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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/12/2026 has been entered.
Priority
The present application was filed 11/22/2021 and claims benefit under 35.U.S.C. 119(e) to provisional application No. 63/116,953, filed on 11/23/2020.
Status of the claims
Claims 1 and 4-20 are currently pending; claims 8-20 are withdrawn. Claims 2-3 are cancelled. Claim 1 is amended. Claims 1 and 4-7 are examined below.
Withdrawn rejections
After further consideration of the arguments, pertaining to amended claim 1, and the prior art as applied to claim 1 and canceled claim 3, the limitations of which have been moved to claim 1, the rejection under 35 U.S.C. §103 has been withdrawn.
See new grounds of rejection below.
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 and 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over Mehra et al., US20170038366A1 (PTO-892, 12/21/2025) in view of Byrnes et al. Competitive SARS-CoV-2 serology reveals most antibodies targeting the spike receptor-binding domain compete for ACE2 binding. MSphere. 2020 Oct 28;5(5):10-128 (PTO-892, 02/28/2025).
Regarding claim 1, Mehra teaches composite nanomaterial labeled partners in solution to determine the binding of specific binding partners in a qualitative or quantitative manner (Mehra, page 1, see entire paragraph [0007]). Mehra further teaches nanomaterial capable of being used in a homogenous assay wherein the separation of reacted and unreacted assay components is unnecessary as the binding events change the characteristics of the nanoparticles and provide amplification of the final modulated signals (Mehra, page 3, paragraph [0039], lines 10-17). Mehra teaches a first and a second detection conjugate which comprise metallic nanostructures coupled to binding partners (Mehra, page 1, paragraph [0008], lines 4-6). Mehra teaches a local surface plasmon resonance coupling effect between different nanoparticle types which are attached to different antibodies (Mehra, page 3, see entire paragraph [0022] and figure 3). Mehra further teaches that different particle types comprise nanospheres, nanostars or nanorods (Mehra, page 11, paragraph [0091], lines 28-30). Mehra further teaches that the binding partners comprise antibodies, as well as antigens, receptors, or ligands (Mehra, page 4, paragraph [0047], lines 6-9). Mehra teaches for the first detection conjugate of Mehra, the conjugate comprising metallic nanostructures coupled to the target analyte of interest and for the second detection conjugate, the conjugate is capable of specifically binding to the target analyte. Mehra further teaches that the first detection conjugate will bind to the second detection conjugate initially, and if there is displacement of the metallic nanostructures in the first detection conjugate from the second detection conjugate, it will proportionately reduce the wavelength shift in the peak absorption wavelength (Mehra, page 4, see entire paragraph [0045]). Mehra further teaches that the detection conjugates comprise metallic nanostructures coupled to binding partners, specifically binding to another detection conjugate and that in a competitive assay format, at least one of the detection conjugates comprises metallic nanostructures coupled to target analytes (Mehra, page 4, paragraph [0046], lines 1-14). Mehra further teaches that any analyte can be detected, particularly those that are significant in the diagnoses of diseases and that a target analyte can include an antibody (Mehra, page 9, paragraph [0080]). Mehra further teaches that plasmon coupling between the metallic nanostructures in the detection conjugates, resulting from complex formation between the binding partners and target analyte, produces a change in the localized surface plasmon resonance spectrum of the metallic nanostructures (plasmonic metal nanoparticles; Mehra, page 8, paragraph [0077], line 1-page 9, line 2). Mehra further teaches that the metallic nanoparticle by itself exhibits an optical spectrum that is dependent on metal composition, size, and shape and that slight changes at the surface of the nano-particle due to first primary binding and subsequent secondary binding cause progressive changes in the characteristics of the light interacting with the nanoconjugates and that such changes can be recorded by a suitable spectrometer (Mehra, page 2-3, see entire paragraph [0020] and figure 2). Mehra further teaches two distinct types of nanoparticles coupled to two distinct binding proteins with distinct characteristics and further teaches a local surface plasmon resonance coupling effect between different nanoparticles (Mehra, page 3, see entire paragraph [0022] and figure 3).
Put another way, Mehra teaches a first and a second plurality of metallic nanostructures coupled to binding partners that can be an antibody, antigen, ligand, or receptor with specifically bind each other and are suitable for spectrometric detection, wherein differences can be detected between nanoparticles with primary binding, secondary binding, and those nanostructures forming a complex comprising two different shapes of nanoparticles.
Although Mehra teaches a competitive assay where an unlabeled or free target analyte in the sample will compete with the first detection conjugate and that there is a change in optical signal resulting from the displacement of the metallic nanostructures in the first detection conjugate from the second detection conjugate, Mehra does not teach a first binding partner that is a SARS-CoV-2 receptor binding domain (RBD) or a fragment thereof, nor a second binding partner that is an angiotensin-converting enzyme 2 (ACE2) or a fragment thereof. Mehra further does not teach that the structures of the first and second pluralities of MNPs exhibit signals that differentiate non-neutralizing binding, partial neutralizing binding, and effectively neutralizing binding when the first and second pluralities of metallic nanoparticles do not form a complex in the presence of the target antibody that recognizes the SARS-CoV-2 RBD or a fragment thereof.
Byrnes teaches a competitive serological assay comprising viral spike protein receptor-binding domain (RBD)-containing antigens and soluble ACE2-Fc competing with serum antibody to detect the proportion of ACE2 blocking anti-RBD antibodies (Byrnes, page 1, ‘Abstract’, lines 8-11). Byrnes teaches an enzyme linked immunosorbent assay comprising a SARS-CoV-2 receptor binding domain immobilized on a surface and a labeled protein L which can bind an RBD-specific antibody if present in the sample (Byrnes, page 3, see Figure 1 A and figure legend). Byrnes further teaches an ACE2-Fc that competes with patient antibodies for RBD binding (Byrnes, page 5, see Figure 2A and figure legend). Byrnes further teaches that SARS-CoV-2 has placed a significant public health burden on countries worldwide and that viral entry is dependent on a binding interaction between the receptor-binding domain of the viral Spike protein and ACE2 on the cell surface. Byrnes further teaches that there is a continued need for assays to profile patient responses to infection, especially with respect to the antiviral antibodies generated and whether or not a patient has acquired humoral immunity against SARS-CoV-2 (Byrnes, page 8, ‘Discussion’, see entire first paragraph). Byrnes further teaches that the assay can screen patient antibodies that compete with ACE2 for RBD binding and that therefore may disrupt RBD binding to ACE2 and block viral entry. Byrnes further teaches that the competition reactions enable rapid, reproducible characterization of a patient’s anti-Spike antibody profile (Byrnes, page 2, 3rd paragraph, lines 6-10).
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 composition of Mehra comprising nanoparticles comprising binding partners such as receptors or ligands for a competitive assay with the SARS-CoV-2 RBD on one plurality of nanoparticles and ACE2 on a second plurality of nanoparticles, because of the teaching of Byrnes that SARS-CoV-2 has placed a significant health burden on countries worldwide and that viral entry is dependent on a binding interaction between the receptor-binding domain of the viral Spike protein and ACE2 on the cell surface. One having ordinary skill of the art would be motivated to modify the composition of Mehra for the detection of SARS-CoV-2 specific antibody, because Mehra teaches a composition for a competitive homogenous assay wherein the separation of reacted and unreacted assay components is unnecessary as the binding events change the characteristics of the nanoparticles and provide amplification of the final modulated signals and because SARS-CoV-2 is a significant health burden. One of ordinary skill in the art would further be motivated to have modified the composition with the SARS-CoV-2 RBD and ACE2 as taught by Byrnes because the composition can be used to screen patient antibodies that compete with ACE2 for RBD binding and therefore screen for antibodies that can block viral entry.
The composition of Mehra comprises metallic nanoparticles that differ in shape that by themselves exhibit an optical spectrum and slight changes at the surface of the nano-particles due to first primary binding and subsequent secondary binding cause progressive changes in the characteristics of the light interacting with the nanoconjugates. The teachings of Byrnes disclose that there is a need for assays to profile patient responses to infection, especially with respect to the antiviral antibodies generated and determine whether or not a patient has acquired humoral immunity against SARS-CoV-2. The optical spectrum of the metallic nanoparticle would change when the antibody binds to the SARS-CoV-2 RBD, but not the second plurality of nanoparticles (neutralizing binding), it would further change if the two pluralities of nanoparticles form a complex (non-neutralizing binding), and if there was a complex with a secondary binding (partially neutralizing).
One having ordinary skill in the art would have a reasonable expectation of success, because Mehra’s plasmonic nanoparticles comprising binding partners such as antigens, receptors, or ligands which exhibit a change in optical signal resulting from the displacement of the metallic nanostructures in the first detection conjugate from the second detection conjugate for example in a competitive binding assay and Byrnes teaches success detecting neutralizing and non-neutralizing SARS-CoV-2 receptor binding domain specific antibody in a competitive assay where the presence of a target analyte, an antibody, causes displacement of the initial binding partners.
Regarding the wherein clauses, as previously explained in detail above, the combination of the art teaches a first plurality of metallic nanostructures coupled to a binding partner, for example a ligand (see Mehra), such as SARS-CoV-2 RBD (see Byrnes). The combination of the prior art further teaches a second plurality of metallic nanostructures that differs in shape, coupled to a binding partner, for example a receptor (see Mehra), such as ACE2 (see Byrnes).
Applying the teaching of Byrnes of a competitive assay for the detection of ACE2 blocking anti-RBD antibodies, the combination of the prior art teaches a composition that allows for the first and second pluralities of metallic nanoparticles bind to teach other in the absence of neutralizing antibody, via the interaction of the SARS-CoV-2 RBD on the first plurality and ACE2 on the second plurality of metallic nanoparticles, resulting in complexes of first and second nanoparticles (first aggregations), which produces a specific local surface plasmon resonance coupling effect between the different nanoparticle types (see Mehra).
In the presence of neutralizing antibodies, the binding between SARS-CoV-2 receptor binding domain and ACE2 is interrupted by the neutralizing antibodies binding to the SARS-CoV-2 receptor binding domain (see Byrnes), therefore it would be expected that when the composition of the cited prior art is used in the presence of neutralizing antibodies, the result would be formation of complexes of the first plurality of metallic nanoparticles bound to anti-SARS-CoV-2 RBD antibodies (second aggregation). The displacement of the metallic nanostructures in the first detection conjugate from the second detection conjugate would be expected to result in a local surface plasmon resonance coupling effect specific for the nanoparticle not interacting with the other type of nanoparticle (see Mehra) and further binding of the antibody causes progressive changes in the characteristics of the light interacting with the nanoconjugates. As a result, the composition taught by the cited prior art would be expected to achieve the same results as claimed.
Finally, in the presence of less effectively neutralizing anti-SARS-CoV-2 receptor binding domain, i.e. antibody that binds the SARS-CoV-2 receptor binding domain in a way that does only partially interfere with ACE2 binding, it would be expected that some first and second pluralities of metallic nanoparticles would form complexes as described in the first aggregation further comprising an anti-SARS-CoV-2 RBD antibody bound to SARS-CoV-2 RBD and some first and second pluralities would be inhibited from binding to each other, forming complexes as described in the second aggregation further comprising an anti-SARS-CoV-2 RBD antibody, as such, a composition as taught by the prior art (comprising the first and second conjugates as indicated above) would be expected capable of resulting in a third aggregation that comprises first aggregations and second aggregations bound to anti-SARS-CoV-2 RBD antibody.
The binding of the first plurality of metallic nanoparticles to the second plurality of metallic nanoparticles and subsequent secondary binding of the non-neutralizing antibody causes progressive changes in the characteristics of the light interacting with the nanoconjugates which is recordable by a suitable spectrometer (Mehra). Put another way, the combined prior art teaches a composition that would be expected capable of forming the first, second, and third aggregation and it would be expected that the different aggregation could be differentiated by the different signal generated from the different types of metal nanoparticles in the different aggregation states. As such the prior art teaches a composition that, when used, would be expected capable of the same use and produce the same observed results as claimed.
Regarding claim 4, Mehra teaches that the test sample can be any type of liquid sample, including biological samples such as whole blood, plasma, serum, saliva, urine, pleural effusion, sweat, bile, cerebrospinal fluid, and others (Mehra, page 7, paragraph [0065], lines 1-7).
Regarding claim 5, Mehra and the cited art above teaches a method of detecting a target analyte in a sample. Mehra teaches mixing the sample with a first detection conjugate and a second detection conjugate.
Mehra further teaches a method wherein the first and second detection conjugates comprise metallic nanostructures coupled to binding partners capable of specifically binding to a target analyte, form a complex between the first detection conjugate, the analyte, and the second detection conjugate and exposing the complex to a light source at a wavelength range within the ultraviolet-visible-infrared spectrum and measuring an optical signal from the complex, wherein a change in the optical signal indicates the presence of the target analyte in the sample (Mehra, page 1, paragraph [0008], lines 1-14). Mehra further teaches that the assay may use extinction measurement to monitor specific binding events (Mehra, page 2, paragraph [0013], lines 4-7).
As discussed previously above, it would have been prima facie obvious one having ordinary skill before the effective filing date of the claimed invention to have modified the method of Mehra of detecting an analyte using plasmonic nanoparticles by having modified the composition as used in Mehra’s method with the antigen of Byrnes, and as such result in a method of using the composition of claim 1, as claimed (i.e. a composition of claim 1 comprising a first detection conjugate coupled to a SARS-CoV-2 antigen and a second detection conjugate comprising ACE2, in order to detect neutralizing, non-neutralizing, and partially neutralizing SARS-CoV-2 receptor binding domain specific antibody for the reasons as discussed in detail previously above).
Claims 6 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Mehra and Byrnes as applied to claim 5 above, and further in view of Groves, JT, US11680900B2 (PTO-892, 12/21/2025), as evidenced by Zumbahlen Chapter 3, Linear Circuit Design Handbook, 2008, Elsevier (PTO-892, 12/21/2025).
Regarding claim 6 and 7, Mehra and the cited art above teaches a composition and method substantially as claimed.
Mehra further teaches a system comprising a spectrophotometric cuvette (a receptacle) and an analyte detection device, an analytical rotor, a microwell plate, or a clinical analyzer (a system; Mehra, page 2, paragraph [0016], lines 4-6). Mehra further teaches a light source for applying electromagnetic energy suitable for use in the method of the invention, including any source that may apply a wavelength range with the ultraviolet-visible spectrum or ultraviolet-visible-infrared spectrum and a light source equipped with a monochromator so that specific wavelengths of light may be applied (light source; Mehra, page 8, paragraph [0074], lines 9-16). Mehra further teaches that spectrophotometric or photometric instruments are suitable for the disclosed method, comprising those with means for measuring optical signals at different wavelengths and acquiring extinction and other spectra (photodetector capable of detecting transmitted light; Mehra, page 9, paragraph [0078], lines 1-5). In summary, Mehra teaches a light source suitable for use in the method of the invention and further teaches instruments with means for acquiring extinction spectra. As such, it would be obvious that the light source is capable of emitting an MNP extinction wavelength.
Mehra fails to teach an electronic assay comprising a means for determining a voltage and/or current readout.
Groves teaches a biosensor, comprising a capture component and a reporter component, where the binding of the analyte and the capture element produces an alteration in the reporter element producing a signal which indicates the presence or concentration of the target analyte (Groves, column 20, lines 43-54). Grove further teaches that the reporter element can be a metal nanoparticle (Groves, column 21, lines 4-7) and further teaches that the reporter molecules may comprise a chromophore (Groves, column 23, line 37) and that the chromophore is a plasmonic nanoparticle, which may be functionalized to bear a capture element (Groves, column 24, lines 22-25). Groves further teaches that binding of an analyte changes induces a change in the nanoparticle’s spectral properties (Groves, column 24, lines 29-31). Groves further teaches a recording device that converts the optical signal to an electrical signal, such as a charge-coupled device (Groves, column 10, lines 44-46).
Zumbahlen teaches that charge coupled devices comprise image sensor elements which are illuminated by light and during this exposure the image sensor elements acquires an amount of charge which is proportional to its illumination, which is converted into a string of photo-dependent output voltage levels (Zumbahlen, Chapter 3-3, page 241, see second paragraph). Groves further teaches that this digital molecular assay system is capable of particle-by-particle readout and report binding in a binary format and can be useful in a variety of applications, such as on mobile electronic devices for use in the field (Groves, column 1, lines 25-36). Groves further teaches that inexpensive, but accurate, point-of-care assays that provide quick and accurate results are needed (Groves, column 1, lines 22-24). Groves further teaches that conventional biochemical assays cannot be reliably miniaturized because they are inherently analog measurements and that digital assays eliminate inherent uncertainties of analog assays , because they are based on binary events, eliminate errors originating from the unknown fraction of inactive assay molecules and eliminate problems associated with spatial inhomogeneity such as non-uniform illumination (Groves, column 2, lines 36-45).
It would have been prima facie obvious to one having ordinary skill before the effective filing date, to have modified the system of Mehra in view of Byrnes to comprise a means for determining a voltage and/or current readout (claim 7), because of the teaching of Groves that conventional biochemical assays cannot be reliably miniaturized and that digital assays eliminate inherent uncertainties of analog assays and errors. The ordinary artisan would further be motivated to do so because inexpensive, but accurate, point of care assays are needed.
The ordinary artisan would have a reasonable expectation of success, because both the assays of Mehra and Groves use plasmonic nanoparticles functionalized with a binding agent and plasmonic resonance to detect binding of the analyte to the nanoparticle and both teach instruments comprising means for measuring optical signals at different wavelength and acquiring extinction spectra.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1 and 5 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13-19 of copending Application No. 18/868,993 in view of Byrnes.
Regarding claim 1, claim 13 of the copending application ‘993 recites a first plurality of plasmonic metal nanoparticles having a viral antigen bound to its surface and a second plurality of plasmonic metal nanoparticles having a viral antigen binding moiety bound to its surface. Claim 13 further recites that the viral antigen binding moiety specifically binds to the target epitope and that a first, second, or third metallic nanoparticle extinction wavelength is detected whereas the first extinction wavelength is indicative of the presence of a neutralizing antibody in the sample, the second extinction wavelength is indicative of the presence of a non-neutralizing antibody in the sample and wherein the third extinction wavelength is indicative of the absence of an antibody in the sample. As such the copending application recites plasmonic metal nanoparticles that are suitable for colorimetric, spectrometric, or electronic detection. Claim 18 of the copending application ‘993 recites that the viral antigen is a SARS-CoV-2 antigen. Claim 19 of the copending application ‘993 recites that the viral antigen binding moiety is a SARS-CoV-2 antigen binding moiety. Claim 14 of the copending application ‘993 teaches that the first ad second plurality of MNPs differ from one another.
The copending application does not recite that the SARS-CoV-2 antigen is the SARS-CoV-2 RBD nor does it recite that the SARS-CoV-2 antigen binding domain is ACE2.
Byrnes teaches a competitive serological assay comprising viral spike protein receptor-binding domain (RBD)-containing antigens and soluble ACE2-Fc competing with serum antibody to detect the proportion of ACE2 blocking anti-RBD antibodies (Byrnes, page 1, ‘Abstract’, lines 8-11). Byrnes teaches that in SARS-CoV-2 infection viral entry is dependent on a binding interaction between the receptor-binding domain of the viral Spike protein and angiotensin-converting enzyme 2 on the cell surface and that the receptor-binding domain binding to ACE plays a crucial role in infection (Byrnes, page 2, lines 4-6). Byrnes further teaches that the competition reactions enable rapid, reproducible characterization of a patient’s anti-Spike antibody profile (Byrnes, page 2, 3rd paragraph, lines 6-10).
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 SARS-Co-V2 receptor binding domain and angiotensin converting enzyme 2 as taught by Byrnes as the SARS-CoV2 antigen and the SARS-CoV-2 antigen binding domain as recited by the copending application because of the teaching of Byrnes that viral entry is dependent on binding of the receptor-binding domain of the viral Spike protein to angiotensin-converting enzyme 2 and that a competition reaction comprising the said proteins enables rapid and reproducible characterization of a patient’s anti-Spike antibody profile.
One of ordinary skill in the art would have a reasonable expectation of success using SARS-Co-V2 receptor binding domain and angiotensin converting enzyme 2 as taught by Byrnes as the vial protein and viral antigen binding domain because Byrnes teaches success using said proteins in a competitive assay evaluating competitive binding of antibodies in SARS-CoV-2 infection and the composition as claimed is also applied in an assay evaluating competitive anti-SARS-CoV-2 antibodies.
Although the copending application does not specifically disclose the wherein clauses comprising a first aggregation, a second aggregation, or a third aggregation state, see this limitation as discussed previously above under 35 U.S.C. §103, the same reasoning as applied previously above also applies presently (the plasmonic metal nanoparticles as taught by the copending application would be expected to form the different complexes as formed in the presence or absence of neutralizing or partially neutralizing antibodies).
Regarding claim 5, the copending application and the cited art above teach a composition substantially as claimed.
Claim 13 of the copending application ‘993 recites a method of analyzing a sample by contacting said sample with a first plurality of plasmonic metal nanoparticles having a viral antigen bound to its surface and a second plurality of plasmonic metal nanoparticles having a viral antigen binding moiety bound to its surface to form a binding composition, and detecting a first, second, or third extinction wavelength from the binding composition indicative of the presence of a neutralizing antibody in the sample.
Claim 4 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13-19 of copending Application No. 18/868,993 in view of Wang et al. Neutralizing antibodies responses to SARS-CoV-2 in COVID-19 inpatients and convalescent patients. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2020 Jun 4:ciaa721.
Regarding claim 4, the copending application ‘993 and the cited art above teach a composition substantially as claimed.
The copending application does not recite that the sample is obtained from a subject’s body fluid.
Wang teaches a method of analyzing the dynamics of neutralizing antibody levels in the blood samples of COVID-19 patients (Wang, page 2688, Summary, see ‘Methods’). Wang further teaches that that serum from COVID-19 convalescent patients can fully neutralize cellular infectivity of the isolated virus and that administration of convalescent plasma containing neutralizing antibody was followed by improvement in the clinical status of critically ill patients, which raises the hypothesis that convalescent plasma transfusion could be beneficial in COVID-19 patients. Wang further teaches that an analysis of antibody levels of patients with COVID-19 might help develop rapid diagnostic reagents, vaccines, drugs, and other treatments and would be of great significance for the long-term control and treatment of COVID-19 (Wang, page 2688, 2nd paragraph, line 6 -page 2689, line 8).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used a body fluid sample such as plasma or serum (as taught by Wang) in the composition as claimed because of the teaching of Wang that administration of plasma containing neutralizing antibodies was followed by improvement in the clinical status of critically ill patients and that analysis of antibody levels might help develop rapid diagnostic reagents, vaccines, drugs and other treatments.
One of ordinary skill in the art would have a reasonable expectation of success using body fluid such as serum or plasma in the assay of the copending application because Wang teaches evaluating COVID-19 specific neutralizing antibodies as does the copending application.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 03/12/2026 have been fully considered but they are not persuasive.
Applicant argues, starting on page 7 that the rejection of claim 1 is overcome by the amendment to claim 1.
Applicant argues that the assay as taught by Mehra and Byrnes fails to teach or suggest plasmonic metal nanoparticles of different shapes or sizes for the two pluralities, nor any motivation to select such heterogeneous geometries.
This argument is not persuasive.
As discussed previously in detail above, Mehra does teach an assay with different types of nanoparticles, different types comprising different shapes of nanoparticles, wherein each type comprises a different binding molecule on the surface. As such Mehra does teach nanoparticles of different shapes for two pluralities of nanoparticles.
Applicant further argues that Mehra describes a general local surface plasmon resonance assay in which two detection conjugates with similar nanostructures bind a target analyte to produce a single wavelength shift and that in competitive mode, a free competitor displaces one conjugate, proportionally reducing the shift. Applicant argues that Mehra uses identical or composite nanostructures for both conjugates and does not disclose or suggest conjugating SARS-CoV-2 RBD to one and ACE2 to a second plurality, forming three specific aggregation types, or employing MNPs of deliberately different shapes/sizes to generate distinct, differentiable signals for each type. Applicant argues that Byrnes does not teach nanoparticles, aggregation, plasmonic detection, nor plasmonic metal nanoparticle geometries and that there is no motivation to modify the conjugates to use plasmonic metal nanoparticles of different shapes or sizes nor any reasonable expectation that doing so would produce the claimed three different aggregations with signals that differentiate them in the precise manner required by amended claim 1. Applicant argues that the examiner’s “expected” competitive inhibition rely on hindsight reconstruction using the present specification’s teachings and that without the claimed heterogeneous geometries, Mehra’s system produces only a single, proportional shift, not three distinct signals expressly enabled by applicant’s different-shape/size limitation.
This argument is not persuasive.
Mehra does teach different nanoparticles (see final rejection, 12/17/2025, page 5, lines 17-19; “Mehra further teaches a local surface plasmon resonance coupling effect between different nanoparticles (Mehra, page 3, see entire paragraph [0022] and figure 3)”) and as discussed in more detail above, the different types of nanoparticles (as evident in figure 3) comprise nanospheres, nanostars, and nanorods. As such, Mehra teaches an assay that comprises different shapes of nanoparticles each bound to a different detection agent. Figure 3 further shows that the different types of nanoparticles have distinct, differential signals for each binding partner. As explained previously in detail above, Mehra further teaches a competitive assay where the two binding partners (which can be antibodies, antigens, or ligands) are conjugated to nanoparticles. As such, Mehra does teach a competitive assay where the binding partners, for example a receptor and a ligand, are conjugated to nanoparticles of heterogeneous geometry. Regarding the argument that Byrnes does not teach nanoparticles, aggregation, or plasmonic detection, as explained previously above, Mehra teaches the composition as claimed and Byrnes is relied on to teach motivation to modify the system of Mehra applying the SARS-CoV-2 RBD instead of the generic “ligand” of Mehra and ACE2 in place of the “receptor” in a competitive assay as taught by Mehra. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Because Mehra teaches the composition and method for a competitive assay comprising different geometries of plasmonic metal nanoparticles and Byrnes provides the teaching and motivation for a competitive assay comprising SARS-CoV-2 receptor binding domain and angiotensin-converting enzyme 2, the claim is obvious over the prior art and the composition would be expected to result in three different aggregation signals as claimed.
Applicant further argues on page 8 that the combination of Mehra, Byrnes, Mancuso ad Bartonella does not teach the limitations of amended claim 1.
Mancuso and Bartonella are not relied on to teach any limitations of claim 1 and therefore the argument is moot.
Applicant further argues on page 8 that the rejection of claims 6 and 7 is overcome for the same reasons as set forth regarding claim 5 and further that there is no motivation to arrive at the full claimed system.
This argument is not persuasive.
The rejection of claim 5 is maintained for the reasons previously explained in detail above and Groves provides the motivation to combine the assay with a system for performing the electronic assay.
For all the reasons above, the arguments are not persuasive.
Communication
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/STEFANIE J. KIRWIN/Examiner, Art Unit 1677
/Soren Harward/Primary Examiner, TC 1600
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