DETAILED ACTION
Final Rejection
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
2. The present application claims the benefit of U.S. Provisional patent application 63/065,993 filed August 14, 2020.
Status of Claims
3. Claims 1-32 as amended on 04/07/2026 are pending and under consideration.
In response to the non-final rejection office action dated 01/14/2026 the arguments or remarks filed on 04/07/2026 applicant indicated that claims 12-15, 18, 20, and 24-28 are withdrawn. However, the amended claim listing filed on 04/07/2026 has not withdrawn the claims 12-15, 18, 20, and 24-28. Additionally, all the claims were previously treated on the merits. Accordingly, the assertion of the withdrawal of these claims appears to be an inadvertent mistake.
Information Disclosure Statement
4. The information disclosure statements (IDSs) submitted on 04/09/2023, 12/10/2024, 01/13/2026, 03/18/2026 was filed in time. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawal of Claim Rejection
5. Withdrawn rejection of claims 10-12 and dependent claims 13-26 under 35 U.S.C. 112(b) in view of applicants claim amendments filed on 04/07/2026.
6. Withdrawn rejection of claims 10-12 and dependent claims 13-26 under 35 U.S.C. 112(a) in view of applicants claim amendments filed on 04/07/2026.
Claim Interpretation
7. The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 1: The instant claim 1 is directed to a method of detecting the presence of intact SARS-CoV-2 virions in one or more individuals comprising:
a) individually combining anti-SARS-CoV-2 surface antigen antibody-coated beads with a saliva sample from each of said one or more individuals to form an admixture corresponding to each individual;
b) mixing the beads and saliva sample of each individual's admixture;
c) incubating the admixture(s); and
d) detecting whether agglutination has occurred in each individual's admixture.
The instant claim 1 is interpreted to be directed to a method of detection of an intact SARS-CoV-2 virion in a saliva sample of an individual by agglutination of beads coated with antibody to surface-antigen of SARS-CoV-2 virus.
Claim Rejections - 35 USC § 103
(Modified in response to applicant’s amendment of the claims)
8. 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.
9. Claims 1-4, and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Cheung et al 2006 (US20060188519A1, published 08/24/2006), and further in view of Chen et al 2020 (Cellular & Molecular Immunology, 17:647 – 649, published 20 April 2020), Azzi et al 2020 (J Infect. 2020 Sep;81(3): e75-e78), Hughes et al 1984 (J of Clinical Microbiology, Vol 20 No 3, Sept. 1984, p. 441-447), Kasempimolporn et al 2014 (PDF printout, Current Laboratory Techniques in Rabies Diagnosis, Research and Prevention. 2014, Pages 37-42. ISBN. 978-0-12-800014-4), Mary Louise Turgeon 2013 (PDF printout, Immunology & Serology in Laboratory Medicine 5th Edition. ISBN-100323085180), and Onchoema Key 2016 (PDF printout, published online https://oncohemakey.com/antigen-antibody-interactions-immune-assays-and-experimental-systems/).
Claims 1-4 and 27: Cheung et al 2006 (US20060188519A1) is in the instantly claimed prior art area and teaches a method of detecting SARS and SARS-like coronavirus infections in one or more individuals comprising:
a) individually combining anti-SARS-CoV surface antigen, such as spike protein peptide SARS-AgS5 (SEQ ID NO: 6) (see para [0039] and [0056]; Figure 11), antibody-coated carboxylated microspheres (Luminex) (See para [0130]) with a saliva sample (see para [0045]) from each of said one or more individuals to form an admixture;
b) mixing the beads and saliva sample of each individual's admixture;
c) incubating the admixture(s); and
d) detecting whether agglutination by disclosing the detection can be via any standard assay for detecting interaction between molecules. Assays that can be used include but are not limited to … and other methods for detection of antigens and antibodies well known in a clinical laboratory setting are contemplated by the present invention include agglutination (see para [0112]) has occurred in each individual's admixture. Cheung et al 2006 teaches a saliva sample is comprised in an oral rinse fluid (saliva ...swabbed sample from a mucus membrane ... a buccal surface, (See, para [0045]).
Cheung et al 2006 teaches (See, para [0010]) that said method can be used for detecting not only SARS but also other SARS-like coronaviruses.
Cheung et al 2006 teaches saliva sample obtained from SARS-CoV infected host (See, para [0021], [0045]). Therefore the saliva sample obtained from SARS-CoV infected subject contains intact SARS- CoV virions because the saliva sample obtained from an infected subject is infectious without prior treatment of the sample with detergent or other reagent to disrupt the virus in saliva sample. Cheung et al 2006 teaches agglutination assay as one of the assay for detection of SARS-CoV in the saliva sample and therefore based on the principle of the agglutination assay of a virus in a saliva sample and antibody coated beads, Cheung et al 2006 inherently teaches detection of intact SARS-CoV virion in a saliva sample from SARS-CoV infected individual or host or subject.
Cheung et al 2006 does not teach SARS CoV-2 and beads coated with anti-SARS CoV-2 antibody.
Chen et al 2020 is in the art and teaches human monoclonal antibodies that bind to SARS-CoV-2 spike protein with the specificity of mAbs (311mab–31B5, −32D4 and −31B9 clones) to SARS-CoV-2 RBD protein by ELISA (See, Fig. 1 f and legend). Chen et al 2020 teaches Spike protein of SARS-Cov-2 typed pseudovirus was produced for neutralization assay. The pseudovirus is an intact virus with surface Spike protein of SARS-Cov-2 (See, Combined article PDF supplementary information article, page 3).
Azzi et al 2020 is in the art and comments on (provides motivation) and emphasizes rapid salivary test that uses saliva as a sample is suitable for a mass screening program to detect SARS-CoV-2 (See, entire article). The saliva sample obtained from SARS-CoV-2 infected subject or individual is reasonably expected to comprise intact SARS-CoV-2 virion because the sample is normally infectious if the individual is infected and has symptoms of the infection.
Hughes et al 1984 is in the virology art and teaches a latex agglutination (LA) test that uses antibody coated beads or microspheres for the detection of intact rotaviruses in stool specimens. Stool specimens containing rotavirus and treated like the SA-11 viral samples had mostly intact virions (See, page 443, col 1, para on Specificity, sensitivity …). In contrast, SA-11 virus taken directly from infected cells always gave positive LA reactions. The SA-11 virus
used in Rotazyme kits is heat inactivated (Abbott Laboratories, personal communication) and is highly fragmented when viewed by EM. The lack of agglutination by SA-11 virus from Rotazyme test kits may be due to an insufficient amount of intact virus needed for agglutination (See, page 445, col 1, para 1). Therefore, Hughes et al 1984 teaches that intact rotavirus is required in a sample for the antibody coated bead based agglutination test/assay.
Kasempimolporn et al 2014 is in the virology art and teaches detection of intact rabies virus in saliva samples using anti-rabies virus antibody coated latex beads (See, abstract enclosed. Also independently access and refer entire article).
Mary Louise Turgeon 2013 is in the art and teaches principles of agglutination test of a particulate antigen or intact pathogen (read on a virus) and specific antibody to the antigen. The principles of agglutination of latex bead coated antibody and intact pathogen particle or intact virus or particulate antigen are taught. The intact pathogen (reads on a virus) has multiple epitopes to which the antibody coated on different beads bind and result in formation of an aggregate or agglutination (See, Fig 10-2, pdf printout page 5, please see entire chapter).
Please see the cropped figure Fig 10-2 below (Mary Louise Turgeon 2013 the applied reference) that shows antibody coated beads with a particulate antigen with multiple epitope (similar to an intact virus) teaches principle of agglutination assay.
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Onchoema Key 2016 is in the agglutination test art and teaches principle of agglutination test of a particulate antigen with multiple epitopes and specific antibody and enhancement of agglutination by a second antibody directed to Fc region of a primary antibodies binding to multiple epitopes on the antigen (See, Fig 6.2 Agglutination, page 4 PDF printout, entire article). The disclosed design choice of agglutination teaches that agglutination test requires an intact or particulate antigen with multiple epitopes (reads on a intact virus) for agglutination to occur by binding of antibodies.
The instant claims 1 and 27 are similar in scope and the combined prior art teachings as recited supra teaches the limitations and renders obvious the claims 1 and 27.
It would have been obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to modify the prior art teachings of Cheung et al 2006 teaching detection of SARS-CoV intact virion by the agglutination assay as recited supra with the additional teachings of Chen et al 2020 on anti-SARS CoV-2 RBD binding monoclonal antibodies (mAbs binding to spike protein of SARS CoV-2 virus) and coat the beads with the antibodies disclosed by Chen et al 2020 and intact pseudovirus comprising SARS-CoV-2 spike protein and an opinion on suitability by Azzi et al 2020 for use of saliva sample from SARS-CoV-2 infected individual or a subject that comprise intact SARS-CoV-2 virion, and additional teachings on requirement of intact virus or particulate viral antigen with multiple epitopes specific to the used antibody coated on beads or microsphere as taught by Hughes et al 1984, and principles of agglutination of particle antigen (reads on a virus) and specific Ab taught by Kasempimolporn et al 2014, Mary Louise Turgeon 2013, and Onchoema Key 2016 to arrive at the invention of claims 1-4 and 27.
One of the ordinary skills in the art would have been motivated to develop a bead-based agglutination assay to detect intact SARS CoV-2 virus or intact SARS CoV-2 virion in a sample including saliva for simplicity of the assay for diagnosis of SARS-CoV-2 infection and improving the sensitive and/or specific diagnostic assays that can detect, and in particular, that can detect SARS-CoV-2 virus in a manner that reduces the level of false positive results (See, para [0007]-[0008]) in one or more individual for commercial success and overcome the difficulties of ELISA and PCR based assays to detect and quantify intact SARS CoV-2 virus or intact SARS CoV-2 virion. Azzi et al 2020 teaches rapid salivary test suitable for a mass screening program to detect SARS-CoV-2 and indicates that saliva is one of the preferable samples (See, abstract, entire article). There would be a reasonable expectation of success given the applied prior art teachings in the art as recited supra. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claims 1-4 and 27. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A, C-E).
10. Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Cheung et al 2006 (US20060188519A1, published 08/24/2006), and Chen et al 2020 (Cellular & Molecular Immunology, 17:647 – 649, published 20 April 2020), Azzi et al 2020 (J Infect. 2020 Sep;81(3): e75-e78), Hughes et al 1984 (J of Clinical Microbiology, Vol 20 No 3, Sept. 1984, p. 441-447), Kasempimolporn et al 2014 (PDF printout, Current Laboratory Techniques in Rabies Diagnosis, Research and Prevention. 2014, Pages 37-42. ISBN. 978-0-12-800014-4), Mary Louise Turgeon 2013 (PDF printout, Immunology & Serology in Laboratory Medicine 5th Edition. ISBN-100323085180), and Onchoema Key 2016 (PDF printout, published on line https://oncohemakey.com/antigen-antibody-interactions-immune-assays-and-experimental-systems/) as applied to claims 1-4 above and further in view of Franzmann et al 2009 (US20090325201A1, published 12/31/2009).
Claim 5: The combined teachings of prior arts as recited supra teaches claim 4, however, does not explicitly teach added limitation of claim 5.
Franzmann et al 2009 is in the field of biomarkers and methods for diagnostics (abstract) and teaches an oral rinse fluid is obtained by having each of the one or more individuals swish and gargle a saline solution in their oral cavity and then expectorate into a collection vessel, whereby the oral rinse fluid is obtained ([t]he subject sample may be selected, for example, from the group consisting of oral rinse, saliva, (See, para [0017]); collection of oral rinse: Samples are collected from patients at the clinic or screening site. For collection, five milliliters of normal saline is placed in the subject's mouths. Patients are asked to, swish for five seconds, gargle for five seconds and then spit into a specimen cup (See, para [0075]).
It would have been obvious to one of ordinary skill in the art at the time of the invention to modify the combined prior art teachings as applied to claim 4 above with the teaching of Franzmann et al for the purpose of ensuring saliva samples have contact with all mucosal surfaces of interest (para [0076]) and would be obvious to the ordinary skills to use the approach recover the viral sample to enhance the detection the bead-based agglutination assay to detect intact SARS CoV-2 virus or intact SARS CoV-2 virion in a sample including saliva for simplicity of the assay for diagnosis of SARS-CoV-2 infection and improving the sensitive and/or specific diagnostic assays that can detect, and in particular, that can detect SARS-CoV-2 virus in a manner that reduces the level of false positive results (See, para [0007]-[0008]) in one or more individual for commercial success and overcome the difficulties of ELISA and PCR based assays to detect and quantify intact SARS CoV-2 virus or intact SARS CoV-2 virion in saliva sample and increase sensitivity limit of the assay for commercial success. There would be a reasonable expectation of success given the applied prior art teachings in the art as recited supra. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claim 5. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A, C-G).
11. Claims 6-9 are rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Cheung et al 2006 (US20060188519A1, published 08/24/2006), and Chen et al 2020 (Cellular & Molecular Immunology, 17:647 – 649, published 20 April 2020), Azzi et al 2020 (J Infect. 2020 Sep;81(3): e75-e78), Hughes et al 1984 (J of Clinical Microbiology, Vol 20 No 3, Sept. 1984, p. 441-447), Kasempimolporn et al 2014 (PDF printout, Current Laboratory Techniques in Rabies Diagnosis, Research and Prevention. 2014, Pages 37-42. ISBN. 978-0-12-800014-4), Mary Louise Turgeon 2013 (PDF printout, Immunology & Serology in Laboratory Medicine 5th Edition. ISBN-100323085180), and Onchoema Key 2016 (PDF printout, published on line https://oncohemakey.com/antigen-antibody-interactions-immune-assays-and-experimental-systems/), Franzmann et al 2009 (US20090325201A1, published 12/31/2009) as applied to claims 5 above, and further in view of Agilent Technologies, Inc (published 11/15/2016), Bangs Lab 2013 (published 20 March 2013), and Castro et al 2018 (Genes, 2018, 9, 281).
Claims 6-9: The combined teachings of prior art as applied and recited supra teaches claim 5, however, does not teach added limitation of claims 6-9.
Agilent Technologies 2016 is in the bead agglutination art for analytes and teaches intensely colored and dark shade latex beads (intensely colored HiDye particles) that can be used for developing bead agglutination assay to detect analyte (See, page 1-3, PDF printout).
Bangs Lab 2013 is in the papilloma virus agglutination assay and teaches magnetic microspheres (beads) (See, page 9 col 1-2, section X Microsphere), colored microspheres (beads) (See, page 2 col 2 section 5 Mixed colors) streptavidin-coated magnetic particles are also used as a solid support in IGEN’s human papilloma virus assay (See, page 9 col 1 last para; entire PDF printout).
Castro et al 2018 teaches high-throughput incubation and quantification of agglutination assays in a microfluidic system that comprise biotin-streptavidin, a specific protein-protein interaction, as a model agglutination assay, consisting of streptavidin microbeads and biotinylated bovine serum albumin (BSA) (See, abstract, page 6, section 2.2 assay protocol).
It would have been obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to modify the combined prior art teachings as applied to claim 5 with the additional teachings of Agilent Technologies 2016, Bangs Lab 2013 and Castro et al 2018 to arrive at the invention of claims 6-9. One of the ordinary skills in the art would have been motivated to develop colored bead based assay for color coding of different SARS CoV-2 surface antigen epitope targeted mAbs for different epitope target and magnetic colored beads with streptavidin-linked antibodies to enable the rapid (high through-put semi-automated assays), efficient capture, separation, and machine visualization of target antigen and readout by a machine enabling the bead-based agglutination assay to detect intact SARS CoV-2 virus or intact SARS CoV-2 virion in a sample including saliva for simplicity of the assay for diagnosis of SARS-CoV-2 infection and improving the sensitive and/or specific diagnostic assays that can detect, and in particular, that can detect SARS-CoV-2 virus in a manner that reduces the level of false positive results (See, para [0007]-[0008]) in one or more individual for commercial success and overcome the difficulties of ELISA and PCR based assays to detect and quantify intact SARS CoV-2 virus or intact SARS CoV-2 virion. There would be a reasonable expectation of success given the applied prior art teachings in the art as recited supra. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claims 6-9. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A, C-E).
12. Claims 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Cheung et al 2006 (US20060188519A1, published 08/24/2006), and Chen et al 2020 (Cellular & Molecular Immunology, 17:647 – 649, published 20 April 2020), Azzi et al 2020 (J Infect. 2020 Sep;81(3): e75-e78), Hughes et al 1984 (J of Clinical Microbiology, Vol 20 No 3, Sept. 1984, p. 441-447), Kasempimolporn et al 2014 (PDF printout, Current Laboratory Techniques in Rabies Diagnosis, Research and Prevention. 2014, Pages 37-42. ISBN. 978-0-12-800014-4), Mary Louise Turgeon 2013 (PDF printout, Immunology & Serology in Laboratory Medicine 5th Edition. ISBN-100323085180), and Onchoema Key 2016 (PDF printout, published on line https://oncohemakey.com/antigen-antibody-interactions-immune-assays-and-experimental-systems/), Franzmann et al 2009 (US20090325201A1, published 12/31/2009), Agilent Technologies, Inc (published 11/15/2016), Bangs Lab 2013 (published 20 March 2013), and Castro et al 2018 (Genes, 2018, 9, 281) as applied to claim 9 above, and further in view of Lee et al 2014 (US20140227679A1, published 08/14/2014).
Claims 10-12: The combined teachings of prior arts as applied above teaches the claim 9 as recited supra, however, does not teach added limitation of claims 10-12 on bead diameter size.
The claims are examined in view of the support in specification para [0043] and elsewhere for bead diameter size in µm (micrometer).
Lee et al 2014 (US20140227679A1) is directed magnetic bead aggregation assay system, provided are a method and system for detecting analytes (can be read on SARS CoV-2 viral antigen in view of combined prior arts as applied to claims 10-12) in a sample by characterizing the magnetic bead aggregates on an aggregate-by-aggregate basis by measuring physical properties of the aggregates (See, abstract). The magnetic beads are selected from beads having a size range of the order of 10 nm to 10,000 nm diameter. The beads are preferably in the range of 0.1 to 5 micron size in diameter (micrometer or µm), most preferably 0.2 to 2 microns. The aggregation of magnetic beads to form aggregates is controllable by controlling magnetic bead size. The rate of aggregation of the magnetic beads increases with a decrease in magnetic particle size (See, para [0020]. The beads of a first type or second type are preferably uniform in physical properties, i.e., magnetization, color and size (See, para [0012], claim 169, entire prior art).
It would have been obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to modify the combined prior art teachings as applied to claim 9 above with the additional teachings of Lee et al 2014 to arrive at the invention of claims 10-12. One of the ordinary skills in the art would have been motivated to develop colored magnetic bead of the claimed diameter size (See, Lee et al 2014 para [0012], [0020]) for improved aggregation and sensitivity for detection of intact SARS CoV-2 virions. There would be a reasonable expectation of success given the applied prior art teachings in the art as recited supra. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claims 10-12. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A, C-E).
13. Claims 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Cheung et al 2006 (US20060188519A1, published 08/24/2006), and Chen et al 2020 (Cellular & Molecular Immunology, 17:647 – 649, published 20 April 2020), Azzi et al 2020 (J Infect. 2020 Sep;81(3): e75-e78), Hughes et al 1984 (J of Clinical Microbiology, Vol 20 No 3, Sept. 1984, p. 441-447), Kasempimolporn et al 2014 (PDF printout, Current Laboratory Techniques in Rabies Diagnosis, Research and Prevention. 2014, Pages 37-42. ISBN. 978-0-12-800014-4), Mary Louise Turgeon 2013 (PDF printout, Immunology & Serology in Laboratory Medicine 5th Edition. ISBN-100323085180), and Onchoema Key 2016 (PDF printout, published on line https://oncohemakey.com/antigen-antibody-interactions-immune-assays-and-experimental-systems/), Franzmann et al 2009 (US20090325201A1, published 12/31/2009), Agilent Technologies, Inc (published 11/15/2016), Bangs Lab 2013 (published 20 March 2013), and Castro et al 2018 (Genes, 2018, 9, 281), Lee et al 2014 (US20140227679A1, published 08/14/2014) as applied to claim 12 above, and further in view of Buffin et al 2018 (J Virol Methods. 2018 Jan;251: 46-53).
Claims 13-14: The combined teachings of prior arts as applied and recited above teaches claim 12, however, does not teach added limitation of claims 13-14 on quantity of anti-SARS CoV-2 S antibody per mg of beads.
Buffin et al 2018 is in the virial antigen detection latex agglutination assay to quantify the amount of hemagglutinin protein in adjuvanted low-dose influenza monovalent vaccines (See, abstract). Buffin et al 2018 teaches coating of beads with antibody, two amounts of antibodies were tested: 20 and 40 mg per gram of beads that corresponds to (20 µg and 40 µg/mg of beads). This optimization was carried out using beads-coated with three reference epidemic strain serums. The best result was obtained with 40 mg (40 ug/mg of beads) of purified anti-serum per gram of beads (See, page 49, col 2, results section 3.1.).
Furthermore, as applicable to instant claims 13-14, according to section 2144.05 of the MPEP, differences in concentration (antibody coating concentration/mg of beads) or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages”).
It would have been obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to modify the combined prior art teachings as applied to claim 12 above with the additional teachings of Buffin et al 2018 to arrive at the invention of claims 13-14. One of the ordinary skills in the art would have been motivated to develop colored magnetic bead agglutination assay of sensitivity for detection of intact SARS CoV-2 virions and therefore optimization of antibody quantity coating on the beads is a routine as per the bead size used (See, Lee et al 2014 para [0012], [0020]). There would be a reasonable expectation of success given the applied prior art teachings in the art as recited supra. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claims 13-14. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A, C-E).
14. Claims 15-26, and 28-30 are rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Cheung et al 2006 (US20060188519A1, published 08/24/2006), and Chen et al 2020 (Cellular & Molecular Immunology, 17:647 – 649, published 20 April 2020), Azzi et al 2020 (J Infect. 2020 Sep;81(3): e75-e78), Hughes et al 1984 (J of Clinical Microbiology, Vol 20 No 3, Sept. 1984, p. 441-447), Kasempimolporn et al 2014 (PDF printout, Current Laboratory Techniques in Rabies Diagnosis, Research and Prevention. 2014, Pages 37-42. ISBN. 978-0-12-800014-4), Mary Louise Turgeon 2013 (PDF printout, Immunology & Serology in Laboratory Medicine 5th Edition. ISBN-100323085180), and Onchoema Key 2016 (PDF printout, published on line https://oncohemakey.com/antigen-antibody-interactions-immune-assays-and-experimental-systems/), Franzmann et al 2009 (US20090325201A1, published 12/31/2009), Agilent Technologies, Inc (published 11/15/2016), Bangs Lab 2013 (published 20 March 2013), and Castro et al 2018 (Genes, 2018, 9, 281), Lee et al 2014 (US20140227679A1, published 08/14/2014), Buffin et al 2018 (J Virol Methods. 2018 Jan;251: 46-53) as applied to claim 14 above, and further in view of Bhaskar et al 2003 (FEMS Immunology and Medical Microbiology 39 (2003) 235-239), Schaff et al 2016 (US9244065B1, 01/26/2016).
Claims 15-26, and 28-30: The combined teachings of prior arts as applied and recited above teaches claim 14. The added limitations of claims 15-26, 28 are taught by the prior arts as recited below:
Claims 15-18, and 28-30: Cheung et al 2006 (US20060188519A1) teaches incubation step (See, para [0113], [0115].
Bhaskar et al 2003 is in the art of latex bead agglutination test and teaches mixing by a stick and incubation of antibody coated latex beads with serum from Mycobacterium tuberculosis at room temperature on a black slide for 2 minutes under field conditions and obtaining positive or negative agglutination result in 2 minutes of incubation (See, Bhaskar et al 2003, abstract, page 236, col 2, section 2.4 Test Procedure). Bhaskar et al 2003 disclosed a simple, inexpensive, sensitive and visually detectable slide agglutination test
which takes just 2 min for diagnosis of pulmonary as well as extrapulmonary TB (See, page 235, col 2 last para).
Incubation of a sample comprising a viral antigen and antibody coated beads or beads coated with viral antigen and a sample comprising an antibody e.g. serum/plasma for diagnostics assays at a room temperature or 370C is known in the art and it is within the routine laboratory practice for bead agglutination assay method optimization skills of the ordinary skills and does not involve inventive concepts. See MPEP 2144.05.
Claim 19: Batistoni et al 2013 (US8417002B2) is in the art of agglutination assay to detect viral infection disease and teaches added limitation of claim 19, wherein the detecting comprises use of a camera (See, US8417002B2, col 7 lines 17-19, col 5 lines 14-15, col 2 lines 40-45).
Claim 20: Moulds et al 2004 (US20040166551A1, published 08/26/2004) is in the art and teaches added limitation of instant claim 20, wherein the detecting comprises use of an optical density meter by disclosing detection may then be performed via methods such as magnetic detection, capacitive measurements, optical density measurements, optical imaging, spectrophotometric, the structure and design of the present invention allows for these alternatives (See, para [0051], [0012]-[0014], [0037], [0001], entire prior art publication).
Claim 21-22: Makino 2001 (Annals of Clinical & Laboratory Science, vol. 31, no. 2, 2001) is in the art and teaches added limitation of claim 22-23, wherein the detecting comprises use of a microplate reader by disclosing use of microtiter plates for latex agglutination immunoassay, an adaptation of the latex agglutination immunoassay, in conjunction with polystyrene microtiter plates and a microtiter plate reader, for the analysis of serum AMG concentrations, and mixing of a sample and antibody coated beads (See, page 205 col 2 para 1, page 207 col 1, Results, reaction time - mixing). The instant claim 21 method comprising the step comprising transferring an aliquot from each individual's admixture to a well of a multi-well plate after the mixing or incubating step and detecting whether agglutination has occurred for each individual's admixture is a design choice and does not contribute to the inventive concept and it is within the routine laboratory practice for bead agglutination assay method optimization skills for performing method for quantification of an analyte (analyte reads on amount of virions) of the ordinary skills and does not involve inventive concepts. See MPEP 2144.05.
Claim 23: Zaiko et al 2008 (Clinical Lab 2008, 54 (7- 8;) p. 273 – 279) is in the art and teaches added limitation of instant claim 23, wherein the detecting comprises use of a microarray digital reader by disclosing A microarray analytical system for performing tests of latex agglutination reaction in microformat with digital image registration was developed. The system allows the application of latex microdrops to the surface of the carrier in the form of a regular microarray and mixing of the latex droplets with the individual samples in each droplet of the microarray. The reaction is performed in a total mixture volume of about 1 microl for each of 30 samples simultaneously with video registration and interpretation of the results using a scanning device and specially developed software. The results of the semi-quantitative determination of C-Reactive Protein, Rheumatoid Factor and Anti-Streptolysin O concentrations by traditional macro- and proposed micro-array agglutination method were compared with the immunoturbidimetric measurements used as reference method. It was concluded that the suggested method for performing latex agglutination reactions on the basis of a microarray approach with digital image evaluation of results can provide a high throughput and reliable results and also offers significant advantages to the traditional latex agglutination tests with visual interpretation. Comprehensive documentation and objectification of readouts show a siginificant improvement to the present methodology (See, Zaiko et al 2008, abstract).
Claims 24-25: Schaff et al 2016 (US9244065B1, published 01/26/2016) is in the art of systems, devices, and methods for agglutination assays and teaches the added limitations of claims 23-24, further comprising adding a viscosifying agent to the admixture after the incubating step but before the transferring step (instant claim 24); and, wherein the viscosifying agent is FICOLL (instant claim 25) by disclosing Percoll as a viscosifying agent, an example of a suitable density media is Percoll™, available from GE Lifesciences. Particular densities may be achieved by adjusting a percentage of Percoll™ in a salt solution (See, US9244065B1 page 12, col 1 lines 44-64, abstract, entire prior art).
Claim 26: Buffin et al 2018 is in the art and teaches a latex agglutination assay to quantify the amount of hemagglutinin protein in adjuvanted low-dose influenza monovalent vaccines (See, abstract, page 47-48 method, Fig 3-5, entire research paper).
Additionally, Batistoni et al 2013 (US8417002B2) teaches a method of an agglutination assay to generate a quantitative result value representative of the degree of agglutination of the sample. The method includes computing the actual concentration of the sample and computing a quantitative result for each sample in the assay (See, abstract, claims 1-9, Fig. 1-11, entire prior art US8417002B2). The instant claim 26 step (d) is an assay method design choice and does not contribute to the inventive concept and it is within the routine laboratory practice for bead agglutination assay method optimization skills for performing method for quantification of an analyte (analyte reads on amount of virions) of the ordinary skills and does not involve inventive concepts. See MPEP 2144.05.
It would have been obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to modify the combined prior art teachings as applied to claim 14 above with the additional teachings of Bhaskar et al 2003, Schaff et al 2016 to arrive at the invention of claims 15-26, and 28-30. One of the ordinary skills in the art would have been motivated to develop inventions of claims 15-26, and 28-30 comprising bead agglutination assay for sensitivity and point-of-care use or field use for detection of intact SARS CoV-2 virions in a saliva or other patients sample from suspected COVID-19 disease or suspected SARS-CoV-2 virus infected subjects. There would be a reasonable expectation of success given the applied prior art teachings in the art as recited supra. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claims 15-26, and 28-30. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A, C-E).
15. Claims 31-32 are rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Cheung et al 2006 (US20060188519A1, published 08/24/2006), and Chen et al 2020 (Cellular & Molecular Immunology, 17:647 – 649, published 20 April 2020), Azzi et al 2020 (J Infect. 2020 Sep;81(3): e75-e78), Hughes et al 1984 (J of Clinical Microbiology, Vol 20 No 3, Sept. 1984, p. 441-447), Kasempimolporn et al 2014 (PDF printout, Current Laboratory Techniques in Rabies Diagnosis, Research and Prevention. 2014, Pages 37-42. ISBN. 978-0-12-800014-4), Mary Louise Turgeon 2013 (PDF printout, Immunology & Serology in Laboratory Medicine 5th Edition. ISBN-100323085180), and Onchoema Key 2016 (PDF printout, published on line https://oncohemakey.com/antigen-antibody-interactions-immune-assays-and-experimental-systems/), Franzmann et al 2009 (US20090325201A1, published 12/31/2009), Agilent Technologies, Inc (published 11/15/2016), Bangs Lab 2013 (published 20 March 2013), and Castro et al 2018 (Genes, 2018, 9, 281), Lee et al 2014 (US20140227679A1, published 08/14/2014), Buffin et al 2018 (J Virol Methods. 2018 Jan;251: 46-53), Bhaskar et al 2003 (FEMS Immunology and Medical Microbiology 39 (2003) 235-239), Schaff et al 2016 (US9244065B1, 01/26/2016) as applied to claim 30 above, and further in view of Hanke et al 2020 (bioRxiv preprint doi: https://doi.org/10.1101/2020.06.02.130161; version posted June 2, 2020).
Claims 31-32: The combined teachings of prior arts as applied to claim 30 and recited above teaches claim 30. The added limitations of claims 31-32 are taught by the prior arts as recited below:
Hanke et al 2020 is in the art and teaches added limitations of instant claims 31, wherein the anti-SARS-CoV-2 surface antigen antibody is an alpaca-derived nanobody (instant claim 31); and added limitations of instant claims 32, wherein the nanobody is Ty1 (instant claim 32) by disclosing the isolation and characterization of an alpaca-derived single domain antibody fragment, Ty1, that specifically targets the receptor binding domain (RBD) of the SARS-CoV-2 spike. Ty1 binds the RBD with high affinity to an epitope on the RBD accessible in both the ‘up’ and ‘down’ conformations, sterically hindering RBD and ACE2 receptor interaction/binding. Ty1 extremely potent and shows high level of specificity as Ty1 neutralizes SARS-CoV-2 spike pseudovirus as a 12.8 kDa nanobody. Ty can be expressed in high quantities in bacteria, presenting opportunities for manufacturing at scale. Therefore, Ty1 is an excellent candidate as an intervention against COVID-19 and can be used for SARS-CoV-2 viral antigen diagnostics assay development (See, abstract).
It would have been obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to modify the combined prior art teachings as applied to claim 30 above with the additional teachings of Hanke et al 2020 to arrive at the invention of claims 31-32. One of the ordinary skills in the art would have been motivated to develop inventions of claims 31-32 bead agglutination assay comprising beads coated with alpaca-derived Ty1 nanobody for higher sensitivity and point-of-care use or field use for detection of intact SARS CoV-2 virions in a saliva or other patients sample from suspected COVID-19 disease or suspected SARS-CoV-2 virus infected subjects. There would be a reasonable expectation of success given the applied prior art teachings in the art as recited supra. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claims 31-32. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A, C-E).
Response to Arguments
16. Applicant’s arguments filed on 04/07/2026 with respect to the amended claims 1-32 have been considered but are moot because the new ground of rejection relies on additional reference and teachings and obviousness analysis applied in the prior rejection of record for any teaching or matter specifically challenged in the arguments filed on 04/07/2026.
Applicants Arguments against Rejections under 35 U.S.C 103
Applicant’s arguments against rejection of claims 1-32 under 35 U.S.C 103 and examiners responses are given below:
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In Response to Arguments:
The rejection of the amended claims 1-32 (filed on 04/07/2026) under 35 U.S.C. 103 obviousness in the final rejection as recited supra has applied additional prior arts as recited in the rejection that teaches antigen-antibody agglutination test principle and requirement of an intact virus particle or a particulate antigen for binding with specific antibody for the agglutination phenomenon and agglutination assay.
As recited in the modified final rejection office action under obviousness rejection, the primary reference Cheung et al 2006 applied to claim 1 and dependent claims teaches saliva sample obtained from SARS-CoV infected host (See, para [0021], [0045]). Therefore the saliva sample obtained from SARS-CoV infected subject contains intact SARS- CoV virions because the saliva sample obtained from an infected subject is infectious without prior treatment of the sample with detergent or other reagent to disrupt the virus in saliva sample. Cheung et al 2006 teaches agglutination assay as one of the assay for detection of SARS-CoV in the saliva sample and therefore based on the principle of the agglutination assay of a virus in a saliva sample and antibody coated beads, Cheung et al 2006 inherently teaches detection of intact SARS-CoV virion in a saliva sample from SARS-CoV infected individual or host or subject. Further modification of the prior art teachings of Cheung et al 2006 with additional teachings of the prior arts on the SARS-CoV-2 as recited supra in the office action arrives at the invention of claim 1 and dependent claims. The amended claims 1-32 are rendered obvious by modification of the office action in view of the additional prior arts and teachings applied.
The applicant, inter alia, has argued and shown the benefits/superiority of the claimed bead coated specific antibody agglutination assay for SARS CoV-2 virus by comparing with ELISA and PCR based method and argued that the agglutination assay / method is less prone to false positive results arising from residual RNA (PCR) or antigen (ELISA), after the SARS CoV-2 virus infection is resolved in a subject, safety issues with infectious SARS CoV-2 virus to perform assay and use of heat inactivated virus.
Applicant has argued the sensitivity of the assay is about 10 virions per/ml verses LOD of PCR to about 15 virions/ml based on disclosures in the instant specification para [0089], and [0156].
The applied combined prior art teachings for the obviousness rejection of the instant claims 1-32 teaches a sensitive agglutination assay for detection of intact SARS-CoV-2 virions. It is within the skills of the ordinary to optimize the assay to detect about 10 virions/ml in a saliva sample collected from SARS-CoV-2 infected individual in view of the applied prior art teachings. Applicant has not shown unexpected sensitivity results in view of the applied prior art in the field and teachings in the rejection.
The applicant is arguing and showing superior results via argument by using an incomplete comparison approach. Applicant is arguing and claiming an “apple” (e.g. SARS-CoV-2 agglutination assay requiring the intact virus or SARS-CoV-2 particulate antigen) to “orange” (e.g. ELISA can be performed with peptide or broken SARS-CoV-2, RT-PCR performed with SARS-CoV-2 RNA) comparison and superiority. To be fair in comparing the agglutination assay of the intact SARS CoV-2 virion and specific antibody coated beads, applicant is required to compare the claimed assay based on the principle of agglutination with the applied prior art in the rejection. This is an apple to apple or orange to orange comparison. Therefore, the applicant is unable to demonstrate superior results over. See, MPEP 716.02, Any differences between the claimed invention and the prior art may be expected to result in some differences in properties, The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). See, MPEP 716.02(a) I-IV. "A greater than expected result is an evidentiary factor pertinent to the legal conclusion of obviousness.
The applicant’s arguments and secondary evidence is considered but found unpersuasive in view of the modified 35 U.S.C 103 rejection office action. The additionally applied prior art based 35 U.S.C. 103 obviousness rejection as recited supra is made final in view of the Applicant's amendment that necessitated the new ground(s) of rejection presented in this office action.
17. Relevant Prior Arts
Rivera et al 1987. A solid-phase fluorescent immunoassay for detecting canine or mink enteritis parvoviruses in fecal samples. (Veterinary Microbiology. Volume 15, Issues 1–2, October 1987, Pages 1-9). Disclosed is detection of canine or mink enteritis parvoviruses in fecal samples by using beads coated with specific antibodies, thus teaches intact virus agglutination assay.
Schmidt et al 2023 (EP3670669B1, published 09/20/2023 with filing date of 03/24/2020). Detection of sars-cov-2 in a plurality of biological samples.
Conclusion
18. No Claim is allowed.
19. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
20. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMADHAN J JADHAO whose telephone number is (703)756-1223. The examiner can normally be reached M-F 8:00-5:00.
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/SAMADHAN JAISING JADHAO/Examiner, Art Unit 1672
/BENNETT M CELSA/Primary Examiner, Art Unit 1600
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