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 and examined herein.
Priority
The claims examined herein are treated as having an effective filing date of 03/24/2023.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1- are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
First, claims 1, 5, and 15 recites the phrase “can bind.” Specifically, claim 1 recites “an aptamer that can bind a protein,” and claims 5 and 15 recite that “the aptamer can bind to antigens.” In each instance, the phrase “can bind” denotes only a capability or potential to bind, rather than requiring that binding actually occurs during use of the claimed biosensor or diagnostic method. As written, the claims encompass aptamers that are theoretically capable of binding a protein or antigen under some undefined condition, even if such binding does not occur, is negligible, or is insufficient to generate a detectable signal. For a biosensor or diagnostic test to function as claimed, the aptamer must bind the target protein or antigen during operation of the sensor. However, claims 1, 5, and 15 do not require that binding occurs, nor do they specify binding conditions, affinity, or performance criteria. As a result, a person having ordinary skill in the art (PHOSITA) cannot determine with reasonable certainty whether a given aptamer falls within the scope of the claims. Accordingly, claims 1, 5, and 15 are indefinite. To obviate this rejection, applicant may amend claims 1, 5, and 15 to remove the term “can,” such that the claims recite “an aptamer that binds a protein” or “an aptamer that binds an antigen,” thereby requiring actual binding consistent with operation of a biosensor or diagnostic method.
Also, claims 2-4 and 6-10, are rejected under 35 U.S.C. 112(b) as being dependent upon an indefinite base claim (claim 1). Claim 1 is indefinite because the phrase “can bind” fails to provide objective boundaries for the claimed aptamer. Claims 2-4 and 6-10 depend from claim 1, and do not add limitations that clarify or cure this indefiniteness. Appropriate correction is required.
Next, the term “approximately equal volume” in claim 4 is a relative term which renders the claim indefinite. The term “approximately equal volume” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In particular, the claim does not specify: a numerical ratio, an acceptable tolerance, a range of volumes, or any criterion for determining when volumes cease to be “approximately equal.” As written, the scope of the claim is unclear as to whether mixtures such as 60:40, 55:45, or other unequal proportions fall within the claim. The specification confirms this lack of objective boundaries. The disclosure refers to “approximately equal volume” only in the context of preferred or exemplary embodiments, indicating that the phrase is not used as a defining limitation. Although the specification states a “fluorescently labeled-SARS-CoV-2 specific aptamer mixed (ratio 1:1) with graphene oxide (paragraph [0047]), the specification does not define permissible deviation from equality, does not tie “approximately” to any measurable performance metric, and does not state that any specific ratio is required. Thus, since claim 4 relies on a subjective relative term untethered to objective boundaries, a PHOSITA cannot determine the metes and bounds of claim 4 with reasonable certainty. For purposes of compact prosecution, claim 4 will be interpreted to mean the following: the biosensor of claim 1, wherein the biosensor includes a mixture in which the volume of graphene oxide and the volume of the 6-carboxyfluorescein-conjugated aptamer are generally similar in amount, without any specific numerical ratio, tolerance, or quantitative boundary, such that the two components are not grossly disproportionate in volume. Appropriate correction is required.
Additionally, claim 11 is directed to “an aptamer-based method for detecting SARS-CoV-2”; however, the claim does not recite affirmative method steps that define how the method is performed. The body of the claim merely describes the composition of a biosensor and the presence or arrangement of components, rather than reciting actions constituting performance of a method (e.g., contacting a sample, incubating, detecting a signal, or determining the presence of SARS-CoV-2). As written, claim11 reads on the existence or preparation of a biosensor rather than on a sequence of acts, rendering it unclear what conduct constitutes performance of the claimed method. Accordingly, claim 11 fails to distinctly claim a method and is indefinite.
Also, the term “approximately equal volume” in claim 11 is a relative term which renders the claim indefinite. Similarly, to claim 4, the claim does not specify a numerical ratio, an acceptable tolerance or range, a performance-based criterion, or any method for determining when the volumes cease to be “approximately equal.” Since, claim 11 relies on a subjective relative term untethered to objective boundaries, a PHOSITA cannot determine the metes and bounds of the claim with reasonable certainty. For purposes of compact prosecution, claim 11 will be interpreted to mean the following: the method of claim 11, wherein graphene oxide and the fluorescence-conjugated aptamer are combined in generally similar volumetric amounts, without any specific numerical ratio, tolerance, or quantitative boundary, such that the two components are not grossly disproportionate in volume. Appropriate correction is required.
Also, claims 12-20 are rejected under 35 U.S.C. 112(b) as being dependent upon an indefinite base claim (claim 11). Since claim 11 fails is indefinite because it is directed to a method for detecting SARS-CoV-2 yet fails to recite affirmative method steps, and because it recites the relative term “approximately equal volume” without objective boundaries. Claims 12-20 depend from claim 11 and do not add limitations that clarify or cure this indefiniteness. Appropriate correction is required.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 7-10 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
In particular, claims 7-9 are dependent upon claim 1. Claim 1 is directed to a biosensor device. Claims 7-9 attempt to further limit the biosensor by reciting characteristics of patient samples, including patient clinical status and sample source (e.g., symptomatic or asymptomatic patients, nasopharyngeal swabs, saliva). However, these limitations do not recite any additional structural, compositional, or inherent functional features of the biosensor itself. The biosensor remains unchanged regardless of the source or nature of the sample used during testing. Since biological samples are external to the biosensor and are collected at the time of an assay, limitations directed to samples source or patient condition merely describe an environment of use, rather than further limiting the device. Accordingly, claims 7-9 do not further limit claim 1 and are rejected under 35 U.S.C. 112(d).
Likewise, claim 10 depends from claim 1, but recites that “the samples are analyzed and the results are collected,” which describes steps of conducting a test or assay, rather than reciting any structural, compositional, or inherent functional limitation of the biosensor itself. A proper dependent product claim must further limit the claimed product. Claim 10 does not add any additional structure, configuration, or functional characteristic of the biosensor. Instead, it recites actions performed by a user during use of the biosensor, which do not distinguish the biosensor from other biosensors and do not alter the structure or properties of the device. The biosensor of claim 1 remains unchanged regardless of whether samples are analyzed or results are collected. Since claim 10 improperly introduces method-of-use limitations into a dependent product claim, and does not further limit the biosensor of claim 1, claim 10 is an improper dependent claim and is rejected under 35 U.S.C. 112(d).
Therefore, applicant may cancel the claims, amend the claims to place the claims in proper dependent form, rewrite the claims in independent form, or present a sufficient showing that the dependent claims complies with the statutory requirements.
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.
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 capable of binding SARS-CoV-2 spike 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 configured to bind 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, as explained in the rejection under 35 U.S.C. 112(d) above, claim 7 is directed to the same biosensor as claim 1 and merely characterizes the biosensor by its intended detection target. The ‘931 patent discloses an aptamer-based biosensor configured to bind SARS-CoV-2 antigens, including the SARS-CoV-2 S (spike) protein (page 39, column 21, lines 21-24), thereby teaching a biosensor capable of detecting SARS-CoV-2 protein S. Since claim 7 does not positively limit the biosensor beyond claim 1, and the recited detection of protein S in samples from symptomatic or asymptomatic patients constitutes an intended use rather than a structural or functional distinction – claim 7 does not patentably distinguish the claimed biosensor from the biosensor disclosed in the prior art.
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).
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), thereby establishing that these figures depict analysis of biological samples using the aptamer-functionalized sensor and generation of a measurable electrical signal corresponding to the presence of SARS-CoV-2 targets.
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.
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 Liu et al. (A Novel Fluorescent Aptasensor for the Highly Sensitive and Selective Detection of Cardiac Troponin I Based on a Graphene Oxide Platform. Analytical and Bioanalytical Chemistry. Vol. 410, No. 18, May 2018).
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 a mixture of graphene oxide and 6-carboxyfluorescein conjugated aptamer using approximately equal volumes (claim 4).
However, Liu et al. expressly teaches a graphene oxide-based fluorescent aptasensor using 6-carboxyfluorescein-labeled aptamers. In particular, Liu et al. states that “we developed a highly sensitive and selective fluorescence assay to detect cTnI using anti-cTnI aptamers labeled by 6-carboxyfluorescein (6-FAM) based on a GO fluorescence sensing platform. Given its strong adsorption to the aptamers, GO can adsorb the fluorescent anti-cTnI aptamers onto its surface and subsequently quench its fluorescence” (page 4286, paragraph 3). Liu et al. further states that the “final concentrations of the mixture were adjusted to 50 nM 5’-6-FAM modified anti-cTnI aptamers (FMAA) and 40 mg/L GO. Then, the mixed solution was incubated at 37 °C for 5 min” (page 4287, paragraph 1).
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 the fluorophore-labeled aptamer with graphene oxide in approximately equal volumes, as taught by Liu et al. Liu et al expressly demonstrates that 6-carboxyfluorescein-labeled aptamers function effectively in graphene-oxide-based fluorescence sensing platforms, 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, Liu et al. expressly teaches that the graphene oxide/6-carboxyfluorescein-labeled aptamer sensing system is prepared by mixing these components and that their relative concentrations are parameters subject to adjustment. This disclosure establishes that the relative amounts of graphene oxide and fluorophore-labeled aptamer are result-effective variables that are routinely adjusted by those skilled in the art to achieve effective fluorescence quenching and signal response. Once Liu et al. teaches that graphene oxide and a 6-carboxyfluorescein-labeled aptamer are combined to form a functional sensing composition, selecting approximately equal volumes of the two components 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 Liu et al. because the ‘931 patent establishes that the disclosed aptamers specifically bind SARS-CoV-2 targets, while Wang et al. and Liu 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. represents the substitution of a known signal-transduction modality for another without altering the underlying aptamer-target binding interaction that governs detection. Further, Liu 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, with adjustment of component amounts 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 approximately equal volumes 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, 12, and 14-20 are rejected under 35 U.S.C. 103 as being unpatentable over ‘931 in view of Wang 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 and 12, 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 claim in failing to teach or specify adding a mixture of a fluorescently conjugated aptamer and graphene oxide to a detection area on a glass-based reading substrate.
However, McCauley et al. teaches 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). These disclosures teach performing fluorescence-based aptamer detection on a glass support, thereby addressing the glass-based reading substrate limitation of claim 11.
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 method of the ’931 patent as modified by Wang et al. to perform detection on a glass-based reading substrate, as taught by McCauley et al., because Wang et al. teaches a well-established and predictable fluorescence-based signal-generation architecture in which a fluorescently labeled aptamer is combined with graphene oxide to transduce aptamer–target binding events into measurable fluorescence signals. Both the ’931 patent and Wang et al. operate within the same technical field of aptamer-based biosensing and rely on the same fundamental molecular recognition mechanism—specific binding between an aptamer and its target molecule—such that Wang et al.’s fluorescence-based sensing architecture would have been readily applicable to the SARS-CoV-2 aptamer detection method disclosed in the ’931 patent. Incorporating this known fluorescence signal-generation approach into the method of the ’931 patent represents the substitution of one known signal-transduction modality for another within an already-established biosensor framework and does not alter the principle of operation of the method.
Furthermore, McCauley et al. expressly teaches performing fluorescence-based aptamer detection on a glass substrate, demonstrating that fluorescently labeled aptamers immobilized on glass supports are suitable for sensitive detection of target molecules. At the time of the invention, glass substrates were widely recognized as conventional platforms for fluorescence-based biosensing due to their optical transparency and compatibility with standard fluorescence detection instrumentation. Accordingly, a PHOSITA would have been motivated to perform the fluorescence-based aptamer/graphene oxide sensing method derived from the ’931 patent and Wang et al. on a glass-based reading substrate as a routine design choice to place the known biosensor method into a conventional and well-understood sensing environment.
Additionally, a PHOSITA would have had a reasonable expectation of success in making these modifications because aptamer–graphene oxide fluorescence sensing architectures were well characterized and demonstrated to function reliably for molecular detection, as evidenced by Wang et al., and fluorescence-based aptamer detection on glass substrates was likewise well established in the art, as demonstrated by McCauley et al. The modifications do not require altering the aptamer’s binding function, introducing unconventional chemistry, or changing the fundamental sensing mechanism, but instead apply known components—fluorescently labeled aptamers, graphene oxide, and glass substrates—according to their established functions. As a result, combining the teachings of the ’931 patent, Wang et al., and McCauley et al. would have been expected to yield a functioning fluorescence-based biosensor method that generates stable and detectable optical signals in a predictable manner.
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 SARS-CoV-2 antigens (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), for use in a biosensor.
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).
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over ‘931, Wang et al., and McCauley et al., as applied to claim 11 above, and further in view of Liu et al.
With respect to the teachings of the ‘931 patent, Wang et al., and McCauley., see the discussion above, which applies equally here. These references differ from the instant claim in failing to teach or specify that the fluorophore conjugated to the aptamer is 6-carboxyfluorescein.
On the other hand, Liu et al. teaches the use of 6-carboxyfluorescein as a fluorophore in fluorescence-based biosensing (page 4286, paragraph 3).
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 method of Claim 11, as taught by the ’931 patent in view of Wang et al. and McCauley et al., by selecting 6-carboxyfluorescein as the specific fluorophore conjugated to the aptamer, as taught by Liu et al. Liu et al. expressly teaches the use of 6-carboxyfluorescein-labeled aptamers in fluorescence-based biosensing applications, thereby identifying 6-carboxyfluorescein as a known and reliable fluorophore within the broader class of fluorophores already contemplated by Wang et al. Selecting a specific, well-known fluorophore from among known alternatives represents a routine design choice that does not alter the underlying aptamer–target binding mechanism or the principle of operation of the fluorescence-based sensing method taught by the prior art.
Additionally, a PHOSITA in the art would have had a reasonable expectation of success in making this substitution because 6-carboxyfluorescein was widely used at the time of the invention as a fluorescent label for aptamers, and its optical properties and compatibility with fluorescence detection systems were well understood. Liu et al. demonstrates that 6-carboxyfluorescein-labeled aptamers function effectively in fluorescence-based biosensing platforms, confirming that this fluorophore performs predictably in such systems. Accordingly, substituting 6-carboxyfluorescein for another known fluorophore within the aptamer-based fluorescence sensing method taught by the ’931 patent, Wang et al., and McCauley et al. would have been expected to yield predictable results without undue experimentation, as the substitution merely selects a particular species from a known class of fluorophores already used in the art.
Ultimately, for the reasons set forth above, claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over combinations of prior art references directed to aptamer-based biosensors and detection methods. The cited references are within the same field of endeavor and rely on the same fundamental aptamer-target binding principles. The combinations represent the predictable use of prior art elements according to their established functions, with routine substitutions, selections, or design choices that would have been obvious to a PHOSITA with a reasonable expectation of success.
For the reasons stated above, all claims are rejected.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELIZABETH OGUNTADE whose telephone number is (571)272-6802. The examiner can normally be reached Monday-Friday 6:00 AM - 3 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bao-Thuy Nguyen can be reached at 571-272-0824. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/E.O./
Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 February 3, 2026