DETAILED ACTION
Response to Amendment
This is a final office action in response to a communication filed on August 27, 2025. Claims 1-2, 4-6, 10, 12, 15-16, 19-21, 23-25, 30-31, and 33-35 are pending in the application.
Status of Objections and Rejections
All objections from the previous office action are withdrawn in view of Applicant’s amendment.
All rejections from the previous office action are maintained.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1-2, 4-6, 10, 12, 19-21, and 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Le (US 2015/0219652) in view of Henkens (US 2004/0072158), and further in view of Hassibi (US 2019/0323070).
Regarding claim 1, Le teaches a biosensor (¶2: protein-responsive DNA devices and assemblies) for detecting a target analyte in a sample (¶19: detection of prostate specific antigen PSA) comprising:
(a) a double-stranded oligonucleotide in solution (Fig. 1: T*C*:C) comprising an overhang on a first strand of the oligonucleotide (Fig. 1: the first strand T*C* having an overhang on its left end), and a second strand of the oligonucleotide that is a reporter moiety comprising a detectable label (Fig. 1: the second strand C having a quencher (Q));
(b) a first detection probe in solution (Fig. 1: TB) comprising a recognition moiety and a junction forming moiety, wherein the junction forming moiety comprises a first portion capable of binding by complementarity to the overhang of the first strand of the double-stranded oligonucleotide (Fig. 1: indicating the TB probe binding the overhang of T*C* in the formed junction “TB:B*C:T*C*”; further the TB probe has a recognition moiety for binding the target PSA);
(c) a second detection probe in solution (Fig. 1: B*C*) comprising a recognition moiety and a junction forming moiety, wherein the junction forming moiety comprises a first portion capable of binding by complementary to an internal segment of the first strand of the double-stranded oligonucleotide (Fig. 1: indicating the B*C probe binding the internal section of T*C* in the formed junction “TB:B*C:T*C*”; further the B*C* probe has a recognition moiety for binding the target PSA);
wherein the junction forming moiety of the first detection probe comprises a second portion complementary to a second portion of the junction forming moiety of the second detection probe (Fig. 1: indicating the first detection probe TB having a portion complementary to the second detection probe B*C* in the formed junction),
wherein in the presence of the target analyte, i) the recognition moiety of the first detection probe binds to the target analyte (Fig. 1: indicating the recognition moiety of TB binding to the target PSA), and ii) the recognition moiety of the second detection probe binds to a different portion of the target analyte (Fig. 1: indicating the recognition moiety of B*C* binding to the target PSA at a different portion), whereby the binding in i) and ii) brings the first detection probe and the second detection probe into proximity sufficient to allow for the second portion of the first detection probe to bind by complementarity to the second portion of the second detection probe, whereby the first detection probe and the second detection probe form a stable duplex (Fig. 1: indicating the first detection probe TB and the second detection probe B*C* are brought to proximity due to their bindings to the target PSA and form a duplex by complementarily binding to each other),
wherein in the presence of the target analyte, the first portion of the first detection probe binds by complementarity to the overhang of the first strand of the double-stranded oligonucleotide (Fig. 1: indicating the first portion of probe TB complementarily binding to the overhang of T*C*), and the first portion of the second detection probe binds by complementarity to the internal segment of the first strand of the double-stranded oligonucleotide (Fig. 1: indicating the first portion or probe B*C* complementarily binding to the internal segment of T*C*), whereby the binding of the first detection probe and the second detection probe to the first strand of the double-stranded oligonucleotide in solution releases the second strand from the double-stranded oligonucleotide in a) (Fig. 1: indicating the formation of the junction TB:B*C*:T*C* releases the strand C).
Le does not explicitly disclose (d) a capture probe functionalized on a surface of an electrode, wherein the capture probe comprises an immobilized strand attached to the electrode.
However, Henkens teaches a quantitative electrochemical detection of selected nucleic acid sequences (¶4). A biosensor array comprise a plurality of working and reference electrodes, with a plurality of labeled nucleic acid segments are attached to the surface of the working electrode (¶25). The labeled segments will generate an electric current when an electric potential is applied to the working electrode after the attached labeled nucleic acid segments are hybridized with a target nucleic acid (¶25). Of course a plurality of labeled proteins, peptides, polypeptides or protein nucleic acids may likewise be attached to the working electrode and will produce an electric signal under similar conditions Subsequent to binding or combining with a selected substrate or receptor (¶25).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Le by incorporating an electrode with a capture probe functionalized on as taught by Henkens because the immobilized capture probe would be able to hybridize with a target and generate a current upon the application of a potential on the electrode for quantitative electrochemical detection of selected nucleic acid or protein (¶¶4, 25). Here, the claimed limitations are obvious because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results. MPEP 2143(I)(A).
Le teaches the first strand labeled with a fluorophore (Fig. 1: F; ¶23) and the second strand (Fig. 1: strand C) including a quencher (Fig. 1: Q), but fails to teach the second strand having a reporter moiety comprising a detectable label. Le and Henkens do not disclose wherein the reporter moiety would be released when the second strand is released or wherein the released reporter moiety in solution binds by complementarity to the immobilized strand of the capture probe on the surface of the electrode.
However, Hassibi teaches electrochemical signals are correlated with analyte binding during amperometric and voltammetric measurements, which involve the oxidation or reduction of redox species (¶180). For example, the analyte can be labeled with a compound which undergoes an oxidation or reduction reaction and the oxidative or reductive current can be correlated with the amount of analyte bound to surface probes (¶180). In Fig. 27, a florescent label may be attached to a target analyte that would bind with the immobilized capturing probe (Fig. 27, ¶321).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Le and Henkens by switching the detectable label on the first strand to be on the second strand so that the labeled analyte is capable of binding to the capture probe attached to the electrode as taught by Hassibi because it is an alternative way to labelling the immobilized probe for binding and detecting the target nucleic acid in Henkens, and the substitution of one known element for another would yield nothing more than predictable results. MPEP 2141(III)(B). Further, the position of the detectable label for the electrochemical measurement on the detectable label upon the hybridization of the capture probe and target analyte only has two options, on the capture probe or on the target analyte. Choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success is prima facie obvious. MPEP 2141(III)(E). The combined Le, Henkens, and Hassibi would necessarily result in the labeled target (the second strand of Le) being released and then binding to the capture probe to be detected.
The limitation “and optionally a displaceable strand binding to the immobilized strand by partial complementarity” is optional and not required in the prior art. As a result, the limitation “whereby the binding displaces the optional displaceable strand and brings the detectable label on the reporter moiety close to the electrode surface for producing a detectable electrochemical signal” is optional and not required in the prior art.
The designation “wherein the target analyte is a protein” is directed to a material or article worked upon. "Expressions relating the apparatus to contents thereof during an intended operation are of no significance in determining patentability of the apparatus claim." Ex parte Thibault, 164 USPQ 666, 667 (Bd. App. 1969). Furthermore, "[i]nclusion of material or article worked upon by a structure being claimed does not impart patentability to the claims." In re Young, 75 F.2d. 25 USPQ 69 (CCPA 1935) (as restated in In re Otto, 312 F.2d 937, 136 USPQ 458, 459 (CCPA 1963)). MPEP 2115.
Regarding claim 2, Le teaches wherein the recognition moiety of the first detection probe and the recognition moiety of the second detection probe, each independently, comprises a nucleic acid (¶5: a first nucleic acid motif and a second nucleic acid motif).
The limitation “optionally wherein the protein is an antibody or an antigen-binding fragment thereof” is optional and not required in the prior art.
Regarding claim 4, Le teaches wherein the junction forming moiety of the first detection probe and the junction forming moiety of the second detection probe, each independently, comprises a nucleic acid (¶23: DNA motif T*C and motif C).
Regarding claim 5, Le, Henkens, and Hassibi disclose all limitations of claim 1 as applied to claim 1. Le and Hassibi do not explicitly disclose wherein the immobilized strand of the capture probe comprises a nucleic acid.
However, Henkens teaches the immobilized strand of the capture probe as an attached labeled nucleic acid segments (¶25).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Le and Hassibi by utilizing a nucleic acid as the capture probe as taught by Henkens. The suggestion for doing so would have been that nucleic acid is a suitable capture probe for hybridizing a target nucleic acid for electrochemical detection of the nucleic acid sequences and the selection of a known material, which is based upon its suitability for the intended use, is within the ambit of one of ordinary skill in the art. MPEP § 2144.07.
The limitation “the displaceable strand of the capture probe comprises a nucleic acid” is optional and not required in the prior art.
Regarding claim 6, Le, Henkens, and Hassibi disclose all limitations of claim 1 as applied to claim 1. Le and Henkens do not explicitly disclose wherein the detectable label comprises a redox species.
However, Hassibi teaches the analyte can be labeled with a compound which undergoes an oxidation or reduction reaction (¶180), and thus the compound would be a detectable label comprising a redox species.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Le and Henkens by utilizing a redox species that would be able to undergo an oxidation or reduction reaction as a detectable label to generate electrochemical signals as taught by Hassibi. The suggestion for doing so would have been that redox species is a suitable material for generating electrochemical signals undergoing an oxidation or reduction reaction during electrochemical measurements and the selection of a known material, which is based upon its suitability for the intended use, is within the ambit of one of ordinary skill in the art. MPEP § 2144.07.
The limitation “optionally wherein the redox species is selected from the group consisting of methylene blue, methylene blue succinimide, methylene blue maleimide, Atto MB2 maleimide, other methylene blue derivatives, 3,7-Bis-[(2-Ammoniumethyl) (methyl)aminolphenothiazin-5-ium trifluoroacetate, 3,7-Bis-(piperazin-4-ium-1-yl)phenothiazin-5-ium trifluoroacetate, 3,7-Bis-[(2-ammoniumethyl)(methyl)aminol phenothiazin-5-ium chloride, 3,7-Bis-(piperazin-4-ium-1-yl)phenothiazin-5-ium chloride, and ferrocene” is optional and not required in the prior art.
Regarding claim 10, the designation “wherein the detectable electrochemical signal is a change in current, voltage or impedance” is deemed to be functional limitation in apparatus claims. MPEP 2114 (II). It does not differentiate the claimed apparatus from a prior art apparatus because the prior art apparatus as taught by Le, Henkens, and Hassibi teaches all the structural limitations of the claim. Ex parte Masham, 2 USPQ2d 1647 (Bd. Pat. App. & Inter. 1987). Further, Henkens teaches an electric potential applied to the working electrodes to allow measurement of any current produced on binding of the attached nucleic acid binding with a target molecule (¶26).
The limitation “optionally wherein the detectable electrochemical signal is an increase in current compared to in the absence of the target analyte” is optional and not required in the prior art.
Regarding claim 12, Le, Henkens, and Hassibi disclose all limitations of claim 1 as applied to claim 1. Le and Hassibi do not explicitly disclose wherein the electrode comprises a metal.
However, Henkens teaches the working electrodes may be metal electrodes (¶28).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Le and Hassibi by substituting the electrode with one made of metal as taught by Henkens. The suggestion for doing so would have been that metal is a suitable material of electrode for electrochemical measurements and the selection of a known material, which is based upon its suitability for the intended use, is within the ambit of one of ordinary skill in the art. MPEP § 2144.07.
Regarding claim 19, Le, Henkens, and Hassibi disclose all limitations of claim 1 as applied to claim 1. Le and Hassibi do not explicitly disclose further comprising a reference electrode.
However, Henkens teaches an electrochemical cell comprise two or more electrodes, such as a reference electrode and a working electrode (¶98). A controlled potential is applied to the working electrode using the reference electrode (¶152).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Le and Hassibi by incorporating a reference electrode in the electrochemical cell as taught by Yang because the reference electrode would enable the potential applied to the working electrode controllable (¶152). Here, the claimed limitations are obvious because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results. MPEP 2143(I)(A).
Regarding claim 20, Le teaches wherein the sample is an aqueous solution (¶24).
Regarding claim 21, Le teaches wherein the protein is prostate specific antigen (¶84).
The designation “wherein the protein is prostate specific antigen” is directed to a material or article worked upon. "Expressions relating the apparatus to contents thereof during an intended operation are of no significance in determining patentability of the apparatus claim." Ex parte Thibault, 164 USPQ 666, 667 (Bd. App. 1969). Furthermore, "[i]nclusion of material or article worked upon by a structure being claimed does not impart patentability to the claims." In re Young, 75 F.2d. 25 USPQ 69 (CCPA 1935) (as restated in In re Otto, 312 F.2d 937, 136 USPQ 458, 459 (CCPA 1963)). MPEP 2115.
Regarding claim 23, Le teaches wherein the biosensor is for use in clinical diagnostics (¶14).
Further, the designation “wherein the biosensor is for use in clinical and agricultural diagnostics, agri-food quality control, environmental monitoring, health screening, health monitoring, and/or pharmaceutical development” is deemed to be functional limitation in apparatus claims. MPEP 2114 (II). It does not differentiate the claimed apparatus from a prior art apparatus in view of Le, Henkens, and Hassibi because the prior art apparatus teaches all the structural limitations of the claim. Ex parte Masham, 2 USPQ2d 1647 (Bd. Pat. App. & Inter. 1987).
Claim(s) 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Le in view of Henkens and Hassibi, and further in view of Kelley (US 2005/0084881).
Regarding claim 15, Le, Henkens, and Hassibi disclose all limitations of claim 1 as applied to claim 1. Le, Henkens, and Hassibi do not explicitly disclose wherein the electrode comprises three-dimensional nanostructures.
However, Kelley teaches a new nucleic acid detection assay that reports nucleic acid hybridization between a nucleic acid probe and a nucleic acid (¶8), by yielding an electrochemical signal that reports at the electrode surface upon hybridization of a target nucleic acid (¶11). The used electrode is a 3D NEE (¶128: nanoelectrode ensembles) which are useful substrates for biosensing (¶254). The 3D nanostructures of the electrode are more suitable for practical application to obtain larger electrocatalysis currents due to its increased active surface area, and produce electrodes with smaller capacitive currents and more stable background signals during DNA hybridization experiments (¶254).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Le, Henkens, and Hassibi by substituting the electrode with the one comprising three-dimensional nanostructures as taught by Kelley because the 3D nanostructures would increase the electrode active surface area, and produce electrodes with smaller capacitive currents and more stable background signals during DNA hybridization experiments (¶254).
Claim(s) 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Le in view of Henkens and Hassibi, and further in view of Yang (US 2019/0323070).
Regarding claim 16, Le, Henkens, and Hassibi disclose all limitations of claim 1 as applied to claim 1. Le, Henkens, and Hassibi do not explicitly disclose the biosensor further comprising a surface blocker functionalized on the electrode.
However, Yang teaches an electrochemical aptamer-based (E-AB) sensor that has target-induced conformational changes (¶176) by measuring a signal generated upon binding of the target with the E-AB sensor (¶178). The E-AB sensor comprises aptamers that are immobilized on the electrode (¶180), and further comprises a backfiller to fill vacant areas on the electrode surface, for example, MCH (¶181). Optimization of DNA surface coverage and backfiller would achieve a maximal signal gain (¶246).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Le, Henkens, and Hassibi by incorporating a surface blocker, e.g., MCH, on the electrode surface as taught by Yang because the surface block would fill the vacant areas on the electrode surface (¶181) and the optimized backfiller would achieve a maximal signal gain (¶246). Here, the claimed limitations are obvious because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results. MPEP 2143(I)(A).
The limitation “optionally wherein the surface blocker comprises a poly-A oligonucleotide and/or mercaptohexanol” is optional and not required in the prior art.
Response to Arguments
Applicant’s arguments have been considered but are unpersuasive.
Applicant argues the amended claim 1 specifies that the target analyte is a protein (p. 13, last para.). Examiner notes that the limitation is directed to a material or article worked upon. "Expressions relating the apparatus to contents thereof during an intended operation are of no significance in determining patentability of the apparatus claim." Ex parte Thibault, 164 USPQ 666, 667 (Bd. App. 1969). Furthermore, "[i]nclusion of material or article worked upon by a structure being claimed does not impart patentability to the claims." In re Young, 75 F.2d. 25 USPQ 69 (CCPA 1935) (as restated in In re Otto, 312 F.2d 937, 136 USPQ 458, 459 (CCPA 1963)). MPEP 2115.
Applicant argues Le has no disclosure of any re-capture step on an electrode surface, nor any indication that the method can be adapted for electrochemical detection on an electrode (p. 14, para. 2). This argument is unpersuasive. Examiner notes that the claims under examination were elected by Applicant and directed to apparatus claims. Thus, there is no requirement that the prior art disclose the claimed method of withdrawn claims. Thus, Applicant’s argument regarding the method steps, including (i) a solution-phase event and (ii) a surface-phase event (p. 14, para. 1) is moot.
Applicant argues there is no teaching, suggestion, or motivation in the cited art to combine the systems of the cited references (p. 15, para. 2). It seems that Applicant argues they are not analogous art by asserting Le describes binding-induced formation of DNA structures for detecting non-DNA targets (p. 14, para. 2); Henkens discloses detection of nucleic acid sequences instead of non-nucleic acid targets (p. 14, para. 3); although Hassibi teaches detecting nucleic acids or protein, it uses antibodies or nucleic acids as independent capture agents (p. 14, last para.). Examiner disagrees. Henkens explicitly discloses the working electrodes are linked or attached to bioreporter molecules that are typically a protein or a nucleic acid (¶24). The labeled segments will generate an electric current when an electric potential is applied to the working electrode after the attached labeled nucleic acid segments are hybridized or annealed with a target nucleic acid (¶25). Of course a plurality of labeled proteins, peptides, polypeptides or protein nucleic acids may likewise be attached to the working electrode and will produce an electric signal under similar conditions subsequent to binding or combining with a selected substrate or receptor (¶25). Further, Hassibi also discloses that the analytes and/or the probes comprises nucleic acids or proteins (¶31), detected a signal such as electrochemical, electrical, magnetic, or optical signal (¶45). The cited references are analogous art and it would be obvious to one of ordinary skill in the art to combine them to arrive the claimed invention. Examiner notes here that the hybridization occurs between two complementary molecules, tailored to the analytes of interest. The combined sensor would be able to detect various analytes, such as nucleic acid, proteins, peptides.
Interview with the Examiner
If at any point during the prosecution it is believe an interview with the Examiner would further the prosecution of an application, please consider this option.
The Automated Interview Request form (AIR) is available to request an interview to be scheduled with the Examiner. First, an authorization for internet communications regarding the case should be filed prior or with an AIR online request.
The internet communication authorization form (SB/0439), which authorizes or withdraws authorization for internet-based communication (e.g., video conferencing, email, etc.) for the application must be signed by the applicant or the attorney/agent for applicant. The form can be found at:
https://www.uspto.gov/sites/default/files/documents/sb0439.pdf
The AIR form can be filled out online, and is automatically forwarded to the Examiner, who will call to confirm a requested time and date, or set up a mutually convenient time for the interview. The form can be found at:
https://www.uspto.gov/patent/uspto-automated-interview-request-air-form.html
The Examiner encourages, but does not require, interviews by the USPTO Microsoft Teams video conferencing. This system allows for file-sharing along audio conferencing. Microsoft Teams can be used as an internet browser add-on in Microsoft IE, Google Chrome, or Mozilla Foxfire, or as a temporary Java-based application on these browsers. Steps for joining an Examiner setup Microsoft Teams can be found at the USPTO website:
https://www.uspto.gov/patents/laws/interview-practice#step3. Additionally, a blank email to the Examiner at the time of a telephonic interview can be used for a reply to easily allow for Microsoft Teams communication. Please note, policy guidelines regarding Internet communications are detailed at MPEP §500-502.3, and office policy regarding interviews are detailed at MPEP §713.
Conclusion
THIS ACTION IS MADE FINAL. 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 extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAITLYN M SUN whose telephone number is (571)272-6788. The examiner can normally be reached M-F: 8:30am - 5:30pm.
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, Luan Van can be reached on 571-272-8521. 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.
/C. SUN/Primary Examiner, Art Unit 1795