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 .
Disposition of Claims
Claims 1-19 are pending and will be examined on their merits.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US 2023/0393135 A1, Published 07 December 2023.
Applicant is encouraged to utilize the new web-based Automated Interview Request (AIR) tool for submitting interview requests; more information can be found at https://www.uspto.gov/patent/laws-and-regulations/interview-practice.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The information disclosure statement filed on 20 April 2023 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered. Specifically, Non-Patent Literature Documents CC, CE, and CF (Abe et al., Bracken et al., and Hsieh et al.) are all very difficult to read. At times, the documents are barely or completely illegible.
The information disclosure statement (IDS) submitted on 20 April 2023 has been considered. Any individual references with strikethroughs, however, have not been considered unless they have been cited on the attached PTO-892 Form.
Drawings
The Drawings are objected to for referring to colors. Specifically, Figures 7-10 all refer to colors (i.e., red, blue) in the figure legends within the Specification. Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification: “The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.”
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
The objection to the drawings will not be held in abeyance.
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.
Specification; Sequence Disclosure Requirements
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 below or on the attached Notice To Comply With Requirements For Patent Applications Containing Nucleotide Sequence And/Or Amino Acid Sequence Disclosures.
The specification is objected to because the incorporation by reference statement was not updated for the amended Sequence Listing filed on 23 May 2023. Also, the “no new matter” statement for said amended Sequence Listing is missing. Additionally, the file size should be given in bytes, not kilobytes (see MPEP § 2413.04).
Furthermore, there are duplicate sequences present in the amended Sequence Listing filed on 23 May 2023. Specifically, the following pairs of sequence are 100% identical and the exact same length: instant SEQ ID NOs: 7 and 17; 8 and 18; 9 and 19; 10 and 20; and 23 and 24 (i.e., they are the exact same sequence). Please see the attached sequence alignments for reference. Each sequence identifier is meant for each unique sequence. Please remove the duplicate sequences from the Sequence Listing. Examiner also kindly requests that Applicant thoroughly review the Sequence Listing and remove all instances of duplicate sequences.
Applicants must comply with sequence rules in order to be considered a complete response to this Office Action.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claims 1-3, 7, 9, 13, and 15-18 are objected to because of the following informalities: In Claims 1 and 2, it is suggested that all instances of “virus neutralizing” be replaced with “virus-neutralizing”. The hyphen is missing.
In Claim 3, it is suggested that it say “a Rhabdovirus” instead of “a aRhabdovirus”.
In Claims 3 and 16, it is suggested that they say “an Asfivirus” instead of “a Asfarviridae” or “Asfarviridae”.
In Claims 7 and 18, it is suggested that they say “the cell receptor protein consisting of” instead of “the cell receptor protein consists of” in the “a)” option. Also, in the “a)” option, it is suggested that it say “SEQ ID NO: 2 or having at least” instead of “SEQ ID NO: 2 or has at least”.
In Claims 7 and 18, options “b)” through “m)”, it is suggested that all instances of “or at least 90% sequence identity thereto” be replaced with “or having at least 90% sequence identity thereto”.
In Claims 9 and 17, it is suggested that they say “SARS-CoV-2” instead of “SARS-CoV-2 virus”. The use of the word “virus” is redundant.
In Claim 15, it is suggested that it say “…entry of a virus into a cell susceptible to viral infection…” or “…entry of a virus into a cell susceptible to infection with said virus…” instead of “…entry of a virus into a cell susceptible to a virus infection…”.
In Claims 7, 13, and 18, as noted above, there are duplicate sequences present, namely instant SEQ ID NOs: 7 and 17; 8 and 18; 9 and 19; 10 and 20; and 23 and 24. These claims are objected to for reciting duplicate embodiments.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b); Second Paragraph
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.
Claim 15, and dependent claims 18-19 thereof, 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.
Regarding Claim 15, it recites the limitation “wherein the virus is an enveloped virus” in Line 3. The claim recites “a virus” twice in Line 2. As such, it is unclear which virus is being referenced for further limitation as each recitation of “a virus” could refer to a different virus. This lack of clarity renders the claim indefinite. It is suggested that the claim be amended to recite “… to block entry of an enveloped virus…” and all subsequence virus references be changed to “the virus”. However, Applicant is free to amend the claim as they deem necessary.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claim 15 is rejected on the grounds of being indefinite. Claims 18-19 are also rejected since they depend upon Claim 15, but do not remedy the deficiencies of Claim 15.
Claims 16-17 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.
Regarding Claims 16-17, they both recite “The method of claim 14”. Claim 14 is not a method claim, however. Claim 14 recites “The kit of claim 12”. As such, it is unclear which method they are referring to. This lack of clarity renders the claims indefinite. It is suggested that the claims be amended to be dependent upon Claim 15, which does recite a method and would provide proper antecedence, but Applicant is free to amend the claims as they deem necessary.
Additionally, Claims 16-17 recite the limitation “the virus” in Line 1 of each respective claim. There is insufficient antecedent basis for this limitation in the claims. Neither Claim 14, which Claims 16 and 17 both depend upon, nor Claim 12, which Claim 14 depends upon, recite the limitation of “a virus”. They recite “prefusion viral protein(s)”, which is not the same thing as “a virus”. This renders the claims indefinite. It is suggested that the claims be amended to be dependent upon Claim 15, which does recite “a virus” and would provide proper antecedence, but Applicant is free to amend the claims as they deem necessary.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claims 16-17 are rejected on the grounds of being indefinite.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
For the purposes of examining the claims on their merits, the “consists of”/“consisting of” language used in Claims 7-8, 10, 13-14, and 18-19 is being interpreted such that the claimed sequences are limited to the amino acids present. In other words, any prior art sequences must be 100% identical to the claimed sequence and have the exact same number of amino acid residues in order to meet those claim limitations. It should be noted, however, that this language is recited in the alternative, so that the prior art is not necessarily required to meet those claim limitations.
Additionally, Claims 16-17 will be interpreted as being dependent upon Claim 15.
Claim Rejections - 35 USC § 112(a); First Paragraph
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 7-8, 10, 13-14, 18-19 are 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 amino acid sequences which are 100% identical to the claimed sequences, namely SEQ ID NOs: 1-20, 22-24, and 26-36, does not reasonably provide enablement for variants of the claimed sequences with less than 100% sequence identity. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). See also MPEP § 2164.01(a) and § 2164.04. Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including: the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
Nature of the invention/Breadth of the claims. The claims are drawn to a method for quantifying virus-neutralizing antibodies in a biological sample of a subject, wherein the method comprises, in part, providing at least one prefusion viral protein stabilized in a prefusion conformation and that is reactive with virus-neutralizing antibodies, coupling said prefusion viral protein to at least one solid support, contacting said viral protein with a biological sample to provide a mixture, and contacting the mixture with one or more cell receptor proteins that bind to the at least one viral protein, wherein the prefusion viral proteins consist of or have at least 90% sequence identity to SEQ ID NOs: 1, 3, 5, 7, 9, 12, 14-15, 17, 19, 22, 24, 26, 28, or 30-36 and wherein the cell receptor proteins consist of or have at least 90% sequence identity to SEQ ID NOs: 2, 4, 6, 8, 10, 13, 16, 18, 20, 23, 27, or 29.
State of the prior art/Predictability of the art. The art teaches that protein chemistry is probably one of the most unpredictable areas of biotechnology. For example, replacement of a single “lysine” residue at position 118 of acidic fibroblast growth factor by “glutamic acid” led to the substantial loss of heparin binding, receptor binding and biological activity of the protein (Burgess et al., J of Cell Bio. 111:2129-2138, 1990). In transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen (Lazar et al. Molecular and Cellular Biology 8:1247-1252, 1988). As these references illustrate, it is unpredictable that a polypeptide variant of a known target protein binder will also bind said target. It is also unpredictable that they would bind said target in the same way, having the same effect on the target (i.e. inhibit or activate). Ju (Proceedings of the National Academy of Sciences, U.S.A., Vol. 88, Pg. 2658-2662, 1991) teaches that the interleukin 1 receptor (IL-1R) antagonist IL-1ra is a naturally occurring protein with no agonist activity in vitro or in vivo (Abstract). However, substitution of a single amino acid lysine145 to aspartic acid changes the property of this peptide to a partial agonist of IL-1R (Abstract). Thus, even a single substitution can change the biological property of a peptide.
This substitution need not be at a position where said residue would contact the target protein. Baker (Immunity, Vol. 13, Pg. 475-484, 2000) teaches that Tax-peptide is an agonist of the of T cell activity (Abstract). However, mutation of proline at position 6 of this peptide to alanine creates a T cell antagonist (Abstract). Importantly, this residue does not contact the T cell receptor (Abstract).
In another case, Huang (The Journal of Biological Chemistry, Vol. 272, No. 43, Pg. 27155-27159, 1997) teaches that conjugation of peptides to other proteins can change their biological properties. They teach that multiple conjugation of the peptide TGFβ1 (residues 41-65) to carrier proteins enhances its antagonist activity but also confers partial agonist activity as well (Abstract). Thus, the chemical context of a biologically active peptide is also important.
Truncation of proteins can also lead to adverse effects on protein structure and thus protein function. Martindale (Nature Genetics, Vol. 18, Pg. 150-154, 1998) teaches that truncation of huntingtin leads to aggregate development which compromises cell viability (Abstract). Nonaka (Human Molecular Genetics, Vol. 18, No. 18, Pg. 3353-3364, 2009) teaches that truncation of TDP-43 to its C-terminal fragments causes abnormally phosphorylated and ubiquitinated inclusions of the protein (Abstract). Taken together, not just any truncation of a protein will yield a soluble, functional, protein fragment.
In summary, these examples teach that the biological function of peptide variants is unpredictable because even a single mutation can abolish activity or give a different function. For example, agonist and antagonist peptides can be interconverted through conjugation or mutagenesis. Importantly, binding can still occur after mutation or conjugation in the literature examples provided above, illustrating that a simple show of binding is not predictive of the nature of a peptide’s biological activity. This point is underlined by Montrose-Rafizadeh (The Journal of Biological Chemistry, Vol. 272, Pg. 21201-21206, 1997) who teaches that receptor binding does not predict agonist or antagonist activity (Pg. 21205, Column 2, Paragraph, first full, Sentence, first). The prior art additionally teaches that antibody epitopes function as such based in large part on protein primary sequences. Polyak and Deans (Blood, Vol. 99, No. 9, Pg. 3256-3262, 2002) teach that mutation of an epitope can have serious consequences on antibody binding. They teach that the sequence AxP at positions 170-172 in human CD20 is critical to the secondary structure of an extracellular loop and its loss causes the loss of binding of three anti-CD20 monoclonal antibodies (Pg. 3261, Column 1, Paragraph, second full). Changes in antigen primary sequences can greatly affect secondary, tertiary, and even quaternary protein structure and in so doing, modify the ability of antibodies to recognize their epitopes. Munodzana et al. (Infection and Immunity, Vol. 66 No. 6, Pg. 2619-2624, 1998) teach that induction of immunity to Anaplasma marginale requires antibodies to conformationally dependent epitopes on the pathogen (Pg. 2622, Column 2, Paragraph, first partial). Epitope mapping on one of the pathogen surface proteins MSP5 revealed antibody dependence on two sets of amino acid sequences 1-91 and 125-161 (Pg. 2622, Column 2, Paragraph, first partial). A dependence on so many amino acids indicates heavy structural requirements for the antibody epitope. Importantly, the N-terminal amino acid sequences include conserved cysteines that participate in intramolecular disulfide bonds (Pg. 2622, Column 2, Paragraph, first partial). Loss of monoclonal antibody ANAF16C1 binding to MSP5 was found after disulfide bond reduction and covalent modification of the reduced sulfhydryl groups (Pg. 2622, Column 2, Paragraph, first partial).
Since the prior art teaches that it is unpredictable if variants of known prefusion viral proteins and cell receptor proteins will fold correctly and still properly interact with each other and that it is unpredictable if an antibody will bind any variant of the native proteins, and the specification does nothing to ameliorate these concerns, one would be burdened with undue experimentation to use the products of the instant claims as broadly as they are currently claimed.
Working examples. No working examples of the claimed variants are disclosed in the specification.
Guidance in the specification. The specification provides guidance towards constructs which are presumably 100% identical to the claimed sequences. The instant Specification, however, fails to disclose the critical or essential amino acid residues which must be present and also fails to disclose any variants of the claimed sequences. While the instant Specification does mention S proteins containing one or more substitutions or deletions (see Paragraphs 0032-0033 of the PGPub) and does mention, in very general terms, that some sequences can have substitutions, deletions, or insertions (see Paragraphs 0044, 0046) and that the prefusion viral proteins can have substitutions, deletions, or insertions (see Paragraphs 0076-0077), it fails to disclose which regions can tolerate such changes. The instant Specification even fails to state that said substitutions must be conservative substitutions.
Amount of experimentation necessary. Since the art teaches that it is unpredictable whether or not peptide variants of known sequences will function as intended, and the specification does nothing to ameliorate these concerns, one would be burdened with undue experimentation to carry out and/or use the methods and kits of the instant claims as broadly as they are currently claimed.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to carry out and/or use the claimed methods and/or kits.
Claims 7-8, 10, 13-14, 18-19 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 instant application attempts to ties function to sequence identity in the context of a method for quantifying virus-neutralizing antibodies in a biological sample of a subject, wherein the method comprises, in part, providing at least one prefusion viral protein stabilized in a prefusion conformation and that is reactive with virus-neutralizing antibodies, coupling said prefusion viral protein to at least one solid support, contacting said viral protein with a biological sample to provide a mixture, and contacting the mixture with one or more cell receptor proteins that bind to the at least one viral protein, wherein the prefusion viral proteins consist of or have at least 90% sequence identity to SEQ ID NOs: 1, 3, 5, 7, 9, 12, 14-15, 17, 19, 22, 24, 26, 28, or 30-36 and wherein the cell receptor proteins consist of or have at least 90% sequence identity to SEQ ID NOs: 2, 4, 6, 8, 10, 13, 16, 18, 20, 23, 27, or 29. While a percent identity threshold is provided in the claims for the claimed sequences, the instant Specification fails to disclose the critical or essential amino acid residues which must be present and that therefore cannot be changed. While the instant Specification does mention S proteins containing one or more substitutions or deletions (see Paragraphs 0032-0033 of the PGPub) and does mention, in very general terms, that some sequences can have substitutions, deletions, or insertions (see Paragraphs 0044, 0046) and that the prefusion viral proteins can have substitutions, deletions, or insertions (see Paragraphs 0076-0077), it fails to disclose which regions can tolerate such changes. The instant Specification even fails to state that said substitutions must be conservative substitutions. As such, it would be unclear to a person having ordinary skill in the art to know what to change and what not to change.
Furthermore, while it is not explicitly stated, it is assumed that the constructs shown in the data provided have sequences which are 100% identical to the claimed sequences. Even if that is not the case, the data shown do not explicitly include any claimed variants having as little as 90% sequence identity, or even 91-99% sequence identity, raising questions about how effective these claimed variants would be in the experiments performed. Thus, it is not clear what was tested, it does not appear that any claimed variants were tested, and the essential characteristics of the genera being claimed by Applicant have not been identified or disclosed. One way to obviate the instant Written Description rejection is for Applicant to show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that Applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPZ2d at 1613.
As such, it does not appear Applicant was in possession of the full scope of the claimed invention at the time of filing and thus Claims 7-8, 10, 13-14, 18-19 do not meet the written description requirement. It is suggested that the claims be amended to recite only proteins made and tested and shown to be functional in the claimed methods.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-6, 11-12, and 15-17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Abe et al. (Abe KT, Li Z, Samson R, Samavarchi-Tehrani P, Valcourt EJ, Wood H, Budylowski P, Dupuis AP 2nd, Girardin RC, Rathod B, Wang JH, Barrios-Rodiles M, Colwill K, McGeer AJ, Mubareka S, Gommerman JL, Durocher Y, Ostrowski M, McDonough KA, Drebot MA, Drews SJ, Rini JM, Gingras AC. A simple protein-based surrogate neutralization assay for SARS-CoV-2. JCI Insight. 2020 Oct 2;5(19):e142362.) (cited on IDS filed by Applicant on 20 April 2023).
Abe et al. teach a method for detecting and quantifying multiple virus-neutralizing antibodies against a virus in patient plasma or serum samples wherein the virus is SARS-CoV-2, wherein the viral protein, the spike protein, is stabilized in its prefusion form, attached to a solid support, contacted with the patient sample, and contacted with one or more cell receptor proteins, such as ACE2, or one or more competing antibodies (see Abstract; Page 2, Paragraphs 4-6; Page 3, Paragraph 1; Page 4, Last Paragraph; Page 8, Paragraph 2; Figures 1 and 3C-D and corresponding figure legends), which reads on instant Claims 1-3 and 11. Abe et al. also teach a multiplex method wherein the at least one prefusion viral protein is a multiplex of S proteins as a trimer stabilized in a prefusion conformation (see Page 2, Last Paragraph; Page 7, Last Paragraph; Page 8 Paragraphs 1-2; Page 10, Paragraphs 6 and 8; Figure 1B; Supplemental Figures 1-3), which reads on instant Claims 4-6.
Additionally, Abe et al. teach a kit comprising a prefusion viral protein stabilized in a prefusion conformation that is reactive with neutralizing antibodies, a cell receptor protein that binds to said prefusion viral protein, and instructions for use (see Page 2, Last Paragraph; Page 7, Last Paragraph; Page 8, Paragraphs 1-2; Page 10, Paragraphs 6 and 8; Figure 1; Supplemental Figures 1-3; Methods section), which reads on instant Claim 12. Neither the instant claims nor the instant Specification provide any structural limitations on the composition of the kit, such as the presence of the reagents in bottles or vials (see at least Paragraphs 0015-0018, 0170, 0178-0179). As such, Abe et al. teach the limitations of the instant kit because it discloses the same components and instructions for use (i.e., the Methods section).
Furthermore, Abe et al. teach a method for measuring the ability of an agent, such as an antibody, to block viral entry into a susceptible cell, wherein the virus is SARS-CoV-2, and wherein the viral protein is attached to a solid support, contacted with the patient sample, and measuring the binding of the cell receptor to the prefusion viral protein as means to indirectly determine the ability of the agent to inhibit entry of the virus into the cell (see Abstract; Page 2, Paragraphs 4-6; Page 3, Paragraph 1; Page 4, Last Paragraph; Figures 1 and 3B-D and corresponding figure legends), which reads on instant Claims 15-17. In the instant Specification, Applicant states that “the agent can be an inhibitor, a blocker, or an antagonist protein, e.g., an antibody or portion of the antibody…” (see Paragraph 0187) [emphasis added]. As such, the antibodies disclosed by Abe et al. are encompassed by Applicant’s own definition of “agent” and thus meet the limitations of said claims.
For at least these reasons, Abe et al. teach the limitations of instant Claims 1-6, 11-12, and 15-17 and anticipate the invention encompassed by said claims.
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.
Claims 1-19 are rejected under 35 U.S.C. 103 as being unpatentable over Abe et al. (Abe KT, Li Z, Samson R, Samavarchi-Tehrani P, Valcourt EJ, Wood H, Budylowski P, Dupuis AP 2nd, Girardin RC, Rathod B, Wang JH, Barrios-Rodiles M, Colwill K, McGeer AJ, Mubareka S, Gommerman JL, Durocher Y, Ostrowski M, McDonough KA, Drebot MA, Drews SJ, Rini JM, Gingras AC. A simple protein-based surrogate neutralization assay for SARS-CoV-2. JCI Insight. 2020 Oct 2;5(19):e142362.) (cited on IDS filed by Applicant on 20 April 2023), Yu et al. (US 2023/0364219 A1, earliest Priority Date 16 April 2020), and Wells et al. (US 2023/0176057 A1, earliest Priority Date 11 May 2020).
Abe et al. teach a method for detecting and quantifying multiple virus-neutralizing antibodies against a virus in patient plasma or serum samples wherein the virus is SARS-CoV-2, wherein the viral protein, the spike protein, is stabilized in its prefusion form, attached to a solid support, contacted with the patient sample, and contacted with one or more cell receptor proteins, such as ACE2, or one or more competing antibodies (see Abstract; Page 2, Paragraphs 4-6; Page 3, Paragraph 1; Page 4, Last Paragraph; Page 8, Paragraph 2; Figures 1 and 3C-D and corresponding figure legends) Abe et al. also teach a multiplex method wherein the at least one prefusion viral protein is a multiplex of S proteins as a trimer stabilized in a prefusion conformation (see Page 2, Last Paragraph; Page 7, Last Paragraph; Page 8 Paragraphs 1-2; Page 10, Paragraphs 6 and 8; Figure 1B; Supplemental Figures 1-3).
Additionally, Abe et al. teach a kit comprising a prefusion viral protein stabilized in a prefusion conformation that is reactive with neutralizing antibodies, a cell receptor protein that binds to said prefusion viral protein, and instructions for use (see Page 2, Last Paragraph; Page 7, Last Paragraph; Page 8, Paragraphs 1-2; Page 10, Paragraphs 6 and 8; Figure 1; Supplemental Figures 1-3; Methods section). Neither the instant claims nor the instant Specification provide any structural limitations on the composition of the kit, such as the presence of the reagents in bottles or vials (see at least Paragraphs 0015-0018, 0170, 0178-0179). As such, Abe et al. teach the limitations of the instant kit because it discloses the same components and instructions for use (i.e., the Methods section).
Furthermore, Abe et al. teach a method for measuring the ability of an agent, such as an antibody, to block viral entry into a susceptible cell, wherein the virus is SARS-CoV-2, and wherein the viral protein is attached to a solid support, contacted with the patient sample, and measuring the binding of the cell receptor to the prefusion viral protein as means to indirectly determine the ability of the agent to inhibit entry of the virus into the cell (see Abstract; Page 2, Paragraphs 4-6; Page 3, Paragraph 1; Page 4, Last Paragraph; Figures 1 and 3B-D and corresponding figure legends). In the instant Specification, Applicant states that “the agent can be an inhibitor, a blocker, or an antagonist protein, e.g., an antibody or portion of the antibody…” (see Paragraph 0187) [emphasis added]. As such, the antibodies disclosed by Abe et al. are encompassed by Applicant’s own definition of “agent” and thus meet the limitations of said claims, as well as a method wherein the virus is SARS-CoV-2, wherein the at least one prefusion viral protein is a SARS-CoV-2 protein, the cell receptor protein is ACE2, and the one or more competing antibodies bind to the prefusion SARS-CoV-2 protein (see Abstract; Page 2, Paragraphs 4-6; Page 3, Paragraph 1; Page 4, Last Paragraph; Figures 1 and 3C-D and corresponding figure legends).
Abe et al., however, do not teach a method wherein the cell receptor protein is an ACE2-Fc fusion protein or a method or kit wherein the prefusion viral proteins consist of or have at least 90% sequence identity to SEQ ID NOs: 1, 3, 5, 7, 9, 12, 14-15, 17, 19, 22, 24, 26, 28, or 30-36 and wherein the cell receptor proteins consist of or have at least 90% sequence identity to SEQ ID NOs: 2, 4, 6, 8, 10, 13, 16, 18, 20, 23, 27, or 29.
Wells et al. teach SEQ ID NO: 55, which is 886 amino acids long and 91.6% identical to instant SEQ ID NO: 2 (see Sequence Listing). Wells et al. also teach fusion proteins comprising the SARS-CoV-2 spike protein or the receptor thereof, such as ACE2 fused to a human IgG Fc region (see Paragraphs 0186-0187; Figures 1, 11; Table 3). SEQ ID NO: 55 corresponds to the ACE2-Fc-5aa-SmBiT fusion construct (see Figure 1; Table 3), which is a functional variant of the natural ACE2 protein and which was demonstrated to encode a fusion protein that can bind to different forms of the SARS-CoV-2 spike protein, such as the full-length Spike RBD domain, full-length Spike trimer, and Spike RBD-Fc fusion constructs (see Paragraphs 0018-0025, 0064; Figures 3-10).
Yu et al. teach SEQ ID NO: 223, which comprises a sequence that is 100% identical to instant SEQ ID NO: 1 (see Sequence Listing). SEQ ID NO: 223 corresponds to a functional variant of the SARS-CoV-2 spike protein, Spike_FL-2P SAM (pJW19), in which the protein has been stabilized in its prefusion conformation through the introduction of two proline mutations at residues 986 and 987 (see Paragraph 0332; Figure 1), and which was demonstrated to encode a protein which can still bind to human ACE2 (hACE2) (see Paragraphs 0385, 0416).
A person having ordinary skill in the art would have been motivated to modify the teachings of Abe et al. with those of Wells et al. and Yu et al. in order to develop a cell-free method and kit for quantitatively measuring the levels of neutralizing antibodies against SARS-CoV-2 in a sample. The spike protein disclosed by Yu et al. is stabilized through the use of proline substitutions at residues 986 and 987, which keeps the protein in its prefusion conformation and thus more effective in the method and kit taught by Abe et al. as the antibodies which tightly bind to the protein in this conformation would be more likely to inhibit and/or prevent entry of the virus into a cell, for example. The ACE2-fusion protein taught by Wells et al. can be used for the development of assays capable of screening reagents that inhibit binding of the SARS-CoV-2 spike protein to human ACE2. As such, it would have been obvious to use such a construct in the method and kit taught by Abe et al. to make the process more cost-effective and easier to run. The combination of these teachings renders the inventions encompassed by the instant claims obvious and thus render instant Claims 1-19 obvious over the prior art.
Such modifications, combining prior art elements according to known methods in order to yield predictable results, would have had a reasonable expectation of success and arrived at the claimed invention prior to the effective filing date of the instant application. For at least these reasons, instant Claims 1-19 are rejected under 35 U.S.C. 103 as being unpatentable over the prior art.
Conclusion
No claims are allowed.
The prior art made of record, but not relied upon, and considered pertinent to applicant's disclosure is listed below:
Chen et al. (US 2022/0002701 A1, earliest Priority Date 19 May 2020)
Chen et al. teach polypeptide monomers comprising an ACE2 ectodomain and an oligomerization domain and oligomeric complexes comprising said monomers for use in the diagnosis, prevention, and treatment of SARS-CoV-2 infection. This reference has not been utilized, as rejection would have been redundant to those set forth above.
Booth et al. (US 2024/0400618 A1, earliest Priority Date 17 August 2020)
Booth et al. teach SEQ ID NO: 83, which is 647 amino acids long and 95.0% identical to instant SEQ ID NO: 2. Booth et al. also teach fusion proteins comprising the SARS-CoV-2 spike protein or the receptor thereof, such as ACE2 fused to the mouse or human IgG Fc region. This reference has not been utilized, as rejection would have been redundant to those set forth above.
Kuo et al. (US 2021/0308257 A1, earliest Priority Date 01 March 2020)
Kuo et al. teach SEQ ID NO: 14, which is 100% identical to and the exact same length as instant SEQ ID NO: 1. This reference has not been utilized, as rejection would have been redundant to those set forth above.
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