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 .
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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 07/13/2026 has been entered.
Priority
This application is the U.S. National Stage (371) application of PCT/US18/15440 filed on 01/26/2018 which claims priority to U.S. Provisional Application No. 62/544,393 filed on 08/11/2017 and to U.S. Provisional Application No. 62/450,623 filed on 01/26/2017.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/16/2026 has been received. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner, and all references are considered except where they were lined through.
Claim Status
The Applicant cancelled claims 1-12, 14-34, 39-41, 43 and 48-50. The Applicant amended claims 13 and 42 and noted that no new matter is added. The Applicant previously presented claims 35-38 and 44-47.
Thus, claims 13, 35-38, 42 and 44-47 are under examination.
Withdrawn Rejections
The previous rejection of claims 41 and 50 under 35 U.S.C. 103, regarding obviousness, is withdrawn in lights of Applicants cancellation of the claims.
Claim Objections
Claim 42 is objected to because of the following informalities: the claim recites on step (c) an incomplete sentence “applying a magnetic field to the analysis chamber to pull down a complex formed between the analyte of interest bound to the magnetic conjugate, the reporter binding moiety, and the reporter by;” and it is not clear what “by” is for. It is suggested to delete “by” from the sentence so that claim 42 recites “applying a magnetic field to the analysis chamber to pull down a complex formed between the analyte of interest bound to the magnetic conjugate, the reporter binding moiety, and the reporter;”. Appropriate correction is required.
Maintained Rejections
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 (PHOSITA) 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 13, 35-38, 42 and 44-47 are rejected under 35 U.S.C. 103 as being unpatentable over Lau et el. (US 2009/0142772 A1) in view of Song et al. (Biosensors and Bioelectronics 26 (2011) 3818–3824), Agrawal et al. ((“Single-Bead Immunoassays Using Magnetic Microparticles and Spectral-Shifting Quantum Dots”, 2007, Journal of Agricultural and Food Chemistry), Li et al. (US 2008/0135490 A1) and Oldenburg et al. (US 2016/0250612 A1).
Claim 13 recites:
“A method for detecting the presence, absence, or level of an analyte of interest
in a sample in a microfluidic apparatus, wherein the analyte of interest comprises a
protein, and wherein the analyte of interest is not a bacteria, bacterial biomarker, or
virus, the method comprising:
adding the sample to an analysis chamber of the microfluidic apparatus and
contacting the sample with:
(i) a magnetic conjugate comprising a magnetic, metallic nanoparticle conjugated to
a capture moiety comprising an antibody configured to bind the analyte of
interest in the analysis chamber of the microfluidic apparatus; and
(ii) a reporter binding moiety comprising an antibody and a biotin label, the
antibody being configured to bind the analyte of interest, and wherein the
capture moiety and the reporter binding moiety bind different portions of the
analyte of interest;
(b) binding the analyte of interest with the capture moiety and binding the analyte of
interest with the reporter binding moiety;
(c) applying a magnetic field to the analysis chamber to pull down the magnetic conjugate
with analyte of interest and the reporter binding moiety associated therewith;
(d) removing a volume of the sample from the analysis chamber using the microfluidic
apparatus;
(e) adding a volume of buffer to the analysis chamber using the microfluidic apparatus to
contact the analyte of interest bound to the magnetic conjugate and the reporter
binding moiety with (iii) a reporter, wherein the reporter comprises a plurality of
quantum dots impregnated in a core particle that is functionalized with streptavidin,
(f) resuspending the magnetic conjugate with the analyte of interest and the reporter
binding moiety associated therewith with the reporter;
(g) binding the magnetic conjugate with the analyte of interest and the reporter binding
moiety associated therewith with the reporter via streptavidin-biotin binding;
(h) reapplying the magnetic field to the analysis chamber to pull down a complex formed
between the analyte of interest bound to the magnetic conjugate, the reporter binding
moiety and the reporter;
(i) removing a volume of the sample from the analysis chamber using the microfluidic
apparatus;
(j) adding a volume of buffer to the analysis chamber;
(k) resuspending the magnetic conjugate with the analyte of interest and the reporter
binding moiety associated therewith with the reporter; and
(l) detecting, in the analysis chamber of the microfluidic apparatus, the presence, absence,
or level of the analyte of interest by detecting fluorescence of the reporter with a light
source and photodetector, and
wherein the analyte of interest is thyroid stimulating hormone, troponin, luteinizing
hormone (LH), or prostate specific antigen (PSA)”.
Regarding claim 13, Lau teaches a method for detecting the presence, absence, or level of an analyte of interest in a sample in a fluidics system (Abstract; [0020-0028]; [0032]; [0103]; page 14, claim 38). Lau also teaches the capillary microchannels as flow channels which are the elements of a microfluidics system [0105]. Lau further teaches that the analyte of interest comprises a protein [0113]. And Lau teaches adding the sample to an analysis chamber of the apparatus and contacting the sample with a magnetic conjugate comprising a magnetic particle conjugated to a capture moiety comprising an antibody configured to bind the analyte of
interest in the analysis chamber of the fluidics system (Sheet 4 of 29, FIG. 4, “MAGNETIC BEAD 1”, “LIGAND 1” “MAGNETIC BEAD 2”, “LIGAND 2”, “LIGAND3”; [0008]; [0011-0012]; [0021]; [0096]; [0114]; [0120]). Lau also teaches contacting the sample with a reporter binding moiety comprising an antibody that is configured to bind the analyte of interest ([0096]; [0113-0114]; [0120] and [0163]). Lau further teaches that the capture moiety and the reporter binding moiety bind to different portions of the analyte of interest (Sheet 4 of 29, FIG. 4, (b), “PATHOGEN CAPTURE & VERIFICATION, TWO LEVELS OF SPECIFICITY”; [0025]; [0114]). Lau also teaches applying a magnetic field to the analysis chamber to pull down the magnetic conjugate with analyte of interest and the reporter binding moiety associated therewith ([0023]; [0025]; [0114]). Lau further teaches removing a volume of the sample from the analysis chamber by washing [0024]; [0027]. And Lau teaches adding a volume of buffer to the analysis chamber using the fluidic apparatus to contact the analyte of interest bound to the magnetic conjugate and the reporter binding moiety with (iii) a reporter ([0025]; [0114]; [0027]). Lau also teaches that the reporter comprises a plurality of quantum dots impregnated in a core particle ([0157]; [0166]). Lau further teaches resuspending the magnetic conjugate with the analyte of interest and the reporter binding moiety associated therewith with the reporter [0025]. And Lau teaches reapplying the magnetic field to the analysis chamber to pull down a complex formed between the analyte of interest bound to the magnetic conjugate, the reporter binding moiety and the reporter [0025-0027]. Lau further teaches removing a volume of the sample from the analysis chamber using the apparatus [0026]. Lau also teaches adding a volume of buffer to the analysis chamber [0027]. And Lau teaches resuspending the magnetic conjugate with the analyte of interest and the reporter binding moiety associated therewith with the reporter [0027]. Lau further teaches detecting, in the analysis chamber of the microfluidic apparatus, the presence, absence, or level of the analyte of interest by detecting fluorescence of the reporter with a light source and photodetector ([0020]; [0028]; [0013-0114]; [0152-0156]).
Claim 42 recites:
“A method for detecting the presence, absence, or level of an analyte of interest
in a sample in a microfluidic apparatus, wherein the analyte of interest comprises a protein and
wherein the analyte of interest is not a bacteria, bacterial biomarker, or virus, the method comprising:
(a) adding the sample to an analysis chamber of the microfluidic apparatus and contacting the
sample with:
(i) a magnetic conjugate comprising a magnetic, metallic nanoparticle conjugated to a
capture moiety comprising an antibody configured to bind the analyte of interest in
the analysis chamber of the microfluidic apparatus;
(ii) a reporter binding moiety comprising an antibody and a biotin label, the antibody
being configured to bind the analyte of interest, and wherein the capture moiety and the reporter binding moiety bind different portions of the analyte of interest and
(iii) a reporter, wherein the reporter comprises a plurality of quantum dots impregnated
in a core particle that is functionalized with streptavidin;
(b) binding the analyte of interest with the capture moiety, binding the analyte of interest with
the reporter binding moiety, and binding the reporter binding moiety with the reporter via
streptavidin-biotin binding;
(c) applying a magnetic field to the analysis chamber to pull down a complex formed
between the analyte of interest bound to the magnetic conjugate, the reporter binding
moiety, and the reporter by
(d) removing a volume of the sample from the analysis chamber using the microfluidic
apparatus;
(e) adding a volume of buffer to the analysis chamber;
(f) resuspending the magnetic conjugate with the analyte of interest and the reporter binding
moiety associated therewith with the reporter; and
(g) detecting, in the analysis chamber of the microfluidic apparatus, the presence, absence, or
level of the analyte of interest by detecting fluorescence of the reporter with a light source
and photodetector, and
wherein the analyte of interest is thyroid stimulating hormone, troponin, luteinizing hormone (LH), or prostate specific antigen (PSA)”.
Regarding claim 42, Lau teaches a method for detecting the presence, absence, or level of an analyte of interest in a sample in a fluidics system (Abstract; [0020-0028]; [0032]; [0103]; page 14, claim 38). Lau also teaches capillary microchannels as flow channels which are the elements of a microfluidics system [0105]. Lau further teaches that the analyte of interest comprises a protein [0113]. And Lau teaches adding the sample to an analysis chamber of the apparatus [0011]. Lau also teaches contacting the sample with a magnetic conjugate comprising a magnetic particle conjugated to a capture moiety comprising an antibody configured to bind the analyte of interest in the analysis chamber of the fluidic apparatus (Sheet 4 of 29, FIG. 4, “MAGNETIC BEAD 1”, “LIGAND 1” “MAGNETIC BEAD 2”, “LIGAND 2”, “LIGAND3”; [0008]; [0011-0012]; [0021]; [0096]; [0114]; [0120]). Lau further teaches contacting the sample with a reporter binding moiety comprising an antibody that is configured to bind the analyte of interest ([0096]; [0113-0114]; [0120]; [0163]). And Lau teaches that the capture moiety and the reporter binding moiety bind to different portions of the analyte of interest (Sheet 4 of 29, FIG. 4, (b), “PATHOGEN CAPTURE & VERIFICATION, TWO LEVELS OF SPECIFICITY”; [0025]; [0114]). Lau also teaches contacting the sample with a reporter ([0025]; [0027]; [0114]). Lau further teaches that the reporter comprises a plurality of quantum dots impregnated in a core particle ([0157]; [0166]). And Lau teaches binding the analyte of interest with the capture moiety, binding the analyte of interest with the reporter binding moiety, and binding the reporter binding moiety with the reporter (Sheet 4 of 29, FIG. 4, “MAGNETIC BEAD 1”, “LIGAND 1” “MAGNETIC BEAD 2”, “LIGAND 2”, “LIGAND3”; [0008]; [0011-0012]; [0021]; [0025]; [0027]; [0096]; [0113-0114]; [0120]; [0163]). Lau also teaches applying a magnetic field to the analysis chamber to pull down a complex formed between the analyte of interest bound to the magnetic conjugate, the reporter binding moiety, and the reporter ([0023]; [0025]; [0114]). Lau further teaches removing a volume of the sample from the analysis chamber using the fluidics apparatus [0024]; [0027]. And Lau teaches adding a volume of buffer to the analysis chamber ([0025]; [0114]; [0027]). Lau also teaches resuspending the magnetic conjugate with the analyte of interest and the reporter binding moiety associated therewith with the reporter [0025]. Lau further teaches detecting, in the analysis chamber of the apparatus, the presence, absence, or level of the analyte of interest by detecting fluorescence of the reporter with a light source and photodetector ([0020]; [0028]; [0013-0114]; [0152-0156]).
Regarding claims 13 and 42, Lau does not teach the analyte of interest to be thyroid stimulating hormone, troponin, luteinizing hormone (LH), or prostate specific antigen (PSA). Lau also does not teach that the magnetic particle is metallic nanoparticle. Lau does not teach a biotin-labeled reporter binding moiety nor a streptavidin-labeled reporter.
Regarding claims 35 and 44, Lau does not teach that the reporter comprises a gold core particle.
Regarding claims 36 and 45, Lau does not teach that the gold particle comprises a silica shell.
Regarding claims 37 and 46, Lau does not teach that the silica shell is impregnated with the one or more quantum dots.
Regarding claims 38 and 47, Lau does not teach that the one or more quantum dots comprises about 100-600 quantum dots.
Regarding claim 42, Song teaches using a sandwich immunoassay using two antibodies directed to different epitopes of the target analyte of troponin (Fig. 1. “C) Schematic diagram of the sandwich immunoassay using antigen/antibody binding (System 1) and avidin/biotin affinity binding (System 2)”).
Regarding claim 42, Agrawal teaches using a metallic magnetic particle as part of an immunoassay (Page 3778, right column, “These magnetic beads are composed of iron oxide nanoparticles embedded in a polymeric matrix and are well suited for target capturing, enrichment, and isolation”).
Moreover, regarding claims 42, Li teaches a biotin-labeled reporter binding moiety such as a biotin-labeled antibody and a streptavidin-labeled reporter such as a streptavidin conjugated quantum dot (Sheet 1 of 9, FIG. 2, “Quantum Dot-Streptavidin”, “Biotin-Ab” and FIG. 3, “Streptavidin Conjugated Quantum Dot”, “Biotin-labeled Antibody”).
Regarding claim 42, Li teaches binding the reporter binding moiety with the reporter (Sheet 1 of 9, FIG. 2, “Ab-magnetic Bead”, “Target Bacterium”, “Biotin-Ab”, “Quantum Dot Streptavidin”, “λEx 473 nm”, “λEm 609 nm”). Li teaches that the target analyte is a contaminant that is selected from a group consisting of a prokaryote, a eukaryote, a virus, and a polypeptide (Page 2, [0016]; page 9, claim 8).
Moreover, regarding claims 35 and 44, Oldenburg teaches that the reporter comprises a gold core particle ([0013]; [0049]; [0099]; [0136]).
Regarding claims 36 and 45, Oldenburg teaches that wherein the gold particle comprises a silica shell ([0078-0082]; [0086]; [0136]).
Regarding claims 37 and 46, Oldenburg teaches that wherein the silica shell is impregnated with the one or more quantum dots ([0115]; [0124-0125]; [0136]).
Regarding claims 38 and 47, Oldenburg teaches that one or more quantum dots comprises about 100-600 quantum dots ([0103]; [0115]).
It would have been obvious for a PHOSITA before the effective filing date of the application to combine the sandwich immunoassay of troponin of Song with the magnetic method of Lau to improve the sensitivity of the detection method of an analyte of interest in an immunoassay because Song noted the suitability of their method to detect troponin from blood samples (Page 3819, right column, first paragraph). And Song also teaches integrating each immunoassay into a microfluidic channel to minimize procedural steps (Page 3824, left column, third paragraph). A skilled artisan would have been motivated to combine the metallic magnetic particle of Agrawal with the methods of Song and Lau because Agrawal showed how to use a metallic magnetic particle as part of an immunoassay for the sensitive capture and separation of an analyte by a magnetic field (Abstract) and to have a sensitive detection of an analyte by using an antibody-conjugated semiconductor quantum dots (QDs) (Abstract). Agrawal further noted that QDs exhibit unique optical properties such as size-tunable fluorescence emission (spectral shifting), large absorption coefficients, improved brightness, and superior photostability (Abstract). A skilled artisan would have been motivated to combine the three-component method of detection of Li with the methods of Agrawal, Song and Lau because Li teaches used a capture moiety, a reporter moiety and a reporter in a three-component method to increase the sensitivity of signal detection of an analyte in an immunoassay (Sheet 1 of 9, FIG.2; [0042]). Li further teaches using their method to detect a wide range of analytes [0033]. A skilled artisan would have been motivated to combine the gold core particles of Oldenburg with the methods of Li, Agrawal, Song and Lau because Oldenburg teaches using a gold core particle with a silica shell that is impregnated with one or more quantum dots for optical detection and to provide protective coating of the particles ([0005-0006]; [0102]). Thus, a skilled artisan would have been motivated to combine the above methods and inventions to improve the sensitivity of detection of an immunoassay and the stability of capture particles. A PHOSITA would have had a reasonable expectation of success in combining the methods of Oldenburg, Li, Agrawal, Song and Lau, and based on the methods being in the field of detecting a target analyte by an immunoassay. It would have been obvious for a PHOSITA to bring the improvements of Oldenburg, Li, Agrawal and Song to the method of Lau to achieve a sensitive detection of proteins, pathogens or even contaminants.
Response to Arguments
Applicant's arguments filed 07/13/2026 have been fully considered but they are not persuasive.
First, the Applicant alleged that the combination of the different methods of references used in the 103 rejection of the instant claims results in a nonfunctional method. Specifically, the Applicant alleged that Reference Song does not teach all the limitations of the instant application and that it cannot be combined with other references in the 103 rejection of claims. The Applicant further alleged that Song does not provide a teaching, suggestion, or motivation to adapt the teachings of Lau et al., Agrawal et al., Li et al., and/or Oldenburg et al.
This argument is not persuasive because the different methods are in the area of immunoassays and the different adaptations of references are advantageous additives to the method of Lau. Specifically, a skilled artisan would have been motivated to combine the sandwich immunoassay of troponin of Song with the magnetic method of Lau to improve the sensitivity of the detection method of an analyte of interest in an immunoassay because Song noted the suitability of their method to detect troponin from blood samples (Page 3819, right column, first paragraph). Song further noted integrating each immunoassay into a microfluidic channel to minimize procedural steps (Page 3824, left column, third paragraph). A skilled artisan would have been motivated to combine the metallic magnetic particle of Agrawal with the methods of Song and Lau because Agrawal showed how to use a metallic magnetic particle as part of an immunoassay for the sensitive capture and separation of an analyte by a magnetic field (Abstract) and to have a sensitive detection of an analyte by using an antibody-conjugated semiconductor quantum dots (QDs) (Abstract). Agrawal further noted that QDs exhibit unique optical properties such as size-tunable fluorescence emission (spectral shifting), large absorption coefficients, improved brightness, and superior photostability (Abstract). A skilled artisan would have been motivated to combine the three-component method of detection of Li with the methods of Agrawal, Song and Lau because Li teaches using a capture moiety, a reporter moiety and a reporter in a three-component method to increase the sensitivity of signal detection of an analyte in an immunoassay (Sheet 1 of 9, FIG.2; page 4, [0042]). Li further teaches using their method to detect a wide range of analytes (Page 3, [0033]) and teaches that the logical approach to detecting an analyte is by detecting different epitopes to an analyte to achieve specific detection [0056]. A skilled artisan would have been motivated to combine the gold core particles of Oldenburg with the methods of Li, Agrawal, Song and Lau because Oldenburg teaches using a gold core particle with a silica shell that is impregnated with one or more quantum dots for optical detection and to provide protective coating of the particles (Page 1, [0005-0006]; pages 6-7, [0102]). Thus, a skilled artisan would have been motivated to combine the above methods and inventions to improve the sensitivity of detection of an immunoassay and the stability of capture particles.
Second, the Applicant provided a fourth Koussa’s Declaration (submitted July 13, 2026) that relied on a microfluidic device from a non-patent publication to overcome the previous 103 rejection of claims (Koussa et al., VitalOne™: a point-of-care platform for rapid, comprehensive, central-lab quality blood testing; Sens. Diagn., 2024, 3, 1899–1922). The Applicant alleged that none of the references teach such a microfluidics device.
This argument is not persuasive because the claims are directed to a method for detecting an analyte and not a device. Furthermore, the references do teach a fluidics system and microfluidic channels. Specifically, Lau teaches a fluidics system and method for detecting an analyte (Abstract; [0020-0028]; [0032]; [0103]; [0105]; page 14, claim 38). Song further teaches microfluidics channels (Page 3824, left column, third paragraph). Also, the declaration relies on a non-patent publication that was published after the priority date (01/26/2017) of the instant application. The non-patent publication was even published after the filing date (07/22/2019) of the instant application. Thus, it cannot be used to overcome prior art rejections.
Also, the fourth Koussa’s declaration did not resolve the deficits of previous Koussa’s declarations. Specifically, the first Koussa Declaration (originally submitted February 21, 2024) compares TSH three-component assay to two-component assays. However, the first Koussa Declaration does not compare the same amount of reagents (e.g., 5x or 10x) of three-component assay to two-component assay nor does it use the same experimental conditions in the comparison. Also, the claims do require the amount of reagents used in the declaration for performing the three-component assay of TSH. Thus, the claims are not commensurate in scope with the first Koussa Declaration.
The second Koussa Declaration (originally submitted October 2, 2024) only cover the improved sensitivity of the three-component assay for Troponin, luteinizing hormone (LH) and prostate specific antigen (PSA) by covering the limit of detection (LOD). The second Koussa Declaration does not show the comparison of the LOD of three-component assay of troponin, LH or PSA to a two-component assay of troponin, LH or PSA. The second Koussa Declaration does not cover TSH. Last, the claims of the instant application do not teach the LOD to use. Thus, the claims are not commensurate in scope with the second Koussa Declaration.
The third Koussa Declaration (originally submitted March 19, 2025) teaches the data of the first and second declaration along with mathematical modeling and kinetics calculations. The claims of the instant application do not recite any of the calculations nor the experimental conditions for any of the three declarations. Thus, the claims are still not commensurate in scope with the third Koussa Declaration.
For these reasons, the previous rejection of claims 13, 35-38, 42 and 44-47 under 35 U.S.C. 103 is still maintained.
Conclusion
No claims are allowed.
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/OMAR RAMADAN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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