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 .
Preliminary Amendment and Status of the Claims
The preliminary amendment filed 01/27/2026, in which claim 2 was amended, claims 4, 7, 11-15, 18, 20, 22, 26-27, 30, 32-34, 42-43, 46, 49-51, 54, 56-60, and 64-67 are canceled, is acknowledged and has been entered.
Claims 1-3, 6, 8-10, 16-17, 19, 21, 23-25, 28-29, 31, 35-41, 44-45, 47-48, 52-53, 55, 61-63 and 68-71 are pending.
Election Restrictions
Applicant’s election of without traverse of Group I, claims 1-3, 6, 8-10, 16-17, 19, 21, 23-25, 28-29, 31, 35-41 drawn to a modified SARS-CoV-2 spike polypeptide, in the reply filed on 01/27/2026 is acknowledged. Further, Applicant’s election with traverse of the following species in the reply filed on 01/27/2026 is acknowledged:
Species Election:
Claim 2:
Applicants elect:
Options recited in claim 2, alternative feature 1, list 1: "the carboxy-terminal residue of
the upstream portion is immediately upstream of an amino acid corresponding to any one of Pro681, Ser680, Asn679, Thr678, Gln677, and Thr676 (...) of the full-length wild- type SARS-CoV-2 spike protein amino acid sequence set forth in SEQ ID NO:1"
In response, Applicants elect "Ser680" - i.e., the carboxy-terminal residue of the upstream portion is immediately upstream of an amino acid corresponding to
Ser680
Options recited in claim 2, alternative feature 1, list 2: "the amino-terminal residue of the downstream portion is immediately downstream of an amino acid corresponding to any one of Ser686, Val687, Ala688, Ser689, Gln690 and Ser691 of the full-length wild- type SARS-CoV-2 spike protein amino acid sequence set forth in SEQ ID NO:1"
In response, Applicants elect "Gln690" - i.e., the amino-terminal residue of the
downstream portion is immediately downstream of an amino acid corresponding
to Gln690
Options recited in claim 2, alternative feature 2, list 1: "the carboxy-terminal residue of
the upstream portion is immediately downstream of an amino acid corresponding to any one of Gln675, Thr676, Gln677, Thr678, Asn679, and Ser680 (...) of the full-length
wild-type SARS-CoV-2 spike protein amino acid sequence set forth in SEQ ID NO:1"
In response, Applicants elect "Thr678" - i.e., the carboxy-terminal residue of the upstream portion is immediately downstream of an amino acid corresponding to
Thr678
Options recited in claim 2, alternative feature 2, list 2: "the amino-terminal residue of the downstream portion is immediately upstream of an amino acid corresponding to any one of Ser691, Gln690, Ser689, Ala688, Val687, and Ser686 of the full-length wild- type SARS-CoV-2 spike protein amino acid sequence set forth in SEQ ID NO:1"
In response, Applicants submit that this species election is rendered moot by the instant amendment to claim 2.
EXAMINER NOTE: As written, both species for Options recited in claim 2, alternative feature 2, list 1: and Options recited in claim 2, alternative feature 2, list 2: as written are rendered moot by the amendment to instant claim 2.
Claim 3:
Asn679 for the carboxy-terminal residue of the upstream portion
Ser691 for the amino-terminal residue of the downstream portion
Claim 6:
Pro681 and Ala684 for the deleted amino acid residues
Claim 23:
(a-b-c-d-e-f-g-)n as a repeated 7- residue pattern of amino acid types
Claims 44-45, 47-48, 52-53, 55, 61-63 and 68-71 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim.
The traversal is on the grounds that “to the extent that the Restriction Requirement states that the pending claims do not make a contribution over the prior art, Applicants disagree” (pg. 9) and that “additional species could be searched without an undue burden” (pg. 11). This is not found persuasive because Applicant has not explained the reason of disagreement nor how the instant claims make a contribution over the prior art, and because as explained previously, under PCT Rule 13.2, sequences encoding different proteins are structurally distinct chemical compounds and are unrelated to one another. These sequences are thus deemed to constitute independent and distinct inventions within the meaning of 35 U.S.C. § 121.
Examiner Note: search burden is not a consideration for lack of unity.
Claims 1-3, 6, 8-10, 16-17, 19, 21, 23-25, 28-29, 31, 35-41 are under consideration.
Priority
Applicant’s claim for foreign priority of prior-filed application No. AU2020903050 filed on 08/26/2020 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS), submitted on 06/27/2024, 10/29/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings were received on 02/24/2023. The drawings are objected to because the labels should read “FIG.” instead of “FIGURE”. Further, the resolution on Figures 1A, 1C, 1D, 1F-H; 9 is too low, it is recommended that larger graphs be presented.
Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). 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.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code, for example on page 32. Applicant is required to delete the embedded hyperlink and/or other form 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.
The use of the term “Tween 80” on page 61, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Note that “Tween 80” is merely an example and all improper uses of trademarks in the specification should be identified by Applicant and properly addressed.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/patents-application- process/filing-online/legal-framework-efs-web), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is defective because the size of the ASCII text file is in kilobytes instead of bytes.
Required response - Applicant must:
• Provide a substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Claim Objections
Claims 1 and 38 are objected to because of the following informalities:
Claim 1: For improved clarity, change “at the location” to “at the location corresponding to the furin cleavage site of the wild-type SARS-CoV-2 spike protein”.
Claim 38: Remove the comma between “polypeptide” and “as defined”.
Appropriate correction is required.
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 1-3, 6, 8-10, 16-17, 19, 21, 23-25, 28-29, 31, 35-41 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.
Claims 1-3, 6, 29, 31: Claims 1-3, 6, 29, and 31 have one or more instances where some form of the word corresponds (e.g., corresponds, corresponding) is recited. The specification defines “corresponds to” or “corresponding to” as a nucleic acid sequence or an amino acid sequence that displays substantial sequence similarity or identity to a reference nucleic acid sequence or amino acid sequence, respectively (p. 15, [0073]). However, “substantial sequence similarity or identity” still suggests some degree of ambiguity.
For example, in claim 2, change “the carboxy-terminal residue of the upstream portion is immediately upstream of an amino acid corresponding to any one of…” to “the carboxy-terminal residue of the upstream portion is immediately upstream of any one of Pro681, Ser680…”. For another example, in claim 3, change “…wherein the carboxy-terminal residue of the upstream portion corresponds to an amino acid residue selected from…” to “…wherein the carboxy-terminal residue of the upstream portion is an amino acid residue selected from…”.
Claim 1: Without any identifying amino acid sequence reference for the furin cleavage site of the wild-type SARS-CoV-2 spike protein, e.g., amino acid residual positions 680-689 (S1/S2) region, it is unclear what is meant by an “absence of a furin cleavage site”. It is unclear if “absence” refers to a deletion of all amino acids that surround a cleavage site, such as the highly conserved region; a specific motif and the actual cleavage site; or amino acids, followed by a SARS-COV-2 motif and the actual cleavage site between two amino acids or something else.
Interestingly, as evidenced by Xing et al. (Xing)(as cited in the IDS submitted 06/24/2024)(p. 2, Figure 1) who defines the site as amino acid residual positions AA680-689 or Johnson et al. (Johnson)(See PTO-892 Notice of References Cited) who defines the site as amino acid residual positions AA680-685 (p. 25, Figure 1), and also acknowledging Coutard et al. (as annotated in the specification on p. 18 as a reference for a SARS-CoV-2 furin cleavage site; and as cited on the IDS submitted 10/29/2024), there appears to be variability in the art as to what the metes and bounds of the “furin cleavage site” are, with many providing additional amino acids, the motif (SPRRAR), and the actual cleavage site (between two amino acids such as SPRRAR|S) in their references to a “furin cleavage site”. Walls et al. (Walls)(See PTO-892 Notice of References Cited) teaches in Figure 1C. SARS-COV-2 S1/S2 furin cleavage site (p. 282). In fact, Whittaker et al. (Whittaker)(See PTO-892 Notice of References Cited) teaches “one feature of the S1–S2 junction for the SARS-CoV-2 spike from the original outbreak is the presence of a leading proline residue, which might have promoted furin cleavage. As new variants emerged, the leading proline was first replaced by a histidine in B.1.1.7 and now with an arginine in variants such as B.1.617 to turn the tri-basic PRRAR|S sequence to RRRAR|S, with these cleavage site changes occurring on the background of other genomic adaptations” (p. e488). Finally, and more recently, Zhang et al. (Zhang) described a second functional furin site in the SARS-CoV-2 spike protein (Title).
Additionally, the terminology “wild-type SARS-CoV-2 spike protein” is also unclear without a reference sequence, like for example, SEQ ID NO: 1, used in subsequent claims.
Finally, “heterologous flexible linker” is vague as to what it is. A heterologous polypeptide flexible linker is a clearer. As written, it is unclear how many and what amino acids make up the heterologous flexible linker.
Claim 2: It is unclear if the meaning of “immediately upstream…immediately downstream” is literally the next amino acid or interpreted as something else.
Claims 8 and 9: Claims 8 and 9, without more clarity on the cleavage site, it is unclear what constitutes either the “upstream and downstream portions” (as recited in claim 8) and the “first and second polypeptides” (as recited in claim 9).
Claim 21: The phrase “that associate with each other under conditions suitable for their association to…” is unclear. To overcome the rejection, change to “first heptad repeat (HR1) and second heptad repeat(HRS) regions that form an anti-parallel, two helix bundle”.
Claim 29: Claim 29 recites the limitation “SARS-CoV-2 ectodomain polypeptide”. There is insufficient antecedent basis for this limitation in the claim. A “SARS-CoV-2 ectodomain polypeptide” is not found in either claims 1 or 16.
Claim 31: Without a reference sequence, e.g., SEQ ID NO: 1, the recited position Gly1204 is unclear for the carboxy-terminal residue.
Claim Rejections – 35 USC § 101
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claim 41 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals – Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
See claim 41 as submitted 01/27/2026.
Claim 41 recites “A host cell that contains a nucleic acid construct as defined in claim 40” and “A host cell” reads on a human organism. To overcome this rejection, the claim should be amended to recite “An isolated host cell…”.
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, 10, 16-17, 19, 21, 23, 24, 25, 28, 35-41 are rejected under 35 U.S.C. 103 as being unpatentable over Chappell et al. (Chappell)(US20200040042A1)(See PTO-892 Notice of References Cited) in view of Graham et al. (Graham)(US20200061185A1)(See PTO-892 Notice of References Cites) and Walls et al. (Walls) (See PTO-892 Notice of References Cites)
See claims 1, 10, 16-17, 19, 21, 23, 24, 25, 28, 35-41 as submitted 01/27/2026.
Regarding claim 1, 10, 16-17, Chappell teaches a chimeric polypeptide comprising an enveloped virus fusion ectodomain polypeptide operably connected downstream to a heterologous, structure-stabilizing moiety comprising complementary first heptad repeat (HR1) and second heptad repeat (HR2) regions that associate with each other under conditions suitable for their association (e.g., in aqueous solution) to form an anti-parallel, two-helix bundle [0008]; wherein the ectodomain polypeptide corresponds to a Class I enveloped virus fusion protein ectodomain (reference claim 15); wherein the Class I fusion protein is one from a Class I enveloped fusion protein virus selected from orthomyxoviruses, paramyxoviruses, retroviruses, coronaviruses, filoviruses and arenaviruses (reference claim 17). With respect to the ectodomain polypeptide, one or more endogenous proteolytic cleavage sites (e.g., one or more furin cleavage sites) of a wild-type or reference fusion protein may be altered or deleted to render the ectodomain polypeptide less susceptible to proteolytic cleavage by a protease (e.g., a cellular protease such as furin)[0129, reference claim 22]. Chappell also teaches, generally, typical (frequently used) amino acids in flexible linkers are serine and glycine. Less preferably, flexible linkers may also include alanine, threonine and proline. Thus, an intervening linker of the structure-stabilizing moiety is preferably flexible in conformation to ensure relaxed (unhindered) association of HR1 and HR2 as two-helix bundle that suitably adopts an α-helical coiled coil structure [0119]. Finally, Chappell teaches there is a pressing need for new approaches to produce stabilized recombinant fusion proteins that remain substantially in their pre-fusion form to stimulate more efficacious immune responses against enveloped viruses.
Regarding claim 19, Chappell teaches “In addition to its utility in stabilizing an ectodomain polypeptide of the invention against rearrangement to a post-fusion conformation, the structure-stabilizing moiety is useful as a universal oligomerization domain (UOD) for oligomerizing any heterologous molecules of interest into oligomers, particularly trimers. In specific embodiments, a UOD is fused upstream or downstream of a heterologous proteinaceous molecule to form a chimeric polypeptide. Typically, the UOD is fused downstream of the heterologous proteinaceous molecule. As with the ectodomain embodiments described herein, association of the complementary heptad repeats of the UOD to one another under conditions suitable for their association (e.g., in aqueous solution) results in formation of an anti-parallel, two-helix bundle that trimerizes to form a highly stable six-helix bundle, thus permitting trimerization of the chimeric polypeptide to form a trimeric polypeptide complex” (0304). The heterologous proteinaceous molecule may be a natural or non-natural polypeptide. In certain embodiments, the heterologous polypeptide is or comprises a therapeutic polypeptide. A vast variety of therapeutic polypeptides, including both ligands and receptors, are known in the art to be useful for treating a variety of diseases. Various examples of known targets and indications for therapeutic polypeptides are shown in Table 8 (0305).
Regarding claim 21, Chappell teaches reference claim 1, A chimeric polypeptide comprising an enveloped virus fusion ectodomain polypeptide operably connected downstream to a heterologous, structure-stabilizing moiety comprising complementary first heptad repeat (HR1) and second heptad repeat (HR2) regions that associate with each other under conditions suitable for their association (e.g., in aqueous solution) to form an anti-parallel, two-helix bundle.
Regarding claim 23, Chappell teaches reference claim 3, The chimeric polypeptide of claim 1 or claim 2, wherein each of the HR1 and HR2 regions is independently characterized by a n-times repeated 7-residue pattern of amino acid types, represented as (a-b-c-d-e-f-g-)n or (d-e-f-g-a-b-c-)n, wherein the pattern elements ‘a’ to ‘g’ denote conventional heptad positions at which the amino acid types are located and n is a number equal to or greater than 2, and at least 50% (or at least 51% to at least 99% and all integer percentages in between) of the conventional heptad positions ‘a’ and ‘d’ are occupied by hydrophobic amino acid types and at least 50% (or at least 51% to at least 99% and all integer percentages in between) of the conventional heptad positions ‘b’, ‘c’, ‘e’, ‘f’ and ‘g’ are occupied by hydrophilic amino acid types, the resulting distribution between hydrophobic and hydrophilic amino acid types enabling the identification of the heptad repeat regions.
Regarding claim 24, Chappell teaches reference claim 4, The chimeric polypeptide of any one of claims 1 to 3, wherein one or both of the HR1 and HR2 regions comprises, consists or consists essentially of an endogenous Class I enveloped virus fusion protein heptad repeat region amino acid sequence.
Regarding claim 25, Chappell teaches reference claim 5, The chimeric polypeptide of claim 4, wherein the HR1 and HR2 regions comprise, consist or consist essentially of complementary endogenous heptad repeat A (HRA) and heptad repeat B (HRB) regions, respectively, of one or more Class I enveloped virus fusion proteins.
Regarding claim 28, Chappell teaches reference claim 8, The chimeric polypeptide of any one of claims 1 to 7, wherein the HR1 and HR2 regions are independently selected from HRA and HRB regions of fusion proteins expressed by orthomyxoviruses, paramyxoviruses, retroviruses, coronaviruses, filoviruses and arenaviruses.
Regarding claim 35, Chappell teaches reference claim 9, The chimeric polypeptide of any one of claims 1 to 8, wherein the structure-stabilizing moiety (e.g., including one or both of HR1 and HR2 regions) comprises an immune-silencing moiety that inhibits elicitation of an immune response to the structure-stabilizing moiety.
Regarding claim 36, Chappell teaches reference claim 10, The chimeric polypeptide of claim 9, wherein immune-silencing moiety is a glycosylation site that is recognized and glycosylated by a glycosylation enzyme (e.g., a glycosyltransferase).
Regarding claims 37, 38, 39, 40, Chappell teaches reference claim 31. A nucleic acid construct that comprises a coding sequence for a chimeric polypeptide according to any one of claims 1 to 30, operably linked to a regulatory element that is operable in the host cell. Chappell also teaches RNA nucleic acid molecules in constructs [0066].
Regarding claim 41, Chappell teaches reference claim 32. A host cell that contains the nucleic acid construct of claim 31.
Chappell does not teach SARS-CoV-2 spike polypeptide nor teach a presence of a heterologous flexible linker at “the location” corresponding to the furin cleavage site of the wild type SARS-CoV-2 spike protein.
Regarding claim 1 and 10, Graham, however, teaches single chain CoV S ectodomain protomers can be generated by mutating the S1/S2 and S2′ protease cleavage sites to prevent cleavage and formation of distinct S1 and S2 polypeptide chains. In some embodiments, the S1 and S2 polypeptides in the single chain CoV S ectodomain protomers are joined by a linker, such as a peptide linker. Examples of peptide linkers that can be used include glycine, serine, and glycine-serine linkers. Any of the stabilizing mutations (or combinations thereof) disclosed herein can be included in the single chain coronavirus S ectodomain protomers as long as the coronavirus S ectodomain trimer composed of such protomers retains the desired properties (e.g., the prefusion conformation)[0229].
Graham does not teach a modified SARS-CoV-2 spike polypeptide.
Regarding claim 1, Walls teaches Sequence analysis of SARS-CoV-2 S reveals the presence of a four amino acid residue insertion at the boundary between the S1 and S2 subunits compared with SARS-CoV S and SARSr-CoV S (p. 284, Figure 1. C. ). To study the influence on pseudovirus entry of the SARS-CoV-2 S1/S2 furin cleavage site, Walls designed an S mutant lacking the four amino acid residue insertion and the furin cleavage site by mutating Q677TNSPRRARYSV687 (wild-type SARS-CoV-2 S) to Q677TILRYSV683 (SARS-CoV-2 Sfur/mut)(p. 284).
One of ordinary skill in the art would have been motivated to try to make a chimeric [modified] polypeptide comprising an enveloped virus fusion ectodomain polypeptide [coronavirus] with deleted furin-cleavage site as taught by Chappell, insertion of a GS linker as taught by Graham between the resulting first and second polypeptides separated with deletion of the furin cleavage site, and with the emergent coronavirus, SARS-CoV-2 spike protein in order to examine the spike protein as a potential immunogen, in a stabilized recombinant fusion protein construct that enables it to remain substantially in its pre-fusion form to stimulate more efficacious immune responses against enveloped viruses as taught by Chappell and especially in light of the COVID-19 pandemic and lack of prophylactic and treatment options early in the pandemic. As for deletion of the furin-cleavage site, one would have been motivated to delete it so that the ectodomain polypeptide is less susceptible to proteolytic cleavage by a protease such as furin (See MPEP 2143 Rationale A. Combining prior art elements according to known methods to yield predictable results; Rationale G. Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention).
One of ordinary skill in the art would have had a reasonable expectation of success for combining the teachings of Chappell, Graham and Walls to devise a modified SARS-CoV-2 spike polypeptide whose furin cleavage site has been replaced with a heterologous flexible linker. There would have been a reasonable expectation of success given the underlying materials and methods are known, successfully demonstrated in the context of coronaviruses, protein biochemistry and vaccinology, therapeutics and/or immunity principles, and commonly used as evidenced by the applied prior art.
Therefore the invention as a whole would have been prima facie obvious to one of
ordinary skill in the art before the effective filing date of the claimed invention.
Claims 8 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Chappell in view of Graham and Walls, as applied to claims 1, 10, 16-17, 19, 21, 23, 24, 25, 28, 35-41, and further in view of Qin et al. (Qin)(CN111088283-A)(See PTO-892 Notice of References Cited)
See claims 8 and 9 as submitted 01/27/2026.
Chappell, Graham and Walls teach claim 1 but do not teach the modified polypeptide of claim 1, wherein the upstream and downstream portions of the wild-type SARS-CoV-2 spike protein comprise an amino acid sequence having at least 75%, 76%, 77%, 78%, 79% 80%, 81%, 82%, 83%, 84%, 85%,86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence similarity or identity to the amino acid sequence set forth in SEQ ID NO:1 (as recited in claim 8) or the modified polypeptide of claim 1, wherein the first and second polypeptides of the modified polypeptide have at least 75%, 76%, 77%, 78%, 79% 80%,81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98% or 99% sequence similarity or identity to the amino acid sequence set forth in SEQ ID NO:1 (as recited in claim 9).
Qin, however, teaches a vaccine, comprising the mVSV viral vector, where a heterologous antigen gene of a target virus is integrated into the gene of the mVSV viral vector. The target virus is a novel corona pneumonia virus SARS-CoV-2 and the heterologous antigen gene is a SARS-CoV-2 spike protein S gene comprising a nucleotide sequence of SEQ ID NO: 1 (see BHT59642) which encodes a protein comprising an amino acid sequence of SEQ ID NO: 2 (see BHT59643). The viral vector and the vaccine have a better prevention or treatment effect on a person infected with the novel corona pneumonia virus. The reference SEQ ID NO: 2 has 99.6% identity to the amino acid sequence set forth in instant SEQ ID NO: 1 and 100% identity to the upstream/downstream portions and first/second polypeptides (See Result 20, BHT59643, us-18-023-136a-1_sub680_690_gsg.align45.rag, 04/30/2026, see supplementary contents tab).
One of ordinary skill in the art would have had a reasonable expectation of success for substituting the upstream/downstream or 1st and 2nd polypeptides as taught by Qin because they have a 100% match in identity to the instant application SEQ ID NO: 1 and as a result should not disrupt the goal of maintaining a pre-fusion conformation of the modified SARS-CoV-2 spike polypeptide (See MPEP 2143 Rationale B. Simple substitution of one known element for another to obtain predictable results).
One of ordinary skill in the art would have had a reasonable expectation of success for substituting the upstream/downstream or 1st and 2nd polypeptides as taught by Qin because they have a 100% match in identity to the instant application SEQ ID NO: 1. There would have been a reasonable expectation of success given the underlying materials and methods are known, successfully demonstrated in the context of molecular biology, and commonly used as evidenced by the applied prior art.
Therefore the invention as a whole would have been prima facie obvious to one of
ordinary skill in the art before the effective filing date of the claimed invention.
Claims 2, 3, and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Chappell in view of Graham and Walls, as applied to claims 1, 10, 16-17, 19, 21, 23, 24, 25, 28, 35-41, and further in view of Qin, Xing and Johnson.
See claims 2, 3 and 6 as submitted 01/27/2026.
Chappell, Graham and Walls teach claim 1 and altering the furin cleavage site but do not teach specific residues for altering the furin cleavage site.
Qin, however, teaches both the first and second polypeptides as well as Ser680, Gln690 (as recited in claim 2) as well as ASN679 and Ser691 (as recited in claim 3).
Xing defines the furin cleavage site as amino acid residual positions AA680-689 (p. 2, Figure 1) and Johnson defines the furin cleavage site as amino acid residual positions AA680-685 as well as the generation of a ΔPRRA mutant (e.g., Pro681 to Ala684)(p. 25, Figure 1).
One of ordinary skill in the art would have been motivated to make the deletions in and around the furin cleavage site, particularly in light of the teachings by Johnson and Xing, in order to make the modified SARS-CoV-2 spike polypeptide less susceptible to proteolytic cleavage by a protease such as furin (See MPEP 2143 Rationale A. Combining prior art elements according to known methods to yield predictable results; Rationale G. Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention).
One of ordinary skill in the art would have had a reasonable expectation of success for altering the furin cleavage site as taught by Qin, King, and especially Johnson. There would have been a reasonable expectation of success given the underlying materials and methods are known, successfully demonstrated in the context of coronaviruses, protein biochemistry and vaccinology, therapeutics and/or immunity principles, and commonly used as evidenced by the applied prior art.
Therefore the invention as a whole would have been prima facie obvious to one of
ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claims allowed.
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/C.C./Examiner, Art Unit 1672
/M FRANCO G SALVOZA/Primary Examiner, Art Unit 1672
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