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 .
Priority
The present application, 17/220,888 was filed 04/01/2021, claims benefit to provisional applications No. 63/004,439, filed on 04/02/2020, No. 63/005,112, filed on 04/03/2020, and No. 63/007,315, filed on 04/08/2020 is acknowledged.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Applications No. 63/004,439 and 63/005,112, fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Claim 90 recites the method of claim 79, wherein one or more immunoglobulin types comprises IgG, IgM, IgA, IgD, or IgE. Although the prior filed applications do recite Immunoglobulin types IgA, IgG and IgM, they do not recite IgD or IgE and therefore the claim does not comply with one of more conditions for receiving the benefit of the earlier filing date.
The effective filing date for claim 90 is 04/08/2020.
Further, the disclosure of the prior-filed application, Applications No. 63/004,439, 63/005,112, and 63/007,315 fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
Claim 99 recites the method “wherein the SARS-CoV-2 infection is caused by a SARS-CoV-2 variant. Claim 100 recites a plurality of SARS-CoV-2 variants. Claim 107 further recites “a SARS-CoV-2 variant infection”. Although the prior-filed applications do recite a SARS-CoV-2 infection, they do not disclose an infection by a variant of the virus and therefore the claim does not comply with one or more conditions for receiving the benefit of the earlier filing date.
Claims 114 and 115 recite a plurality of antigens comprising one or more SEQ ID Nos: 1-8 (claim 114), and SEQ ID Nos: 4-8 (claim 115). Although the prior filled applications do recite antigen, they do not disclose specific antigen sequences and therefore the claims do not comply with one or more conditions for receiving the benefit of the earlier filing date.
Claims 117 and 118 recite performing a machine learning algorithm (claim 117), in particular a random forest machine learning algorithm (claim 118). The prior filled applications do not recite any machine learning algorithm and therefore the claims do not comply with one or more conditions for receiving the benefit of the earlier filing date.
The effective filing date for claims 99, 100, 114-115, and 117-118 is 04/01/2021.
Information Disclosure Statement
The Information Disclosure Statement (IDS), filed 09/10/2025, has been considered, initialed and is attached hereto.
Status of the claims
Claims 1, 10, 79-80, 82, 84, 86-97, 99-111, 113-115, and 117-119 are pending in this application. Claims 1, 10, 79-80, 90-92, 97, 105, and 113 are amended, claim 119 is new, and claims 2-9, 11-78, 81,83, 85, 98, 112, and 116 are cancelled. Claims 1, 10, 79-80, 82, 84, 86-97, 99-111, 113-115, and 117-119 are examined below.
Claim Interpretation
Claims 97 and 113 as currently amended, recites “at least one antigen with a protein sequence of a SARS-CoV-2 protein selected from the group consisting of the S protein, M protein, N protein, E protein, and HE protein”. When given broadest reasonable interpretation, the claims, and dependent claims 114 and 115 comprise a protein sequence that is either the full length protein species of the proteins cited above or fragments of said proteins. The specification discloses:
“Exemplary reference sequences of SARS-CoV-2 proteins or portions thereof are provided herein. […] Additional SARS-CoV-2 proteins sequences and modifications thereof are also exemplified herein. SEQ ID NO: 5 refers to the RBD of the SARS-CoV-2 S protein, spanning amino acids 319-541 of the S protein”. (page 35, see paragraph [0193).
Thus, the specification provides support for “a protein sequence of a SARS-CoV-2 protein” comprising both full length proteins and fragments thereof.
Withdrawn Objections/Rejections
The objections to claims 10, 97, and 113 have been withdrawn due to the amendment of the claims.
After further consideration, the rejection of claims 97, 99, 100, and 113 under 35 USC 112(a) has been withdrawn.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 79-80, 82, 84, 89-95, 102-111 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bailey et al., USPGPUB 20130295688 (see PTO-892, 07/20/2023).
Regarding claim 79, Bailey et al. teaches a method of performing a multiplexed immunoassay, namely for detecting an antibody of interest with a detection antibody (immunoassay; Bailey et al., page 23, paragraph [0246], lines 1-4) with multiplex capacity (multiplex for detecting multiple antigens; Bailey et al., page 23, paragraph [0246], lines 18-21). Bailey et al. further teaches obtaining a sample from a subject such as a human patient suspected of having a disease associated with antibody biomarkers and applying it to an optical sensor to allow an antibody biomarker to bind to the capture probe (contacting a sample from a subject comprising a plurality of immunoglobulins; Bailey et al., page 24, paragraph [0252], lines 1-7). Bailey et al. further teaches that the capture probe, comprising an antigen that is capable of binding an antibody, is attached to the surface of an optical ring resonator (Bailey et al., page 22, paragraph [0246], lines 4-7). Bailey et al. further teaches that multiplex formats refer to a plurality of different capture probes on the same surface of an optical sensor or multiple optical sensors (ring resonator), wherein each sensor (optical ring resonator) can comprise one or more of the same (multiple copies of a single antigen) or different (plurality of different antigens) capture probes (Bailey et al., page 23, paragraph [0265], lines 3-6). Bailey further teaches a ring resonator disposed over lower cladding and upper cladding, the latter being attached to the lower cladding on each side of a cavity comprising the ring resonator and waveguide (Bailey, page 8, see entire paragraph [0108] and figure 5). Bailey further teaches the cladding disposed over most of the area, with exception to a window which provides exposure to portions of the linear waveguide and the ring resonator (Bailey, page 8, paragraph [0107] and Figure 4). As such, Bailey teaches different antigens each attached to the interior surface of a ring resonator cavity. Bailey et al. further teaches flow channels configured to direct flow of solution across the optical sensors, e.g. the ring resonators (Bailey et al., page 11, paragraph [0143, lines 4-6). Bailey et al. further teaches 5 antigens in a multiplex chip, where each optical ring was spotted with one of 5 antigens (plurality of optical ring resonators comprises a plurality of antigens; Bailey et al., Figure 25 and page 33, see paragraph [0326]) and serum samples were flowed over the chip allowing antibodies present in the serum to bind to the antigen capture probes (Bailey et al., page 33, paragraph [0327], lines 1-6).
In particular, as shown in Fig. 25, multiple optical ring sensors are placed at different loci within a single chip, with a common, single flow path across the multiple sensors, thereby reading on a plurality of optical ring resonators “positioned within a fluidic channel.” See also Fig. 5, depicting multiple resonators 208 within the same flow channel 502. Further, Fig. 25 depicts that each optical ring sensor is functionalized with a different antigen, thereby reading on “a plurality of different antigens are attached to the fluidic channel at respectively different loci in the fluidic channel.” Figures 8 G and F and paragraphs [0120-0122] also teach “Various embodiments may incorporate more than one ring resonator” (para [0120]) “although two resonators are shown in FIG. 8F, more ring resonators may be added (para [0121] and “multiple ring resonators aligned along the length of and adjacent to the input/output waveguide” (lines 1-4).
Bailey et al. further teaches providing a detection antibody that binds to the antibody of interest, wherein this detection antibody can be anti-human IgG, IgA, or IgM antibody (Bailey et al., page 23, paragraph [0246], lines 3-13). Bailey et al. also teaches flowing probes over the multiplex chip that bind to antibodies previously bound to the antigen capture probes (probes specific to one or more immunoglobulin type; Bailey et al., page 33, paragraph [0327], lines 6-8).
Bailey et al. further teaches that multiple optical sensors can be manipulated in a multiplex format at the same or different times (Bailey, page 23, paragraph [0266], lines 1-3). Bailey further teaches that reagents for any of the primary, secondary, or tertiary binding events described can be administered at different times to populations of optical sensors in a multiplex platform and that a reagent can be provided to one population of optical sensors at a first time, and the reagent can be provided to another population of optical sensors at different times, wherein each population comprises one or more optical sensors. Bailey further teaches that in various embodiments, the analyte of interest can be detected in one population of optical sensors at one time and in another population of optical sensors at different times, wherein each population comprises one or more optical sensors (Bailey, pages 25-26, see entire paragraph [0267]). Bailey further teaches that temporally or spatially manipulating distinct populations of optical sensors in a multiplex platform, the extent of cross-talk can be reduced (Bailey, page 26, paragraph [0269], lines 3-7). As such, Bailey teaches contacting, at a first time a first probe specific for a first immunoglobulin type and contacting, at a second time that is different from the first time, a second probe specific for a second immunoglobulin type.
Bailey et al. further teaches real-time analyte detection, including, but not limited to detecting the primary binding event between an analyte and a capture probe, a secondary binding event between an antibody and the analyte bound to the capture probe (Bailey et al., page 26, paragraph [0273], lines 4-10).
Regarding claim 80, Bailey et al. teaches detecting an antibody of interest with an antigen capable of binding to the antibody, wherein the antigen is attached to an optical ring resonator. Bailey et al. further teaches detecting the presence or absence of the antibody of interest, by a change in the optical property of the optical ring resonator. Bailey et al. further teaches that the detection antibody can be anti-human IgG, IgA, or IgM antibody (Bailey et al., page 22-23, see paragraph [0246]).
Regarding claim 82, Bailey et al. teaches detecting an antibody of interest against an antigen by using an anti-human IgG, IgA, IgM or IgE antibody (the immunoglobulin that specifically binds to the single antigen comprises an immunoglobulin type to which the one or more probes specifically bind; Bailey et al., page 23, paragraph [0246], lines 12-19).
Regarding claim 84, Bailey et al. teaches a chip having input and output couples connected to waveguide optical sensors comprising ring resonators, the chip including flow channels for flowing solution across the optical sensors and in particular the ring resonators (device; Bailey et al., page 5, see paragraph [0069] and Figure 11).
Regarding claim 89, Bailey et al. teaches 5 antigens in a multiplex chip, where each optical ring was spotted with one of 5 antigens (comprises 2-28 optical ring resonators; Bailey et al., Figure 25 and page 33, see paragraph [0326]).
Regarding claims 90 and 91, Bailey et al. teaches detecting an antibody of interest against an antigen by using an anti-human IgG, IgA, IgM or IgE antibody to detect auto-antibody or to detect antibody subtype associated with allergies, such as IgE (Bailey et al., page 23, paragraph [0246], lines 12-19).
Regarding claim 92, Bailey et al. teaches determining the presence or absence of an antibody of interest by detecting altered optical property of the optical ring resonator when the antibody of interest and the capture probe (antigen) bind to form a complex that is bound by the detection antibody. Bailey et al. further teaches that the detecting and/or measuring the concentration of an antibody can be done in real-time and/or in multiplex with other analytes of interest (Bailey et al., page 23, see entire paragraph [0246]). Put another way, Bailey teaches detecting the concentration of an antibody in a multiplex format with another analyte (such analyte can be an antibody as taught by Bailey) and as such Bailey teaches detecting of immunoglobulins of the first and second types.
Regarding claim 93 and 95, Bailey et al. teaches that capture probes can comprise a viral antigen capable of binding to an antibody specific against the viral antigen and that the presence of such an antibody would indicate that the subject has been infected by the virus (Bailey et al., page 15, paragraph [0181], lines 10-15).
Regarding claim 94, Bailey et al. teaches that a multiplex assay comprising 5 auto-antigens associated with auto-immune diseases (Bailey et al., page 33, paragraph [0326], lines 6-9) was up to 10-fold more sensitive at detecting the antigens than a different assay (Bailey et al., page 33, see paragraph [0328]).
Regarding claim 102, Bailey et al. teaches that the sample can include blood, plasma, and serum (Bailey et al., page 13, paragraph [0158], lines 6-8).
Regarding claim 103, Bailey et al. teaches adding the sample in volume of 35 µl. 35 µl falls within the claimed range of 10-250 µl and therefore the art anticipates the claim.
Regarding claim 104, Bailey et al. teaches that results were obtained within 15 minutes (Bailey et al., page 33, paragraph [0327], lines 14-16), 15 minutes as taught by Bailey falls directly within the claimed range of 5-60 minutes, therefore Bailey addresses the claim.
Regarding claim 105, Bailey et al. teaches that the capture probe can be a viral antigen capable of binding an antibody specific against the viral antigen and further that detection of the antibody indicates that that the subject has been infected and mounted a specific immune response to it (antigen with high specificity for an immunoglobulin associated with at least one […] disease; Bailey et al., page 15, paragraph [0181], lines 10-15). Bailey et al. further teaches that the assay is 10-fold more sensitive than ELISA at detecting antigens (high sensitivity; Bailey et al., page 33, paragraph [0328].
Regarding claims 106 and 107, Bailey et al. teaches a multiplex chip comprising 5 antigens associated with 3 autoimmune diseases (two or more diseases […] comprising […] an immune disorder; Bailey et al., page 33, paragraph [0326], lines 5-10).
Regarding claim 108, Bailey et al. teaches that the capture probe can be a viral antigen capable of binding an antibody specific against the viral antigen and further that detection of the antibody indicates that that the subject has been infected and mounted a specific immune response to it (antigen with high specificity for an immunoglobulin associated with at least one […] disease; Bailey et al., page 15, paragraph [0181], lines 10-15).
Regarding claim 109, Bailey et al. is teaching detecting changes in resonance wavelength for a plurality of optical ring resonators (Bailey, page 34, paragraph [0335], lines 1-2) and detecting and/or measuring the concentration of an analyte of interest in a sample providing real-time detection and measurement of biomolecules with high sensitivity and specificity. Bailey further teaches that it is possible to detect and/or measure binding-induced shifts in the resonance wavelength of individual binding events in real-time (Bailey, page 22, see entire paragraph [0243]). As such the method of Bailey is necessarily determining an overall sensitivity and specificity for the plurality of disorders (the cited reference is performing the same method in the same way as claimed, as such it would necessarily follow that Baily is determining overall sensitivity and specificity as claimed).
Regarding claims 110 and 111, Bailey et al. teaches an assay wherein the presence of immunoglobulins that are specific for an antigen (bound to an optical ring resonator) with high specificity and sensitivity (one that binds antigen) and as such reduces false positives or false negatives respectively. Bailey et al. is addressing the method as claimed (performing the method in the same way, with the same steps and features of the present claims), as such, upon binding , it would necessarily follow that Bailey et al. is also reducing a false positive or false negative reading of the infection or disorder.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 10, and 86-88 are rejected under 35 U.S.C. 103 as being unpatentable over Bailey et al., in view of Iqbal et al. (2015) “Silicon Photonic Micro-Ring Resonators for Drug Screening and Kinetic Analysis” Chapter 7, pages 133-154 In: Fang, Y. (eds) Label-Free Biosensor Methods in Drug Discovery. Methods in Pharmacology and Toxicology. Humana Press, New York, NY (see PTO-892, 07/20/2023).
Claims 79-80, 82, 84, 89-95, 102-111 are anticipated by Bailey et al. as discussed in detail above.
Regarding claim 1, Bailey et al. teaches a method substantially as claimed, as recited in detail previously above.
Bailey et al. fails to teach flowing a wash buffer through the fluidic channel.
Iqbal et al. teaches a microchip comprising ring resonators covered by a microfluidic channels, with rings functionalized to bind antibodies or other biomarkers of interest (Iqbal et al., page 133, Abstract, lines 5-7). Iqbal et al. further teaches flowing a sample comprising immunoglobulin over a chip comprising nuclear antigens (step (a); Iqbal et al., page 143, (3.) lines 1-2) followed by a wash solution (Iqbal et al., page 144, (4.) lines 2-3) washing away any loosely bound antibodies (Iqbal et al., page 146, (4.) lines 3-4).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Bailey et al. to add a wash step after contacting the sample with the antigen. The ordinary artisan would have been motivated to do so, because of the teaching of Iqbal et al. that this washes away loosely bound antibody.
The ordinarily skilled artisan would have had a reasonable expectation of success, because Iqbal et al., like Bailey et al. teaches a method of detecting immunoglobulin in a sample using optical ring resonators functionalized with specific antigen to detect antibodies.
Regarding claim 10, Bailey et al. teaches a method of performing a multiplexed immunoassay substantially as claimed, as recited in detail previously above.
Bailey et al. fails to teach flowing a wash buffer through the fluidic channel.
Iqbal et al. teaches a microchip comprising ring resonators covered by a microfluidic channels, with rings functionalized to bind antibodies or other biomarkers of interest (Iqbal et al., page 133, Abstract, lines 5-7). Iqbal et al. further teaches flowing a sample comprising immunoglobulin over a chip comprising nuclear antigens (step (a); Iqbal et al., page 143, (3.) lines 1-2) followed by a wash solution (Iqbal et al., page 144, (4.) lines 2-3) washing away any loosely bound antibodies (Iqbal et al., page 146, (4.) lines 3-4).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Bailey et al. to add a wash step after contacting the sample with the antigen. The ordinary artisan would have been motivated to do so, because of the teaching of Iqbal et al. that this washes away loosely bound antibody.
The ordinarily skilled artisan would have had a reasonable expectation of success, because Iqbal et al., like Bailey et al. teaches a method of detecting immunoglobulin in a sample using optical ring resonators functionalized with specific antigen to detect antibodies.
Regarding claim 86, Bailey et al. teaches a method substantially as claimed.
Bailey et al. fails to teach a washing step between contacting the sample with the plurality of optical ring resonators removing immunoglobulins that do not bind or bind only weakly to the antigen bound to the optical ring resonators.
Iqbal et al. teaches a microchip comprising ring resonators covered by a microfluidic channels, with rings functionalized to bind antibodies or other biomarkers of interest (Iqbal et al., page 133, Abstract, lines 5-7). Iqbal et al. further teaches flowing a sample comprising immunoglobulin over a chip comprising nuclear antigens (step (a); Iqbal et al., page 143, (3.) lines 1-2) followed by a wash solution (Iqbal et al., page 144, (4.) lines 2-3) washing away any loosely bound antibodies (Iqbal et al., page 146, (4.) lines 3-4).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Bailey et al. to add a wash step after contacting the sample with the antigen. The ordinary artisan would have been motivated to do so, because of the teaching of Iqbal et al. that this washes away loosely bound antibody.
The ordinarily skilled artisan would have had a reasonable expectation of success, because Iqbal et al., like Bailey et al. teaches a method of detecting immunoglobulin in a sample using optical ring resonators functionalized with specific antigen to detect antibodies.
Regarding claim 87, Bailey et al. teaches a method substantially as claimed.
Bailey et al. further teaches real time measuring of the sensor response showing discrete jumps in resonance frequency (Bailey et al., sheet 29, Figure 23, and page 31, paragraph [0312], lines 7-8).
Bailey et al. fails to teach detecting changes in wavelength during the washing step, after the washing step and before contacting the bound antibody with secondary antibody or during the washing and after washing before detection.
Iqbal et al. teaches a microchip comprising ring resonators covered by a microfluidic channels, with rings functionalized to bind antibodies or other biomarkers of interest (Iqbal et al., page 133, Abstract, lines 5-7). Iqbal et al. further teaches continuous monitoring for each sensor, including before, during, and after the washing step (Iqbal et al., page 143, see Figure 4 with figure legend). Iqbal et al. further teaches that continuous measurement as shown in Figure 4, can detect primary binding of molecules to the spots (Iqbal et al., page 143, Figure 4 legend and (3.), lines 2-3). Iqbal et al. further teaches a wash step washing away any loosely bound antibodies (see above; Iqbal et al., page 146, (4.) lines 3-4) and figure 4 shows that continuous monitoring allows monitoring of the response after the first wash step removes the loosely bound antibody (Iqbal et al., page 143, Figure 4).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Bailey et al. in order to detect changes before, during and after the washing step and be able to monitor the response before and after the wash step removes the loosely bound antibody.
The ordinarily skilled artisan would have had a reasonable expectation of success, because Iqbal et al., like Bailey et al. teaches a method of detecting immunoglobulin in a sample using optical ring resonators functionalized with specific antigen to detect antibodies.
Regarding claim 88, Bailey et al. teaches a method substantially as claimed.
Bailey et al. fails to teach washing by flowing a wash buffer through a fluidic channel to contact the wash buffer with the immunoglobulins and optical ring resonators.
As explained previously above (see claim 86), Iqbal et al. teaches washing away loosely bound antigen after applying sample to a microchip comprising optical ring resonators.
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention for the reasons as discussed in detail above; as the same reasoning also applies here.
Claim 96 is rejected under 35 U.S.C. 103 as being unpatentable over Bailey et al. as applied to claim 95 above, and further in view of Han et al., KR 102019008 B1, 09/05/2019 (see PTO-892, 07/20/2023).
Regarding claim 96, Bailey et al. and the cited art above teach a method substantially as claimed.
Bailey et al. teaches that capturing an antibody specific against a viral antigen indicates that the subject has been infected with the virus, as discussed in detail previously above (Bailey et al., page 15, paragraph [0181], lines 10-15).
Bailey et al. does not teach that the viral infection is a coronavirus infection.
Han et al. teaches detecting MERS coronavirus specific antibody (Han et al., page 2, ‘Technical-Field’, lines 1-2). Han et al. further teaches that MERS is a respiratory infection caused by MERS-CoV, with a mortality rate of 20-46%, 6 times higher than SARS (Han et al., page 2, ‘Background Art’, see 1st-3rd paragraphs). Han et al. further teaches that there is no effective antiviral agents and that given the continuing threat to human health and high mortality rates, continuous serological testing is necessary (Han et al., page 3, see 4th paragraph).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to apply the method of Bailey et al. of detecting anti-virus antibodies indicating an infection, to detect anti-MERS-CoV antibodies (viral infection that is a coronavirus infection), because there is no effective treatment and the infection has a mortality rate of 20-46%.
The ordinary artisan would have a reasonable expectation of success, because of the teaching of Bailey et al. that optical ring resonators can be used to detect anti-viral antibodies and the teaching of Han et al. that detecting anti-MERS-CoV antibody indicates an infection with coronavirus.
Claims 97, 114-115, and 119 are rejected under 35 U.S.C. 103 as being unpatentable over Bailey et al., in view of Han et al. as applied to claim 96 above and further in view of Ahmed et al. (2020) “Preliminary Identification of Potential Vaccine Targets for the COVID-19 Coronavirus (SARS-CoV-2) Based on SARS-CoV Immunological Studies” Viruses, 12, 3, pages 1-15 (see PTO-892, 07/20/2023).
Regarding claims 97, 114-115, and 119, Bailey et al. and the cited art above teaches a method substantially as claimed.
Bailey et al. teaches that capturing an antibody specific against a viral antigen indicates that the subject has been infected with the virus, as discussed in detail previously above (Bailey et al., page 15, paragraph [0181], lines 10-15).
Han et al. teaches detecting antibody to a coronavirus infection (see above).
Bailey et al. and the cited art above does not teach that the coronavirus infection is a SARS CoV-2 infection and that the plurality of antigens comprises at least one immunogenic peptide of SARS-CoV-2.
Ahmed et al. teaches determining immunogenic epitopes in spike (S; SEQ ID No: 1; claims 97/114/119) and nucleocapsid (N; SEQ ID No: 4; claims 97/115/119) protein of SARS-CoV-2 by comparing the immunogenic epitopes known in SARS-CoV to SARS-CoV-2 proteins and finding no mutations (Ahmed et al., page 1, see Abstract). Ahmed et al. further teaches that 49 B cell epitopes of SARS-CoV have an identical match in the SARS-CoV-2 sequence and 20 of those sequences were derived from S, 22 from N and 4 from the M protein (Ahmed et al., page 8, 3.3., see 2nd paragraph).
SEQ ID Nos.:1-4 comprise sequences of the SARS-CoV-2 S, M, E, and N proteins and as such Ahmed also teaches epitopes comprised in SEQ ID Nos: 1-4.
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Bailey et al. and Han et al. with the antigen of Ahmed et al., which differs from the claimed invention only by the source of the immunogenic peptides (MERS-CoV as opposed to SARS-CoV-2), in order to detect antibody to SARS-CoV-2.
Both the antigen of Han et al. and the B cell epitopes (immunogenic antigen) that are shared between SARS-CoV and SARS-CoV-2 of Ahmed et al. where known in the art, usable for capture of antibodies. One of ordinary skill in the art would have found it obvious to substitute one for the other, in order to include those SARS-CoV peptides that are shared by SARS-CoV-2, as a simple substitution of one antigen over another in order to capture SARS-CoV-2 specific antibodies.
The ordinarily skilled artisan would have had a reasonable expectation of success, because Wong et al. shows that SARS-CoV antibodies can be captured by antigen and Ahmed et al. shows that some of the immunogenic B cell antigens are shared between SARS-CoV and SARS-CoV-2.
Claims 99-100 are rejected under 35 U.S.C. 103 as being unpatentable over Bailey et al., in view of Han et al., and Ahmed et al. as applied to claim 97 above, and further in view of Sun et al., WO2021/226348A2 (see PTO-892, 07/20/2023).
Regarding claims 99 and 100, Bailey et al. and the cited art above teaches a method substantially as claimed.
Bailey et al. teaches that capturing an antibody specific against a viral antigen indicates that the subject has been infected with the virus, as discussed in detail previously above (Bailey et al., page 15, paragraph [0181], lines 10-15).
Han et al. teaches detecting antibody to a coronavirus infection (see above).
Bailey et al. and the cited art above do not teach that the infection is caused by a SARS-CoV-2 variant.
Sun et al. teaches SARS-CoV-2 diagnostic reagents, comprising proteins that can be used as substrates to measure SARS-CoV-2 spike-specific antibody titers (Sun et al, page 160, paragraph [0239, lines 5-7). Sun et al. further teaches that the spike gene can be from a SARS-CoV-2 variant (Sun et al., page 74, paragraph [0135], lines 2-5) and Sun further teaches that the variant can be B.1.1.7, B.1.351, B.1.525, P.2, or B.1.429 (Sun et al, page 77, paragraph [0138}, lines 1-3).
Ascoli teaches that the emergence of SARS-CoV-2 variants raises concerns that new SARS-CoV-2 variants may evade detection by diagnostics and compromise the ability to accurately track disease (Ascoli et al., page 274, see columns 1 and 2).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Bailey et al. with the methods of Han et al. and Ahmed as explained previously in detail above to use SARS-CoV-2 specific antigen. It would further be obvious to use antigen from a SARS-CoV-2 variant (comprising for example, variants B.1.1.7, P.2, as taught by Sun) in an assay taught by the prior art above, as a simple substitution of one antigen for the other. The ordinary artisan would have been motivated to do so by the teaching of Ascoli et al. that virus variants may evade detection and compromise the ability to accurately track the disease.
Both the antigen of Han et al. and Sun et al. where known in the art, usable for capture of antibodies. One of ordinary skill in the art would have found it obvious to substitute one for the other, in order to include peptides from the SARS-CoV-2 variants, as a simple substitution of one antigen over another in order to capture SARS-CoV-2 specific antibodies.
The ordinarily skilled artisan would have had a reasonable expectation of success, because Wong et al. shows that SARS-CoV antibodies can be captured by antigen and Sun et al. teaches that the antigen can be used to measure SARS-CoV-2 antibody titers. Further because the method of Baily is for binding and detection of viral associated antibodies.
Claim 101 is rejected under 35 U.S.C. 103 as being unpatentable over Bailey et al., in view of Bryan et al. (2019), “Silicon optical sensor arrays for environmental and health applications”, Current opinion in environmental Science & Health, 10, pages 22-29 (see PTO-892, 07/20/2023).
Regarding claim 101, Bailey et al. teaches a method substantially as claimed.
Bailey et al. further teaches that capture probes can comprise a viral antigen capable of binding to an antibody specific against the viral antigen and that the presence of such an antibody would indicate that the subject has been infected by the virus (Bailey et al., page 15, paragraph [0181], lines 10-15).
Bailey et al. fails to teach that the viral infection is an influenza infection.
Bryan et al. teaches a label free reflectometric approach to detect influenza hemagglutinin specific antibodies in human serum to distinguish between vaccinated subjects and controls (Bryan et al., page 23, 4th paragraph, lines 1-9). Bryan et al. further teaches that the influenza viruses constitute one of the most important threats to human health throughout history, with up to 650 000 flu-related fatalities worldwide each year (Bryan et al., page 23, ‘Antigen and antibody arrays for influenza’, lines 1-5).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Bailey in order to use influenza hemagglutinin as capture antigen because of the teaching of Bryan et al. that influenza is one of the most important threats to human health, causing up to 650 000 flu related deaths a year.
The ordinary artisan would have had a reasonable expectation of success, because of the teaching of Bailey et al. that a viral antigen can be used in an optical ring resonator assay to probe for virus specific antibody and the success of Bryan et al. using multiple influenza antigen to bind anti-influenza antibody in a label free, reflectometric method.
Claim 113 is rejected under 35 U.S.C. 103 as being unpatentable over Bailey et al. as applied to claim 93 above, in view of Gralinski et al. (2020), “Return of the Coronavirus: 2019-nCoV”, Viruses, 12, 135, pages 1-8 and Smits et al. (2012), “Development of a bead-based multiplex immunoassay for simultaneous quantitative detection of IgG serum antibodies against Measles, Mumps, Rubella, and Varicella-Zoster virus” Clinical and Vaccine Immunology, 19, 3 pages 396-400 (see PTO-892, 07/20/2023).
Regarding claim 113, Bailey et al. teaches a method substantially as claimed.
Bailey et al. fails to teach an antigen with a protein sequence unique to SARS-CoV-2 and at least 1 antigen with a protein sequence that associate with a virus that is not SARS-CoV-1.
Smits et al. teaches a multiplex assay for simultaneous quantitative detection of IgG serum antibodies against 4 different viruses (Smits et al., page 396, 2nd paragraph, lines 18-20). Smits et al. further teaches that the multiplex assay considerably reduces the cost compared with separate ELISAs (Smits et al., page 398, ‘Discussion’, 2nd paragraph, lines 1-4). Smits et al. further teach that the multiplexed assay is a good alternative for large-scale immunosurveillance studies (Smits et al., page 400, see 2nd paragraph).
Gralinski et al. teaches that the N protein is well conserved across CoV families, including the 2019 SARS-CoV N protein having about 90% amino acid sequence identity to the SARS-CoV protein (Gralinski, page 3, 5th paragraph, lines 2-3). Gralinski et al. further teaches that the cross reactivity allows for a serum based assay to determine exposure to the novel CoV in asymptomatic cases and that this information may provide insights about susceptibility and potential routes of spread through asymptomatic carriers (Gralinski, page 3, 5th paragraph, line 5-page 4, line 1). Gralinski et al. further teaches that the SARS-CoV-2 spike protein is less conserved than other Coronaviridae (Gralinski, page 4, 2nd paragraph, lines 2-3). Gralinski et al. further teaches that SARS-CoV-2 appears to be less virulent than SARS-CoV (10% mortality) and MERS-CoV (35% mortality), except to the elderly and those with underlying health conditions (Galinsky et al., page 2, 1st paragraph, lines 14-17).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have applied the method of detecting antibody using a multiplex assay as taught by Bailey by using antigen from conserved regions of coronavirus proteins and antigens from regions of a protein that are not conserved, such as part of the spike protein, as taught by Gralinski, in order to diagnose coronavirus and to differentiate between different types of coronavirus infection. The ordinary artisan would have been motivated to do so, in order to accurately diagnose patients to determine which strain of coronavirus the patient is infected with, because of the difference in virulence and susceptible patient population.
It would have been further prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have used a multiplex assay with antigen from SARS-CoV-2 and from different virus strains, such as different coronavirus strains or other viruses, in the method of Bailey et al., in order to detect a variety of viruses in a more cost-efficient way, compared to ELISAs and to use the assay in immunosurveillance studies.
Claims 117 and 118 are rejected under 35 U.S.C. 103 as being unpatentable over Bailey et al. as applied to claim 92 above, in view of Chen et al. (2015), “Prediction of Protein-protein interactions using random decision forest framework” Bioinformatics, 21 25, pages 4394-4400 (see PTO-892, 07/20/2023).
Regarding claims 117 and 118, Bailey et al. teaches a method substantially as claimed.
Bailey et al. fails to teach determining whether a subject has previously had an infection or immune disorder by a machine learning algorithm (claim 117), specifically a random forest machine learning algorithm (claim 118).
Bailey et al. further teaches that in various embodiments, binding events can be observed by stochastic recording of binding events (Bailey et al., page 25, Paragraph [0263], lines 1-2) and that stochastic recording methods offer an advantage may make it possible to distinguish between non-specific and specific binding events, allowing for non-specific binding to be filtered out. Therefore trace components can be detected or measured in extraordinarily complex media, such as blood (Bailey et al., page 25, see Paragraph [0264], lines 1-2).
Bailey et al. does not teach a machine learning algorithm that is a random forest machine learning algorithm.
Chen et al. teaches using a random forest algorithm to predict protein-protein interactions that are localized to specific structural domains (Chen et al., see Abstract). Chen et al. further teaches that understanding protein interactions at the domain level gives detailed functional insights into proteins (Chen et al., page 4399, ‘Conclusion’, lines 6-7).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have used the random forest machine learning algorithm in the method of Bailey et al. to determine if a subject has previously had an infection or immune disorder, because the algorithm predicts protein-protein interactions that are localized to specific structural domains, which together with the teaching of Bailey et al. that it is possible to distinguish between non-specific and specific binding, might give insight in the type of non-specific binding that occurs.
The ordinary artisan would have had a reasonable expectation of success, because of the teaching of Bailey et al. that binding of antibody to viral antigen shows a previous infection (see above) and the ability of the algorithm to predict protein-protein interactions.
Response to Arguments
Applicant’s arguments, see entire page 14, filed 09/10/2025, with respect to the rejection of claims 97, 99, 100, and 113 under 35 U.S.C. 112(a) have been fully considered and are persuasive. The rejection of claims 97, 99, 100, and 113 under 35 U.S.C. 112(a) has been withdrawn.
Applicant's arguments filed 09/10/2025 have been fully considered but they are not persuasive.
Applicant further argues, starting on page 16, that a multiplexed optical system is disclosed, where the multiplexing can occur spatially or temporally and that the specification explains that “the multiplex embodiments described above are particularly advantageous in reducing cross-talk from the individual detection systems in a multiplex platform. For instance, by temporally or spatially manipulating distinct populations of optical sensors in a multiplex platform, the extent of cross-talk from the individual detection systems can be reduced. Applicant further argues that the specification explains that “cross-talk can be temporally reduced by providing reagent(s) for any of the primary , secondary, or tertiary binding events described herein at different times […] In various embodiments, cross-talk can be reduced by detecting or measuring an analyte of interest in different populations of optical sensors at different times.” Applicant argues that claim 79 recites “contacting at a first time, a first probe […] at a second time that is different from the first time, a second probe”.
Applicant argues that Bailey does not disclose this feature of contacting different probes at different times with the bound immunoglobulins and using the results to determine the presence or absence of particular immunoglobulin types and it would not have been obvious to a person of sill in the art to flow a first label or probe in the channel, observe its interaction with the particular immunoglobulin types and then to flow a second label and observe its interactions and to expect to get a meaningful signal from the second probe.
This argument is not persuasive.
Bailey teaches that the system described can be used in multiplex formats and that multiple optical sensors can be manipulated together temporally or spatially (Bailey, see entire paragraph [0265]).
Further, paragraph [0269] of Bailey teaches the advantages of multiplexing spatially or temporally:
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Bailey further teaches that in various embodiments cross-talk can be reduced by detecting or measuring an analyte of interest in different populations of optical sensors at different times (Bailey, paragraph [0271], lines 12-15) and that reagent(s) for any of the primary, secondary, or tertiary binding events described herein can be administered at different times to populations of optical sensors in multiplex platform (Bailey, page 25, paragraph [0267], lines 1-4).
As such, Bailey does disclose the feature of contacting different probes at different times with the bound immunoglobulins and using the results to determine the presence or absence of particular immunoglobulin types.
Applicant further argues regarding the rejection under 35 U.S.C. 103 that Bailey does not disclose the features related to temporally reducing cross-talk by providing different probes at different times and that Iqbal does not cure the deficiencies of Bailey and that therefore claims 1 and 10 are allowable.
This argument is not persuasive.
As explained previously in detail above, Bailey teaches temporally reducing cross-talk by providing different probes at different times.
For all the reasons stated above, the arguments are not persuasive.
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 nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Communication
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/STEFANIE J. KIRWIN/Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 March 2, 2026