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 .
Claims 4, 16, 18-20, 23-24, and 27-50 are cancelled.
Claims 1-3, 5-15, 17, 21-22, 25-26, and 51 are pending.
Applicant’s election without traverse of SEQ ID NO: 1 in the reply filed on 11/26/2025 is acknowledged.
Claims 3, 10, and 15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Groups/species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/26/2025.
Claims 1-2, 5-9, 11-14, 17, 21-22, 25-26, and 51 are under examination on the merits.
Priority
This application is a 371 of PCT/US2021/051143, filed 09/20/2021, which claims benefit of US Provisional Application No. 63/080,568, filed 09/18/2020, and claims benefit of US Provisional Application No. 63/083,671, filed 09/25/2020.
However, the claims are not afforded priority to any of these documents because SEQ ID NOs: 1-16 are not disclosed in any of the documents to which priority is claimed. Furthermore, the sequences of the recited tables are not disclosed in a legible manner in any of the priority documents. The claims shall receive a priority date of the effective filing date of 03/17/2023. If Applicant believes this is in error, Applicant must provide a clear and evidenced showing of where the sequences/epitopes are legibly and unambiguously disclosed in the one or more priority documents.
IDS
The information disclosure statement (IDS) filed 12/13/2024 has been considered.
Drawings
The drawings are objected to because many of the key features are illegible. Legibility issues are exemplified in, but not limited to figures 1-5, 9, and 11-18 in their entirety. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Sequence compliance
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821 (a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825 for the reason(s) set forth on the attached Notice To Comply With Requirements For Patent Applications Containing Nucleotide Sequence And/Or Amino Acid Sequence Disclosures. A copy of the "Sequence Listing" in computer readable form has not been submitted as required by 37 C.F.R. 1.821 (e). Applicant is required to comply with the corrections for the sequence listing as per above as part of a complete response to this official action. Said sequence listing must comply with ST.26 sequence guidelines (see the Applicability section (f) of 87 Fed. Reg. 30806). Applicant is requested to return a copy of the attached Notice to Comply with the response.
The disclosure is objected to because of the following informalities: The drawings at figures 10-11, 14, and 17-18 depict amino acid sequences that must be identified by a sequence identifier. Appropriate correction is required.
Applicant's assistance in identifying any other instances where the specification and/or figures disclose nucleotide/amino acid sequences within the sequence rules, is respectfully requested.
Claim Interpretation
The term ‘peptide(s)’ is given a limiting definition at lines 15-17 of page 11 of the specification which provides that a peptide is about 10-35 amino acids in length. The recited SARS-CoV-2 peptide(s) are being interpreted in accordance with the limiting definition from the specification.
An epitope as recited in instant claim 51 is interpreted to claim a sequence consisting of the one of the recited options because the recitation of an epitope recites that the epitope is selected from a closed group of sequences which invokes a Markush language interpretation (see MPEP §2117(I)).
Claim Objections
Claim 1 is objected to because of the following informalities: “one or more peptide” is grammatically incorrect and should read “one or more peptide(s)” or “one or more peptides” (see line 3 of claim 1).
Claim 2 is objected to because of the following informalities: “one or more peptide” is grammatically incorrect and should read “one or more peptide(s)” or “one or more peptides” (see line 1 of claim 2).
Claims 1, 6, 11, 26, and 51 are objected to because of the following informalities: the claims do not conform to standard Markush drafting. Redrafting the alternatives recited to be ‘from the group consisting of option a, option b,….and the final alternatively recited option’ is requested to promote clarity of the record. Standard Markush drafting language is exemplified in instant claims 8 and 17, for reference.
Claims 1-2, 6, and 11 are objected to because of the following informalities: the claims fail to provide a connecting term between the respectively recited tables. For example, claim 1 recites: “one or more peptide selected from SEQ ID NO:1-16 and Tables 1, 2, 6, 9-12 or a peptide having at least 90% sequence similarity to a peptide of SEQ ID NO:1-16 or in Tables 1, 2, 6, 9-12.” There is no connecting term between “Tables 1, 2, 6, 9-12 “ at either of the two places where this recitation occurs in the claim. Applicant should add an ‘and’ for grammatical accuracy in the Markush group.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 5-9, 11-14, 17, 21-22, and 25-26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B. V. v. Dianwnd Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. This is a written description rejection.
The instant Application only clearly discloses/teaches peptides having 100% identity/similarity to one of SEQ ID NOs: 1-16 or to the sequences of Table 1 (note that the other tables are illegible and/or do not clearly disclose any primary (sequential) structure). Therefore, in view of this disclosure, Applicant is claiming a broad genus of peptides (such as those with no disclosed structure or having 10% variation from SEQ ID NOs: 1-16 (Table 2) or from one or more of the sequences of Table 1) without a representative number of species of said genera or a clearly demonstrated structure/function correlation. The specification does not provide adequate written description for the entire claimed genera of species having at least 90% identity/similarity to the recited SEQ ID NOs or otherwise attempted to be disclosed (noting again, the illegibility of the filings (in this domestic case and its international counterparts and/or the failure to disclose any primary structure), because in the absence of empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically, which mutants/variants encompassed by the genus would function as claimed in the method(s).
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. Applicant has not clearly disclosed species other than those having 100% sequence identity to the enumerated sequences of Tables 1 and/or 2 for consideration. Thus, given the substantial structure variation within the genus of peptides as well as the high level of unpredictability in the art, the disclosure of the species of Tables 1 and 2 (having 100% identity to the disclosed sequences) is not sufficiently representative of the entire genus.
Although screening techniques can be used to isolate variant polypeptides/proteins/peptides that possess the ability to function as claimed, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the 'written description' requirement is broader than to merely explain how to 'make and use'; the applicant must also convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed.”
Applicant is further directed to In re Alonso (545 F.3d 1015 (Fed. Cir. 2008), which involved claims that were directed to methods of using antibodies wherein the court found that the claims lacked adequate written description for the recited genus of antibodies recited in the methods. (C) See p. 8, 3rd paragraph, where Applicant argues that the claims recite all essential features of the invention. Therefore, products used in methods are rightfully subject to the written description requirement.
Regarding the state of the art, Listov et al (Opportunities and challenges in design and optimization of protein function. Nat Rev Mol Cell Biol 25, 639–653 (2024)) teach that the primary amino acid sequence determines downstream structure (protein folding), which then determines function (presenting both the inverse folding problem and the inverse function problem (see for example Figure 1 and its caption; see also Mishra et al (Inaccurate secondary structure predictions often indicate protein fold switching. Protein Sci. 2019 Aug;28(8):1487-1493. doi: 10.1002/pro.3664. Epub 2019 Jun 17)). Expanding on these problems in proteomics, Reardon (Nature 635, 246-248 (2024)) explains that the goal of designing a protein with known and predictable function, binding partners, size, location, and other traits is, for the moment, a dream. Reardon teaches that further challenges in protein design include predicting how a protein, even if it binds to target, will function upon said binding. Reardon teaches that the primary structure (amino acid sequence) of a protein is critical to function, noting that even proteins of similar shape do not execute the same functions, while those with different shapes may carry out the same tasks. Reardon goes on to teach that it is not always apparent which parts of the primary sequence are important; a seemingly useless amino-acid chain on the side of an enzyme, for instance, might affect how tightly a protein can bind to other molecules or its ability to flip between conformational states. Moreover, Reardon explains that when researchers attempt to solve the structure of a protein experimentally, they often end up seeing only the most stable conformation, which is not necessarily the form the protein takes when it is active (see for example, pages, 246-247 of Reardon). Additionally, Miller et al (Front Immunol. 2022 Jun 17;13:904609. doi: 10.3389/fimmu.2022.904609) teach that viral surface proteins are typically the immunodominant antigens that are targeted for antibody-mediated neutralization by the humoral immune response by the host. These viral proteins present numerous surfaces known as epitopes which are recognized by antibodies that are generated by the host immune system to specifically bind to these virus epitopes via the antibody’s functional ‘paratope’ domain in an epitope-paratope interaction (EPI). EPIs are key aspects of the dynamic interplay between the virus and the host immune response to neutralize the virus. Epitopes on pathogenic surface proteins have varying levels of conformational, dynamic, and post-translational complexity, all of which can have significant effects on the binding, specificity and neutralization potential of an antibody targeting that epitope. Conformationally, epitopes range from relatively simple, in that they are comprised of a linear stretch of amino acids on a monomeric protein domain, to complex, in that they are discontinuous and sample distinct conformations in a monomeric or even multimeric (quaternary) assembly of protein domains on the viral surface. Additionally, epitopes on viral surface proteins are not static in time. Many undergo significant conformational changes, including rearrangement of entire protein domains across the various stages of the viral life cycle. Finally, post-translational modifications such as glycosylation of viral surface proteins can either mask the underlying protein epitope surface or be part of epitope surfaces that are targeted by host antibodies as epitope constituents. Therefore, the primary structure informs the complex interactions and secondary, tertiary, and quaternary features of the epitope such that a change in the primary sequence (a reading frame shift, mutation, truncation, etc.) could change the higher order structure of the epitope resulting in failure to elicit or bind antibody.
Therefore, the peptides comprising a sequence with 90% identity/similarity to the recited SEQ ID NOs (or to peptides with no clearly disclosed primary structure (such as the peptides of figures 5 and 9, for example)) are insufficiently described through a demonstrated correlation of a conserved/identifying structure with the claimed function(s) or through a representative number of species.
Furthermore, the prior art supports that epitope selection is a critical step in immunoassay design and that said selection is unpredictable. Proteintech (The importance of epitope selection in experimental design, Proteintech, obtained from: https://www.ptglab.com/news/blog/the-importance-of-epitope-selection-in-experimental-design/?srsltid=AfmBOophB0oOURPWVt8-Ev696rJUsE1_yPXsMEFvA57ECk6diMWAmt6D; accessed 02/10/2026) teaches that, when designing an experiment that uses antibodies, one often overlooked parameter is the exact binding site of your antibody on the protein of interest, also known as the epitope. An antibody’s primary role is to bind to a specific protein (also known as the antigen or immunogen) which in turn allows for the detection, neutralization, or modification of the protein’s activity. Carefully choosing your antibodies based on epitope binding site can greatly influence experimental outcomes, therapeutic strategies, and diagnostic accuracy (see for example, paragraph 1 of page 1-13). Additionally, Proteintech teaches that an epitope which functions in one assay method may fail in another) see for example, pages 1/13-2/13). The artisan is effectively invited to screen for epitopes which function in the assay method as claimed due to the absence of description which enables the artisan to readily envisage which members of the recited genus of epitopes would function as claimed.
Further still, the state of the art supports that truncation of SARS-CoV-2 epitopes is unpredictable. Pomplun et al (ACS Cent Sci. 2021 Jan 27;7(1):156-163. doi: 10.1021/acscentsci.0c01309) teach that, even once a consensus region of a SARS-CoV-2 spike protein is known, mutation in or around the consensus sequence, even where the sequence is only 4 amino acids, one of which is variable, the Kd (a measure of binding affinity, Kd stands for the dissociation constant (see for example, the abstract at page 156)) may be so altered as to totally abrogate binding (see for example, pages 157-158, focusing particularly at figure 2 and its caption).
Therefore, the claims fail to meet the written description requirement of 35 USC §112(a) as presently drafted.
35 USC § 112(b)
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.
Claims 1-2, 5-9, 11-14, 17, 21-22, 25-26, and 51 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 MPEP provides that "where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table 'is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.' Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993)" (MPEP 2173.05(s)). Claims 1-2, 5-9, 11-14, 17, 21-22, 25-26, and 51 all recite and reference back to some combination of tables 1-12, either explicitly or via dependency, of the specification. This is improper and the limitations should be added into the claims for clarity of the claim scope of record.
The scope of claim 17 is indefinite because the claim is presently drafted to depend from cancelled claim 16. The artisan cannot know what limitations claim 17 is intended to encompass or to incorporate by reference. Redrafting to indicate the dependence of claim 17 from a currently pending claim or to make claim 17 independent is recommended for clarity of the claim scope.
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.
Claim(s) 11-13 and 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cao et al (Cell. 2020 Jul 9;182(1):73-84.e16. doi: 10.1016/j.cell.2020.05.025. Epub 2020 May 18) in view of BXB (CN 111303254 A).
Regarding claim 11, Cao et al, working to detect and discover neutralizing antibodies against SARS-CoV-2, teach that convalescent patients’ plasma contains neutralizing antibodies [against SARS-CoV-2] produced by the adaptive immune response which can be used therapeutically (see for example, page 73 bridging 74). Cao et al teach that ELISA plates were coated with SARS-CoV-2 RBD or spike (S) protein at 0.01 mg/mL and 1 mg/mL in PBS at 4C overnight (said RBD/S protein(s) being antigenic epitopes reading on the instantly recited capture agent). 100 mL1mg/mL antibodies was added to each well. After a 2 h incubation at room temperature, plates were washed and incubated with 0.08 mg/mL goat anti-human IgG (H+L)/HRP (JACKSON) for 1 h incubation at room temperature. Chromogen solution was used as the substrate, and absorbance at 450nm was measured by a microplate reader (see for example, page e5; note that a double sandwich ELISA may also be used (see for example, the caption of Figure 6 at page 81).
While Cao et al teach a number of SARS-CoV-2 epitopes (RBDs and Spike (S) proteins; see for example, figure 6 at page 81), they do not explicitly teach the sequence of instantly elected peptide SEQ ID NO: 1.
However, BXB teach a SARS-CoV-2 antigen comprising SEQ ID NO: 9, which comprises a sequence with 100% similarity to instant SEQ ID NO: 1 (see for example, claim 1 and the alignment provided below).
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It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed to detect the presence of SARS-CoV-2 antibodies in a sample. Cao et al teach that the ELISA (singular or double sandwich method) can be successfully used to immobilize SARS-CoV-2 antigens/epitopes on the well bottoms of an ELISA plate such that antibodies (from sample) added to the plate bind the immobilized epitope(s)/antigen(s), said antibodies them being capable of being bound by a detection (goat anti-human IgG) antibody for detection of the anti-SARS-CoV-2 antibody that has bound the epitope(s)/antigens(s). Cao et al further teach that convalescent plasma is a biological sample known to contain ant-SARS-CoV2 antibodies, making the use of convalescent plasma obvious to use with a reasonable expectation of success of detecting anti-SARS-CoV-2 antibodies. Additionally, the peptide SARS-CoV-2 antigen of BXB would have been an obvious functional equivalent for immobilization to the ELISA well plate because BXB disclose that this is an antigen of SARS-CoV-2 to which anti-SARS-CoV-2 antibodies bind (see for example, claims 1-2 of BXB). It is prima facie obvious to swap one known equivalent for another to achieve the same purpose, here, to swap one known SARS-CoV-2 antigenic epitope for another (see MPEP sections 2143(I)(B) and 2144.06 (II)). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references prior to the effective filing date.
Regarding claim 12, as discussed above, Cao et al in view of BXB teach and make obvious the method of instant claim 11 wherein the SARS-CoV-2 antigen/epitope(s) of Cao et al are immobilized on the ELISA well plate, said antigen/epitope(s) of Cao et al being obvious functional equivalents for the SARS-CoV-2 antigenic epitope/peptide of BXB.
Regarding claim 13, as discussed above, Cao et al in view of BXB teach and make obvious the method of instant claim 11 wherein after a 2 h incubation at room temperature, plates were washed and incubated with 0.08 mg/mL goat anti-human IgG (H+L)/HRP (JACKSON) (as the secondary detection antibody) where chromogen solution was used as the substrate, and absorbance at 450nm was measured by a microplate reader (see for example, page e5; note that a double sandwich ELISA may also be used (see for example, the caption of Figure 6 at page 81).
Regarding claim 17, as discussed above, Cao et al in view of BXB teach and make obvious the method of instant claim 11 wherein after a 2 h incubation at room temperature, plates were washed and incubated with 0.08 mg/mL goat anti-human IgG (H+L)/HRP (JACKSON) (as the secondary detection antibody) where chromogen solution was used as the substrate, and absorbance at 450nm was measured by a microplate reader (see for example, page e5; note that a double sandwich ELISA may also be used (see for example, the caption of Figure 6 at page 81). The HRP conjugate on the goat anti-human IgG secondary detection antibody is deemed to read upon an enzymatic tag as recited in instant claim 17. It is noted that claim 17 is presently drafted to depend from cancelled claim 16. In an effort to advance prosecution, the Examiner is interpreting claim 17 to depend from claim 11.
Claim(s) 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cao et al and BXB, as applied to claims 11-13 and 17 above, in further view of BDB (CN111393532A).
Regarding claim 14, it is noted that Applicant did not provide an election for this second peptide. In an effort to advance prosecution, the Examiner selects a second peptide (spike (S) peptide so as to be inclusive/read upon a majority of the pending claims) from table 2 for examination purposes. As discussed above, Cao et al in view of BXB teach and make obvious the method of instant claim 11 using a SARS-CoV-2 peptide which comprises a sequence 100% identical to instant SEQ ID NO: 1, a membrane protein, and teaches the use of a spike protein in the ELISA assay method.
Cao et al in view of BXB do not explicitly teach the use of a spike protein comprising instant SEQ ID NO: 8.
However, BDB teach a dominant S protein epitope comprising SEQ ID NO: 5 which comprises a sequence that is 100% identical to instant SEQ ID NO: 8 (see for example, claim 1 and the alignment provided below).
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It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. . Cao et al teach that the ELISA (singular or double sandwich method) can be successfully used to immobilize SARS-CoV-2 antigens/epitopes on the well bottoms of an ELISA plate such that antibodies added to the plate bind the immobilized epitope(s)/antigen(s), said antibodies them being capable of being bound by a detection (goat anti-human IgG) antibody for detection. Of the antibody that has bound the epitope(s)/antigens(s). Cao et al further teach that convalescent plasma is a biological sample known to contain ant-SARS-CoV2 antibodies, making the use of convalescent plasma obvious to use with a reasonable expectation of success of detecting anti-SARS-CoV-2 antibodies. Additionally, the peptide SARS-CoV-2 antigen of BXB would have been an obvious functional equivalent for immobilization to the ELISA well plate because BXB disclose that this is an antigen of SARS-CoV-2 to which anti-SARS-CoV-2 antibodies bind (see for example, claims 1-2 of BXB). It is further obvious, where Cao et al teach a combination of SARS-CoV-2 epitopes for use in the ELISA assay (see for example, figure 6 and its caption at page 81) to use a second epitope, such as an S protein (as taught by Cao et al), where the S peptide of BDB is an obvious functional equivalent of the more generically disclosed S proteins of Cao et al. It is prima facie obvious to swap one known equivalent for another to achieve the same purpose, here, to swap one known SARS-CoV-2 antigenic epitope for another (see MPEP sections 2143(I)(B) and 2144.06 (II)). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references prior to the effective filing date.
Claim(s) 21-22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cao et al and BXB, as applied to claims 11-13 and 17 above, in further view of Madiyal et al (J Clin Diagn Res. 2016 Nov;10(11):DC22-DC25. doi: 10.7860/JCDR/2016/24108.8921. Epub 2016 Nov 1).
Regarding claim 21, as discussed above, Cao et al in view of BXB teach and make obvious the method of instant claims 1 and 11 using ELISA, the method being high-throughput (see for example, the title of Cao et al).
Cao et al in view of BXB do not explicitly teach the use of CMIA or CLIA.
However, Madiyal et al, looking to compare the performance of Enzyme Linked Immunosorbent Assay (ELISA) and Chemiluminescence Immunoassay (CLIA) for detecting antibodies against hepatitis B, teach that ELISA and CLIA are two frequently employed tests for quantification of anti-viral antibodies. Quantitative ELISA is a direct, antibody sandwich enzyme assay which utilizes native viral antigenic epitopes as solid phase and also horseradish peroxidase (HRP) labelled antibodies as a conjugate, with the underlying principle being a calorimetric method. CLIA on the other hand, utilizes recombinant viral antigenic epitope coated paramagnetic micro particles that bind to anti-viral antibodies in serum and acridinium labelled antigen coated particles as conjugates. Antibody concentration is determined by the light emitted on antigen-antibody reaction and measured using Relative Light Units (RLU). Where the only limitation is that the assay is a CLIA assay, the prior art assay is presumed to be a high-throughput assay as instantly claimed.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as to detect anti-SARS-CoV-2 antibodies because Madiyal et al teach that both ELISA and CLIA are commonly used in the art to detect anti-viral antibodies where CLIA has the advantage of being automated test with low turnaround time and that both CLIA and ELISA can be reliably used in place of each other for detection of anti-viral antibodies (see for example, page 22 and the conclusion at page 24). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 22, as discussed above, the combined references make obvious the method of instant claim 21, where Cao et al in view of BXB and BDB further make obvious the method using a membrane protein comprising a sequence identical to instant SEQ ID NO: 1 (see for example, SEQ ID NO: 9 of BXB and the rejection of instant claim 5 above) and a spike protein comprising a sequence identical to instant SEQ ID NO: 8 (see for example, SEQ ID NO: 5 of BDB and the rejection of instant claim 5 above).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed to detect the presence of SARS-CoV-2 antibodies in a sample. Cao et al teach that the ELISA (singular or double sandwich method) can be successfully used to immobilize SARS-CoV-2 antigens/epitopes on the well bottoms of an ELISA plate such that antibodies added to the plate bind the immobilized epitope(s)/antigen(s), said antibodies them being capable of being bound by a detection (goat anti-human IgG) antibody for detection. Of the antibody that has bound the epitope(s)/antigens(s). Cao et al further teach that convalescent plasma is a biological sample known to contain ant-SARS-CoV2 antibodies, making the use of convalescent plasma obvious to use with a reasonable expectation of success of detecting anti-SARS-CoV-2 antibodies. Additionally, the peptide SARS-CoV-2 antigen of BXB would have been an obvious functional equivalent for immobilization to the ELISA well plate because BXB disclose that this is an antigen of SARS-CoV-2 to which anti-SARS-CoV-2 antibodies bind (see for example, claims 1-2 of BXB). It is further obvious, where Cao et al teach a combination of SARS-CoV-2 epitopes for use in the ELISA assay (see for example, figure 6 and its caption at page 81) to use a second epitope, such as an S protein (as taught by Cao et al), where the S peptide of BDB is an obvious functional equivalent of the more generically disclosed S proteins of Cao et al. It is prima facie obvious to swap one known equivalent for another to achieve the same purpose, here, to swap one known SARS-CoV-2 antigenic epitope for another (see MPEP sections 2143(I)(B) and 2144.06 (II)). The artisan would have understood that ELISA and CLIA are both well-known immunoassay formats which may be equivalently used (swapped as equivalent assays; (see MPEP sections 2143(I)(B) and 2144.06 (II)) for the shared purpose of detecting anti-viral antibodies, with CLIA being cheaper and faster to perform as taught by Madiyal et al. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references prior to the effective filing date.
Claim(s) 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cao et al, BXB, BDB and Madiyal et al, as applied to claims 21-22 above, in further view of Burbelo et al (medRxiv [Preprint]. 2020 Apr 24:2020.04.20.20071423. doi: 10.1101/2020.04.20.20071423).
Regarding claim 25, as discussed above, Cao et al in view of BXB, BDB, and Madiyal et al teach and make obvious the method of instant claim 22. It is noted that the active steps and reagents required by claim 25 are not different and that the only recitation of claim 35 beyond the recitation of claim 22 is that the detection of peptide to (clearly meaning an antibody against; see pages 10-11 of the instant specification) membrane protein can distinguish between a subject having had SARS-CoV-2 and a subject vaccinated (understood to mean a subject exclusively vaccinated (not having experienced SARS-CoV-2 infection) as this is what is disclosed and enabled in the specification with Figure 8 c being exemplary). The Examiner is examining the recitation as an active step of distinguishing (not merely as a passive result which can be obtained, as presently drafted) in an effort to advance compact prosecution.
The combined references do not explicitly teach that the detection of peptide to membrane protein can distinguish between a subject having had SARS-CoV-2 and a subject vaccinated.
However, Burbelo et al teach that antibodies to the nucleocapsid protein are the most sensitive target for serologic diagnosis of infection with SARS-CoV-1. Antibodies against the spike protein of SARS-CoV-1 are the target of neutralizing antibody and vaccine development. Recently, several groups have reported serological diagnostic tests using the nucleocapsid and/or spike protein from SARS-CoV-2 by ELISA, immunofluorescence and even a lateral flow test. One study that used ELISA to measure only antibodies to the nucleocapsid protein found that patients become seropositive 10–18 days after the onset of symptoms (see for example page 4 bridging page 5).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to perform the assay of instant claim 22 for reasons noted in the rejection of instant claim 22 above. The only addition over claim 22 by claim 25 is that detection of peptide to (antibody against) membrane protein can distinguish between convalescent subjects and exclusively vaccinated subjects. The artisan would have found it obvious to assay for nucleocapsid and/or membrane proteins of SARS-CoV-2 to distinguish between convalescent and exclusively vaccinated subjects because Burbelo et al teach that vaccines utilize S proteins (where logically antibodies produced thereto would be anti-S-protein antibodies, not ant-Nucleocapsid-protein or anti-Membrane-protein antibodies because the exclusively vaccinated subject would be expected to be naïve to those proteins, unlike the convalescent subject). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references prior to the effective filing date.
Conclusion
No claim is allowed.
Notice:
Cao et al (Cell. 2020 Jul 9;182(1):73-84.e16. doi: 10.1016/j.cell.2020.05.025. Epub 2020 May 18) working to detect and discover neutralizing antibodies against SARS-CoV-2, teach that convalescent patients’ plasma contains neutralizing antibodies [against SARS-CoV-2] produced by the adaptive immune response which can be used therapeutically (see for example, page 73 bridging 74). Cao et al teach that ELISA plates were coated with SARS-CoV-2 RBD or spike (S) protein at 0.01 mg/mL and 1 mg/mL in PBS at 4C overnight (said RBD/S protein(s) being antigenic epitopes reading on the instantly recited capture agent). 100 mL1mg/mL antibodies was added to each well. After a 2 h incubation at room temperature, plates were washed and incubated with 0.08 mg/mL goat anti-human IgG (H+L)/HRP (JACKSON) for 1 h incubation at room temperature. Chromogen solution was used as the substrate, and absorbance at 450nm was measured by a microplate reader (see for example, page e5; note that a double sandwich ELISA may also be used (see for example, the caption of Figure 6 at page 81).
While Cao et al teach a number of SARS-CoV-2 epitopes (RBDs and Spike (S) proteins; see for example, figure 6 at page 81), they do not explicitly teach the sequence of elected peptide SEQ ID NO: 1.
However, BXB (CN 111303254 A) teach a SARS-CoV-2 antigen comprising SEQ ID NO: 9, which comprises a sequence with 100% similarity to instant SEQ ID NO: 1 (see for example, claim 1 and the alignment provided below).
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However, as noted in the claim interpretation section above, Applicant’s limiting definition of a peptide (being about 10-35 amino acids in length) precludes the epitopes of Cao et al and BXB from serving as prior art because Cao et al and BXB teach significantly longer sequences with no motivation or reasonable expectation of success to truncate or otherwise arrive at a peptide consisting of a sequence having 100% similarity to the instantly claimed SEQ ID NOs 1-16 (seen at Table 2).
Regarding the state of the art, Listov et al (Opportunities and challenges in design and optimization of protein function. Nat Rev Mol Cell Biol 25, 639–653 (2024)) teach that the primary amino acid sequence determines downstream structure (protein folding), which then determines function (presenting both the inverse folding problem and the inverse function problem (see for example Figure 1 and its caption; see also Mishra et al (Inaccurate secondary structure predictions often indicate protein fold switching. Protein Sci. 2019 Aug;28(8):1487-1493. doi: 10.1002/pro.3664. Epub 2019 Jun 17)). Expanding on these problems in proteomics, Reardon (Nature 635, 246-248 (2024)) explains that the goal of designing a protein with known and predictable function, binding partners, size, location, and other traits is, for the moment, a dream. Reardon teaches that further challenges in protein design include predicting how a protein, even if it binds to target, will function upon said binding. Reardon teaches that the primary structure (amino acid sequence) of a protein is critical to function, noting that even proteins of similar shape do not execute the same functions, while those with different shapes may carry out the same tasks. Reardon goes on to teach that it is not always apparent which parts of the primary sequence are important; a seemingly useless amino-acid chain on the side of an enzyme, for instance, might affect how tightly a protein can bind to other molecules or its ability to flip between conformational states. Moreover, Reardon explains that when researchers attempt to solve the structure of a protein experimentally, they often end up seeing only the most stable conformation, which is not necessarily the form the protein takes when it is active (see for example, pages, 246-247 of Reardon). Additionally, Miller et al (Front Immunol. 2022 Jun 17;13:904609. doi: 10.3389/fimmu.2022.904609) teach that viral surface proteins are typically the immunodominant antigens that are targeted for antibody-mediated neutralization by the humoral immune response by the host. These viral proteins present numerous surfaces known as epitopes which are recognized by antibodies that are generated by the host immune system to specifically bind to these virus epitopes via the antibody’s functional ‘paratope’ domain in an epitope-paratope interaction (EPI). EPIs are key aspects of the dynamic interplay between the virus and the host immune response to neutralize the virus. Epitopes on pathogenic surface proteins have varying levels of conformational, dynamic, and post-translational complexity, all of which can have significant effects on the binding, specificity and neutralization potential of an antibody targeting that epitope. Conformationally, epitopes range from relatively simple, in that they are comprised of a linear stretch of amino acids on a monomeric protein domain, to complex, in that they are discontinuous and sample distinct conformations in a monomeric or even multimeric (quaternary) assembly of protein domains on the viral surface. Additionally, epitopes on viral surface proteins are not static in time. Many undergo significant conformational changes, including rearrangement of entire protein domains across the various stages of the viral life cycle. Finally, post-translational modifications such as glycosylation of viral surface proteins can either mask the underlying protein epitope surface or be part of epitope surfaces that are targeted by host antibodies as epitope constituents. Therefore, the primary structure informs the complex interactions and secondary, tertiary, and quaternary features of the epitope such that a change in the primary sequence (a reading frame shift, mutation, truncation, etc.) could change the higher order structure of the epitope resulting in failure to elicit or bind antibody.
Therefore, the peptides comprising a sequences with 90% identity/similarity to the recited SEQ ID NOs (or to peptides with no clearly disclosed primary structure (such as the peptides of figures 5 and 9, for example)) are insufficiently described through a demonstrated correlation of a conserved/identifying structure with the claimed function(s) or through a representative number of species.
Furthermore, the prior art supports that epitope selection is a critical step in immunoassay design and that said selection is unpredictable. Proteintech (The importance of epitope selection in experimental design, Proteintech, obtained from: https://www.ptglab.com/news/blog/the-importance-of-epitope-selection-in-experimental-design/?srsltid=AfmBOophB0oOURPWVt8-Ev696rJUsE1_yPXsMEFvA57ECk6diMWAmt6D; accessed 02/10/2026) teaches that, when designing an experiment that uses antibodies, one often overlooked parameter is the exact binding site of your antibody on the protein of interest, also known as the epitope. An antibody’s primary role is to bind to a specific protein (also known as the antigen or immunogen) which in turn allows for the detection, neutralization, or modification of the protein’s activity. Carefully choosing your antibodies based on epitope binding site can greatly influence experimental outcomes, therapeutic strategies, and diagnostic accuracy (see for example, paragraph 1 of page 1-13). Additionally, Proteintech teaches that an epitope which functions in one assay method may fail in another) see for example, pages 1/13-2/13). The artisan is effectively invited to screen for epitopes which function in the assay method as claimed due to the absence of description which enables the artisan to readily envisage which members of the recited genus of epitopes would function as claimed.
Further still, the state of the art supports that truncation of SARS-CoV-2 epitopes is unpredictable. Miller et al (Front Immunol. 2022 Jun 17;13:904609. doi: 10.3389/fimmu.2022.904609) teach that epitopes on viral surface antigens have several layers of complexity in epitope-paratope interactions owing to 1) the quaternary assembly and higher-order structure of protein domains on the viral surface, 2) protein glycosylation including at clustered sites (that lead to predominance of non-self surface glycans such as high-mannose type structures), and 3) large conformational transitions of the surface proteins owing to their role in both receptor binding and membrane fusion during various stages of maturation in the viral infection cycle (see for example, page 9 bridging page 10). Additionally, Pomplun et al (ACS Cent Sci. 2021 Jan 27;7(1):156-163. doi: 10.1021/acscentsci.0c01309) teach that, even once a consensus region of a SARS-CoV-2 spike protein is known, mutation in or around the consensus sequence (even where the sequence is only 4 amino acids, one of which is variable, the Kd (a measure of binding affinity, Kd stands for the dissociation constant (see for example, the abstract at page 156)) may be so altered as to totally abrogate binding (see for example, pages 157-158, focusing particularly at figure 2 and its caption).
There is nothing in the prior art that guides that artisan to use a peptide consisting of a sequence having 100% similarity to SEQ ID NOs: 1-16 in an assay to screen for/detect antibodies against SARS-CoV2 with a reasonable expectation of success without the benefit of hindsight reasoning to guide selection (see for example MPEP §2144.08(II)(e)).
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Chen et al (Ther Clin Risk Manag. 2018 Jun 11;14:1091-1097. doi: 10.2147/TCRM.S159227) teach that, for CLIA with immobilized antigen on a well plate, serum was obtained from all patients. Serum anti-MP antibody was detected by a PA assay using Serodia-MYCO II (Fuji Rebio Ltd., Tokyo, Japan) according to the manufacturer’s instructions. Serum IgG- and IgM-specific anti-MP antibodies were determined using MP IgG and IgM ELISA kits (Savyon Diagnostics, Ashdod, Israel) following the manufacturer’s instructions. Briefly, serum was diluted (1:200) and incubated on a plate coated with MP antigens. The optical density was detected by a TECAN-sunrise microplate reader and converted to an antibody value using a standard curve. Serum IgG- and IgM-specific anti-MP antibodies were also performed using the MP IgG and IgM CLIA kits (YHLO Biotech, Shenzhen, China) according to the manufacturer’s instructions on a YHLO iFlash 3000 CLIA analyzer. Briefly, 50 μL calibrators/serum samples and 50 μL horseradish peroxidase enzyme–labeled triiodothyronine analog were added into the wells of the coated plate and incubated at 37°C for 45 min. All unbound components were aspirated by the washer and washed 5 times using washing buffer. After an enzymatic reaction, the light emitted from the chemiluminescent reaction was measured by the chemiluminescence microplate reader and was proportional to the free triiodothyronine content in each well.
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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