh et al. teaches “Aptamers Chemistry: Chemical Modifications and Conjugation Strategies” (Title).
Relevant to claim 27, Odeh teaches “Thiol maleimide coupling chemistry or Michael addition of a thiol to a maleimide” (page 27, Section “4.3. Thiol Maleiimide and Related Chemistry”); and “N-hydroxysuccinimide-activated QD [quantum dot] was covalently linked to… aptamer” (last sentence of page 25 continued to first sentence of page 26).
These teachings read on claim 27 the nucleic acid aptamer and the label are conjugated through a chemical substituent selected from the group consisting of… N-hydroxysuccinimide, maleimide.
Although Wu et al., Schmitz et al. and Juang et al. do not include these chemical substituent fusions, it would have been prima facie obvious to the skilled artisan. Wu et al. and Odeh et al. are analogous disclosures to the instant aptamer-enabled detection methodology.
The skilled artisan would find it obvious – and be motivated – to use the chemical substituents disclosed by Odeh et al., as Odeh et al. teaches that “introducing chemical modifications into nucleic acid libraries increases the interaction capabilities of aptamers and thereby their target spectrum [citation]. Modified aptamers may show improved chemical diversity relative to aptamers composed entirely of natural DNA or RNA nucleotides and expand their applications in diagnostics, therapeutics, and nanotechnology” (page 2, paragraph 2).
The skilled artisan would have a reasonable expectation of success based on the disclosures of Wu et al. in view of Schmitz et al. and Juang et al., and further in view of Odeh et al., as discussed in the preceding paragraphs.
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over Wu et al. (2016; NPL citation U in PTO-892 filed 11/3/25; "Screening and development of DNA aptamers as capture probes for colorimetric detection of patulin"; Analytical Biochemistry 508 (2016) 58-64; http://dx.doi.org/10.1016/j.ab.2016.05.024) in view of Schmitz et al. (2020; NPL citation U in PTO-892, page 2, filed 5/14/25; "A SARS-CoV-2 spike binding DNA aptamer that inhibits pseudovirus infection in vitro by an RBD independent mechanism". bioRxiv preprint. https://doi.org/10.1101/2020.12.23.424171) and Juang et al. (2018; NPL citation 1 on IDS filed on 4/15/22; “Proton-ELISA: Electrochemical immunoassay on a dual-gated ISFET array”; Biosensors and Bioelectronics 117 (2018) 175–182. https://doi.org/10.1016/j.bios.2018.06.012), as applied to claims 23, 25-26, and 29-30 above, and further in view of Song et al. (2020; NPL citation 2 on IDS filed on 4/15/22; “Discovery of Aptamers Targeting the Receptor-Binding Domain of the SARS-CoV-2 Spike Glycoprotein”. Anal. Chem. 2020, 92, 9895−9900. DOI: 10.1021/acs.analchem.0c01394).
The teachings of Wu et al. in view of Schmitz et al. and Juang et al. are applied to instantly rejected claim 28 as they were applied to claims 23, 25-26, and 29-30 as rendering obvious a method for detecting a target substance. Wu et al. in view of Schmitz et al. and Juang et al. is silent to specifics regarding chemically synthesizing the binding substance (claim 28). However, these limitations were known in the prior art and taught by Song et al.
Relevant to claim 28, Song et al. teaches that “The smaller size of aptamers (about 2−3 nm in diameter), as compared to antibodies (about 12−15 nm in diameter), subjects them to less steric hindrance on the surface of coronavirus (about 100 nm in diameter). In theory, the smaller size allows for the binding of more recognition molecules on the same surface area of coronavirus. Due to the chemical nature of nucleic acid, aptamers can be chemically synthesized, precisely modified, and high thermally stable and possess little batch-to-batch variation. These traits make for convenient transportation, storage, and standardization. Additionally, aptamers can be combined with other technologies to expand their performance and applications” (page 9895, column 2, paragraph 1). Song et al. performs SELEX to generate SARS-CoV-2 RBD-directed aptamers (page 9896, Sections “SELEX Procedures” and “Enrichment of DNA Library against SARS-CoV-2 RBD”).
These teachings read on claim 28 wherein the nucleic acid aptamer is chemically synthesized in vitro.
Although Wu et al. methodology does not include chemically synthesizing the binding substance, it would have been prima facie to the skilled artisan to include the Song et al. binding substance limitations within the detection methodology rendered obvious by Wu et al. in view of Schmitz et al. and Juang et al. It is noted that Wu et al., Schmitz et al., Juang et al., and Song et al. are all analogous disclosures to the instant method for detection.
The skilled artisan would be motivated by the Song et al. teachings regarding the benefits of nucleic acid aptamer syntheses (overcoming steric hindrance, stability, standardization, extensive application; see page 9895, column 2, paragraph 1). Thus, the skilled artisan would be motivated to include the Song et al.-taught limitations within the detection methodology rendered obvious by Wu et al. in view of Schmitz et al. and Juang et al. to include chemical syntheses in order to take advantage of the “chemical nature of the nucleic acid”.
The skilled artisan would have a reasonable expectation of success based on the disclosures of Wu et al. in view of Schmitz et al. and Juang et al., and further in view of Song et al.
Conclusion
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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/SARAH JANE KENNEDY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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