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
Claims 1-20 are pending. Claims 1, 4-5, 7-11, 15, and 19 are amended. Accordingly, claims 1-20 are examined herein.
Priority
The claims examined herein are treated as having an effective filing date of 03/24/2023.
Maintained 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The rejections under 35 U.S.C. § 103 are maintained. The rejections have been updated, where appropriate, in view of Applicant’s claim amendments. Any modification to the statement of the rejection, including the reliance on additional prior art, is necessitated by Applicant’s amendments to the claims and is made to address the newly added or clarified claim limitations.
Claims 1, 2, and 5-10 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent No. 11946931 referred as ‘931 (Ban et al. Methods and devices for detecting a pathogen and its molecular components. Filing date: February 1, 2021) in view of Wang et al. (Aptamer/Graphene Oxide Nanocomplex for in Situ Molecular Probing in Living Cells. Journal of the American Chemical Society. Vol. 132, No. 27, June 2010).
Regarding claims 1 and 2, ‘931 teaches a biosensor device comprising graphene-based sensing structure and an aptamer probe for detecting pathogens, including SARS-CoV-2. In particular, ‘931 states that “the disclosed technology includes biosensor devices for detecting one or more pathogens. In an example, the biosensor device includes a detection chip, which includes a substrate with a graphene surface (page 38, column 20, lines 61-64), and “one or more probes, which are attached to the graphene surface, specifically bind to one or more target molecules of the one or more pathogens (page 39, column 21, lines 2-4). The ‘931 patent further discloses that “in some embodiments, at least one of the one or more probes is an aptamer” (page 39, column 21, lines 9-10) and “in some embodiments, the probe comprises an aptamer for specific recognition of target molecules, for example, DNAs, RNAs, or proteins associated with a pathogen of interest” (page 32, column 7, lines 14-17). Additionally, the ‘931 patent states that “in some embodiments, the one or more pathogens are one or more variants of a coronavirus. In some examples, the one or more variants of the coronavirus include SARS-CoV, SARS-CoV-2, and MERS-CoV” (page 39, column 21, lines 17-20). The ‘931 patent further teaches that “in some embodiments, the target molecule is a nucleic acid or a protein. In some embodiments, the target molecule includes an S protein of SARS-CoV-2” (page 39, column 21, lines 21-24). Lastly, ‘931 discloses a finite aptamer set including the claimed sequence, stating that “in some examples, the nucleic acid aptamer is selected from Table 2 (page 39, column 21, lines 12-13). Table 2 of the ‘931 patent lists SEQ ID NO: 2 (Aptamer-S1), which corresponds to SEQ ID NO: 1 recited in claim 1, and that the sequence was screened as an aptamer candidate to be used in the biosensor.
Although ‘931 teaches a biosensor for detecting SARS-CoV-2 comprising a graphene-based detection chip and an aptamer probe selected from a defined set of screened sequences, including the sequence recited in claim 1, and wherein the aptamer binds a SARS-CoV-2 protein — the ’931 patent does not teach the following: a fluorescent dye conjugated to the aptamer; a graphene oxide solution used as part of a fluorescence-based biosensor composition; or an optical fluorescence-based detection mechanism. Instead, the ’931 patent relies on graphene-based electrical sensing.
On the other hand, Wang et al. teaches how aptamers (once selected) are used in a graphene oxide-based fluorescent biosensor, stating “an aptamer-carboxyfluorescein (FAM)/graphene oxide nanosheet (GO-nS) nanocomplex to investigate its ability for molecular probing in living cells” (Abstract, page 9274). Wang et al. further discloses that “ATP aptamer labeled with the fluorophore carboxyfluorescein (FAM) was incubated with GO-nS to form aptamer-FAM/GO-nS” (paragraph 3, page 9274). Here, Wang et al. teaches a biosensing platform comprising: an aptamer, a fluorescent dye conjugated to the aptamer, and graphene oxide.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the biosensor of the ’931 patent to incorporate the fluorescence-based sensing architecture taught by Wang et al. because Wang et al. teaches a well-established and predictable signal-generation approach in which a fluorescent dye is conjugated directly to an aptamer and combined with graphene oxide to transduce aptamer–target binding events into measurable fluorescence signals. Both the ‘931 patent and Wang et al. are directed to the same field of endeavor– aptamer-based biosensing - and rely on the same fundamental molecular recognition principle, namely, specific aptamer binding to a target molecule. Accordingly, the fluorescence-based architecture disclosed by Wang et al. would have been readily applicable to the SARS-CoV-2 aptamer biosensor disclosed in the ’931 patent.
A PHOSITA would have been further motivated to make this modification in order to provide an optical, fluorescence-based readout of the aptamer–target interaction already taught by the ’931 patent. While the ’931 patent relies on graphene-based electrical sensing, substituting Wang’s fluorescence-based detection modality represents the use of a known alternative signal-transduction technique within an already-established biosensor framework. Such substitution would have been viewed as a routine design choice to achieve a different but well-understood type of output signal, without altering the biological recognition function of the biosensor or the role of the aptamer as the binding element.
Furthermore, the ‘931 patent teaches, that in some examples, the nucleic acid of the subject aptamer is selected from the disclosed sequence listing, which includes SEQ ID NO: 2 (Aptamer-S1), corresponding to the aptamer sequence recited in Claim 1. The disclosure of a finite, defined set of screened aptamer sequences suitable for SARS-CoV-2 binding teaches a PHOSITA that any of the listed sequences may be selected for use in the biosensor based on routine design considerations. Accordingly, selecting Aptamer-S1 (SEQ ID NO: 1) from among the disclosed candidates represents a predictable and routine selection from a known group, rather than an inventive departure from the teachings of the ‘931 patent.
Additionally, a PHOSITA would have had a reasonable expectation of success in applying Wang et al.’s fluorophore-labeled aptamer/graphene oxide sensing configuration to the SARS-CoV-2 biosensor of the ’931 patent because fluorescently labeled aptamers and graphene-oxide-based fluorescence quenching systems were well characterized and widely used in the art at the time of the invention. Wang et al. demonstrates that conjugation of a fluorescent dye to an aptamer and its combination with graphene oxide produces a functional biosensing system capable of generating measurable fluorescence signals upon target interaction. Moreover, the ’931 patent teaches that the aptamer sequences disclosed in its sequence listing were screened and are suitable for binding SARS-CoV-2 targets. Combining a known fluorescence signal-generation mechanism with an aptamer expressly disclosed as a candidate for use in a SARS-CoV-2 biosensor would have been expected to yield a functioning biosensor without undue experimentation. The modification does not require altering the aptamer’s binding function or introducing unconventional chemistry, but instead applies known components according to their established functions, leading a PHOSITA to reasonably expect successful operation of the modified biosensor.
Regarding claims 5 and 6, the ‘931 patent explicitly discloses an aptamer-based biosensor wherein an aptamer binds SARS-CoV-2 antigens, including the S (spike) protein. Specifically, ‘931 describes the use of aptamer probes that specifically bind target molecules of pathogens, stating that “in some embodiments, the probe comprises an aptamer for specific recognition of target molecules, for example, DNAs, RNAs, or proteins associated with a pathogen of interest” (page 32, column 7, lines 14-17). The ‘931 patent further explains that the disclosed biosensor is applicable to SARS-CoV-2, stating that “in some embodiments, the one or more pathogens are one or more variants of a coronavirus. In some examples, the one or more variants of the coronavirus include SARS-CoV, SARS-CoV-2, and MERS-CoV” (page 39, column 21, lines 17-20). Lastly, with respect to the nature of the target molecule, the ‘931 patent teaches that the biosensor detects protein targets and identifies the SARS-CoV-2 spike (S) protein as a target molecule of the biosensor. Specifically, ‘931 states that “in some embodiments, the target molecule is a nucleic acid or a protein. In some embodiments, the target molecule includes an S protein of SARS-CoV-2” (page 39, column 21, lines 21-24).
Regarding claim 7, the ’931 patent discloses an aptamer-based biosensor configured to detect SARS-CoV-2 protein S. Specifically, ’931 teaches that “in some embodiments, the target molecule is a nucleic acid or a protein. In some embodiments, the target molecule includes an S protein of SARS-CoV-2” (page 39, column 21, lines 21-24), thereby teaching a biosensor configured to detect SARS-CoV-2 protein S. The ’931 patent further teaches aptamer probes that specifically bind target molecules of pathogens, stating that “in some embodiments, the probe comprises an aptamer for specific recognition of target molecules, for example, DNAs, RNAs, or proteins associated with a pathogen of interest” (page 32, column 7, lines 14-17). Thus, ’931 teaches that the aptamer binds the SARS-CoV-2 protein S. The ’931 patent further discloses detection of SARS-CoV-2 in samples obtained from subjects, including symptomatic or asymptomatic COVID-19 subjects. Specifically, ’931 discloses experimental detection of SARS-CoV-2 in an asymptomatic individual, stating that “for an RT-PCR positive individual (who is asymptomatic), there is a significant shift in the Dirac potential when the aptamer is present” (page 38, column 20, lines 5-10). Thus, ’931 teaches detection of SARS-CoV-2 from subjects presenting symptomatic or asymptomatic COVID-19.
Although ’931 teaches a biosensor configured to detect SARS-CoV-2 protein S using an aptamer that binds the SARS-CoV-2 protein S in samples obtained from symptomatic or asymptomatic subjects, ’931 does not expressly teach that the aptamer generates a detectable fluorescence signal upon binding because ’931 relies on graphene-based electrical sensing. However, as discussed above, Wang et al. teaches that aptamer-target binding generates a detectable fluorescence signal in an aptamer/graphene oxide fluorescence sensing system. Also, Wang et al. discloses that “fluorescence emission spectra of 100 nM ATP aptamer-FAM quenched with 3 µg/mL GO-nS (black bottom line) and fluorescence recovery by addition of ATP with concentration” (Figure 2, page 9275).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the SARS-CoV-2 aptamer biosensor of the ’931 patent to use Wang et al.’s fluorescence-based aptamer/graphene oxide signal-generation mechanism, such that binding of the aptamer to the SARS-CoV-2 protein target generates a detectable fluorescence signal. A PHOSITA would have been motivated to make this modification to provide a known optical fluorescence readout for the same aptamer-target binding event already taught by ’931, with a reasonable expectation of success because Wang et al. demonstrates that fluorophore-labeled aptamers and graphene oxide generate measurable fluorescence signals upon target interaction.
Regarding claims 8 and 9, the ‘931 patent explicitly reveals collecting biological samples for SARS-CoV-2 detection from saliva and nasopharyngeal swabs. In particularly, ‘931 states that “in some embodiments, the biological sample comprises saliva, exhaled breath, nasal swab, or nasopharyngeal swab of the subject” (page 39, column 22, lines 10-12). Also, the ‘931 patent further describes sample collection in connection with the biosensor embodiments illustrated in FIG. 3, stating that “in the example shown in FIG. 3, the biological sample containing the protein or viral particle may be collected using a nasal swab, a pharyngeal swab, or saliva” (page 32, column 7, lines 63-66). The ‘931 patent further teaches a sample receiving area configured to receive such samples, stating that “referring now to FIG. 12, in another embodiment of a device 400, a housing 410 includes a port for insertion of a detection chip 420 having all the structural and functional features of the detection chips. In this embodiment the housing 410 further includes circuitry 430, and a visual indicator 440, both of which function the same as the circuitry 330 and visual indicator 340 described hereinabove. The detection chip 420 when inserted into the housing 410 functions in the same way as the detection chip 300 by having electrical connections on a side that communicate electrically with the circuitry 430. In this embodiment, the detection chip 420 can be exposed to sample molecules, for example, by applying saliva to the chip 420 or by breathing or coughing onto the chip 420”(page 34, column 11, lines 4-17).
The ‘931 further discloses a sample receiving area configured to receive such samples. Specifically, FIG. 12 illustrates “Saliva Application” to a “Pathogen Specific Probe-Derivatized Graphene Chip” (FIG. 12, page 13), thereby showing that the biosensor includes a sample application/receiving region configured to receive a saliva sample. FIG. 12 also illustrates that the chip is inserted into a “Sensor Cartridge” having a “Port for Chip Insertion,” and further shows output of “Type: SARS-COV2” and “Test Result: Positive” (FIG. 12, page 13), thereby confirming that the sample-applied chip is received and processed by the biosensor device. Although FIG. 12 illustrates saliva application as an example, ’931 expressly discloses that the biological sample may comprise a nasal swab or nasopharyngeal swab, and the disclosed chip/sample receiving region would have been suitable for receiving biological sample material obtained from such swabs.
Furthermore, the ‘931 patent depicts sample receiving and delivery structures in FIGS 1A and 2A. FIG. 1A illustrates a workflow in which a “sample” is collected, followed by “isolation of sample,” “detection,” and capture of protein/RNA/DNA (FIG. 1A, page 3). FIG. 2A similarly illustrates “sample,” “saliva-antigen screening,” “detection,” and “capture/detection of cognate antibody or antigen” (FIG. 2A, page 4) at the 2D-transistor sensor surface. These figures further support that the biosensor includes an area configured to receive a biological sample for detection.
Lastly, the ’931 patent teaches biological sample collection and detection using a handheld device. Specifically, the ’931 patent states that “FIG. 3 is a schematic showing the collection of the biological sample and the detection of the pathogen using a handheld device” (column 2, page 29). This disclosure further demonstrates that the biosensor is configured to receive biological samples and analyze such samples for pathogen detection.
Regarding claim 10, the ‘931 patent expressly discloses that biological samples are analyzed using a biosensor device and that analytical results are generated, recorded, and collected, as set forth in the description in connection with Figures 1A-1C, 2A-2C, and 26A-26B. Specifically, the ‘931 patent describes the structure and operation of the disclosed diagnostic device, stating that “a portable diagnostic device for highly specific and sensitive detection of coronavirus SARS-CoV-2 was developed (FIGS. 1A-1C and 2A-2C). The device contains high affinity aptamers against the spike proteins of SARS-CoV-2 for active virus screening and records an electrical output to indicates a positive response. The device has in-built wireless functionality which allows rapid tracing and communication with interested decision makers (e.g., doctors, administrators, policy makers)” (page 35, column 13, lines 6-14). The ‘931 patent further explains that “FIGS. 1A-1C and 2A-2C are schematics showing the design and mechanism of a portable chip-based electronic biosensor device with a wireless communication module that facilitates efficient detection of viral RNA/DNA targets and surveillance of the viral pandemic” (page 29, column 2, lines 45-50).
Additionally, the ‘931 patent further provides experiments results demonstrating actual analysis of biological samples and collections of results using the disclosed device. Specifically, ‘931 states that “FIGS. 26A and 26B show example detection results of human saliva samples during the January 2022 Omicron wave for the N-aptamer and S-aptamer, respectively (page 38, column 20, lines 31-33), and further explains that “a total of 17 samples were analyzed using S-aptamer GFET devices, of which 10 samples resulted in a positive score, yielding an estimated 59% infection rate in the US (page 38, column 20, lines 39-42). This disclosure establishes that biological samples are analyzed using the biosensor device and that the resulting detection outputs are recorded, aggregated, and collected.
The ‘931 patent further discloses structural components corresponding to the claimed signal detection module, stating that “FIG. 12, in another embodiment of a device 400, a housing 410 includes a port for insertion of a detection chip 420 having all the structural and functional features of the detection chips. In this embodiment the housing 410 further includes circuitry 430, and a visual indicator 440, both of which function the same as the circuitry 330 and visual indicator 340 described hereinabove. The detection chip 420 when inserted into the housing 410 functions in the same way as the detection chip 300 by having electrical connections on a side that communicate electrically with the circuitry 430” (page 34, column 11, lines 4-17). FIG. 12 further shows the display output “Type: SARS-COV2” and “Test Result: Positive” (FIG. 12, page 13), demonstrating that the circuitry and display operate together to receive sensor signals, analyze the sample, and present collected results to the user. Thus, circuitry 430 and visual indicator 440 collectively teach a signal detection module configured to analyze samples and collect results.
However, the ’931 patent relies upon graphene-based electrical sensing and does not expressly teach that the signal detection module measures a fluorescence signal generated upon binding of the aptamer to SARS-CoV-2 protein. On the other hand, as discussed above, Wang et al. teaches a fluorescence-based aptamer/graphene oxide sensing platform. Wang further explains that target binding results in “extraordinary fluorescence recovery” (page 9274) that is detected as the analytical signal.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the biosensor of the ’931 patent to employ the fluorescence-based aptamer/graphene oxide detection architecture taught by Wang et al. because Wang teaches a well-established and predictable signal-generation mechanism in which a fluorescent dye conjugated to an aptamer generates a measurable fluorescence signal upon target binding. A PHOSITA would have recognized that the signal processing, analysis, display, and result collection functions already performed by the circuitry 430, visual indicator 440, and associated electronics of the ’931 patent could be adapted to process and report the output of a fluorescence detection device, such as the fluorescence-based detection architecture taught by Wang et al. Such substitution represents the predictable use of a known signal-transduction technique within an established biosensor framework and would have yielded the claimed signal detection module configured to analyze samples, collect results, detect a fluorescence signal generated upon aptamer-target binding with a reasonable expectation of success.
Claims 3 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over ‘931 and Wang et al., as applied to claim 1 above, and further in view of Weng et al. (Rapid Detection of Norovirus Using Paper-Based Microfluidic Device. bioRxiv, July 2017).
With respect to the teachings of the ‘931 patent and Wang et al., see the discussion above, which applies equally here. These references differ from the instant claims in failing to teach or specify that the fluorophore comprises a 6-carboxyfluorescein (claim 3); or that the biosensor comprises a mixture of graphene oxide and 6-carboxyfluorescein conjugated aptamer at a volume ratio of 1:1 (claim 4).
However, Weng et al. expressly teaches a graphene oxide-based fluorescent aptasensor using 6-carboxyfluorescein-labeled aptamers. In particular, Weng et al. states that “in this study, we developed a rapid and highly sensitive biosensor towards point-of-care device for noroviruses based on 6 carboxyfluorescein (6-FAM) labeled aptamer and nanomaterials, multi-walled carbon nanotubes (MWCNTs) and graphene oxide (GO). In an assay, the fluorescence of 6-FAM labeled aptamer was quenched by MWCNTs or GO via fluorescence resonance energy transfer (FRET). In the presence of norovirus, the fluorescence would be recovered due to the release of the 6-FAM labeled aptamer from MWCNTs or GO” (Abstract, page 2). Weng et al. further discloses that “in the present work, 6-carboxyfluorescein (6-FAM) labeled norovirus aptamer associated with MWCNTs or GO was employed as the “probe” to sensitively sense the presence of NoV with high specificity. MWCNTs consist of multiple rolled layers (concentric tubes) of graphitic sheets while GO is a single-atom-thick two-dimensional carbon nanomaterial and both of them are efficient quenchers to various fluorophores” (Introduction, page 5). With respect to the claimed 1:1 volume ratio, Weng et al. teaches that, “the ratio of the 6-FAM aptamer solution and MWNCTs/ GO, quenching and recovery time were optimized. In a typical optimization test, 20 µL of 6-FAM aptamer, 20 µL of MWCNTs/ GO solution were well mixed. Fluorescence intensity was measured at the time points of 0, 5 min, 10 min, 15 min and 20 min. Afterwards, 20 µL of NoV VLPs standard solution was added and mixed well. After incubation for a period time, the recovered fluorescence intensity of the resulting solutions was analyzed” (Experimental, page 9).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the biosensor of the ’931 patent as modified by Wang et al. by selecting 6-carboxyfluorescein as the specific fluorophore and by mixing graphene oxide and the 6-carboxyfluorescein-conjugated aptamer at a volume ratio of 1:1, as taught by Weng et al. Weng et al. expressly demonstrates that 6-FAM-labeled aptamers function effectively with graphene oxide in a fluorescence quenching/recovery aptasensor, thereby identifying 6-carboxyfluorescein as a known and reliable fluorophore species within the broader class of fluorophores taught by Wang et al. Selecting a specific, well-known fluorophore from among known fluorophore options represents a routine design choice that does not alter the underlying aptamer-target binding mechanism or the principle of operation of the biosensor. Furthermore, Weng et al. expressly teaches that the ratio of 6-FAM aptamer solution and GO solution was optimized, and provides an example in which 20 µL of 6-FAM aptamer and 20 µL of GO solution were mixed. This disclosure establishes that the relative amounts of graphene oxide and fluorophore-labeled aptamer were result-effective variables routinely adjusted by those skilled in the art to achieve effective fluorescence quenching and signal recovery. Once Weng et al. teaches that graphene oxide and a 6-carboxyfluorescein-labeled aptamer are combined to form a functional sensing composition at equal volumes, selecting a 1:1 volume ratio represents a predictable and routine optimization step within the known sensing architecture, rather than an inventive departure.
Lastly, a PHOSITA would have had a reasonable expectation of success in combining the teachings of the ’931 patent, Wang et al., and Weng et al. because the ’931 patent establishes that the disclosed aptamers specifically bind SARS-CoV-2 targets, while Wang et al. and Weng et al. demonstrate that fluorescently labeled aptamers combined with graphene oxide form reliable and predictable fluorescence-based sensing platforms. Although the ’931 patent employs electrical signal modulation rather than optical detection, modifying the biosensor to use a fluorescence-based readout as taught by Wang et al. and Weng et al. represents the substitution of a known signal-transduction modality for another without altering the underlying aptamer-target binding interaction that governs detection. Further, Weng et al. confirms that 6-carboxyfluorescein-labeled aptamers operate effectively within graphene oxide-based fluorescence sensing systems and that such systems are prepared by mixing graphene oxide with the fluorophore-labeled aptamer at equal volumes to achieve effective fluorescence quenching and response. Since the aptamer binding function remains unchanged and the fluorescence-based signal generation mechanism is well characterized and predictable, a PHOSITA would have reasonably expected that selecting 6-carboxyfluorescein as the fluorophore and using a 1:1 volume ratio of graphene oxide and fluorophore-labeled aptamer in the biosensor of the ’931 patent as modified by Wang et al. would yield a functioning fluorescence-based biosensor without undue experimentation. The combination therefore represents the predictable use of prior art elements according to their established functions.
Claims 11-20 are rejected under 35 U.S.C. 103 as being unpatentable over ‘931 in view of Wang et al., Weng et al., and McCauley et al. (Aptamer-Based Biosensor Arrays for Detection and Quantification of Biological Macromolecules. Analytical Biochemistry. Vol. 319, No. 2, August 2003).
Regarding claims 11-13, with respect to the teachings of the ‘931 patent and Wang et al., see the discussion above, which applies equally here. The references differ from the instant claims in failing to expressly teach or specify: mixing graphene oxide and a fluorescently labeled aptamer at a volume ratio of 1:1 to form a quenched mixture; adding the quenched mixture to a detection area on a glass-based reading substrate; and, with respect to claims 12 and 13, that the fluorescent substance comprises a fluorophore and that the fluorophore comprises 6-carboxyfluorescein.
However, as discussed above, Weng et al. expressly teaches a fluorescence-based aptamer sensing system employing graphene oxide and 6-carboxyfluorescein-labeled aptamers (Abstract, page 2). Weng et al. further discloses preparation of a quenched graphene oxide/fluorescent aptamer mixture and application of the mixture to a detection area, stating that “MWCNTs and GO were diluted with DI water to a series of concentrations ranging from 0.005 to 0.1 mg/mL. Then we mixed the MWCNTs or GO dilutions with 6-FAM aptamer working solutions of specific concentrations and incubated for a period of time to quench the fluorescence of the aptamer. The mixture was then pipetted onto the detection area of the paper based microfluidic device” (Experimental, page 7). Furthermore, as discussed above, Weng et al. teaches mixing equal volumes of fluorescently labeled aptamer and graphene oxide solution, corresponding to the claimed 1:1 volume ratio (Experimental, page 9). Additionally, Weng et al. discloses contacting the quenched mixture with a sample and detecting fluorescence recovery indicative of target presence, stating that “during an assay, the fluorescence intensities of the reaction (sensing) zone were recorded as reference. Then aliquots of varying concentrations of NoV VLPs in PBS buffer (10µL) and controls were loaded onto the central, the liquid would diffuse into the detection area spontaneously due to the capillary force. After incubation, the fluorescence intensities of the reaction (sensing) zone were measured again to quantitatively analyse the sample concentration” (Experimental, page 8). Weng et al. further discloses that “20 µL of NoV VLPs standard solution was added and mixed well. After incubation for a period time, the recovered fluorescence intensity of the resulting solutions was analyzed” (Experimental, page 9).
On the other hand, McCauley et al. teaches performing aptamer-based fluorescence detection performed on glass substrates, stating that “aptamers were each fluorescently labeled and immobilized on a glass substrate” (Abstract, page 244). McCauley et al. further reveals that “a fluorescently labeled anti-thrombin aptamer covalently attached to a glass support detected thrombin in solution with high sensitivity, with thrombin binding measured by changes in evanescent wave-induced fluorescence anisotropy of the immobilized aptamer” (page 245, paragraph 1). Furthermore, McCauley discloses that “for chip studies, aptamers were immobilized on a streptavidin-derivatized glass substrate” (Materials and methods, page 245). These disclosures teach performing fluorescence-based aptamer sensing on a glass-based detection substrate.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the SARS-CoV-2 aptamer detection method of the ’931 patent, as modified by Wang et al., by using the graphene oxide/6-carboxyfluorescein-labeled aptamer fluorescence quenching/recovery workflow taught by Weng et al., including mixing graphene oxide and the fluorescently labeled aptamer at a 1:1 volume ratio to form a quenched mixture, contacting the quenched mixture with a sample, and detecting fluorescence recovery upon target binding. A PHOSITA would have been motivated to do so because Weng et al. teaches that graphene oxide effectively quenches fluorescence of 6-FAM-labeled aptamers and that target binding causes fluorescence recovery, thereby providing a direct, measurable, and predictable optical readout of an aptamer-target binding event. Since the ’931 patent already teaches SARS-CoV-2 aptamer-target recognition, the Weng fluorescence quenching/recovery mechanism would have been a predictable signal-transduction approach for reporting the same type of aptamer-target binding event. It also would have been obvious to select a fluorophore as recited in claim 12 and 6-carboxyfluorescein as recited in claim 13. Wang et al. already teaches labeling an aptamer with the fluorophore carboxyfluorescein in an aptamer/graphene oxide nanocomplex, and Weng et al. further confirms that 6-carboxyfluorescein-labeled aptamers function in graphene oxide-based fluorescence quenching/recovery assays. Selecting 6-carboxyfluorescein would have been a routine selection of a known fluorescent label used for aptamer detection, particularly where the selected dye was already known to be compatible with graphene oxide quenching and target-induced fluorescence recovery. The selection would not alter the aptamer’s target-binding function, but would merely provide a known optical label for detecting binding.
It further would have been obvious to use the 1:1 volume ratio recited in claim 11 because Weng et al. expressly teaches optimizing the ratio of 6-FAM aptamer solution and GO solution and provides an equal-volume example in which 20 µL of 6-FAM aptamer and 20 µL of GO solution are mixed. The relative amounts of fluorescent aptamer and graphene oxide affect fluorescence quenching and recovery, and Weng et al. treats the ratio as an optimization parameter. Accordingly, selecting the 1:1 volume ratio taught by Weng et al. would have been an obvious matter of routine optimization of known result-effective variables to obtain sufficient quenching and measurable recovery signal. It further would have been obvious to add the quenched mixture to a detection area on a glass-based reading substrate as recited in claim 11. Weng et al. teaches placing the quenched aptamer/nanomaterial mixture on a detection area of a microfluidic substrate, and McCauley et al. teaches that glass substrates were suitable and conventional supports for fluorescence-based aptamer biosensor arrays. A PHOSITA would have been motivated to use a glass-based substrate because McCauley et al. demonstrates that fluorescently labeled aptamers immobilized on glass can detect protein targets with high sensitivity, and because glass substrates are optically compatible with fluorescence excitation and emission detection. Substituting or selecting a glass-based reading substrate for the fluorescence-based aptamer detection system would have been a predictable design choice for conducting optical aptamer sensing.
Lastly, a PHOSITA would have had a reasonable expectation of success in combining these teachings because the cited references rely on the same fundamental principle of aptamer-target recognition and known optical signal generation from fluorescently labeled aptamers. The ’931 patent provides the SARS-CoV-2 aptamer detection context; Wang et al. and Weng et al. provide the known graphene oxide/fluorescent aptamer quenching and recovery mechanism; and McCauley et al. provides a known glass-based substrate for fluorescence aptamer detection. Combining these teachings would not require changing the target-recognition function of the aptamer, but only applying known fluorescence transduction and substrate choices to a known aptamer-based detection method. Thus, the claimed method of claims 11-13 would have been the predictable use of prior art elements according to their established functions and would have yielded predictable fluorescence-based detection of SARS-CoV-2 protein without undue experimentation.
Regarding claim 14, the ‘931 patent discloses a nucleotide sequence, SEQ ID NO: 2 (Aptamer-S1), which corresponds to the aptamer sequence recited in claim 14. The ‘931 patent teaches that the nucleic acid sequence was screened as an aptamer candidate and it may be selected as the aptamer used in the biosensor (page 39, column 21, lines 12-13).
Regarding claims 15 and 16, the ‘931 patent discloses aptamers that bind to antigens comprising the SARS-CoV-2 virus (page 32, column 7, lines 14-17 and page 39, column 21, lines 17-20), including the S (spike) protein (page 39, column 21, lines 21-24).
Regarding claim 17, the ‘931 patent explicitly discloses an aptamer-based biosensor configured to bind SARS-CoV-2 antigens, including the S (spike) protein, and further discloses experimental detection of SARS-CoV-2 in an asymptomatic individual. In particular, the ‘931 patent states “as shown therein, in the absence of the aptamer (sensor), there is no to little change in the Dirac potential for both an individual whose RT-PCR tested positive (FIG. 24 E) and an individual whose RT-PCR tested negative (FIG. 24F). However, for an RT-PCR positive individual (who is asymptomatic), there is a significant shift in the Dirac potential when the aptamer is present” (page 38, column 20, lines 5-10). Here, an RT-PCR positive individual is a COVID-19 positive individual. The disclosure that the RT-PCR positive individual is “asymptomatic” establishes that the biosensor of the ‘931 patent is capable of detecting SARS-CoV-2 in samples obtained from an asymptomatic individual.
Regarding claims 18 and 19, as discussed above, the ‘931 patent discloses collecting biological samples for SARS-CoV-2 detection from nasopharyngeal swabs and saliva (page 39, column 22, lines 10-12 and page 32, column 7, lines 63-66).
Regarding claim 20, as discussed above, the ‘931 patent discloses that samples are analyzed using the diagnostic device, and results are recorded as an electrical output and communicated (page 35, column 13, lines 6-14; page 29, column 2, lines 45-50; page 38, column 20, lines 31-33; and page 38, column 20, lines 39-42). Accordingly, the ’931 patent teaches that samples are analyzed and the results are collected.
Response to Arguments
Applicant’s arguments filed 05/04/2026 have been fully considered but are not persuasive, except to the extent that the rejections under 35 U.S.C. 112(b) and 35 U.S.C. 112(d) are withdrawn in view of Applicant’s amendments.
With respect to the rejections under 35 U.S.C. 112(b), Applicant argues that the amendments address the prior indefiniteness issues regarding the phrases “can bind,” “approximately equal volume,” and the lack of affirmative method steps in claim 11. These arguments are persuasive to the extent that the amendments clarify the claim language. Claims 1, 5, and 15 have been amended to recite “binds” rather than “can bind”; claims 4 and 11 have been amended to recite an express 1:1 volume ratio rather than “approximately equal volume”; and claim 11 has been amended to recite affirmative method steps. Accordingly, the rejection of claims 1-20 under 35 U.S.C. 112(b) is withdrawn.
With respect to the rejection under 35 U.S.C. 112(d), Applicant argues that claims 7-10 have been amended to further limit the biosensor of claim 1. These arguments are persuasive. Claims 7-10 now recite additional biosensor configuration, sample receiving, and signal detection limitations. Accordingly, the rejection of claims 7-10 under 35 U.S.C. 112(d) is withdrawn.
With respect to the rejections under 35 U.S.C. 103, Applicant’s arguments have been fully considered but are not persuasive. The rejections under 35 U.S.C. 103 are maintained and have been updated, where appropriate, in view of Applicant’s claim amendments. Any modification to the statement of the rejection, including reliance on additional prior art, is necessitated by Applicant’s amendments to the claims and is made to address the newly added or clarified claim limitations.
Applicant argues that Ban is directed to a fundamentally different detection modality, namely graphene-based electrical sensing using GFET devices, whereas the claimed invention uses optical fluorescence detection based on graphene oxide quenching and recovery. This argument is not persuasive because the rejection of claim 1 is not based on Ban alone. Ban is relied upon for teaching the SARS-CoV-2 aptamer biosensor context, including aptamer-based recognition of SARS-CoV-2 target molecules and the SARS-CoV-2 S protein. Wang is relied upon for the known fluorescence-based aptamer/graphene oxide quenching and recovery architecture. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Applicant’s argument treats the references individually and focuses on differences between Ban’s electrical readout and the claimed optical readout. However, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Ban provides the SARS-CoV-2 aptamer-target recognition framework, while Wang provides the predictable fluorescence signal-transduction mechanism using fluorophore-labeled aptamers and graphene oxide. The modification does not require changing the biological recognition event taught by Ban. Rather, it substitutes a known fluorescence-based signal readout for another known biosensor readout in order to report aptamer-target binding.
Applicant further argues that Ban and Wang represent fundamentally different device architectures requiring different sensor construction, signal processing, and calibration approaches. This argument is not persuasive. The claims do not require the specific calibration approach, GFET circuitry, or complete device architecture of either Ban or Wang. Claim 1 broadly recites a biosensor comprising an aptamer that binds a protein, a fluorescent dye conjugated to the aptamer, and a graphene oxide solution, wherein the aptamer comprises SEQ ID NO: 1. Wang expressly teaches a fluorophore-labeled aptamer/graphene oxide nanocomplex in which graphene oxide quenches fluorescence and target binding produces fluorescence recovery. Wang further teaches that the “super quenching ability and the resulting FRET function suggest GO-nS as a universal sensing platform appropriate for various fluorescent probes.” This teaching further supports the use of graphene oxide nanosheets as a broadly applicable fluorescence quenching/sensing platform and rebuts Applicant’s assertion that Wang’s fluorescence architecture would be technically incompatible with Ban’s aptamer-based SARS-CoV-2 biosensor. Thus, the claimed fluorescence architecture would have been a predictable adaptation of known aptamer/graphene oxide sensing chemistry to the SARS-CoV-2 aptamer system taught by Ban.
Applicant argues that Wang is directed to molecular probing in living cells rather than diagnostic detection of viral pathogens in clinical samples such as nasopharyngeal swabs. This argument is not persuasive. Wang is relied upon for its teaching of a known aptamer/graphene oxide fluorescence sensing platform, not for teaching SARS-CoV-2 clinical diagnostics. Wang teaches that an aptamer labeled with carboxyfluorescein can be incubated with graphene oxide to form an aptamer-FAM/GO nanocomplex, that graphene oxide quenches fluorescence, and that target binding produces fluorescence recovery. Wang also teaches that the “super quenching ability and the resulting FRET function suggest GO-nS as a universal sensing platform appropriate for various fluorescent probes” (page 9275). This broad teaching would have suggested to a PHOSITA that Wang’s graphene oxide fluorescence quenching platform was not limited to living-cell ATP probing, but was applicable to fluorescent aptamer probes generally. Therefore, the applied art is analogous because Ban and Wang are in the same field of aptamer-based biosensing or are at least reasonably pertinent to the problem of detecting target binding using a fluorescence-based aptamer signal.
Applicant argues that a PHOSITA would not have been motivated to combine a cell-based molecular probing technique with a GFET biosensor to arrive at the claimed fluorescence-based clinical diagnostic platform. This argument is not persuasive. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). Here, the motivation is found in the references themselves: Ban teaches SARS-CoV-2 aptamer recognition; Wang teaches fluorescence signal generation using fluorophore-labeled aptamers and graphene oxide and further expressly describes GO-nS as a universal sensing platform appropriate for various fluorescent probes. A PHOSITA would have been motivated to combine these teachings to provide a predictable optical readout for a known aptamer-target binding event.
Applicant argues that the present application demonstrates unexpected results, including 96% sensitivity and 100% specificity, and that these results exceed what would have been expected from the cited art. This argument is not persuasive. This argument alone is insufficient to establish unexpected results. Applicant has not provided persuasive comparative evidence showing that the claimed subject matter achieves results unexpected relative to the closest prior art, nor has Applicant shown that the asserted results are commensurate in scope with the claims. The claims broadly recite aptamer-based fluorescence biosensors and methods and are not limited to the particular testing conditions, sample set, cutoff values, validation population, or assay parameters reported in the specification. Further, Ban already teaches SARS-CoV-2 aptamer detection, while Wang demonstrates that fluorophore-labeled aptamers and graphene oxide produce detectable fluorescence signals upon target interaction. Thus, the generation of a measurable fluorescence signal using known aptamer/GO quench-recovery chemistry would have been expected.
Applicant argues that claims 2 and 5-10 should be allowed because they depend from claim 1. This argument is not persuasive because claim 1 remains unpatentable over the combined teachings of Ban and Wang. Dependent claims are not patentable merely by virtue of dependency where the base claim is unpatentable and the additional limitations are taught or rendered obvious by the prior art.
Applicant further argues that amended claims 7-10 include specific structural features such as a sample receiving area and a signal detection module that Ban and Wang do not disclose or suggest in a fluorescence-based detection platform for SARS-CoV-2. This argument is not persuasive. Ban teaches biological sample collection and detection using a biosensor device and teaches saliva, nasal swab, and nasopharyngeal swab samples. Ban further teaches a detection chip exposed to sample molecules, including by applying saliva to the chip, and a housing, circuitry, and visual indicator that process and display detection results. These teachings support a sample receiving area and signal detection module. Wang supplies the fluorescence-based signal measured upon aptamer-target binding. Thus, the combination of Ban and Wang teaches or renders obvious the amended limitations of claims 7-10.
With respect to claims 3 and 4, Applicant argues that Liu does not teach the amended 1:1 volume ratio and does not cure the alleged deficiencies of Ban and Wang. Applicant’s arguments regarding Liu are moot to the extent Liu is no longer relied upon in the present rejection. Claims 3 and 4 are now rejected over Ban and Wang further in view of Weng. Weng expressly teaches a 6-carboxyfluorescein-labeled aptamer and graphene oxide fluorescence quenching/recovery system. Weng further teaches optimizing the ratio of 6-FAM aptamer solution and MWCNTs/GO and expressly discloses mixing 20 µL of 6-FAM aptamer with 20 µL of MWCNTs/GO solution, corresponding to a 1:1 volume ratio. Accordingly, Weng directly addresses the amended 1:1 volume ratio limitation of claim 4 and the 6-carboxyfluorescein limitation of claim 3.
Applicant argues that the 1:1 volume ratio produces optimized fluorescence quenching and recovery enabling rapid and reliable detection. This argument is not persuasive because Weng teaches that the ratio of 6-FAM aptamer solution and graphene oxide solution was an optimization parameter and provides the equal-volume example. The relative amounts of fluorophore-labeled aptamer and graphene oxide are result-effective variables because they affect fluorescence quenching and recovery. Selecting the 1:1 ratio expressly taught by Weng would have been a predictable optimization of known components to achieve effective quenching and recovery.
With respect to claim 11, Applicant argues that Ban, Wang, and McCauley do not teach or suggest the particular sequence of affirmative method steps, including conjugating, mixing at a specific 1:1 ratio to form a quenched mixture, adding to a glass-based reading substrate, contacting with a sample, and detecting fluorescence signal upon aptamer binding. This argument is not persuasive in view of the updated rejection. The present rejection relies on Ban for SARS-CoV-2 aptamer detection, Wang for the general aptamer/FAM/graphene oxide fluorescence quench-recovery platform, Weng for the specific 6-FAM aptamer/GO quenching and recovery workflow including equal-volume mixing and addition to a detection area, and McCauley for fluorescence-based aptamer detection on glass substrates. The combined teachings render the claimed sequence obvious because Weng teaches forming a quenched 6-FAM aptamer/GO mixture, applying the mixture to a detection area, contacting the system with target-containing sample, and measuring fluorescence recovery. McCauley teaches that glass substrates are suitable supports for fluorescence-based aptamer sensing.
Applicant argues that McCauley uses evanescent wave-induced fluorescence anisotropy and aptamers covalently attached to glass, whereas the claimed invention uses graphene oxide quenching and de-sequestration/recovery. This argument is not persuasive because McCauley is not relied upon to teach the graphene oxide quench/recovery mechanism. Wang and Weng teach that mechanism. McCauley is relied upon for teaching that fluorescent aptamer biosensors can be operated on glass substrates and that glass supports are suitable for fluorescence-based aptamer target detection. The fact that McCauley uses a different fluorescence detection principle does not negate its teaching that glass substrates are suitable for aptamer-based fluorescence sensing. The rejection relies on the combined teachings of the references, not bodily incorporation of McCauley’s entire system into Ban or Weng.
Applicant argues that a PHOSITA would not have been motivated to combine McCauley with Ban and Wang because McCauley employs a different fluorescence detection principle and immobilization strategy. This argument is not persuasive. Weng teaches placing the quenched aptamer/nanomaterial mixture on a detection area of a microfluidic substrate. McCauley teaches that glass substrates are suitable and conventional supports for fluorescent aptamer detection. A PHOSITA would have recognized glass as an optically compatible substrate for fluorescence excitation and emission detection and would have reasonably selected a glass-based reading substrate for optical aptamer sensing. Such selection would have been a predictable design choice that does not change the aptamer-target binding mechanism or the graphene oxide quenching/recovery chemistry.
Applicant argues that claims 12 and 14-20 should be allowed because they depend from claim 11. This argument is not persuasive because claim 11 remains unpatentable over the combined teachings of Ban, Wang, Weng, and McCauley. The additional limitations of claims 12 and 14-20 are also taught or rendered obvious. Claim 12’s fluorophore limitation is taught by Wang and Weng. Claim 14’s SEQ ID NO: 1 limitation is taught by Ban’s corresponding Aptamer-S1 disclosure. Claims 15 and 16 are taught by Ban’s SARS-CoV-2 antigen and S protein disclosures. Claim 17 is taught by Ban’s disclosure of detection in symptomatic/asymptomatic COVID-19 subjects. Claims 18 and 19 are taught by Ban’s disclosure of nasopharyngeal swabs and saliva samples. Claim 20 is taught by Ban’s sample analysis and result collection disclosures and by the fluorescence measurement teachings of Wang and Weng.
Applicant argues that claim 13 is not rendered obvious by Liu and that the selection of 6-carboxyfluorescein in the claimed quench-and-recover fluorescence method yields sensitivity and specificity that would not have been predictable. Applicant’s arguments regarding Liu are moot to the extent Liu is no longer relied upon in the present rejection. Claim 13 is now addressed by Weng, which expressly teaches 6-carboxyfluorescein-labeled aptamers in a graphene oxide fluorescence quenching/recovery biosensor. In addition, Wang teaches carboxyfluorescein-labeled aptamers with graphene oxide. Thus, selecting 6-carboxyfluorescein as the fluorophore would have been a routine selection of a known fluorescent label already shown to function predictably in aptamer/graphene oxide sensing systems.
Ultimately, Applicant’s arguments do not identify a patentable distinction over the combined prior art. The cited references are within the same field of aptamer-based biosensing or are reasonably pertinent to the problem of producing detectable optical signals from aptamer-target binding. The combinations apply known prior art elements—SARS-CoV-2 aptamers, fluorophore-labeled aptamers, graphene oxide quenching/recovery, equal-volume mixing, and glass-based fluorescence substrates—according to their established functions. The amendments have been addressed in the updated rejections, and the claims remain unpatentable under 35 U.S.C. 103.
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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/E.O./Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 June 16, 2026
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