DETAILED ACTION
Non-Final Rejection
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Applicant's election with traverse of Group I claims 1-3, 7, 8, 12, 19-24, 26, 27, 32, and 34,
in the reply filed on 04/09/2026 is acknowledged.
The traversal is on the ground(s) that:
Applicant notes that claim 34 is included in both Group I and Group IV (see page 5 of the Office Action). To the extent that claim 34 is not included in Group I, Applicant respectfully traverses the Requirement on the basis that, as the Office Action acknowledges, the invention of Group I is related to the invention of Group IV (as products and processes), and thus that search results relevant to examination of the product will be likely to be useful in examining use of the product. Accordingly, there would be no serious burden to examine claim 34 as well.
In error, the examiner has included claim 34 directed to a method in Group I. However, the claim 34 is correctly included in Group IV. Applicant has the right of rejoinder if the elected claims are allowable.
Applicant’s traversal is not found persuasive because (See, item (iii) page 3-4 of Restriction/Election office action mailed on 02/09/2026).
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Therefore, the claim 34 directed to a method will not be examined or grouped in Group I inventions. Applicant has the right of rejoinder if the elected claims are allowable.
Species election: Applicant elected without traverse, SEQ ID NO: 9 (ADSAKEEA).
Applicant has indicated that claims 8 and 12 read on the elected species and claims 1, 2, 19-24, 26, 27, 32, and 34 are generic to all species. Applicant argues that accordingly, claims 1, 2, 8, 12, 19-24, 26, 27, 32, and 34 should be examined on the merits.
The examiner agrees with the applicant except for claim 34, as recited above the claim 34 directed to a method will not be examined or grouped in Group I inventions. Applicant has the right of rejoinder if the elected claims are allowable.
The requirement is still deemed proper and is therefore made FINAL.
For compact prosecution, the sequence search was extended to other species of non-elected Markush listing of claimed SEQ ID NOs and search results were considered.
Status of Claims
3. Claims 1-3, 7-8, 12, 19-27, 32-34, 50 and 54 are pending.
4. Claims 33-34, 50 and 54 are withdrawn from examination being in non-elected groups of invention due to Restriction/Election.
5. Claims 1-3, 7, 8, 12, 19-24, 26, 27, and 32 (Group I) under examination.
Priority
6. This application claims the benefit of and priority to U.S. Provisional Application No. 63/403,935, filed on September 6, 2022.
Information Disclosure Statement
7. The two information disclosure statements (IDSs) submitted on 05/29/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
8. 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/PatentLegalFramework), 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 - This application contains sequence disclosures in accordance with 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 - 1.825.
The SEQ ID NO: 19 sequence disclosures are in Specification Table 1 para [0211] page number 70. However, the computer searchable sequence listing do not have sequence although the sequence listing populates SEQ ID NO: 19.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also 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;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.831(a) and 1.831(b). However, this application fails to comply with the requirements of 37 CFR 1.831-1.834. The examiner has noted that:
The SEQ ID NO: 19 sequence disclosures are in Specification Table 1 para [0211] page number 70. However, the computer searchable sequence listing do not have sequence although the sequence listing populates SEQ ID NO: 19.
Applicant must provide:
• A replacement “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2., as well as
• A statement that identifies the location of all additions, deletions, or replacements of sequence information in the “Sequence Listing XML” as required by 1.835(b)(3);
• A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.835(b)(4);
• A statement that the “Sequence Listing XML” includes no new matter in accordance with 1.835(b)(5); and
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(b)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Rejections - 35 USC § 101
9. 35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
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 26 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).
Claim 26 is rejected under 35 U.S.C. 101 and AIA § 33(a) as being directed to or encompassing a human organism. The claim read on cells found in intact mammals, including humans that receive nucleic acids encoding the claimed vectors. 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 e.g. specification para [0022], [0037], [0207] recites that “In various embodiments, the subject is a human”. Note “A cell” is not defined in the specification but reasonably may include a human under the broadest reasonable interpretation (BRI).
Examiner’s Note: To overcome the rejection, applicant may find if support is available in the specification to amend the instant claim 26 to recite “an isolated cell”.
Claim Rejections - 35 USC § 112
10. 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, 7 and 19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 2: The recombinant polynucleotide of claim 1, wherein the engineered spike protein or immunogenic fragment has a reduced effect on downregulation of surface expression of alpha 7 nicotinic acetylcholine receptor (a7nAChR) in host cells compared to a wild-type SARS- CoV-2 spike protein or has substantially no effect on alpha7nAChR surface expression in host cells.
The terms “a reduced effect” and “substantially no effect” in claim 2 are a relative terms which renders the claim indefinite. The terms “a reduced effect” and “substantially no effect” are 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 what % quantity for downregulation of surface expression of alpha 7 nicotinic acetylcholine receptor (a7nAChR) is defined or considered to comprise the terms “a reduced effect” and “substantially no effect” as compared to a wild-type SARS- CoV-2 spike protein.
Claims 3 and 19: The instant claim 3 recites amino acid mutation in the SARS CoV-2 protein at one or more positions (claim 3: L1145, F1148, and L1152) and for claim 19 comprises proline substitutions at amino acids K986 and V987 relative to the wild-type spike protein or orthologous sites in a variant thereof. The instant specification did not define wild type or variant strain of SARS-CoV-2 or did not recite a reference sequence. The wild type strain sequence may vary among different variant strains due to insertion or deletion in the sequence (amino acids encoded by codons) and therefore it is not clear whether the claimed amino acid substitutions will correspond to the intended positions in the wild type or variant sequence.
Claim Rejections - 35 USC § 112
11. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 7, 8, 12, 19-24, 26, 27, and 32 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.
This is a written description rejection.
The Instant claim 1 is directed to a recombinant polynucleotide comprising a nucleic acid sequence encoding an engineered SARS-CoV-2 spike protein (S 12) or an immunogenic (engineering can affect immunogenicity) fragment thereof, wherein the engineered spike protein or immunogenic fragment comprises one or more mutations in the S2 segment of the ectodomain. Under BRI an engineering of SARS-CoV-2 spike protein can comprise insertion, deletion or substitution of one or more amino acids at any position. The instant specification did not define the term “engineering” of SARS-CoV-2 spike protein. The claim has a functional limitation for the Spike protein to be immunogenic and the engineering of spike protein can adversely affect immunogenicity.
The instant claim 2 is dependent on claim and comprise a functional limitation a reduced effect on downregulation of surface expression of alpha-7 nicotinic acetylcholine receptor (a7nAChR) in host cells compared to a wild-type SARS- CoV-2 spike protein or has substantially no effect on alpha-7nAChR surface expression in host cells. Under BRI an engineering of SARS-CoV-2 spike protein can comprise insertion, deletion or substitution of one or more amino acids at any position. The instant specification did not define the term “engineering” of SARS-CoV-2 spike protein and therefore a functional limitation for the Spike protein regarding alpha-7nAChR surface expression in host cells may be adversely affected.
Claims 3 and 19: The instant claim 3 recites amino acid mutation in the SARS CoV-2 protein at one or more positions (claim 3: L1145, F1148, and L1152) and for claim 19 comprises proline substitutions at amino acids K986 and V987 relative to the wild-type spike protein or orthologous sites in a variant thereof. The instant specification did not define wild type or variant strain of SARS-CoV-2 or did not recite a reference sequence. The wild type strain sequence may vary among different variant strains due to insertion or deletion in the sequence (amino acids encoded by codons) and therefore it is not clear whether the claimed amino acid substitutions will correspond to the intended positions in the wild type or variant sequence. The claims inherit the functional limitations “immunogenic” from claim 1 and therefore it is not clear if the engineered claimed spike protein will have intended effect of immunogenicity.
The claimed “engineered SARS-CoV-2 spike protein encoding polynucleotide sequence” is a genus (instant claims 1-2). When a claim covers a genus of inventions, the specification must provide written description support for the entire scope of the genus. Support for a genus is generally found where the applicant has provided a number of examples sufficient so that one in the art would recognize from the specification the scope of what is being claimed. However, the presence of multiple species within a claimed genus does not necessarily demonstrate possession of the genus. See, In re Smyth, 178 U.S.P.Q. 279 at 284-85 (CCPA 1973) (stating “where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus or combination claimed at a later date in the prosecution of a patent application”); and University of California v. Eli Lilly and Co., 43 USPQ2d 1398, at 1405 (Fed Cir 1997)(citing Smyth for support). In the instant case, the specification does not provide adequate written description of of sufficient number of species of “engineered SARS-CoV-2 spike protein encoding polynucleotide sequence” that are reduced to the practice and thus there are no sufficient number of species disclosed as reduced to practice to achieve the claimed function to be “immunogenic” or reduced effect on downregulation of surface expression of alpha-7 nicotinic acetylcholine receptor (a7nAChR) in host cells compared to a wild-type SARS- CoV-2 spike protein or has substantially no effect on alpha-7nAChR surface expression in host cells. The applicable standard for the written description requirement can be found in MPEP§ 2163; University of California v. Eli Lilly, 43 USPQ2d 1398 at 1407; PTO Written Description Guidelines; Enzo Biochem Inc. v. Gen-Probe Inc., 63 USPQ2d 1609; Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111; and University of Rochester v. G.D. Searle & Co., 69 USPQ2d 1886 (CAFC 2004). To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
The instant claims 1-2 encompass a very large genus of “engineered SARS-CoV-2 spike protein encoding polynucleotide sequence”.
Amgen Inc. vs Sanofi (2017-1480, Fed Cir, 2017) states that "an adequate written description must contain enough information about the actual makeup of the claim products - a precise definition such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other material," which may be present in "function "terminology "when the art has established a correlation between structure and function" (page 17,1st paragraph).
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description” Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, Fri. January 5, 2001, see especially page 1106 column 3). In the instant case, the specification does not provide adequate written description of sufficient number of “engineered SARS-CoV-2 spike protein encoding polynucleotide sequence” that are reduced to the practice for achieving the function to be immunogenic or reduced effect on downregulation of surface expression of alpha-7 nicotinic acetylcholine receptor (a7nAChR) in host cells compared to a wild-type SARS- CoV-2 spike protein or has substantially no effect on alpha-7nAChR surface expression in host cells. The legal standard for sufficiency of a patent's (or a specification’s) written description is whether that description "reasonably conveys to the artisan that the inventor had possession at that time of the claimed subject matter", Vas-Cath, Inc. v. Mahurkar, 19 USPQ2d 1111 (Fed. Cir. 1991). In the instant case, the specification does not convey to the artisan that the applicant had possession at the time of invention of the claimed invention. The full breadth of the claims does not meet the written description provision of 35 U.S.C. 112, first paragraph.
Claim Interpretation
12. 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.
Claim 1: The instant claim 1 is interpreted to be directed to a recombinant polynucleotide comprising a nucleic acid sequence encoding (i) an engineered SARS-CoV-2 spike protein (S12) or (ii) an immunogenic fragment thereof, wherein the engineered spike protein or immunogenic fragment comprises one or more mutations in the S2 segment of the ectodomain.
The instant claim 1 is interpreted to be directed and also reads on an engineered SARS-CoV-2 spike protein that can comprise insertion, deletion or substitution of one or more amino acids at any position in the Spike protein. The claim also has a functional limitation to be immunogenic (reads on induction of immune response to develop vaccine or immunogen).
Claim 2: The recombinant polynucleotide of claim 1, wherein the engineered spike protein or immunogenic fragment has a reduced effect on downregulation of surface expression of a7 nicotinic acetylcholine receptor (a7nAChR) in host cells compared to a wild-type SARS- CoV-2 spike protein, or has substantially no effect on a7nAChR surface expression in host cells.
The instant claim 2 is interpreted to be directed to a functional limitation a reduced effect on downregulation of surface expression of a7 nicotinic acetylcholine receptor (a7nAChR) in host cells as compared to a wild-type SARS- CoV-2 spike protein. The claim is interpreted to be directed and also reads on an engineered SARS-CoV-2 spike protein that can comprise insertion, deletion or substitution of one or more amino acids at any position in the Spike protein.
Claim Rejections - 35 USC § 102
13. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claims 1 and 25: The instant claims 1 and 25 are anticipated by Magazine et al 2002 (Viruses 2022, 14, 640).
Magazine et al 2002 disclosed four mutations within the S2 region occur commonly in SARS-CoV-2 variant of concerns (VOCs) other than the recent Omicron strain T716I, D950N, S982A, and D1118H. Although, the mutations are naturally occurring, the mutations in S2 subunit of SARS-CoV-2 spike ectodomain are disclosed. Because the amino acid mutations are disclosed Magazine et al 2002 is in possession of the claimed polynucleotide sequence (See, Magazine et al 2002, Figure 6a and associated legends).
Claim Rejections - 35 USC § 103
14. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1 and 25: The disclosures of Magazine et al 2002 as recited supra are incorporated here in entirety to render obvious instant claims 1 and 25.
Claims 2, 19: The instant claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Magazine et al 2002 (Viruses 2022, 14, 640) as applied to claim 1 above, and further in view of Oliveira et al 2021 (Biophysical journal, 120(6), 983-993), Tanmay et al 2021 (Food and Chemical Toxicology, 152, 112184), Sullivan et al 2021 (US20210290756 A1, published 09/23/2021), and He et al 2021 (US20210139543A1, published 05/13/2021).
Claim 2: Magazine et al 2002 disclosed claim 1 as recited supra, however do not disclose added limitation of instant claim 2.
Oliveira et al 2021 teaches a potential interaction between the SARS-CoV-2 spike protein and nicotinic acetylcholine receptors. Oliveira et al 2021 disclosed that the SARS-CoV-2 spike protein may interact with nicotinic acetylcholine receptors (nAChRs) and that such interactions may be involved in pathology and infectivity. This hypothesis is based on the fact that the SARS-CoV-2 spike protein contains a sequence motif similar to known nAChR antagonists. Here, we use molecular simulations of validated atomically detailed structures of nAChRs and of the spike to investigate the possible binding of the Y674-R685 region of the spike to nAChRs. We examine the binding of the Y674-R685 loop to three nAChRs, namely the human α4β2 and α7 subtypes and the muscle-like αβγδ receptor from Tetronarce californica. Our results predict that Y674-R685 has affinity for nAChRs. The region of the spike responsible for binding contains a PRRA motif, a four-residue insertion not found in other SARS-like coronaviruses. The conformational behavior of the bound Y674-R685 is highly dependent on the receptor subtype; it adopts extended conformations in the α4β2 and α7 complexes but is more compact when bound to the muscle-like receptor. In the α4β2 and αβγδ complexes, the interaction of Y674-R685 with the receptors forces the loop C region to adopt an open conformation, similar to other known nAChR antagonists. In contrast, in the α7 complex, Y674-R685 penetrates deeply into the binding pocket in which it forms interactions with the residues lining the aromatic box, namely with TrpB, TyrC1, and TyrC2. Estimates of binding energy suggest that Y674-R685 forms stable complexes with all three nAChR subtypes. Analyses of simulations of the glycosylated spike show that the Y674-R685 region is accessible for binding. We suggest a potential binding orientation of the spike protein with nAChRs, in which they are in a nonparallel arrangement to one another. (See, abstract, entire article). Therefore, it would have been obvious to one of the ordinary skills in the art to consider teachings of Oliveira et al 2021 Tanmay et al 2021 to engineer SARS-CoV-2 spike protein encoding polynucleotide to reduce the interaction with alpha-7 nicotinic acetylcholine receptor on cells of the subject to reduce or substantially reduce the downregulation of surface expression of alpha 7 nicotinic acetylcholine receptor.
Tanmay et al 2021 questions is SARS-CoV-2 Spike glycoprotein impairing macrophage function via α7-nicotinic acetylcholine receptors? (See, entire article).
Claim 19: Magazine et al 2002 disclosed claim 1 as recited supra, however do not disclose added limitation of instant claim 19.
Sullivan et al 2021 is in the art and is directed to a coronavirus vaccine compositions and nucleic acid molecules encoding antigenic coronavirus proteins or fragments thereof. Further, Sullivan et al 2021 (see, para [0272]) teaches in one aspect, the second polynucleotide of nucleic acid molecules encodes a wild-type SARS-CoV-2 spike glycoprotein or a fragment thereof (SEQ ID NO: 123). In another aspect, the second polynucleotide of nucleic acid molecules encodes a SARS-CoV-2 spike protein comprising one or more mutations as compared to a wild-type SARS-CoV-2 spike glycoprotein sequence. In one aspect, a SARS-CoV-2 spike glycoprotein, or a fragment thereof encoded by transgenes of second polynucleotides included in nucleic acid molecules provided herein includes a K986P mutation, a V987P mutation, or any combination thereof.
He et al 2021 is in the art and teaches stabilized coronavirus spike (S) protein immunogens and related vaccines. He et al 2021 teaches K986P and V987P substitutions in SARS-CoV-2 spike protein (See, claim 3).
Claims 20-21: Sullivan et al 2021 teaches added limitation of instant claims 20 and 21, wherein the nucleic acid sequence comprises a ribonucleic acid (RNA) by disclosing design and expression of a SARS-CoV-2 vaccine in mRNA (See, para [0156], Figs 1A-1D) and “nucleic acid” refers to ribonucleic acid (RNA) molecule, or nucleic acid analogues. Exemplary nucleic acids include, but are not limited to mRNA, tRNA, rRNA, long non-coding RNA, siRNA, micro RNA (miRNA or miR), hnRNA, and viral RNA (See, para [0185]).
Claim 22. Sullivan et al 2021 teaches added limitation of instant claim 22, wherein the RNA is chemically modified with a pseudouridine by disclosing examples of modified or chemically modified nucleotides include 1-methyl-3-(3-amino-3-carboxypropy) pseudouridine (See, para [0225], and N1-alkylpseudouridines, N1-cycloalkylpseudouridines, N 1-hydroxypseudouridines, N 1-hydroxyalkylpseudouridines, N1-phenylpseudouridines (See, para [0229]).
Claim 23. Sullivan et al 2021 teaches added limitation of instant claim 23, wherein the mRNA includes one or more of a stem loop, a chain terminating nucleoside, a poly A sequence, a polyadenylation signal, and/or a 5' cap structure (See, para [[0045], [0046], [0193], claim 37).
Claim 24. Sullivan et al 2021 teaches added limitation of instant claim 24, wherein the engineered spike protein or immunogenic fragment thereof is encoded by a coding sequence, which is codon-optimized and/or the G/C content of which is increased compared to a wild type coding sequence by disclosing codon optimization of SARS-CoV-2 Spike antigenic protein encoding polynucleotide (see, para [0198], [0199] – [0202], [0195], [0008], claim 1).
He et al 2021 disclosed SARS-CoV-2 spike constructs codon-optimization for expression in mammalian cells (See, Example 10, para [0181]).
Claim 26. He et al 2021 taught added limitation of instant claim 26, a cell comprising the recombinant polynucleotide by disclosing the stabilized coronavirus soluble S immunogen proteins and the related vaccine compositions of the invention are typically produced by first generating expression constructs (i.e., expression vectors) and host cells for producing the vaccine immunogens e.g., HEK293E ExpiCHO, and CHO-S cell lines (See, para [0094]-[0095]-[100], [0181]).
Claims 27 and 32. Magazine et al 2002 disclosed claim 1 as recited supra however, do not disclose a vaccine or a pharmaceutical formulation.
He et al 2021 teaches added limitation of claims 27 and 32 by disclosing a vaccine (see, abstract, claims 14-22) and a pharmaceutical formulation (See, claim 24).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the prior art teachings of Magazine et al 2002 with additional teachings of Oliveira et al 2021, Tanmay et al 2021, Sullivan et al 2021 and He et al 2021 as recited supra to arrive at the invention of claims 1-3, 7, 19-24, 26, 27, and 32 to develop a composition comprising a recombinant polynucleotide encoding engineered SARS-CoV-2 Spike protein that is stabilized for a trimer structure, is immunogenic and reduce the interaction with alpha-7 nicotinic acetylcholine receptor on cells of the subject to reduce or substantially reduce the downregulation of surface expression of alpha 7 nicotinic acetylcholine receptor. The motivation would be to develop an improved and safer SARS-CoV-2 spike protein encoding polynucleotide composition (e.g. mRNA vaccine). One of the ordinary skills would have a reasonable expectation of success based on the applied prior arts teachings and motivation would be to achieve a commercial success. It is similar to 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. See, KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), examples of rationales, A-G.
Allowable Subject Matter
15. Claims 8 and 12: The sequences claimed in the instant claims 8 and 12 appears to be free of prior art of record.
Conclusion
16. No claim is allowed.
17. Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMADHAN J JADHAO whose telephone number is (703)756-1223. The examiner can normally be reached M-F 8:00-5:00.
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/SAMADHAN JAISING JADHAO/ Examiner, Art Unit 1672
/BENNETT M CELSA/ Primary Examiner , Art Unit 1600
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