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 .
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Feb. 13, 2026. Claims 1-21 are pending. Claims 6-7, 9-12 and 20-21 are withdrawn. Claims 1-5, 8 and 13-19 are currently examined.
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.
(Previous rejection-withdrawn) Claim 14 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and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.
This rejection is withdrawn in view of the amendments filed on Feb. 13, 2026.
(New rejection) Claims 1-5, 8 and 13-19 are 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.
The amended base claim 1 recites a new phrase at “to form a capture composition-anti-SARS-CoV-2 antibody complex” that renders the claim indefinite. It is unclear if the “capture composition” in this phrase is the same as the “at least one capture composition” in the same claim. Also, it is unclear what the relation between the “anti-SARS-CoV-2 antibody” in the phrase and the “at least one anti-SARS-CoV-2 antibody” claimed in the same claim.
The amended base claim 1 also recites the new terms “at least one detectable label”, “at least one second specific binding partner” and “at least one third specific binding partner” that render the claims indefinite. It is unclear if other “detectable label”, “second specific binding partner” and “third specific binding partner” can form the same “an antibody-detection composition” as the “at least” ones did. Also, it is unclear if the amended “an antibody-detection composition” is the same composition as the claimed “at least one detection composition” in the same claim.
Accordingly, one of ordinary skill in the art will not know the metes and bounds of the claim.
Claim Rejections - 35 USC § 103
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.
(New Rejection-necessitated by amendment) Claims 1-5, 8 and 13-19 are rejected under 35 U.S.C. 103 as being unpatentable over Zhao et al. (medRxiv, Mar. 03, 2020) as evidenced by Automated ELISA (https://www.goldstandarddiagnostics.us/home/products/instruments-equipment/automated-elisa-analysis-systems/) as evidenced by Breg et al. (Cold Spring Harb Protoc. 2019 Sep 3;2019(9)) and Hara et al. (BMC Infect Dis. 2013 Apr 4;13:165) in view of Chen et al. (Eur J Clin Microbiol Infect Dis. 2005 Aug;24(8):549-53) as evidenced by Beta Lifescience (https://www.betalifesci.com/blogs/news/elisa-controls#:~:text=Positive%20controls%20are%20samples%20that,Blank%20Controls).
The base claim 1 is directed to a method for detecting a presence or determining an amount of at least one type of anti-SARS-CoV-2 antibody in a subject, the method comprising the steps of: a) contacting at least one biological sample from the subject, either simultaneously or sequentially, in any order, with at least one capture composition comprising at least one first specific binding partner comprising an isolated polypeptide comprising a receptor binding domain (RBD) of a spike protein from SARS-CoV-2 or a variant thereof, wherein said first specific binding partner binds to at least one anti-SARS-CoV-2 antibody; and at least one detection composition, wherein said detection composition comprises at least one second specific binding partner comprising an isolated polypeptide comprising a RBD of a spike protein from SARS-CoV-2 or a variant thereof, at least one third specific binding partner comprising an isolated polypeptide of a C-terminal domain of a nucleocapsid protein from SARS-CoV-2 or a variant thereof, and at least one label, wherein said second specific binding partner specifically binds to the at least one anti-SARS-CoV-2 antibody, thereby producing at least one first complex comprising the capture composition-anti- SARS-CoV-2 antibody-detection composition; and b) assessing a signal from the first complex, wherein the amount of detectable signal from the detectable label indicates the presence or amount of anti-SARS-CoV-2 antibody in the sample.
Zhao et al. teaches a method for detecting the total antibodies (Ab), IgM and IgG against SARS-CoV-2 using double-antigens sandwich immunoassay (See page 6, paragraph 3; page 7, paragraph 1). Zhao et al. teaches immobilizing the mammalian cell expressed recombinant antigens containing the RBD of spike protein from SARS-COV-2 to the ELISA plate (See page 7, paragraph 1) that teaches the “…one first specific binding partner comprising an isolated polypeptide comprising a receptor binding domain (RBD) of a spike protein from SARS-CoV-2…” as claimed for capturing. Zhao et al. also discloses that using the HRP-conjugate RBD antigen and HRP-conjugated nucleoprotein antigen for a detection antigen (See page 7, paragraph 1) that teaches the detection composition comprises a second specific binding partner of RBD of a spike protein from SARS-CoV-2 and a third specific binding partner of a nucleocapsid protein from SARS-CoV-2 as claimed. Zhao et al. also teaches that the antibody levels were expressed using the relative binding signals compared to the cutoff
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value of each assay (S/CO), and the average levels of antibodies against SARS-CoV-2 among COVID-19 patients since illness onset are shown in Figure 4 based on the antibody binding signal (See page 19, paragraph 4; Figure 4 and below). Here this method teaches b) in the base claim 1 for “assessing a signal from the first complex, wherein the amount of detectable signal from the detectable label indicates the presence or amount of anti-SARS-CoV-2 antibody in the sample”. During the performance of the ELISA, the blood sample needs to be added into the ELISA well coated with the RBD antigen and then mix with the labeled antigen for detecting the antibody in the sample (See page 3), which teaches the base claim a) at contacting at least one biological sample from the subject, either simultaneously or sequentially, in any order, with at least one capture composition”.
As for the newly added limitation of “wherein the at least one second specific binding partner and the at least one third specific binding partner are each bound to the same detectable label …”, Zhao teaches using double-antigens sandwich immunoassay (Ab-ELISA) to detect the total antibodies and the detection antigen is HRP-conjugated RBD as claimed as a second specific binder (See page 7) and using nucleoprotein antigen to detect IgG. Although Zhao does not explicitly point out if the RBD and the nucleoprotein are labeled together, it is common knowledge that HRP contains multiple lysine residues and can have one or more conjugation. One ordinary skilled in the art can conjugate the RBD and nucleoprotein (a third specific binder) together to bind to the same detect label of HRP to increase the specificity of the ELISA. This can be evidenced by Berg and Hara’s study. Berg teaches that antibodies conjugated with horseradish peroxidase (HRP) are one of the most widely used bioreagents in the biological sciences. This protocol is a basic method for adding HRP to a thiolated antibody and can be adapted for use with different cross-linkers. Conjugation methods usually focus on linking through the lysines on HRP because there are only six of them and their modification does not adversely affect enzyme activity (See Abstract), where the antibody can be replaced with other proteins such as antigens as RBD-HRP and nucleoprotein-HRP based on the lysine’s sites. Hara teaches that using multiple-antigens in ELISA resulted in improved sensitivity (88.2%) whilst maintaining superior specificity (See Abstract).
Accordingly, Zhao et al. teaches a method for detecting the presence or determining an amount of at least one type of anti-SARS-CoV-2 antibody in a subject as claimed except the C-terminal domain of a nucleocapsid protein from SARS-CoV-2.
Chen et al. teaches a Double-antigen sandwich ELISA for detection of antibodies to SARS-associated coronavirus in human serum (See Abstract), and teaches that in their primary trials with protein microarray (data not shown), the nucleocapsid protein, especially the second half, which is located at 213aa–423aa of the C-terminal of this protein, showed strong antigenicity. Their use of this polypeptide as an antigen in the development of their double-antigen sandwich ELISA for detecting antibodies to SARS-CoV in serum was based on this finding. This double-antigen sandwich ELISA, which employs recombinant N protein as the serodiagnostic antigen and uses enzyme-conjugated antigen instead of enzyme-conjugated secondary antibody, provides a safe, specific, and sensitive means of detecting or confirming SARS infection (See page 552, right column, paragraph 2). Here the nucleocapsid is conjugated with HRP as GST-N-HRP (See page 551, left column).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to apply the C-terminal domain of a nucleocapsid protein of SARS-CoV-2 into Zhao’s study. Because Chen teaches that the C-terminal of nucleocapsid protein (NP) shows strong antigenicity, one of skill in the art would have been motivated to do so to use Chen’s NP protein of SARS-COV-2 for the double-antigen sandwich ELISA, and there would be a reasonable expectation of success to develop a method for detecting a presence or determining an amount of at least one type of anti-SARS-CoV-2 antibody in a subject as claimed.
Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding claim 2, Zhao et al. teaches that the double-antigen ELISA can detect the seroconversion sequentially appeared for Ab, IgM and then IgG, with a median time of 11, 12 and 14 days, respectively (See page 3, paragraph 3).
Regarding claim 3, Zhao et al. teaches that the IgG antibodies were tested using indirect ELISA kit (IgG-ELISA) based on a recombinant nucleoprotein antigen (See page 7, paragraph 1).
Regarding claim 4, Zhao et al. teaches that all isotypes of antibodies against viral antigen can be detected by double-antigen sandwich-based assay, which may also contribute to the superior performance of Ab test (See page 9, paragraph 1), where the total antibody includes IgA, IgG and IgM. Here the description of Zhao teaches that the coated antigen, RBD, can bind to all or at least one of SARS-COV-2 antibody such as IgA to form a complex. At the same time, the HRP-labeled RBD can also bind to all or at least one of SARS-COV-2 antibody such as IgA or IgM or IgG to form antibody-antigen complexes.
Regarding claim 5, Zhao et al. teaches the total Ab, IgG and IgM are detected by ELISA with HRP conjugated antigen through RBD-HRP and nucleoprotein-HRP (See page 7, paragraph 1), and the signal produced by HRP assessing can be used to indicate the amount of anti-SARS-COV-2 antibody, for example, they compared the average S/CO value of in between total Ab, IgG and IgM and relative quantitative titer of Ab test between critical and non-critical patients (See page 19, paragraph 4; Figure 4 A-B, see above). Zhao et al. further teaches that all isotypes of antibodies against viral antigen, including IgM, IgA and IgG, can be detected by double-sandwich based assay, which may also contribute to the superior performance of Ab test (See page 9, paragraph 1) which indicates all antibody’s isotypes can be detect by the double-antigen sandwich complex.
Regarding claim 8, Zhao et al. teaches the second specific binding partner is HRP-RBD (See page 7, paragraph 1) as claimed.
Regarding claim 13, Zhao et al. teaches the RBD is immobilized on the ELISA plate (See page 7, paragraph 1).
Regarding claims 14-17, Zhao et al. teaches using a double-antigen ELISA to detect a presence or determine an amount of anti-SARS-CoV-2 antibody, where the method include antigen such RBD and NP expression and purification and ELISA development. Although Zhao et al. does not focus on the detailed method, it is a common knowledge that the time for performing ELISA is different depending on the applied reagent, equipment and detection method, and the incubation time can be adjusted based on needs. For example, Chen et al. teaches the wells of microtiter plastic plates (used for double-antigen ELISA) are coated with 40 ng of glutathione sulfotransferase-N protein in 100 μl of 50 mM carbonate buffer (pH 9.6) and are incubated overnight at 4 degrees (See page 550, right column, paragraph 3). Therefore, claim 14 can be achieved though routine experimental optimization unless there is evidence showing that the claimed time can produce unexpected results. Although Zhao et al. does not explicitly disclose using a control in the ELISA permeance, it is a routine protocol for an ELISA to include the positive and negative controls. This can be evidenced by the Beta Lifescience. Beta Lifescience teaches that ELISA controls, positive control, negative control and blank control, are vital components in any ELISA experiment, serving to verify that the assay is functioning correctly and producing accurate results. They act as benchmarks to differentiate true signals from background noise or experimental errors, ensuring that the findings are valid and trustworthy. Without these controls, it becomes difficult to interpret the data reliably, which can lead to false conclusions or inconsistent outcomes. Proper use of ELISA controls helps maintain the integrity of both research and diagnostic applications by confirming reagent performance, assay sensitivity, and specificity (See pages 1-2). Nevertheless, Zhao et al. teaches the “cutoff value” in their antibody tests (See page 19, paragraph 3), which indicates a control in the experiments that is needed for data analysis and thus teaches the claim 15. Zhao et al. also discloses using ELISA (Enzyme-Linked Immunosorbent Assay), e.g., an immunoassay, for antibody detection (See e.g., pages 6 and 7), which teaches claim 16. Zhao et al. teaches claim 17 by stating that their findings provide strong empirical support for the routine application of serological testing in the diagnosis and management of COVID-19 patients (See page 3, paragraph 4), which indicates the method can be used as a point-of-care assay as claimed.
Regarding claim 18, Zhao et al. teaches using double-antigens sandwich immunoassay (Ab-ELISA) for antibody detection. As one type of ELISA assay, it can be performed using an automated system with instruments that handle tasks like washing, reagent dispensing, incubation, and reading. This can be evidenced by the description of the Automated ELISA (https://www.goldstandarddiagnostics.us/home/products/instruments-equipment/automated-elisa-analysis-systems/) . The Automated ELISA teaches that the Gold Standard Diagnostics offers several automated ELISA systems to suit the diverse testing needs of their food and ag, water quality and environmental customers. Installing an automated ELISA workstation can improve your lab’s overall efficiency, reduce analytical costs associated with outsourcing, improve turn-around time and provide greater result reproducibility (See page 1).
Regarding claim 19, Zhao et al. teaches that the double-antigen sandwich ELISA can be used to detect total antibody, IgM and IgG from the blood samples (See page 7, paragraph 1; page 3, paragraph 3), which can be used to understand the epidemiology of SARS-CoV-2 infection and to assist in determining the level of humoral immune response in patients and to monitor the imported cases in naive community (See page 14, paragraph 1). Here the description teaches the claim 19-(a).
Responses to Applicant’s Remarks
Applicant’s arguments filed on Feb. 13, 2026 has been received and fully considered as follows:
1). Applicant’s amendment on the rejection Under §112(b) are considered. The rejection is withdrawn.
2). Applicant’s argument on the rejections under 35 U.S.C. 103 is not found persuasive.
Applicant argued that neither Zhao nor Chen, alone or in combination, teaches or suggests this element of the claims. At best, Zhao (See, e.g., page 7) teaches a double-sandwich immunoassay that uses a single capture molecule and a single detection molecule. There is no teaching or suggestion of using multiple detection molecules or the use of second and third binding partners that are both bound to the same detectable label (See Remarks, page 8).
Applicant’s argument is not persuasive.
Zhao teaches a double-sandwich immunoassay using HRP-RBD, and Chen teaches double-sandwich immunoassay using HRP-GST-N (nucleocapsid). Conjugating protein to a label molecule is an ordinary technique in the art and HRP has multiple sites for conjugation, one of skilled in the art can conjugate two or more antigen/protein to HRP to increase the sensitivity of the ELISA, which is taught by Berg as the antibodies conjugated with horseradish peroxidase (HRP) are one of the most widely used bioreagents in the biological sciences. Conjugation methods usually focus on linking through the lysines on HRP because there are only six of them and their modification does not adversely affect enzyme activity (See Berg, Abstract).
In addition, there is no ‘elements” as allegedly argued in the instant application.
3). Applicant’s declaration submitted on Feb. 13, 2026 is received and fully considered. However, it is not found persuasive,
(i). In the item 2, applicant uses the ALP to conjugate the RBD and nucleocapsid. However, the detected label in the base claim 1 claimed a generic label. There is not enough support to demonstrate if any label can work as an unexpected result for a method for detecting a presence or determining an amount of at least one type of anti-SARS-Co V-2 antibody in a subject as claimed.
(ii). In the items 3 and 4, applicant allegedly shows an unexpected result for using a detection composition comprising a second RDB specific binding partner and third NUC specific binding partner exhibited improved specificity, increased assay slope (for IgG and IgM) and increased signal from seropositive samples compared to methods that used a detection (See Declaration, bridging pages 2-3), where the capture antigen is RBD (see item 3). However, the instant specification disclosed that the CTD Nucleocapsid also be coated on the Microparticles (See instant specification, [0361]).
(iii). The allegedly unexpected data in Appendix A-D (See Declaration, pages 4-6) is based on the RBD as a capture antigen and RBD- ALP-nucleocapsid as a detection antigen. However, the instant claims are for a generic label. There is no data to support how other labels can work. Also, the instant base claim 1 claims “at least one capture composition” and “at least one detection composition”. Thus, there is no evidence for the alleged unexpected results compared with other capture composition and detection composition besides the RBD, ALP and C-terminal domain of a nucleocapsid protein.
In addition, as an initial matter, “the burden of showing unexpected results rests on one who asserts them. Thus, it is not enough to show that results are obtained which differ from those obtained in the prior art: that difference must be shown to be an unexpected difference.” In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972) (citation omitted). Moreover, “[i]t is well settled that unexpected results must be established by factual evidence. Mere argument or conclusory statements in the specification does not suffice.” In re De Blauwe, 736 F.2d 699, 705 (Fed. Cir. 1984) (citation omitted).
Please note: the data shown in Appendix A-D is difficult to read.
Conclusion
No claims are allowed.
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).
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 extension fee 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 date of this final action.
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/RUIXUE WANG/Examiner, Art Unit 1672
/NICOLE KINSEY WHITE/ Primary Examiner, Art Unit 1672
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