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 .
This application has been transferred to Examiner Stacy Chen of Art Unit 1672. Please direct future correspondence accordingly.
Election/Restrictions
Applicant’s election without traverse of Group II, and the species of luciferase, immunoglobulin binding protein, and assay, in the reply filed on October 31, 2025 is acknowledged. Claims 1, 2, 4, 5, 11 and 29 are withdrawn from consideration being directed to non-elected subject matter.
Specification
The disclosure is objected to because of the following informality:
The disclosure contains embedded hyperlinks and/or other forms of browser-executable code. See at least pages 1, 2 and 63. The entire specification should be reviewed for any additional hyperlinks/codes. Applicant is required to delete the embedded hyperlinks and/or other forms of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. Appropriate correction is required.
Drawings
The drawings are objected to because Figure 20D and 21A contain amino acid or nucleic acid sequences without sequence identifiers.
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.
In lieu of filing replacement drawings, Applicant may amend the specification’s description of the figures to include the sequence identifiers.
Claims Summary
Claims 6-8, 10, 12, 13, 16-18, 20, 21, 23 and 24
Claim 16 is directed to a method for detecting a SARS-CoV-2 antigen-specific antibody in a biological fluid sample (e.g., blood (claim 17)). Please note that “SARS-CoV-2 antigen-specific antibody” is understood to mean an antibody that binds a SARS-CoV-2 antigen. The term “specific” does not impart any further meaning. The specification does not provide any further definition of these terms. Thus, the term does not preclude the antibody from binding to other antigens, but it at least binds a SARS-CoV-2 antigen. The method comprises:
Providing a fusion protein comprising a SARS-CoV-2 antigen fused to a light-emitting protein, Renilla luciferase (elected species, claims 18 and 20); the antigen is selected from SARS-CoV-2 proteins or active fragments thereof;
Contacting the biological fluid sample with the fusion protein, forming an immune complex if the antigen-specific antibody is present;
Contacting the immune complex with beads coated with an immunoglobulin-binding protein, Protein G (elected species, claim 21) to form bead-bound immune complexes; and
Detecting emission of light from the isolated bead-bound immune complexes, using a luminometer (claim 23), thereby detecting the presence of antigen-specific antibody in the biological fluid sample.
The detection of antibody to SARS-CoV-2 antigens of ORF8 and ORF3b in the sample indicates a COVID19 infection and generates diagnostic data distinguishing natural infection from vaccination (claim 24). The detection of SARS-CoV-2 antigen-specific antibody is conducted at an early timepoint prior to day 7 or day 14 since exposure/infection (claim 24). The biological fluid sample is from a child (claim 24).
The SARS-COV-2 antigens are selected from structural proteins, and nonstructural proteins (claim 6), with particular closed individual proteins or combinations of proteins being ORF8/ORF3b/N (claim 7), ORF8 (claim 8), ORF3b (claim 8), ORF8/ORF3b (claim 8), and ORF8/ORF3b/NSP1/ORF7a (claim 10). The SARS-CoV-2 antigens comprise at least one nucleic acid sequence selected from SEQ ID NO: 2, 3, 5-9, 11, 12, 14 and 15 (claim 12). The SARS-CoV-2 antigens comprise SEQ ID NO: 3 (sequence is 171 nucleotides, represents ORF3b), and/or SEQ ID NO: 6 (sequence is 366 nucleotides, represents ORF8).
Claim 27
Claim 27 is directed to several embodiments:
A method for detecting a subject who has a current exposure to or infection with SARS-CoV-2
A method for diagnosing a subject who has a current exposure to or infection with SARS-CoV-2
A method for treating a subject who has a current exposure to or infection with SARS-CoV-2
The methods comprise the step of contacting a biological sample of the subject with an immunogenic composition comprising one or more SARS-CoV-2 antigens selected from SARS-CoV-2 proteins or active fragments thereof, which are optionally fused to a light emitting protein, in a luciferase immunoprecipitation assay.
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.
Claims 6-8, 10-13, 16-18, 20, 21, 23, 24 and 27 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.
Claim 6 recites, “SARS-CoV-2 antigens”, which lacks antecedent basis in claim 16. Claim 16 recites “a SARS-CoV-2 antigen”. The reference to singular or plural should be consistent.
Claims 16 and 27 recite “SARS-CoV-2 proteins or active fragments thereof”. The specification does not appear to provide a definition of “active fragments”. It is not clear what activity is meant by “active”. The metes and bounds of the claims cannot be determined. Dependent claims 6-8, 10, 12, 13, 17, 18, 20, 21, 23 and 24 are included in this rejection.
Claim 24 is directed to an embodiment wherein the detection of antibodies to ORF8 and ORF3b “generates diagnostic data distinguishing natural infection from vaccination”. Based on paragraph [0281] of the published application (US20230174590A1), it appears that the detection of antibodies to ORF8 and ORF3b is itself the data that distinguishes between natural infection and vaccination. By using the term “generates”, it implies that further data is produced, however it is not clear how that would be the case. Clarification is required. It is suggested that the term “generates” be removed.
Claim 24 recites, “early timepoint prior to day 7 to day 14 since exposure/infection”. The term “early” is a relative term which renders the claim indefinite. The term “early” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is not clear whether “early” means a particular time prior to day 7 to day 14, or if “early” means any timepoint prior to day 7 to day 14 (i.e., day 0-13). If Applicant intends for the latter meaning, then Applicant is invited to state such on the record, and this aspect of the rejection will be withdrawn.
Claim 24 recites, “the biological fluid sample is from a child”. The specification does not appear to provide the metes and bounds of the ages for which an individual is considered a “child”.
Claim 27 is directed to a method of treating a subject who has a current exposure to or infection with SARS-CoV-2 comprising performing a luciferase immunoprecipitation system assay with a biological sample of the subject. It is not clear how treatment is effected without any treatment steps. The metes and bounds of the treatment cannot be determined.
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.
Claim 24 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of detecting SARS-CoV-2 antigen-specific antibody, does not reasonably provide enablement for the following:
A method wherein the detection of antibody to ORF8 and ORF3b indicates a current COVID 19 infection
A method wherein the detection of antibody to ORF8 and ORF3b distinguishes natural infection from vaccination
A method wherein detection is conducted prior to day 7 to day 14 since exposure or infection
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Addressing 1, the breadth of claim encompasses the detection of “a COVID 19 infection”, which means that the infection is present, as opposed to a past infection. The nature of the invention is that the presence of antibodies to SARS-CoV-2 ORF8 and ORF3b indicates that a subject has been infected with SARS-CoV-2. Since antibodies linger past acute infection, the detection of antibodies would not distinguish between an acute and a past infection. The specification, at paragraph [0014] of the published application notes that if the antibodies are detected, but not virus, the presence of antibodies may be due to a previous exposure or infection. The same paragraph indicates that if antibodies are detected and virus is detected, the subject may be currently exposed or infected. Thus, the specification itself speaks to the lack of predictability to detect a current infection with only the presence of antibodies.
Addressing 2, the breadth of the claim also encompasses the implication that the detection of antibody to SARS-CoV-2 ORF8 and ORF3b distinguishes between natural infection and vaccination. The nature of the invention is that the presence of antibodies to SARS-CoV-2 ORF8 and ORF3b indicates that a subject has been infected with SARS-CoV-2. According to the specification at paragraph [0284] of the published application, ORF8 and ORF3b are able to distinguish natural infection from vaccination because, firstly, ORF8 is a non-structural protein and would only be expected to be present during a natural infection, and secondly, ORF3b does not have much homology to other viral ORF3s, and is thus unique to SARS-CoV-2. With regard to ORF8, Applicant is presuming that a vaccine against SARS-CoV-2 will not include ORF8 because it is a non-structural protein. However, the claim does not define “vaccination” such that it excludes vaccination with constructs comprising ORF8. For example, if a subject is vaccinated with a SARS-CoV-2 whole virus (e.g., inactivated or attenuated), then ORF8 is available to be processed by the immune system and antibodies generated thereto. In that case, antibodies to ORF8 would not distinguish between a natural infection and vaccination. The same reasoning applies to ORF3b. Further, with regard to ORF3b, while paragraph [0284] indicates that the presence of antibodies to ORF3b would distinguish natural infection from vaccination because ORF3b is unique to SARS-CoV-2, this does not address how the presence of antibodies to ORF3b would distinguish between natural infection and vaccination. The presence of antibodies to ORF3b would only serve to confirm that the subject has been infected with SARS-CoV-2. Thus, there is a lack of predictability with regard to the presence of antibodies to ORF8 and ORF3b being able to distinguish between natural infection and vaccination.
Addressing 3, the breadth of the claim encompasses the ability to detect antibody to SARS-CoV-2 ORF8 and ORF3b prior to day 7 to day 14 since exposure/infection. The emphasis here is “day 7 to day 14 since exposure/infection”. In order to determine the time period of day 7 to day 14, one would need to know when the subject was exposed or infected, and begin counting days from the exposure or infection. This knowledge is not readily attainable since individuals would not know for certain when it was day 0. Exposure to SARS-CoV-2 and infection with SARS-CoV-2 usually happen without the individual’s knowledge. Unless an individual is isolated and then intentionally exposed or infected in a controlled environment, the identification of day 0 and thus days 7-14 cannot be determined. Applicant’s own work, Hachim et al. (Nature Immunology, October 2020, 21:1293-1301, cited in the IDS filed 5/8/2024) detects antibodies post-symptom onset (see page 1293, right column, last paragraph). The instant specification provides the same information in paragraph [0163] of the published application, for example. Thus, there is a lack of predictability with regard to the ability to conduct the method prior to day 7 to day 14 since exposure/infection.
In view of the breadth of the claim, the nature of the invention, the state of the art, the teachings and working examples of the specification, and the low level of predictability, it would require undue experimentation to practice the invention as claimed.
Claim 27 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of detecting a subject that has been infected with SARS-CoV-2, by detecting SARS-CoV-2 antigen-specific antibody to at least ORF8 and ORF3b, does not reasonably provide enablement for the following:
A method for detecting or diagnosing a subject who has a current exposure to or current infection with SARS-CoV-2
A method for detecting or diagnosing SARS-CoV-2 based on the presence of antibodies to any SARS-CoV-2 antigen
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Addressing 1, the breadth of the claim encompasses the implication that the presence of antibodies to SARS-CoV-2 indicates a current exposure to or a current infection with SARS-CoV-2. The nature of the invention is that the presence of antibodies to SARS-CoV-2 indicates that a subject has been infected with SARS-CoV-2. Since antibodies linger past acute infection, the detection of antibodies would not distinguish between an acute and a past infection. The specification, at paragraph [0014] of the published application notes that if the antibodies are detected, but not virus, the presence of antibodies may be due to a previous exposure or infection. The same paragraph indicates that if antibodies are detected and virus is detected, the subject may be currently exposed or infected. Thus, the specification itself speaks to the lack of predictability to detect a current infection with only the presence of antibodies.
Addressing 2, the breadth of the claim encompasses detecting or diagnosing SARS-CoV-2 based on the presence of antibodies to any SARS-CoV-2 antigen. The nature of the invention is that the presence of antibodies to certain SARS-CoV-2 antigen(s) is indicative of an individual having been infected with SARS-CoV-2. Applicant’s own work, Hachim et al. (Nature Immunology, October 2020, 21:1293-1301, cited in the IDS filed 5/8/2024) teaches that the detection of antibodies to both ORF3b and ORF8, is indicative of a subject having been infected with SARS-CoV-2, as opposed to S and N which exhibit cross reactivity with SARS-CoV (see page 1294, right column, first and second full paragraphs). The specification confirms these same results, see Figure 20, and paragraph [0273] of the published application. The specification and state of the art speak to the lack of predictability with regard to a definitive SARS-CoV-2 diagnosis based on the detection of antibody to any less than ORF8 and ORF3b.
In view of the breadth of the claim, the nature of the invention, the state of the art, the teachings and working examples in the specification, and the low level of predictability for detecting or diagnosing a current SARS-CoV-2 infection or exposure, it would require undue experimentation to practice the invention as claimed.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 6, 10, 16-18, 20, 21 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Burbelo (WO 2017/039967 A1, cited in the IDS filed 5/8/2024) in view of Wu et al. (Nature, March 12, 2020, 579(7798):265-269, cited in the IDS filed 5/8/2024, “Wu”). The claims are summarized above and correlated with the teachings of the prior art below in bold font. Claim 24 is rejected on the basis of its enabled embodiments.
Burbelo discloses a method for detecting antigen-specific antibodies in a biological fluid sample comprising the method steps of instant claims 16-18, 20, 21 and 23, including blood samples, among others, as well as the use of Renilla luciferase, Protein G and a luminometer (see Burbelo’s claims 1, 2, 5-7 and 14). Burbelo’s method uses a fusion protein comprising an antigen fused to a light-emitting protein, wherein the antigen is from a coronavirus, such as SARS (see page 23, line 10), among others. Burbelo does not disclose SARS-CoV-2 antigen, but generically suggests any viral pathogen protein (see pages 22-23). It would have been obvious to have applied Burbelo’s method to the detection of SARS-CoV-2. Wu discloses WHCV (SARS-CoV-2) as an emerging pathogen and outlines its genome in Figure 1 which includes ORF1a, ORF1b, S, ORF3a, ORF3b, E, M, ORF6, ORF7a, ORF7b, ORF8, N, ORF9a, ORF9b and ORF10. It would have been obvious to have used any of these proteins, such as ORF8 or ORF3b, or used structural or non-structural proteins, in the fusion protein construct of Burbelo (claims 6 and 16, addresses the aspect of SARS-CoV-2 proteins; claim 10, addresses the aspect of ORF8 or ORF3b). One would have been motivated to detect antibodies to those proteins, thus detecting antibodies that bind to the emerging pathogen. One would have had a reasonable expectation of success since Burbelo discloses that the fusion protein may be constructed from any viral pathogen protein and used for detection in the immunoassay (see page 18, lines 10-11, and page 22-23). Fusion protein include at least two different protein or peptides (page 8, lines 8-9), thus it would have been obvious to have included more than one of Wu’s proteins with a reasonable expectation of success (claim 6, addresses the aspect of more than one protein). One would have been motivated to include multiple proteins in order to increase the detection capability of the assay. Therefore, the claimed embodiments would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 12 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Burbelo (WO 2017/039967 A1, cited in the IDS filed 5/8/2024) in view of Wu et al. (Nature, March 12, 2020, 579(7798):265-269, cited in the IDS filed 5/8/2024, “Wu”) as applied to claim 16 above, and further in view of GenBank Accession No. MT299805 (Cloning vector pSF_lenti_SARS-CoV-2_partial-S/E/M/N, dated April 14, 2020, www.ncbi.nlm.nih.gov/nuccore/MT299805, accessed 12/4/2025).
Claims 12 and 13 are directed to embodiments wherein the sequences encoding the proteins are named, for example, SEQ ID NO: 3 and 6, representing ORF3b and ORF8. The teachings of Burbelo and Wu are outlined above. The sequences, SEQ ID NO: 3 and 6, are not taught in Wu, however, it would have been obvious to have used any SARS-CoV-2 sequence, with a reasonable expectation of success. GenBank Accession No. MT299805 represents a SARS-CoV-2 sequence, 13543 nt in length, for which nt 6301-6471 are identical to Applicant’s SEQ ID NO: 3, nt 1-171. In the same sequence, nt 8671-9036 are identical to Applicant’s SEQ ID NO: 6, nt 1-366. It would have been obvious to have used these sequences, in view of Wu’s disclosure of the various proteins of WHCV (SARS-CoV-2), in the method of Burbelo, with a reasonable expectation of success. Burbelo’s method is not limited to any particular sequences encoding the proteins.
Therefore, the claimed embodiments would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure.
The embodiment of claim 7, wherein the SARS-CoV-2 antigens are a closed combination of ORF8/ORF3b/N, is free of the prior art of record. While Wu et al. (Nature, March 12, 2020, 579(7798):265-269, cited in the IDS filed 5/8/2024) discloses these proteins, there is no teaching or fair suggestion to arrive at this particular combination in the context of the teachings of Burbelo (WO 2017/039967 A1, cited in the IDS filed 5/8/2024). The embodiment of claim 8, as it regards the closed combination of ORF8/ORF3b, and the embodiment of claim 10, directed to the closed combination of ORF8/ORF3b/NSP1/ORF7a, are also free of the prior art of record for the same reason.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to Stacy B. Chen whose telephone number is 571-272-0896. The examiner can normally be reached on M-F (7:00-4:30). If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Thomas Visone, can be reached on 571-270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
/STACY B CHEN/Primary Examiner, Art Unit 1672