DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-19 are pending and examined herein.
Priority
This application, filed 01/10/2023, is a 371 of PCT/US2021/041729, filed 07/15/2021, which claims benefit of U.S. Provisional Patent Application 63/052,340, filed 07/15/2020. The benefit is acknowledged and the claims examined herein are treated as having an effective filing date of 07/15/2020.
Information Disclosure Statement
The Information Disclosure Statement(s) filed 01/10/2023 are acknowledged and have been considered.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 13 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 13 recites that the capture antigen “comprises, consists essentially of, or consists of” a human astrovirus spike protein or domain. The use of multiple, alternative transitional phrases in a single claim element renders the scope of the claim unclear, because each transitional phrase defines a different and mutually exclusive scope with respect to additional, unrecited components. As explained in MPEP 2111.03, the transitional phrases “comprising,” “consisting essentially of,” and “consisting of” have different legal meanings, and the use of more than one such phrase in the same claim can render the claim indefinite. In claim 13, it is unclear which transitional phrase governs the scope of the capture antigen, and therefore a person having ordinary skill in the art (PHOSITA) cannot determine the scope of the claim with reasonable certainty. Accordingly, claim 13 is indefinite. For purposes of compact prosecution, this claim will be interpreted under the open transitional phrase “comprising.” Under this interpretation, the scope of the claim is open-ended and does not exclude the presence of additional, unrecited components in the capture antigen.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-9 are rejected under 35 U.S.C. 103 as being unpatentable over Carney et al. (Flexible Label-Free Quantitative Assay for Antibodies to Influenza Virus Hemagglutinins. Clinical and Vaccine Immunology. Vol. 17, No. 9, September 2010 – IDS dated 01/10/2023) in view of Maragos et al. (Signal amplification using colloidal gold in a biolayer interferometry-based immunosensor for the mycotoxin deoxynivalenol. Food Additives & Contaminants. Part A. Vol. 29, No. 7, July 2012 – IDS dated 01/10/2023).
Regarding Claims 1 and 2, Carney et al. discloses a biolayer interferometry (BLI)-based immunoassay using an immobilized viral antigen to detect antibodies in biological samples. In particular, Carney et al. reports “the use of a cell-free and label-free flu antibody biosensor assay (f-AbBA) for influenza research and diagnostics that uses recombinant hemagglutinin (HA) in conjunction with label-free biolayer interferometry technology to measure biomolecular interactions between the HA and specific anti-HA antibodies or sialylated ligands” (Abstract, page 1407). Carney et al. further teaches the optical detection principle recited in Claim 1, stating that “the instrument detects binding to the biosensor tip, which results in a wavelength shift (measured in nanometers)” (Figure 1, page 1410).
Although Carney et al. teaches contacting a sample with a BLI sensor, the BLI sensor having a capture antigen affixed thereto, and detecting the presence of a biomolecule via a wavelength shift (page 1409), Carney et al. does not disclose the use of detecting reagents conjugated to colloidal gold particles.
On the other hand, Maragos et al. discloses the use of colloidal gold-conjugated antibodies in a BLI immunosensor to enhance detection sensitivity, stating that “to monitor deoxynivalenol (DON) in wheat rapidly, a biosensor using the principle of biolayer interferometry (BLI) was developed” (Abstract, page 1108). Maragos teaches “the signal from the sensor was substantially amplified through the use of a primary-antibody-colloidal gold conjugate” (Abstract, page 1108). Maragos specifically states that “the amplification, if any, would come from the additional thickness to the tip of the fibre that would result from binding of the secondary antibody–enzyme conjugate. The second reagent investigated was the primary (anti-DON) antibody to which colloidal gold had been conjugated (i.e. Ab-Au). The gold colloid adds significant size to the primary antibody which results in increased thickness at the sensor tip upon binding of the antibody to the immobilized DON” (Results & Discussion, paragraph 1, page 1112). Here Maragos et al. does not introduce a different detection principle or platform, but instead teach a signal-enhancement strategy that operates directly on the same BLI wavelength-shift readout used by Carney et al. Here, the teachings of Maragos are technically compatible with, and directly applicable to, the assay framework of Carney et al.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Carney by including the colloidal gold-conjugated detection agents taught by Maragos for the advantage of adding thickness to the tip of the fibre which would result in increased thickness at the sensor tip upon binding of the antibody to the immobilised DON thereby increasing sensitivity. It also would have been obvious to modify the method of Carney by adding the antibody-labeled reagents taught by Maragos because the sensitivity of Carney et al’s assay is directly dependent on the magnitude of this wavelength shift, improving signal magnitude would directly improve assay performance, particularly for low-abundance antibodies or diluted biological samples and Maragos teaches colloidal gold-conjugated detection agents will increase thickness at the sensor tip.
Additionally, a PHOSITA would have had a reasonable expectation of success in adapting the method of Carney using the labeled reagents of Maragos because applying this known signal-amplification technique to the BLI antibody-detection assay of Carney et al. would increase signal magnitude without altering the underlying assay architecture, capture antigen, or detection mechanism and is a straightforward substitution of known equivalents for their established purpose. Specifically, Maragos et al., teaches colloidal gold conjugation is used specifically to enhance BLI signal output, and it would have been obvious to a PHOSITA to have recognized this as a routine optimization step applicable to existing BLI assays such as that disclosed by Carney et al., rather than as an inventive departure from the prior art. Lastly, applying known signal-amplification techniques to improve the sensitivity of an existing biosensor assay falls squarely within the realm of ordinary skill and routine assay optimization, particularly where, as here, both references operate within the same technological field, use the same detection modality, and seek to improve the same measurable output (wavelength shift). The combination therefore reflects the application of known techniques to a known device to yield predictable results, consistent with established obviousness principles.
Regarding claims 3 and 4, Carney et al. explicitly discloses that biological fluids such as serum (Materials & Methods, paragraph 4, page 1408) and plasma are suitable sample matrices for BLI-based antibody detection (Abstract, page 1407).
Regarding claims 5 and 6, Carney et al. reveals dilution of biological samples as part of the BLI assay workflow, stating that “f-AbBA is also subject to interference from sialylated components in the sera that may also bind to the HA and affect results. Thus, all the sera used in this study were pretreated with Vibrio cholerae neuraminidase, also known in the influenza field as receptor-destroying enzyme (RDE), according to a previously described procedure and were diluted to working dilutions of 1:10 with phosphate-buffered saline (PBS)” (Materials & Methods, paragraph 3, page 1408). The disclosed “1:10” dilution disclosed by Carney et al. falls squarely within the dilution ranges recited in claim 5 (1:4-1:16) and claim 6 (1:4-1:10).
Regarding claims 7 and 8, Carney discloses identifying multiple immunoglobulin classes, stating that “for isotyping experiments, murine anti-human isotype antibodies against IgG1, IgG2, IgG3, IgG4, IgA, IgE, and IgM were all from Invitrogen” (Materials & Methods, paragraph 4, page 1408).
Regarding claim 9, Carney et al. discloses detection of antibodies that are specific for a viral antigen, stating that the disclosed cell-free and label-free flu antibody biosensor assay (f-AbBA) for influenza research and diagnostics “utilizes recombinant hemagglutinin (HA) in conjunction with label-free biolayer interferometry technology to measure biomolecular interactions between the HA and specific anti-HA antibodies or sialylated ligand” (Abstract, page 1407).
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Carney et al. and Maragos et al. as applied to Claim 1 above, and further in view of Premkumar et al. (The Receptor-Binding Domain of the Viral Spike Protein Is an Immunodominant and Highly Specific Target of Antibodies in SARS-CoV-2 Patients. Science Immunology. Vol. 5, No. 48, June 2020).
See the discussion of Carney et al. and Maragos et al. above. These references differ from the instant claim in failing to teach that the antibodies being detected are specific for SARS-CoV-2 antigens.
However, Premkumar et al. discloses the importance of detecting severe acute respiratory syndrome coronarivus 2 (SARS-CoV-2) (Abstract & Introduction, page 1). Premkumar teaches detecting antibodies that are specific for SARS-CoV-2 antigens, stating that “we use a large panel of human sera (63 SARS-CoV-2 patients and 71 control individuals) and hyperimmune sera from animals exposed to zoonotic CoVs to evaluate RBD’s performance as an antigen for reliable detection of SARS-CoV-2-specific antibodies” (Abstract, page 1). Premkumar et al. additionally states that “the recombinant SARS-CoV-2 RBD antigen was highly sensitive (98)% and specific (100%) for antibodies induced by SARS-CoVs” (Abstract, page 1).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the method of Carney et al. as modified by Maragos et al. to detect antibodies against SARS-CoV-2 because Premkumar et al. discloses these antibodies were known and reliably detectable in infected individuals and further teaches the importance of detecting antibodies specific for emerging viral pathogens using established immunoassay platforms represents a routine and urgent objective in the field of diagnostics, as evidenced by Premkumar et al.’s disclosure that “there is an urgent need for highly specific and sensitive antibody detection assays to answer fundamental questions about the epidemiology and pathogenesis of SARS-CoV-2 and to implement and evaluate population-level control programs” (Introduction, page 1).
A skilled artisan would have had a reasonable expectation of success in applying the known BLI antibody-detection method of Carney et al. as modified by Maragos et al. to detect SARS-CoV-2 specific antibodies using a known and validated antigen, as taught by Premkumar et al., because the BLI-based antibody-detection framework taught by Carney et al. as modified by Maragos is generic to the identity of the viral antigen, and Premkumar et al. identifies SARS-CoV-2 spike RBD as a highly specific antigen suitable for antibody detection. Thus, using the method of Carney as modified by Maragos to detect SARS-CoV-2 antibodies is a straightforward and predictable modification.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Carney et al., Maragos et al., and Premkumar et al., as applied to claims 1, 7, 9, and 10 above, and further in view of Amanat et al. (A serological assay to detect SARS-CoV-2 seroconversion in humans. Nature Medicine. Vol. 26, No. 7, May 2020), and Okba et al (Severe Acute Respiratory Syndrome Coronavirus 2–Specific Antibody Responses in Coronavirus Disease Patients. Emerging Infectious Diseases. Vol. 26, No. 7, July 1,2020, Pre-print version – March 2020).
See the discussion of Carney et al. and Maragos et al. above. These references differ from the instant claim in failing to teach the identity of SARS-CoV-2 capture antigens, namely: SARS-CoV-2 nucleocapsid protein, SARS-CoV-2 spike glycoprotein, SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD), or SARS-CoV-2 spike glycoprotein S1 domain.
On the other hand, Premkumar et al. explicitly identifies the SARS-CoV-2 spike receptor binding domain (RBD) as a suitable and highly specific antigen for antibody detection, stating that “as the receptor-binding domain (RBD) of the spike protein is poorly conserved between SARS-CoVs and other pathogenic human coronaviruses, the RBD represents a promising antigen for detecting CoV-specific antibodies in people” (Abstract, page 1). Premkumar et al. further describes evaluation of “RBD’s performance as an antigen for reliable detection of SARS-CoV-2-specific antibodies” (Abstract, page 1). Additionally, Premkumar et al. further explains the structural context of the RBD within the spike protein, stating that “the S1 and S2 subunits of the spike (S) protein of coronaviruses are required for viral entry. The surface-accessible RBD on the S1 subunit binds to receptors on target cells” (Introduction, page 2).
Amanat et al. corroborates and expand these teachings by explicitly disclosing the use of full-length SARS-CoV-2 spike protein and spike RBD as antigens in serological assays, stating that “we generated two different versions of the SARS-CoV-2 spike protein. The first construct encodes a full-length trimeric and stabilized version of the spike protein, whereas the second produces only the much smaller RBD (paragraph 4, page 1033). Amanat et al. further reports antibody binding to these antigens, stating that “all COVID-19 plasma/serum samples reacted strongly to both RBD and full-length spike protein” (paragraph 2, page 1034).
Okba et al. teaches the SARS-CoV-2 nucleocapsid protein, in addition to spiked-derived antigen, are a major immunogen suitable for serological assays, stating that “among the 4 coronavirus structural proteins, the spike (S) and the nucleocapsid (N) are the main immunogens” (paragraph 1, page 1479). Okba et al. further states that “we describe development of serologic assays for detection of virus neutralizing antibodies and antibodies to the N protein and various S protein domains, including the S1 subunit, and the receptor-binding domain (RBD) of SARS-CoV-2 in an ELISA format” (paragraph 1, page 1479).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the BLI-based antibody detection framework of Carney et al., as enhanced by Maragos et al., by incorporating the SARS-CoV-2 capture antigens taught by Premkumar et al., Amanat et al., and Okba et al. - because the selection of the immobilized capture antigen is the design choice that directs an antibody-detection assay to a specific viral target, while the underlying assay architecture, optical wavelength-shift detection mechanism, and signal enhancement strategy remain unchanged. Premkumar et al. identifies the SARS-CoV-2 spike RBD as a highly specific antigen for serological detection; Amanat et al. corroborates this by disclosing that antibodies in COVID-19 plasma and serum bind both full-length spike protein and RBD; and Okba et al. further teaches that the spike protein, S1 subunit, RBD, and nucleocapsid protein are principal immunogens used in serologic assays for SARS-CoV-2 antibody detection. Together, these references establish that the SARS-CoV-2 antigens recited in claim 11 were known, validated antigen choices for antibody detection prior to the effective filing date, and a PHOSITA would have been motivated to substitute these antigens into the existing BLI assay of Carney et al. to adapt the assay to the newly identified SARS-CoV-2 diagnostic need, a routine practice in immunoassay development.
Additionally, a PHOSITA would have had a reasonable expectation of success in making this modification because Premkumar et al., Amanat et al., and Okba et al. demonstrate that antibodies present in biological samples bind specifically and reproducibly to the SARS-CoV-2 spike protein, spike RBD, spike S1 domain, and nucleocapsid protein under immunoassay conditions. The BLI platform of Carney et al. detects antibody-antigen binding events at the sensor surface through predictable optical wavelength shifts, and Maragos et al. further demonstrate that signal enhancement using colloidal gold-conjugated detecting reagents operates independently of antigen identity. Thus, substituting a known SARS-CoV-2 antigen for another viral antigen in the BLI assay would not alter the detection mechanism, assay workflow, or signal readout, but merely applies the same established technology to a different, well-characterized viral target. Since each substituted antigen performs its established function in antibody binding, the modification represents a predictable use of prior-art elements according to their known properties, providing a reasonable expectation of success.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Carney et al. and Maragos et al. as applied to Claims 1, 7, and 9 above, and further in view of Noel et al. (Typing of Human Astroviruses from Clinical Isolates by Enzyme Immunoassay and Nucleotide Sequencing. Journal of Clinical Microbiology. Vol. 33, No. 4, April 1995).
See the discussion of Carney et al. and Maragos et al. above. These references differ from the instant claim in failing to teach the identity of a human astrovirus antigen.
On the other hand, Noel et al. discloses the use of human astrovirus antigens in immunoassays for detection and typing, stating that “a typing enzyme immunoassay (TYPE-EIA) was used to determine the antigenic types of 64 astrovirus-positive specimens from nine collections from seven countries” (Abstract, page 797). Noel et al. further elaborates that “astroviruses are currently classified into seven antigenic types, HAstV-1 to HAstV-7, on the basis of immune electron microscopy (EM) and immunofluorescence techniques using polyclonal and monoclonal antibodies to cell culture-adapted virus” (paragraph 1, page 797), confirming that astrovirus detection is based on antigen-antibody interactions. Also, Noel et al. further confirms the widespread and routine use of immunoassays for astrovirus detection, stating that “epidemiologic studies using EM and the more recently developed enzyme immunoassays (EIAs) have demonstrated the worldwide distribution of astroviruses” (paragraph 1, page 797).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the BLI-based antibody detection framework of Carney et al., as enhanced by Maragos et al., by incorporating a human astrovirus antigen as taught by Noel et al. - because the selection of the immobilized viral antigen is the design choice that determines which virus-specific antibodies are detected, while the underlying assay platform, optical wavelength-shift detection mechanism, and signal enhancement strategy remain unchanged. Noel et al. establish that human astrovirus antigens were known, characterized, and routinely used in immunoassays for detection and typing of astrovirus infections, demonstrating that astrovirus antigens were accepted immunological targets well before the effective filing date. A PHOSITA would have recognized that when adapting an existing antibody-detection assay to a different viral pathogen, it is routine practice to substitute the capture antigen corresponding to the virus of interest while maintaining the same detection platform. Since Carney et al. teaches a virus-agnostic BLI assay framework and Maragos et al. teaches signal enhancement that operates independently of antigen identity, a PHOSITA would have been motivated to combine these teachings with Noel et al.’s disclosure of human astrovirus antigens to extend the known BLI assay to astrovirus antibody detection.
Furthermore, a PHOSITA would have had a reasonable expectation of success in making this modification because Noel et al. demonstrates that human astrovirus antigens participate in reliable and reproducible antigen-antibody interactions in established immunoassay formats, including enzyme immunoassays used across diverse clinical specimens and geographic settings. The BLI assay of Carney et al. detects antigen-antibody binding events at sensor surface via optical wavelength shifts, a detection principle that depends on the occurrence of binding rather than on the specific viral antigen employed. Maragos et al. further shows that signal amplification using colloidal gold-conjugated detecting reagents functions within the same BLI platform regardless of antigen identity. Since both EIA and BLI rely on the same fundamental antigen-antibody binding interactions, substituting a known human astrovirus antigen into the BLI-based method represents a predictable use of prior-art elements according to their established functions – providing a reasonable expectation of success in detecting human astrovirus-specific antibodies.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Carney et al., Maragos et al., and Noel et al. as applied to Claims 1, 7, 9 and 12 above, and further in view of York et al (Structural, Mechanistic, and Antigenic Characterization of the Human Astrovirus Capsid. Journal of Virology. Vol. 90, No. 5, March 2016).
See the discussion of Carney et al., Maragos et al., and Noel et al. above. These references differ from the instant claim in failing to teach or specify the identity of a human astrovirus spike protein or domain as the capture antigen.
However York et al. supplies the specific antigen identity and antigenic properties missing from Carney et al., Maragos et al., and Noel et al., by explicitly identifying and characterizing the human astrovirus spike domain. In particular, York et al. states that “we report the crystal structures of the two main structural domains of the HAstV capsid protein (CP): the core domain at 2.60-Å resolution and the spike domain at 0.95-Å resolution” (Abstract, page 2254). York et al. further discloses antibody recognition of the spike domain, stating that “to investigate the antigenicity of both the HAstV-1 CP core and spike, we performed ELISAs and assessed binding to anti-HAstV-1 polyclonal antibodies” (Results, paragraph 6, page 2258), and “showed that polyclonal antibodies raised against mature HAstV-1 recognize both recombinant HAstV CP core and spike” (paragraph 2, page 2261).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the BLI-based antibody detection framework of Carney et al., as enhanced by Maragos et al., and applied in the diagnostic context established by Noel et al., to incorporate a human astrovirus spike domain as taught by York et al. - because the identity of the immobilized capture antigen is the variable that determines viral specificity in antibody-detection assay, while the underlying assay platform, detection physics, and signal-enhancement strategy remain unchanged. Noel et al. establishes that human astrovirus antigens were routinely used in immunoassays for serological detection, but does not specify which astrovirus protein provides optimal antigenicity. York et al. supplies this missing information by identifying the astrovirus spike domain as a discrete, structurally characterized, antibody-recognized antigen. A PHOSITA would therefore have been motivated to select the spike domain specifically – rather than an unspecified astrovirus antigen – because York et al. demonstrates that it is antigenic and recognized by antibodies, making it a logical refinement of the diagnostic antigen choice already contemplated by Noel et al. Incorporating a more precisely defined and validated antigen into an existing antibody-detection assay represents routine optimization, not a change in assay principle.
Additionally, a PHOSITA would have had a reasonable expectation of success in making this modification because York et al. demonstrates that antibodies bind specifically and reproducibly to the human astrovirus spike domain in immunoassay formats, confirming that the spike domain functions as an antigen. The BLI platform of Carney et al. detects antigen-antibody binding events at a sensor surface via predictable optical wavelength shifts, and Maragos et al. show that colloidal gold signal enhancement operates independently of antigen identity. Since Noel et al. confirm that astrovirus antibody detection is feasible in immunoassays, and York et al. establish that the spike domain is antibody-recognized, substituting the spike domain for an unspecified astrovirus antigen in the BLI assay requires no change to assay architecture, detection mechanism, or signal chemistry. Since all references rely on the same fundamental antigen-antibody binding interaction, a PHOSITA would reasonably expect that a BLI sensor bearing a human astrovirus spike protein or domain would successfully detect astrovirus-specific antibodies, making the modification a predictable use of prior-art elements according to their established functions.
Claims 14 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Carney et al. in view of Maragos et al. and Kussrow et al (Interferometric Methods for Label-Free Molecular Interaction Studies. Analytical Chemistry. Vol. 84, No. 2, January 2012) .
Regarding claim 14, see the discussion of Carney et al. and Maragos et al. above. These references differ from the instant claim in failing to describe supplying assay components together as a kit.
On the other hand, Kussrow et al. provides the commercialization and deployment context for BLI technology, explaining that “a reflective interferometry technique known as biolayer interferometry has recently been commercialized by ForteBio in a microfluidic-free instrument known as the Octet” (paragraph 5, page 785). Kussrow et al. further discloses that the system operates using disposable sensors coated with capture molecules, stating that “this technology allows analyte in multiple samples to be quantified rapidly (∼200 samples/h) in a standard 96-well plate by coating disposable fiber-optic-based sensors with capture molecules and inserting them into the sample wells” (paragraph 5, page 785).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Carney et al., Maragos et a., and Kussrow et al. to arrive at the kit of claim 14 - because each reference addresses a complementary aspect of implementing and deploying a biolayer interferometry (BLI)-based immunoassay, and their teachings naturally converge toward providing standardized assay components together for intended use. Carney et al. establishes that BLI biosensor tips bearing immobilized capture antigens are core assay elements for antibody detection. Maragos et al. teaches that species-specific antibodies conjugated to colloidal gold particles are used within the same BLI platform to amplify detection signals, thereby improving assay performance without altering assay architecture. Kussrow et al. further provides the commercial and practical context by teaching that BLI technology had been commercialized using disposable, capture-molecule-coated sensors supplied for end-user operation.
This conclusion is further corroborated by applicant’s own admission that BLI systems and disposable biosensor tips were commercially available and provided by manufacturers prior to the effective filing date (page 7, paragraph 1, lines 11-17), confirming that standardized BLI assay components were routinely supplied for user-performed assays. In view of these teachings, a PHOSITA would have been motivated to provide the known BLI sensor bearing a capture antigen together with a known colloidal gold-conjugated detecting antibody as a kit, because assembling compatible, routinely used assay components to facilitate performance of a known assay is a standard and predictable step in assay commercialization and deployment.
Additionally, a PHOSITA would have had a reasonable expectation of success because each component was already shown to function within the BLI assay environment: Carney et al. demonstrates reliable wavelength-shift detection from antigen-antibody binding; Maragos et al. demonstrates effective signal enhancement using colloidal gold-conjugated antibodies in BLI; and Kussrow et al., corroborated by applicant’s admission, confirm that such sensors are routinely manufactured and supplied for user-performed assays. Combining these known, compatible components requires no modification of assay architecture or detection physics, and represents a predictable use of prior-art elements according to their established functions – rather than an inventive advance.
Regarding claim 16, Carney et al. discloses the use of viral antigens immobilized as capture antigens in BLI antibody detection assays, including the use of “recombinant hemagglutinin (HA)” to detect virus-specific antibodies (Abstract, page 1407). This establishes that viral antigens are suitable and intended capture antigens in BLI-based immunoassays and are compatible with the assay components taught in the rejection of claim 14.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Carney et al., Maragos et al., Kussrow et al. as applied to Claim 14 above, and further in view of Phares et al (Rhesus Macaque and Mouse Models for Down-Selecting Circumsporozoite Protein Based Malaria Vaccines Differ Significantly in Immunogenicity and Functional Outcomes. Malaria Journal. Vol. 16, No. 1, March 2017).
See the discussion of Maragos et al., and Kussrow et al. above. These references differ from the instant claim in failing to explicitly limit the species specificity of the detecting antibody to: an anti-human antibody, an anti-mouse antibody, or anti-macaque antibody.
On the other hand, Carney et al. discloses anti-human detecting antibodies, stating that “for isotyping experiments, murine anti-human isotype antibodies against IgG1, IgG2, IgG3, IgG4, IgA, IgE, and IgM were all from Invitrogen” (Materials & Methods, paragraph 4, page 1408). This disclosure teaches the use of anti-human detecting antibodies as standard reagents for serological detection.
Phares et al. explicitly discloses both anti-mouse and anti-rhesus (anti-macaque) secondary antibodies, stating that “the secondary antibody used for the mouse and rhesus ELISA were HRP-conjugated anti-mouse or anti-rhesus IgG, respectively” (paragraph 2, page 4). Since rhesus macaques are macaques, this disclosure directly teaches both anti-mouse antibody and anti-macaque detecting antibodies as standard reagents for serological detection.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the kit of claim 14, as taught by Carney et al., Maragos et al., and Kussrow et al., to specify the species-specific detecting antibody recited in claim 15 - because immunoassays are routinely configured by selecting a detecting antibody corresponding to the species origin of the immunoglobulin being detected. As established in the rejection of claim 14, Carney et al., Maragos et al., and Kussrow et al. teach a BLI-based kit comprising a capture-antigen-coated sensor and colloidal-gold-conjugated detecting antibody, but do not limit the detecting antibody species. Carney et al. expressly teach anti-human detecting antibodies, while Phares et al. expressly teaches anti-mouse and anti-rhesus (anti-macaque) secondary antibodies as standard serological reagents. In the commercial BLI context taught by Kussrow et al., a PHOSITA would have been motivated to include such species-specific detecting antibodies as interchangeable kit components selected according to intended sample type.
Furthermore, a PHOSITA would have had a reasonable expectation of success because Carney et al. demonstrates effective use of anti-human antibodies, Phares et al. demonstrates effective use of anti-mouse and anti-macaque antibodies, and Maragos et al. teaches that detecting antibodies-regardless of species specificity-may be conjugated to colloidal gold for signal enhancement in BLI immunosensors. Selecting among anti-human, anti-mouse, and anti-macaque detecting antibodies does not alter the BLI assay architecture, binding chemistry, or detection physics, but represents a predictable substitution of known reagents for their established purpose.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Carney et al., Maragos et al., and Kussrow et al., as applied to claim 14 and 16 above, and further in view of Premkumar et al.
See the discussion of Carney et al., Maragos et al., and Kussrow et al. above. These references differ from the instant claim in failing to teach that the capture antigen comprises a SARS-CoV-2 antigen.
On the other hand, as discussed above, Premkumar et al. discloses the importance of detecting severe acute respiratory syndrome coronarivus 2 (SARS-CoV-2) (Abstract & Introduction). Premkumar also teaches detecting antibodies that are specific for SARS-CoV-2 antigens (Abstract, page 1).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the kit of claim 14, as taught by Carney et al., Maragos et al., and Kussrow et al., by incorporating a SARS-CoV-2 capture antigen as recited in claim 17 - because the identity of the immobilized capture antigen is the design choice that determines which virus-specific antibodies are detected, while the underlying kit structure, BLI detection platform, and signal-enhancement strategy remain unchanged. As established in the rejection of claim 14, the prior art teaches a BLI-based kit that is antigen-agnostic and intended to accommodate different viral capture antigens depending on the diagnostic target. Premkumar et al. supplies the missing teaching by identifying SARS-CoV-2 spike-derived antigens, including the receptor-binding domain (RBD), as suitable and highly specific antigens for serological detection of SARS-CoV-2 antibodies. A PHOSITA would therefore have been motivated to substitute a SARS-CoV-2 antigen for another viral antigen in the known BLI kit in order to adapt the kit to SARS-CoV-2 serological testing, a routine practice in immunoassay and diagnostic kit development drive by the emergence of a new viral pathogen.
Furthermore, a PHOSITA would have had a reasonable expectation of success in making this modification because Premkumar et al. demonstrates that SARS-CoV-2 spike derived-antigens, including RBD, reliably bind antibodies present in infected individuals and function effectively as capture antigens in serological assays. The BLI-based kit of claim 14 detects antigen-antibody binding events at the sensor surface via optical wavelength shifts, and Maragos et al. shows that colloidal gold-conjugated detecting antibodies enhance signal output in BLI assays independently of the specific capture antigen employed. Since the SARS-CoV-2 antigens disclosed by Premkumar et al. perform the same established function-binding virus-specific antibodies - as other viral antigens used in BLI assays, substituting these antigens does not require modification of the BLI sensor, detection chemistry, or kit configuration, Accordingly, the modification represents a predictable use of prior-art elements according to their established functions, providing a reasonable expectation of success in detecting SARS-CoV-2-specific antibodies using the modified kit.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Carney et al., Maragos et al., Kussrow et al., and Premkumar as applied to claims 14, 16, and 17 above, and further in view of Amanat et al., and Okba et al.
See the discussion of Carney et al., Maragos et al., and Kussrow et al., above. These references differ from the instant claim in failing to teach the identity of SARS-CoV-2 capture antigens, namely: SARS-CoV-2 nucleocapsid protein, SARS-CoV-2 spike glycoprotein, SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD), or SARS-CoV-2 spike glycoprotein S1 domain.
On the other hand, as discussed above, Premkumar et al., explicitly identifies the SARS-CoV-2 spike receptor binding domain (RBD) as a suitable and highly specific antigen for antibody detection (Abstract, page 1). Also, Premkumar et al. explains the structural context of the RBD within the spike protein (Introduction, page 2).
Likewise, Amanat et al., as discussed above, corroborates and expand these teachings by explicitly disclosing the use of both full-length SARS-CoV-2 spike protein and spike RBD as antigens in serological assays (paragraph 4, page 1033). Amanat et al. further reports antibody binding to these antigens (paragraph 2, page 1034).
Lastly, Okba et al., as discussed above, teaches that the SARS-CoV-2 nucleocapsid protein, along with spike-derived domains including S1 and RBD, are a major immunogen suitable for serological assays (paragraph 1, page 1479).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the kit of claim 14, as taught by Carney et al., Maragos et al., and Kussrow et al., by selecting a specific SARS-CoV-2 antigen from among spike protein, spike RBD, spike S1 domain, or nucleocapsid protein as recited in claim 18 - because the identity of the capture antigen is routinely chosen based on the virus of interest and known antigenic properties, while the underlying assay platform and kit architecture remain unchanged. Premkumar et al. identify the SARS-CoV-2 spike RBD as a highly specific antigen for antibody detection and further explain its location within the S1 subunit, thereby teaching both RBD- and S1-based capture strategies. Amanat et al. corroborate and expand these teachings by disclosing both full-length spike protein and RBD as effective serological antigens, while Okba et al. further teach that nucleocapsid protein, along with spike-derived domains including S1 and RBD, are major immunogens routinely used in serological assays. A PHOSITA would therefore have been motivated to select any of these well-characterized SARS-CoV-2 antigens to tailor the known BLI kit of Claim 14 to SARS-CoV-2 antibody detection, as this represents routine antigen selection within a known immunoassay framework rather than a change to assay design.
Furthermore, a skilled artisan would have had a reasonable expectation of success in making this modification because Premkumar, Amanat, and Okba each demonstrate that the recited SARS-CoV-2 antigens—spike protein, RBD, S1 domain, and nucleocapsid—reliably bind SARS-CoV-2-specific antibodies and function effectively as capture antigens in serological assays. The BLI-based kit of Claim 14 detects antigen–antibody binding at the sensor surface via optical wavelength shifts, and Maragos et al. show that colloidal gold-based signal enhancement operates independently of capture antigen identity. Moreover, Kussrow et al. establish that BLI systems were commercially deployed using standardized, interchangeable assay components, confirming that substitution of capture antigens is technically routine and predictable. Since each of the recited SARS-CoV-2 antigens performs the same established function of antibody capture and does not require modification of sensor chemistry, detection physics, or kit configuration, a PHOSITA would reasonably expect that incorporating any of these known antigens into the BLI-based kit would successfully enable detection of SARS-CoV-2-specific antibodies, representing a predictable use of prior-art elements according to their established functions.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Carney et al., Maragos et al., and Kussrow et al., as applied to claim 14 and 16 above, and further in view of Noel et al. and York et al.
See the discussion of Carney et al., Maragos et al., and Kussrow et al., above. These references differ from the instant claim in failing to teach the identity of a human astrovirus antigen.
On the other hand, Noel et al. explicitly placed human astrovirus antigens in a diagnostic immunoassay context (Abstract, page 797), and that such assays relied on antigen-antibody interactions using antibodies directed against human astrovirus (paragraph 1, page 797).
While, Noel et al. establish the diagnostic use of astrovirus antigens, York et al. explicitly identifies and characterize the human astrovirus spike domain (Abstract, page 2254). York et al. further discloses antibody recognition of the spike domain (paragraph 2, page 2261).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the kit of claim 14, as taught by Carney et al., Maragos et al., and Kussrow et al., by incorporating a human astrovirus antigen, as recited in Claim 19 – because the identity of the immobilized capture antigen is the design parameter that determines viral specificity in an antibody-detection assay, while the underlying kit architecture, detection mechanism, and signal-enhancement strategy remain unchanged. Noel et al. establish that human astrovirus antigens were known, characterized, and routinely used in diagnostic immunoassays for serological detection and typing, thereby placing astrovirus antigens squarely within the field of antibody-based diagnostics. However, Noel et al. does not specify which astrovirus protein provides optimal antigenicity. York et al. supplies this missing information by identifying the human astrovirus spike protein as a discrete, antibody-recognized antigen. A PHOSITA would therefore have been motivated to combine these teachings by selecting the astrovirus spike protein—rather than an unspecified astrovirus antigen—for use in the established BLI kit of Claim 14, as this represents routine refinement of antigen selection based on known antigenic properties rather than a change to assay design or kit structure.
Additionally, a PHOSITA would have had a reasonable expectation of success in making this modification because Noel et al. demonstrate that astrovirus antigens reliably participate in antigen–antibody interactions in diagnostic immunoassays, and York et al. further demonstrate that antibodies bind specifically to the human astrovirus spike protein in ELISA formats, confirming its suitability as a capture antigen. The BLI-based kit of Claim 14 detects antigen–antibody binding events at the sensor surface via predictable optical wavelength shifts, and Maragos et al. show that colloidal gold-based signal enhancement operates independently of the identity of the capture antigen. Kussrow et al. further establish that BLI systems were commercially deployed using standardized, interchangeable assay components, confirming that substitution of capture antigens is technically routine. Since the astrovirus spike protein performs the same established function—binding virus-specific antibodies—as other viral antigens used in BLI assays, incorporating it into the known BLI kit requires no modification of detection physics, surface chemistry, or kit configuration. Accordingly, a PHOSITA would reasonably expect that a BLI sensor bearing a human astrovirus spike protein would successfully detect astrovirus-specific antibodies, making the claimed modification a predictable use of prior-art elements according to their established functions.
Ultimately, for the reasons set forth above, claims 1-19 are rejected under 35 U.S.C. 103 as being unpatentable over the cited prior art combinations. The references collectively teach all elements of the claimed invention, and a PHOSITA would have been motivated to combine these teachings with a reasonable expectation of success. The claimed subject merely represents the predictable use of prior-art elements according to their established functions, and any differences between the claimed invention and the prior amount to routine optimization, selection among known alternatives, or application of known techniques to a known device or method.
For the reasons cited above, all claims are rejected.
Conclusion
No claims are allowable.
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/E.O./Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 January 29, 2026