DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Status of the Claims
Claims 1-3, 5, 12-13, 15 and 18-19 were pending. Claims 4, 6-11 and 16-17 were withdrawn.
Claims 2, 12-15, and 18 are canceled. Claim 20 is added.
Claims 1, 3, 5 and 19-20 are examined herein.
Withdrawn Rejections
The objections to claims 1, 3, 5, and 19 are withdrawn in view of claims amendments.
The rejections of claims 2, 12, 13, 15, and 18 are withdrawn in view of claims cancellation.
The rejections of claims 1, 3, 5, and 19 under 35 U.S.C. §112(b) are withdrawn in view of claims 1 and 19 amendments.
Claim Interpretation
Amended claim 1 recites “An ex-situ biosensor system”. The specification fails to disclose the structure of the biosensor system and its components. The term “system” is recited only once in the specification as “The decrease in peak separation voltage and increase in peak currents with the increase in time of gold deposition indicated that increasing gold deposition time considerably improved the electron transfer kinetics of the system” ([0056]), wherein “the system” refers to the cyclic voltammetry (CV) system, which is not the biosensor system of claim 1.
The term “biosensor system” will be interpreted as a biosensor incorporated into a handheld device.
Amended claim 1 recites “a test strip comprising the biosensor” (line 14). The specification fails to disclose the structure of the test strip comprising the biosensor, an arrangement of the biosensor on the test strip, how the biosensor structurally relates to the test strip, or any differences between the test strip and the biosensor.
The term “a test strip comprising the biosensor” will be interpreted as a biosensor mounted on some support, “a test strip”, that in turn is incorporated into a handheld device.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
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.
Claims 1, 3, 5, and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (PGPub 2010/0009432) in view of Springer et al. (Anal Bioanal Chem. 2012 Dec;404(10):2869-75), Amama et al. (J Clin Endocrinol Metab. 1998 Feb;83(2):333-8), Ling et al. (Anal Chem. 2009 Feb 15;81(4):1707-14), and Ongagna-Yhombi et al. (Malar J. 2013 Feb 22; 12:74).
Regarding claims 1, 3, and 19-20, Lee teaches a biosensor to detect a target clinical marker in a biological fluid sample of a patient. Specifically, Lee teaches a conductive CNT-biosensor in which a variety of bioreceptors are attached to the conductive CNTs (carbon nanotubes) comprising:
a substrate, a plurality of carbon nanotubes deposited on the substrate, and a plurality of gold nanoparticles deposited on the plurality of carbon nanotubes “a CNT monolayer dotted with gold nanocrystals is immobilized to the substrate surface” ([0033]);
a biomolecule “bioreceptors capable of reacting with target biomaterials” and “receptors having functional groups that bind to or react with the gold nanoparticles of gold nanoparticle-dotted CNTs” ([0033]);
Regarding an ex-situ nature of the biosensor, Lee teaches in Example 2 that the biosensor can be used for detection of DNA hybridization ([0113]-[0125]). Specifically, Lee teaches a process step “to remove the non-specific bindings of the double stranded oligonucleotides, the solution was left at 100°C” ([0121]), clearly, such temperature can only be achieved ex-situ.
Regarding limitation of claim 1, reciting “a handheld device” MPEP 2144.04 instructs that the fact that a claimed device is portable or movable is not sufficient by itself to patentably distinguish over an otherwise old device unless there are new or unexpected results (In re Lindberg, 194 F.2d 732, 93 USPQ 23 (CCPA 1952)). Additionally, the biosensor of Lee fits on a glass slide ([0113]), therefore, it is inherently small enough to be handheld.
Regarding the limitations of the gold nanoparticles deposited on the carbon nanotube, Lee teaches “the present invention provides conductive CNTs dotted with a metal” and “metal is preferably gold” ([0046]). The limitation of the gold nanoparticles electrodeposited on the carbon nanotube is directed to the process of gold deposition. MPEP 2113 instructs, that “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985)”.
In the present case, the final product is the same gold nanoparticles deposited on the carbon nanotubes. Evidence that the gold nanoparticles are functionally the same, comes from Lee’s teaching that the gold nanoparticles do not have to be electrodeposited to be used in the biosensor “various bioreceptors having functional groups that react with the gold nanocrystals present in the high-density CNT pattern are attached to the CNT pattern or film, to fabricate a biosensor that can detect various target biomaterials directly or by electrochemical signals” ([0061]).
Regarding the limitation of a biotinylated antibody or an aptamer, Lee teaches that avidin-biotin can be used for immobilization of the biomolecules on the biosensor “methods can be classified into several categories, including chemical adsorption, covalent-binding, electrostatic attraction, co-polymerization, and avidin-biotin affinity approaches” ([0018]).
Regarding the limitation of a test strip comprising the biosensor, Lee teaches the biosensor assembled on the surface of a glass slide ([0113]). Fig. 3(d) teaches the carbon nanotubes deposited on the substrate occupy only a portion of the glass slide substrate forming the biosensor. The remaining glass slide surface acts as a test strip supporting the biosensor. Therefore, Lee teaches a test strip comprising the biosensor.
Regarding the mechanism to provide an indication of the presence or absence of the target clinical marker in the biological fluid sample of the patient, Lee teaches that the indication mechanism is already built in to the biosensor in the form of conductive carbon nanotubes “various target biomaterials that bind or react with the bioreceptors can be precisely measured directly or by electrochemical signals at large amounts in one step” (Abstract). The conductive carbon nanotubes are the structure/mechanism in the biosensor that provides an indication of the presence or absence of the target.
Lee does not specifically teach biotinylated antibodies attached to the binding material adsorbed on the plurality of gold nanoparticles, and a target bone or tissue marker.
Springer teaches “Biofunctionalized gold nanoparticles for SPR-biosensor-based detection of CEA in blood plasma” (Title). Springer also teaches biotinylated antibodies attached to the binding material adsorbed on gold nanoparticles. Specifically, Springer teaches gold nanoparticles (Bio-AuNPs) functionalized with streptavidin to provide high affinity for the biotinylated antibody used in a sandwich assay (Abstract), where streptavidin corresponds to the binding material of the instant disclosure. Streptavidin taught by Springer and avidin taught by Lee are widely known in the art for their exceptionally strong and specific interaction with biotin, and are used interchangeably.
Lee and Springer fail to teach a target bone or tissue marker.
Amama teaches “C-Telopeptide and N-Telopeptide: the Predictive Value of Biochemical Markers of Bone Turnover” (Title). Amama also teaches a target clinical bone marker.
Specifically, Amama teaches C-telopeptide as a human bone resorption marker (Abstract, 1st paragraph). The terms C-terminal telopeptide and C-telopeptide are used interchangeably (see Abstract and pg. 334, Col. 1, 2nd paragraph of section “Biochemical markers”). Biotinylating antibody specific for the c-terminal telopeptide meets the limitation of claim 3 reciting biotinylated biomolecule is c-terminal telopeptide antibody.
Additionally, Amama teaches that the c-terminal telopeptide was detected by ELISA using corresponding antibody “obtained by immunizing rabbits with the amino acid sequence specific for a part of the C-terminal telopeptide” (pg. 334, Col. 1, 2nd paragraph of section “Biochemical markers”), where the antibody with the specificity to the c-terminal telopeptide corresponds to the biotinylated biomolecule of the instant disclosure.
Lee, Springer and Amama fail to teach a visual chart or key that correlates the visible color change of the test strip to the presence of the marker in the biological fluid sample of the patient.
Regarding 1, 3, and 19-20, Ling teaches visual sandwich immunoassay system (Title). Ling also teaches a chart or key to correlate the visual change to the presence of a marker in the biological sample.
Specifically, Ling teaches plasmon resonance scattering immunoassay with visual detection of a signal “findings showed that the strong PRS signals from the AgNPs immunotargeted on the glass slides can be clearly seen and distinguished by naked eyes under the excitation of a common white light-emitting diode (LED) torch” (Abstract). Additionally, Ling teaches a visual chart with panels A to F showing glass slides bound with different amounts of analyte, that can be used to estimate the quantity of the analyte (Fig. 10).
It would have been obvious to one having ordinary skill in the art at the time the invention was made to have modified the biosensor of Lee, by employing adsorption of biotinylated antibodies on the streptavidin binding material immobilized on the gold surface as taught by Springer, as a simple substitution of one known element for another to obtain predictable results. Immobilization of biomolecules using avidin-biotin taught by Lee ([0018]) and streptavidin-biotin taught by Springer are well-known approaches in the art and the results would have been reasonably predictable.
It would have been obvious to one having ordinary skill in the art at the time the invention was made to have modified the biosensor of Lee and Springer, by employing an antibody specific to the c-terminal telopeptide as a bone marker as taught by Amama, as an obvious matter of combining prior art elements according to known methods to yield predictable results. Lee is generic with respect to the type of receptor that can be incorporated and the antibody specific for the c-terminal telopeptide as taught by Amama (pg. 334, Col. 1, 2nd paragraph of section “Biochemical markers”) provides a method for monitoring bone turnover (Abstract). Each prior art element would have been expected to independently contribute its own known properties to the final biosensor and the results would have been reasonably predictable.
It would have been obvious to one having ordinary skill in the art at the time the invention was made to have modified the biosensor of Lee, Springer, and Amama, by employing a visual chart as taught by Ling, in order to provide a signal quantitation aid (visual chart) for a simple and inexpensive biosensor. One having ordinary skill in the art would have been motivated to make such a change, because the visual chart replaces expensive, dedicated readers and makes detection of clinical markers very affordable “Figure 10 exhibits the photographs of six pieces of glass slides directly captured with a common digital camera under proper illumination of a white LED torch” (Ling, pg. 1713, Col. 2, last paragraph).
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because the prior art of Ling is relying on light-scattering labels commonly used in “plasmon resonance scattering signals from silver nanoparticles (AgNPs) immunotargeted on glass slides” (Abstract). Biosensors of Ling, Lee, Springer and Amama are similarly drawn to immunoassays.
Lee, Springer, Amama, and Ling fail to teach a test strip with a visible color change of the test strip when contacted with the biological fluid sample of the patient.
Ongagna-Yhombi teaches analysis of a PCR amplicon yield using lateral flow detection with a quantitative up-converting phosphor reporter technology (Abstract. Conclusions). Ongagna-Yhombi also teaches a test strip biosensor with a visible change displayed on the test strip.
Specifically, Ongagna-Yhombi teaches a rapid, non-invasive, and inexpensive point-of-care diagnostic for malaria (Abstract. Background) with a lateral flow test strip (Fig. 2A). The target clinical marker (PCR product of a P. falciparum-specific DNA sequence – pg. 2, col. 2, last par., and Fig. 1) is captured on the lateral flow test strip using avidin, and detection is performed using up-converting phosphors label. The capture is achieved via biotinylated PCR primer U2 (pg. 3, col. 1, par. 1). The up-converting phosphors label attached to the PCR product is detected visually at 455 nm, meeting the limitation of visible color change of the test strip when contacted with the biological fluid sample of the patient.
Additionally, Ongagna-Yhombi teaches sandwich format of analyte detection, wherein the up-converting phosphors label binds to the test strip only when the analyte is present (Fig.2A) – the analyte acts as a bridge between avidin bound to the test line and the label. Therefore, no visible color change of the test strip when contacted with the biological fluid sample of the patient indicates an absence of the target marker in the biological fluid sample of the patient, meeting claim 20. This is an inherent property of the sandwich assay format.
It would have been obvious to one having ordinary skill in the art at the time the invention was made to have modified the biosensor of Lee, Springer, Amama, and Ling, by employing a test strip assay as taught by Ongagna-Yhombi, in order to design a biosensor with a visible color change of the test strip because the combination of the test strip format with a simple, visual detection of the assay results provides rapid and inexpensive point-of-care assays. One having ordinary skill in the art would have been motivated to make such a change to be able to detect target clinical bone or tissue markers in a patient sample at the time of the patient visit. The use of such an assay would have been desirable to those of ordinary skill in the art because faster diagnostics leads to better healthcare.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because both assays of Lee, Springer, Amama, and Ling, and Ongagna-Yhombi are similarly drawn to biotin-avidin capture of the analyte and visual detection of the results: blue light scattering (Lee, Springer, Amama, Ling) and 455 nm emission light (Ongagna-Yhombi). The glass slide of Lee and the strip of Ongagna-Yhombi play support role for the capture components of the assays and do not affect visual detection of the analyte.
Regarding claim 5, Lee teaches that avidin-biotin can be used for immobilization of the biomolecules on the biosensor ([0018]). Avidin meets the limitation of claim 5 reciting the binding material is avidin.
Response to Arguments
Applicant’s arguments filed September 22, 2025 have been fully considered.
Applicant argues that “as acknowledged by the Applicant (and the Office Action, on page 6), Lee does not teach biotinylated antibodies attached to the binding material adsorbed on the plurality of gold nanoparticles, and a target clinical marker selected from the group consisting of a bone marker and a tissue marker, as required in independent claim 1 as amended" (pg. 8, par. 2).
The argument is not persuasive because Lee was not cited for its teaching of biotinylated antibodies. Lee was cited for its teaching of a biosensor to detect a target clinical marker in a biological fluid sample of a patient. Springer teaches gold nanoparticles (Bio-AuNPs) functionalized with streptavidin, to provide high affinity for the biotinylated antibody used in a sandwich assay (Abstract).
Applicant argues that “there is nothing in Lee to teach or suggest a handheld device of the presently claimed invention that requires a test strip including a biosensor and a visual chart or key that correlates the visible color change of the test strip to the presence of the target clinical bone or tissue marker in the biological fluid sample of the patient” (pg. 8, par. 3).
In response to applicant's arguments against the references individually, 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).
Lee was cited of its teaching of a biosensor comprising: a substrate, a plurality of carbon nanotubes deposited on the substrate, and a plurality of gold nanoparticles deposited on the plurality of carbon nanotubes “a CNT monolayer dotted with gold nanocrystals is immobilized to the substrate surface” ([0033]); and a biomolecule “bioreceptors capable of reacting with target biomaterials” and “receptors having functional groups that bind to or react with the gold nanoparticles of gold nanoparticle-dotted CNTs” ([0033]). Additionally, the biosensor of Lee fits on a glass slide ([0113]), therefore, it is inherently small enough to be handheld.
A handheld device that requires a test strip including a biosensor and a visual chart or key that correlates the visible color change of the test strip to the presence of the target clinical bone or tissue marker in the biological fluid sample of the patient is rejected under §103 as being unpatentable over Lee in view of Springer, Amama, Ling, and Ongagna-Yhombi. (see §103 rejection above for details).
Applicant argues that “there is no teaching or suggestion in Springer and Amama that overcomes or cures the shortcomings and deficiencies of Lee” (pg. 8, par. 4).
The argument is not persuasive because the non-final OA (mailed May 23, 2025) clearly states what Lee does not teach and what other references compensate: “Lee does not specifically teach biotinylated antibodies attached to the binding material adsorbed on the plurality of gold nanoparticles, and a target clinical marker selected from the group consisting of a bone marker and a tissue marker” (pg. 6, par. 5). “Springer teaches gold nanoparticles (Bio-AuNPs) functionalized with streptavidin, to provide high affinity for the biotinylated antibody used in a sandwich assay (Abstract)” (pg. 6, par. 6), and “Amama teaches C-telopeptide as a human bone resorption marker (Abstract, 1st paragraph)” (pg. 7, par. 3). The visual chart is taught by Ling – “Ling teaches reagents for plasmon resonance scattering immunoassay with visual detection of a signal “findings showed that the strong PRS signals from the AgNPs immunotargeted on the glass slides can be clearly seen and distinguished by naked eyes under the excitation of a common white light-emitting diode (LED) torch” (Abstract)” (pg. 7, par. 7). The test strip with a visual chart is taught by Ongagna-Yhombi (OA; pg. 10, rejection of claims 18-19).
Applicant argues that “With respect to Ling, the Applicant respectfully, submits that this reference does not teach in any context a test strip comprising a biosensor wherein there is a visible color change of the test strip when it is contacted with a patient's biological fluid sample in which the target clinical bone or tissue marker is present” (pg. 8, last par.), “Ling does not mention a visual chart or key that correlates the visible color change of a test strip to the presence of the target clinical bone or tissue marker in the biological fluid sample” (pg. 9, par. 1) and “Ling does not mention a visible color change of the test strip ("glass slide") when contacted with a patient's biological fluid sample wherein a target clinical bone or tissue marker is present; nor does Ling mention a visual chart or key that correlates the visible color change of the test strip to the presence of the target clinical bone or tissue marker in the biological fluid sample” (id.).
In response to applicant's arguments against the references individually, 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).
The argument is not persuasive because for the purposes of the non-final OA, Ling was cited of its teaching of visual chart – “Ling teaches reagents for plasmon resonance scattering immunoassay with visual detection of a signal “findings showed that the strong PRS signals from the AgNPs immunotargeted on the glass slides can be clearly seen and distinguished by naked eyes under the excitation of a common white light-emitting diode (LED) torch” (Abstract)” (pg. 7, par. 7). The test strip is taught by Ongagna-Yhombi (OA; pg. 10, rejection of claims 18-19) and a bone marker is taught by Amama (Abstract, 1st paragraph)” (OA, pg. 7, par. 3).
Applicant argues that “the change described in Ling is visibly displayed or deposited on the glass slide because of the AgNPs immunotargeted thereon, but the color of the glass slide does not change. Thus, the color of the glass slide would not be correlated to the presence or absence of a target marker in a biological fluid sample as required by claim 1 of the present invention” (pg. 9, par. 1).
The argument is not persuasive because Ling does teach color change as demonstrated on Fig. 10. The color of the glass slide itself does not change because glass does not react with assay components. The glass is a support material; it is not supposed to change in the course of the assay. The color change takes place on the surface of the glass support because of accumulation of the AgNPs. It would have been obvious to one having ordinary skill in the art at the time the invention was made to have modified the biosensor of Lee, Springer, Amama, and Ling, by employing a test strip assay as taught by Ongagna-Yhombi, in order to design a biosensor with a visible color change of the test strip because the combination of the test strip format with a simple, visual detection of the assay results provides rapid and inexpensive point-of-care assays. One having ordinary skill in the art would have been motivated to make such a change to be able to detect target clinical bone or tissue markers in a patient sample at the time of the patient visit. The use of such an assay would have been desirable to those of ordinary skill in the art because faster diagnostics leads to better healthcare.
Applicant argues that “This rejection is moot with respect to canceled claim 15” (pg. 10, par. 2). The argument is persuasive and the rejection is withdrawn.
Applicant argues about rejection of claim 19 under 35 U.S.C. 103 – “The Applicant therefore submits that claim 19 is patentable over the combination of Ongagna with Lee, Springer, Amama and Ling at least for reason of its dependency upon a patentable base claim, i.e., independent claim 1” (pg. 10, par. 4). The argument is not persuasive because Applicant failed to overcome rejection of claim 1 as discussed above. Therefore, claims 1, 3, 5, and 19 are still rejected under 35 U.S.C. 103.
Applicant argues that “Claim 20 depends upon independent claim 1. As aforementioned, claim 1 as amended is patentable over the cited prior art references. Therefore, at least for reason of its dependency upon independent claim 1, i.e., a patentable base claim, the new claim 20 is also patentable over the cited prior art” (pg. 10, last par.). The argument is not persuasive because Applicant failed to overcome rejection of claim 1 as discussed above.
Additionally, Ongagna-Yhombi teaches sandwich format of analyte detection, wherein the up-converting phosphors label binds to the test strip only when the analyte is present (Fig.2A) – the analyte acts as a bridge between avidin bound to the test line and the label. Therefore, no visible color change of the test strip when contacted with the biological fluid sample of the patient indicates an absence of the target marker in the biological fluid sample of the patient, meeting claim 20. This is an inherent property of the sandwich assay format.
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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Alexander Volkov whose telephone number is (571) 272-1899. The examiner can normally be reached M-F 9:00AM-5:00PM (EST).
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bao-Thuy Nguyen can be reached on (571) 272-0824. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALEXANDER ALEXANDROVIC VOLKOV/
Examiner, Art Unit 1677
/REBECCA M GIERE/Primary Examiner, Art Unit 1677