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 .
Election/Restrictions
Claims 1-5, 7-11, 13-20, 22-24 and 74 are currently pending. Claims 6, 12, 21, 25-73 and 75-83 are canceled.
Applicant's election without traverse of Group II (claims 7-11, 13-20, 22 and 24) in the reply filed on 01/22/2026 is acknowledged.
Election of the following species on the reply filed on 01/22/2026 is acknowledged: (1) a highly networked coronavirus CTL epitope: LLYDANYFL (SEQ ID NO: 39) (elected claims 7, 10, 11) (2) a linker (3) a linker sequence: the alanine-alanine-tyrosine (AAY) linker (elected claim 19).
Applicant timely responded to the election requirement in the Paper filed January 22, 2026. Because Applicant did not distinctly and specifically point out the supposed errors in the examiner’s action, and further, did not specifically traverse the election requirement, the election was treated as an election without traverse (MPEP § 818.03(a)).
Claims 1-5, 23 and 74 have been withdrawn from consideration by the Examiner, pursuant to 37 CFR 1.142(b), as being drawn to non-elected inventions, there being no allowable generic or linking claim. Claims 17 and 20 have been withdrawn from consideration by the Examiner, as being drawn to non-elected species, pursuant to 37 CFR 1.142(b), as being drawn to non-elected inventions, there being no allowable generic or linking claim.
The requirement for restriction between Groups I-III is maintained for reasons of record and the foregoing commentary, and hereby made FINAL.
Claims that were drawn to a non-elected invention would have been withdrawn, as being directed to a non-elected invention. Reinstatement of claims drawn to non-elected inventions will be withdrawn during prosecution.
Therefore, claims 7-11, 13-16, 18-19, 22 and 24 have been considered on the merits.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2021/028245, filed April 20, 2021.
Applicant’s claim for the benefit of a prior-filed parent provisional application 63/125,114, filed on 12/14/2020, 63/019,293 filed 05/02/2020 and 63/012,565 filed on 04/20/202 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is April 20, 2020.
Claims 8, 10 and 11 recite Seq ID NO: 39 (LLYDANYFL). Neither Seq ID NO: 39 nor the peptide sequence “LLYDANYFL” are recited in the provisional priority documents (claims, specification, drawings, sequence files) for application 63/012,565 filed on 04/20/2020.
Support for the peptide sequence “LLYDANYFL” (Seq ID NO: 39) is not found in provisional priority documents (claims, specification, drawings, sequence files) for application 63/019,293 filed 05/02/2020.
Support for the peptide sequence “LLYDANYFL” (Seq ID NO: 39) is found in claim 4 of provisional application 63/125,114, filed 12/14/2020.
Thus the earliest priority date given to the claim limitation of Seq ID NO: 39 (LLYDANYFL) is 12/14/2020.
Drawings
Regarding Figures 3, 7, 8, 9, 12: The drawings are objected to under 37 CFR 1.83(a) because they fail to show color as described in the specification (p 5 ¶1 e.g. “residues in blue”, p6 ¶2 e.g. “non-conservative mutations (N, dark blue)”, p7 ¶1 e.g. “4 variants (orange)”, p50 ¶2 e.g. “(>2; blue)”, p67 ¶1 e.g. “linker (blue)”.
Regarding figures 11 and 12: Replacement sheets for Figures 11 and 12 filed on 10/21/2025 which comprise sequence identifiers are acknowledged.
Regarding figures 2, 3, 4, 7, 8, 9, 10, 11 and 12: The drawings are objected to because the font not legible.
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 hyperlinks and/or other form of browser-executable code. 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.
Regarding hyperlinks: Embedded hyperlinks are found on pages 14 ¶2, 45 ¶3, 46 ¶3 and 54 ¶1 of the instant specification. Paragraph identifiers (¶) are approximate due to the absence of clear identifiers or indentations designating individual paragraphs.
Claim Objections
Claim 7 is objected to because of the following informalities: the claim recites the abbreviation “CTL”. When an abbreviation is first time introduced in a claim it should be accompanied by its full description.
Claim 8 improperly states their intended Markush groups; the proper format requires the use of the “selected from the group consisting of“ with the conjunction “and” before the final member of the group.
Claim 11 is objected to because the claim recites “at least one of the two or more highly networked coronavirus CTL epitopes are selected”. The grammar is incorrect. Amending the claim to recite “at least one of the two or more highly networked coronavirus CTL epitopes areselected” would overcome this objection.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 9 is 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.
Regarding claim 9: The claim recites a coronavirus epitope is a variant having at least about 65% homology to a highly networked coronavirus CTL epitope in Table 5. The claim analysis will discuss Seq ID NO: 39 (LLYDANYFL) as a representative sequence, however the analysis applies to all of the claimed sequences of claim 9.
Seq ID No: 39 of the instant disclosure comprises 9 amino acids. A variant having at least about 65% homology to Seq ID No: 39 means the claimed genus comprises all variants which differ from Seq ID NO: 39 (or other reference sequence) by up to ~35%. Thus the claimed sequences can vary from the reference epitope sequences of Table 5 by up to 35%, which for Seq ID N;: 39 is up to 3 residues, and those variable residues can be changed to any one of the 19 other amino acids, or comprise a deletion or insertion of up to three residues.
Teaching of the instant specification
Table 5 of the instant specification discloses ~110 amino acid sequences corresponding to epitopes of Coronavirus. The instant specification does not provide information or guidance on how one of ordinary skill in the art could change up to 35% of the amino acids of the reference sequences of Table 5 while preserving the structure and function of the claimed epitopes.
The state of the art
It is well known in the art that the effect of amino acid substitutions on protein activity is neither predictable nor well characterized for immunogenic epitopes. Ogishi et al (Frontiers in Immunology (2019)10:827;1-20) teach that Immunodominant T cell epitopes are the critical element of successful vaccines (Abstract). Ogishi further teach single amino acid mutations can affect peptide immunogenicity bidirectionally- conferring either acquisition or loss of immunogenicity (p7 col1 ¶2). Ogishi teach that models of epitope immunogenicity may be suboptimal because only a small fraction is experimentally covered and ideally T cell-based assays of identical readouts for all candidate epitopes and their single amino acid variants would be used for defining a universal scale of T cell reactivity (p15 col1 ¶2).
Thus, while epitope variants are known in the art, the effect of changes of even a single amino acid in an epitope sequence is specific to the residue(s) in question and small changes can have large effects on epitope function/immunogenicity.
Therefore the effect of changes of up to 35% of the amino acid residues comprising an immunogenic epitope as claimed must be experimentally tested using trial and error experimentation.
While epitope variants are known in the art, the species examples provided in the art are not of a large enough breadth to impart predictability on the broad genus as claimed.
Conclusion
As described supra, the instant specification provides general guidance on multiple epitopes- Table 5 lists ~110 predicted epitopes for Coronavirus.
However the species of epitopes disclosed in the instant specification are not sufficient to predict the broad genus of “having at least about 65% homology” with the disclosed sequences of Table 5.
Alberts et al (Molecular Biology of the Cell. 4th edition. New York: Garland Science;2002) teach that each of the 20 amino acids is chemically distinct and only a very small fraction of the vast set of conceivable polypeptide chains would adopt a single, stable three-dimensional conformation (p7 para 2-3). In the case of substitution of residues of an epitope for which function can require a specific structure, the effect of amino acid changes would have to be assessed by trial-and-error to determine the effect of specific residue changes.
Ogishi teach even a single point mutation of an immunogenic epitope can change immunogenicity of the epitope in unpredictable ways. Furthermore, one of ordinary skill in the art would understand that epitope function often requires secondary structure to promote binding. One of ordinary skill in the art would also understand that the effect of amino acid substitutions in the epitope sequences can have unpredictable effects on the encoded peptide structure and thus function.
Furthermore, the instant specification provides no guidance as how to avoid losing key structural or binding activity of epitopes with amino acid substitutions of up to ~35% residues and the art does not provide a remedy.
Thus while the instant disclosure complies with the written description requirement for the epitope sequences disclosed in Table 5, the broad genus of all epitopes having at least about 65% homology with the disclosed sequences of Table 5 is not supported in by the written description.
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 7-11, 13-16, 18-19, 22 and 24 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 7: The claim recites “a network score of at least about 3.0”. The instant specification is silent on an explicit definition of “a network score” and the claim does not indicate how one of ordinary skill in the art would determine a network score. Thus a network score is not interpreted as imposing or implying structure to the claimed vector.
Regarding claims 8-9 and 11: The claims refer to tables within the claims. Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993). See MPEP 2173.05(s).
Claims 8, 10, 11 use parentheses to comments on or qualify part of the sentences. It is unclear whether the limitations in parentheses are meant to be limitations in the claims or whether they are only suggestions/examples. As such, the metes and bounds of the claims cannot be determined.
Claim 13 recites the term “and/or” in line 2. It is unclear what the metes and bounds of this term, as “and” could be interpreted to include only an endoplasmic reticulum insertion signal sequence (ERISS), or all of the ERISS and PADRE, or, “or” would imply that the sequence types are in the alternative. Appropriate correction is required.
Claim 14 recites “up to 30 amino acids as delineated in NCBI sequence Accession#: NC_045512”. The specification does not provide any closed definition as to what is meant by “as delineated”. It is unclear if the phrase “as delineated” should be interpreted narrowly to encompass only amino acids that have a structure identical to NCBI sequence Accession#: NC_045512 or if the phrase should be interpreted broadly to encompass materials which have amino acids “similar” to NCBI sequence Accession#: NC_045512. The metes and bounds are not clearly set forth.
Claims 10, 15-16, 18-19 22 and 24 are indefinite insofar as they depend on claim 7.
The examiner notes that the term “Highly networked” is defined at paragraph [0035] of the published application.
Claim Rejections - 35 USC § 102
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)(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 7-11, 14, 17-18, 22 and 24 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Gaynor et al (US 2023/0083931 A1, earliest filing priority 3/20/2020 by provisional application 62/992,666).
Regarding claims 7- 11: Claim 7 recites “highly networked Coronavirus CTL epitopes”. The instant specification defines “highly networked” as “an epitope having a composite epitope network score of at least about 3.00” (p10).
The instant specification defines “about” as a quantity that varies by as much as 15% (p9). Thus the limitation “at least about 3.00” as recited in claim 7 is broadly interpreted as a score of 2.55 or greater. For claim 9, the limitation “having at least about 65% to about 99% homology” is broadly interpreted as having homology of 50-114% to the claimed CTL epitope.
The instant specification teaches the network score for a given epitope is determined by generating a network representing protein structure, and then calculating a set of parameters that generate a score for each amino acid residue with in the protein structure (p3). The network score is then generated for a plurality of epitopes as a weighted combination of the amino acid residues of the epitopes (p3).
The instant specification teaches the epitope network score is calculated from individual amino acid residues within and neighboring a CD8+ T cell epitope were combined and averaged based on their involvement as either an HLA anchor, TCR contact or peptide processing residues (p46).
Table 5 of the instant specification discloses epitopes that are considered to be highly networked (p14; p59). Therefore, the highly networked Coronavirus CTL epitopes are interpreted to be the epitopes disclosed by Table 5.
The claim is drawn to a vector. The instant specification defines the term vector as “a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked” (p9 ¶3).
The network score as disclosed by the instant claim is not considered to impose or imply structure on the claimed vector.
Claims 8, 10 and 11 recite “epitopes in Table 5 having an amino acid sequence of LLYDANYFL (Seq ID NO: 39)”, “epitope having an amino acid sequence of LLYDANYFL (Des ID NO: 39)”, and “epitopes… having an amino acid sequence of LLYDANYFL (Seq ID NO: 39)”. This is broadly interpreted as an epitope comprising two or more of the amino acid residues as disclosed by Seq ID NO: 39 (discussed below).
The claim language recited supra encompasses vectors which encode amino acids that comprise the full-length sequence of SEQ ID NO: 39 or any portion of SEQ ID NO: 39.
Therefore, the claims are anticipated by a vector which encodes any amino acid sequence comprising any polypeptide of two or more residues which are a portion of SEQ ID NO:39.
If the claims were amended to recite “epitopes in Table 5 having the amino acid sequence of LLYDANYFL (Seq ID NO: 39)”, “epitope having the amino acid sequence of LLYDANYFL (Des ID NO: 39)”, and “epitopes… having the amino acid sequence of LLYDANYFL (Seq ID NO: 39)”; the examiner would interpret the claims to encompass only nucleic acids that encode the full length of the specified SEQ ID NO:, with or without additional nucleotides at either or both ends.
The claim is interpreted as a vector comprising a multi-epitope T cell immunogen comprising two or more Coronavirus CTL epitopes based on the claim interpretations discussed supra.
Gaynor teach an immunogenic composition (e.g. a vaccine) that can specifically target one or more T cell response to a polypeptide antigen of SARS-CoV-2 (p1 [0005]). Gaynor further teach the composition comprises at least 2 antigenic peptides comprising epitopes of Table 1A (p43 [0891). Table 1A of Gaynor teach epitope sequences from the ORF3a protein (p4 [0056]; [0063]) including the peptide sequences “LLYDANYFL” and “IPYNSVTSSI”, which are 100% identical to the claimed amino acid sequences of Seq ID NO: 39 and Seq ID NO: 25 as recited in the instant claims (p4 [0063]; Table 1a 2158). Thus the peptide sequences disclosed by Gaynor are considered “highly networked Coronavirus CTL epitopes”.
Gaynor further teaches nucleic acids encoding the viral epitope peptides comprising multiple epitopes may be used to administer nucleic acids encoding the viral epitope peptides (p355 [1153]).
Thus the disclosure of Gaynor teach a vector comprising a multi-epitope T cell immunogen, wherein the vector comprises a sequence encoding two or more highly networked coronavirus CTL epitopes wherein at least one of the epitopes have an amino acid sequence of “LLYDANYFL” (Seq ID NO: 39) as required by the claims.
Regarding claim 14: The claim recites “the vector comprises the natural N-terminal and C-terminal flanking amino acid sequences for each
epitope up to 30 amino acids”. “up to 30 amino acids” does not delineate a lower limit to the natural N-terminal and C-terminal flanking amino acid sequences, thus the limitation is broadly interpreted as 0-30 flanking amino acid sequences for each epitope.
Regarding claims 17-18: The teachings of Gaynor are discussed supra. Gaynor also teach the polynucleotides can encode more than one epitope and that the constructs comprise additional sequences such as linkers which interconnect epitopes (p362 [1214]; p408 [1351]).
Regarding claim 22: The claim recites “a pharmaceutical composition”. The statement “pharmaceutical composition” is not considered to impose or imply structure on the claimed vector.
Regarding claim 24: The teachings of Gaynor are discussed supra. Gaynor further teach the polynucleotides (vectors) can be administered and expressed in human cells (p60 [1070]).
Thus the invention as claimed is anticipated by Gaynor.
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 13 and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable by Gaynor et al (US 2023/0083931 A1) as applied to claims 1-7, 11, 14, 17-18, 22 and 24 above, and further in view of Lu et al (Clinical and Vaccine Immunology (2009) 1-5), and Walker et al (WO 2020/186064 A1; provisional application filed 2/12/2019).
The teachings of Gaynor anticipate claims 1-7, 11, 14, 17-18, 22 and 24 thus they are also rendered obvious (see above).
Regarding claims 13 and 15-16: The teachings of Gaynor are discussed supra. Gaynor do not teach the vector comprises a furin cleavage site or an endoplasmic reticulum insertion signal sequence (ERISS).
Lu teach a prophylactic vaccine targeting SARS is needed to prevent another SARS epidemic after an outbreak of SARS in 2003 (p3/4 col 2/1 ¶3/1). Lu further teach the ORF 3a gene is found in both SARS-CoV and SL-CoV and that vaccines based on the group-specific ORFs induce specific humoral and cellular immune responses (p4 col1 ¶2). Lu also teach amino acids 15-28 of the 3a protein induce an antibody response (p4 col1 ¶1).
Walker teach a multi-epitope immunogen composition comprising two or more HIV CTL epitopes (claim 1). Walker teach the vector comprises a nucleic acid sequence encoding two or more CTL epitopes (p18 [0066]).
Walker further teach the vector can comprise immune-enhancer elements to increase epitope expression and/or de novo cytotoxic T cell responses (p21 [0076]). Walker teach immune-enhancer elements include an endoplasmic reticulum signal sequence and sequences encoding a furin cleavage site (p21/22 [0076]).
It would have been obvious to one of ordinary skill in the art to adapt the vector as taught by Gaynor drawn to a vector which encodes a multi-epitope T cell immunogen by including a furin cleavage site and endoplasmic reticulum signal sequence as taught by Walker.
One of ordinary skill in the art would have been motivated to modify the vector as taught Gaynor by including a furin cleavage site and endoplasmic reticulum signal sequence as taught by Walker because Walker teach the elements are immune-enhancer elements which increase epitope expression and/or de novo cytotoxic T cell responses. One would also have been motivated because Lu teach a prophylactic vaccine targeting SARS is needed to prevent another SARS epidemic after an outbreak of SARS in 2003 (p3/4 col 2/1 ¶3/1) and one of ordinary skill in the art would have recognized that the vector taught by Siu and Wu could provide insight into vaccine design for disease caused by SARS-CoV and SARS-CoV-2.
One would have had a reasonable expectation of success because Lu teach a part of the ORF3a protein induces neutralizing antibodies and the disclosure Gaynor and the disclosure of Walker are drawn to vectors encoding nucleic acid sequences for expression of amino acid peptides. One of ordinary skill in the art would understand that incorporating functional components of one vector expression system into a different vector expression system comprises standard molecular biology methods that are well known in the art and thus have a reasonable expectation of success.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable by Gaynor et al (US 2023/0083931 A1) as applied to claims 1-7, 11, 14, 17-18, 22 and 24 above, and further in view of Lu et al (Clinical and Vaccine Immunology (2009) 1-5) and Shey et al (Scientific Reports (2019) 9:4409;1-18).
The teachings of Gaynor anticipate claims 1-7, 11, 14, 17-18, 22 and 24 thus they are also rendered obvious (see above).
Regarding claim 19: The teachings of Gaynor are discussed supra. Gaynor also teach the polynucleotides can encode more than one epitope and that the constructs comprise additional sequences such as linkers which interconnect epitopes (p362 [1214]; p408 [1351]). Gaynor do not teach the linker comprises Alanine and Tyrosine.
Shey teach a multi-epitope vaccine candidate peptide which comprises B-cell and T-cell epitopes of proteins predicted to be vaccine candidates (abstract). Shey teach epitope-based vaccines represent a novel approach for generating a specific immune response and avoiding responses against other unfavorable epitopes in the complete antigen (p9 ¶2). Shey further teach epitope-based vaccines may have increased safety and the ability to focus immune responses on conserved epitopes (p0¶2). Shey teach the AAY (alanine/tyrosine) linker is incorporated between epitopes to produce sequences with minimized junctional immunogenicity (p10 ¶1).
Lu teach a prophylactic vaccine targeting SARS is needed to prevent another SARS epidemic after an outbreak of SARS in 2003 (p3/4 col 2/1 ¶3/1). Lu further teach the ORF 3a gene is found in both SARS-CoV and SL-CoV and that vaccines based on the group-specific ORFs induce specific humoral and cellular immune responses (p4 col1 ¶2). Lu also teach amino acids 15-28 of the 3a protein induce an antibody response (p4 col1 ¶1).
It would have been obvious to one of ordinary skill in the art to adapt the vector Gaynor drawn to a vector encoding a multi-epitope T cell immunogen by including a linker comprising alanine and tyrosine as taught by Shey.
One of ordinary skill in the art would have been motivated to modify the vector as taught by Gaynor by incorporating a linker comprising alanine and tyrosine as taught by Shey because Shey teach the linker incorporated between epitopes produce sequences with minimized junctional immunogenicity, thus one of ordinary skill in the art would understand that the immunogenicity would be more specific to the encoded epitopes. One would also have been motivated to modify the vector of Siu because Lu teach a prophylactic vaccine targeting SARS is needed to prevent another SARS epidemic after an outbreak of SARS in 2003 (p3/4 col 2/1 ¶3/1) and one of ordinary skill in the art would have recognized that the vector taught by Siu could provide insight into vaccine design for SARS-CoV-2 which causes severe respiratory disease in humans.
One would have had a reasonable expectation of success because the disclosures of Gaynor of Shey are both drawn to vectors encoding nucleic acid sequences for expression of amino acids comprising multiple epitopes and one of ordinary skill in the art would understand that incorporating functional components, such as linkers, from one vector expression system into a different vector expression system comprises standard molecular biology methods that are well known in the art and thus have a reasonable expectation of success.
Thus the invention as claimed is rendered obvious by the disclosures of Gaynor, Walker, Lu and Shey.
Claims 7-11, 14, 18, 22 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Siu et al (FASEB (2019) 1-13) in view of Wu et al (Nature (2020) 579;265-284) and as evidenced by GenBank_MN908947 (Wuhan-Hu-1, complete genome [online]. NCBI [retrieved on 05/13/2026]. Retrieved from the Internet: <https://www.ncbi.nlm.nih.gov/nuccore/MN908947.1) and Priyanka et al (Protein Science (2013) 22:153-167) and NCBI_NP_828852.2 (sars3a [online]. NCBI [retrieved on 05/28/2026]. Retrieved from the Internet: <https://www.ncbi.nlm.nih.gov/protein/NP_828852.2?report=genpept).
Regarding claims 7-11: Claim 7 recites “highly networked Coronavirus CTL epitopes”. The instant specification defines “highly networked” as “an epitope having a composite epitope network score of at least about 3.00” (p10).
The instant specification defines “about” as a quantity that varies by as much as 15% (p9). Thus for claim 7, the limitation “at least about 3.00” is broadly interpreted as a score of 2.55 or greater. For claim 9, the limitation “at least about 65% to 99% homology” is broadly interpreted as homology of 50-114%.
The instant specification teaches the network score for a given epitope is determined by generating a network representing protein structure, and then calculating a set of parameters that generate a score for each amino acid residue with in the protein structure (p3). The network score is then generated for a plurality of epitopes as a weighted combination of the amino acid residues of the epitopes (p3).
The instant specification teaches the epitope network score is calculated from individual amino acid residues within and neighboring a CD8+ T cell epitope were combined and averaged based on their involvement as either an HLA anchor, TCR contact or peptide processing residues (p46).
Table 5 of the instant specification discloses epitopes that are considered to be highly networked (p14; p59). Therefore the highly networked Coronavirus CTL epitopes are interpreted to be the epitopes disclosed by Table 5
The claim is drawn to a vector. The instant specification defines the term vector as “a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked” (p9 ¶3).
The network score as disclosed by the instant claim is not considered to impose or imply structure on the claimed vector.
Claims 8, 10 and 11 recite “epitopes in Table 5 having an amino acid sequence of LLYDANYFL (Seq ID NO: 39)”, “epitope having an amino acid sequence of LLYDANYFL (Des ID NO: 39)”, and “epitopes… having an amino acid sequence of LLYDANYFL (Seq ID NO: 39)”. This is broadly interpreted as an epitope comprising two or more of the amino acid residues as disclosed by Seq ID NO: 39 (discussed below).
The claim language recited supra encompasses vectors which encode amino acids that comprise the full-length sequence of SEQ ID NO: 39 or any portion of SEQ ID NO: 39.
Therefore the claims are anticipated by a vector which encodes any amino acid sequence comprising any polypeptide of two or more residues which are a portion of SEQ ID NO:39.
If the claims were amended to recite “epitopes in Table 5 having the amino acid sequence of LLYDANYFL (Seq ID NO: 39)”, “epitope having the amino acid sequence of LLYDANYFL (Des ID NO: 39)”, and “epitopes… having the amino acid sequence of LLYDANYFL (Seq ID NO: 39)”; the examiner would interpret the claims to encompass only nucleic acids that encode the full length of the specified SEQ ID NO:, with or without additional nucleotides at either or both ends.
The claim is interpreted as a vector comprising a multi-epitope T cell immunogen comprising two or more Coronavirus CTL epitopes based on the claim interpretations discussed supra.
Siu teach SARS-CoV causes a severe and highly lethal respiratory disease in humans characterized by a prominent proinflammatory response (p1 col1 ¶1). Siu teach inflammation can play both antiviral and proviral roles during viral infection (p1 col2 ¶2).
Siu further teach SARS-CoV encodes the ORF3a protein; an ion channel required for viral replication and virulence (p2 col1 ¶2). Siu teach expression of ORF3a in human THP-1 cells using an ORF3a expression vector to assess the role of ORF3a in activation of the inflammasome during virulence (p2 col1 ¶2; p3/4 ¶6/1; Fig 1). Siu teach that ORF3a activates the inflammasome independent of ion channel activity (p11 col1 ¶2) and further teach key residues for the interaction of ORF3a and TRAF3 are mapped and peptide mimetics based on ORF3a residues could be useful in modulating inflammasome activation (p11 col2 ¶3).
Siu do not teach the highly networked epitope regions comprising the peptide sequences “LLYDANYFL” and “IPYNSVTSSI” (Seq ID NO: 39 and Seq ID NO: 25) as recited in the instant claims.
Wu teach a severe respiratory disease was recently reported in Wuhan, Hubei province, China. Wu teach that, as of 25 January 2020, at least 1,975 cases had been reported since the first patient was hospitalized on 12 December 2019 (abstract).
Wu further teach the sequence of the novel coronavirus associated with severe human respiratory disease, designated SARS-CoV-2 (also referred to as WHCV, WH-Human 1 coronavirus, and 2019-nCoV); GenBank accession MN908947 (p266 col1 ¶1; 269 col1 ¶2). Wu teach the viral genome is similar to another coronavirus sequence that is associated with humans (SARS-Cov) and coronavirus sequence that is associated with bats (p266 col2 ¶2).
As evidenced by NCBI sequence GenBank accession MN908947 (SARS-CoV-2; sbjct) and NCBI accession NP_828852.2 (SARS-CoV; query); the amino acid sequences of the ORF3a proteins share high amino acid sequence homology:
Query 1 MDLFMRFFTLRSITAQPVKIDNASPASTVHATATIPLQASLPFGWLVIGVAFLAVFQSAT 60
MDLFMR FT+ ++T + +I +A+P+ V ATATIP+QASLPFGWL++GVA LAVFQSA+
Sbjct 1 MDLFMRIFTIGTVTLKQGEIKDATPSDFVRATATIPIQASLPFGWLIVGVALLAVFQSAS 60
Query 61 KIIALNKRWQLALYKGFQFICNLLLLFVTIYSHLLLVAAGMEAQFLYLYALIYFLQCINA 120
KII L KRWQLAL KG F+CNLLLLFVT+YSHLLLVAAG+EA FLYLYAL+YFLQ IN
Sbjct 61 KIITLKKRWQLALSKGVHFVCNLLLLFVTVYSHLLLVAAGLEAPFLYLYALVYFLQSINF 120
Query 121 CRIIMRCWLCWKCKSKNPLLYDANYFVCWHTHNYDYCIPYNSVTDTIVVTEGDGISTPKL 180
RIIMR WLCWKC+SKNPLLYDANYF+CWHT+ YDYCIPYNSVT +IV+T GDG ++P
Sbjct 121 VRIIMRLWLCWKCRSKNPLLYDANYFLCWHTNCYDYCIPYNSVTSSIVITSGDGTTSPIS 180
Query 181 KEDYQIGGYSEDRHSGVKDYVVVHGYFTEVYYQLESTQITTDTGIENATFFIFNKLVKDP 240
+ DYQIGGY+E SGVKD VV+H YFT YYQL STQ++TDTG+E+ TFFI+NK+V +P
Sbjct 181 EHDYQIGGYTEKWESGVKDCVVLHSYFTSDYYQLYSTQLSTDTGVEHVTFFIYNKIVDEP 240
Query 241 -PNVQIHTIDGSSGVANPAMDPIYDEPTTTTSVPL 274
+VQIHTIDGSSGV NP M+PIYDEPTTTTSVPL
Sbjct 241 EEHVQIHTIDGSSGVVNPVMEPIYDEPTTTTSVPL 275
The amino acid sequence of Orf3a of SARS-CoV-2 comprises the amino acid sequences “LLYDANYFL” and “IPYNSVTSSI” as shown in the sequence alignment as bold/underlined residues in Sbjct. The instant Claim 10 and Table 3 of the instant specification teach the amino acid sequences “LLYDANYFL” and “IPYNSVTSSI” are highly networked Coronavirus CTL epitopes with network scores greater than 3.0.
It would have been obvious to one of ordinary skill in the art to modify the vector of Siu drawn to a vector which encodes the sequence of the ORF3a protein for SARS-CoV by modifying the vector to encode the sequence of ORF3a protein for SARS-CoV2, as taught by Wu based on the sequence homology between the two viruses and the fact that both viruses are associated with human disease.
One of ordinary skill in the art would have been motivated to modify the vector as taught by Siu to express the ORF3a protein of SARS-CoV-2 in place of the ORF3a protein of SARS-CoV because Wu teach SARS-CoV-2 shares genomic and phylogenetic similarities to SARS-CoV and SARS-CoV-2 is associated with severe respiratory disease (abstract, p268 col2 ¶2). Furthermore, Wu teach that in less than two months (12/12/2019-01/25/2020) at least 1,975 cases had been reported since the first patient was hospitalized (abstract). One of ordinary skill in the art would understand that a high number of cases of a novel severe respiratory disease developing within a short timeframe indicates the disease could be a public health concern.
Therefore, one of ordinary skill in the art would understand the need to assess the ability of the ORF3a protein of the novel virus (SARS-CoV-2) in order to map key residues to generate peptide mimetics based on the ORF3a residues that could contribute to inflammation and thus the immune response of the ORF3a protein, particularly because the ORF3a protein is known to play a role in inflammation for the related virus SARS-CoV, which also causes severe respiratory disease in humans.
One would have had a reasonable expectation of success because Siu teach expression of SARS-CoV ORF3a and Wu teach the sequence of the ORF3a protein in the related virus (SARS-CoV-2) which comprises high sequence homology with the ORF3a protein taught by Siu.
One of ordinary skill in the art would understand that exchanging functional components of a vector expression system for the generation of peptides useful in modulating inflammasome activation, such as changing transgenes comprises standard molecular biology methods that are well known in the art and thus have a reasonable expectation of success.
Regarding claim 14: The claim requires the epitope encoded by the vector to comprises natural N-terminal and C-terminal flanking amino acid sequence up to 30 amino acids. This is interpreted as the sequence requires 1-30 natural N- and C-terminal flanking amino acids for each epitope.
The combined teaching of Siu and Wu are discussed supra. Modifying the vector of Siu with the teaching of Wu would generate a vector which comprises the claimed epitope sequences because the modified vector would encode the entire amino acid sequence of the ORF3a protein of SARS-CoV-2 (see below).
The amino acid sequence of the ORF3a protein of SARS-CoV-2 that would be encoded by the combination of Siu and Wu encodes the natural ORF3a protein of SARS-CoV-2; Wu teach the genome was sequenced from bronchoalveolar lavage fluid (p265 col2 ¶3).
Thus the highly networked epitopes expressed by the vector taught by the combination of Siu and Wu would be flanked by natural N- and C-terminal amino acid residues. The peptide sequences are shown below in bold/underline for the ORF3a protein of SARS-CoV-2. “LLYDANYFL” is flanked by “KNP” and “CSH” and “IPYNSVTSSI” is flanked by “DYC” and “VIT”.
1 MDLFMRIFTIGTVTLKQGEIKDATPSDFVRATATIPIQASLPFGWLIVGVALLAVFQSAS 60
61 KIITLKKRWQLALSKGVHFVCNLLLLFVTVYSHLLLVAAGLEAPFLYLYALVYFLQSINF 120
121 VRIIMRLWLCWKCRSKNPLLYDANYFLCWHTNCYDYCIPYNSVTSSIVITSGDGTTSPIS 180
181 EHDYQIGGYTEKWESGVKDCVVLHSYFTSDYYQLYSTQLSTDTGVEHVTFFIYNKIVDEP 240
241 EEHVQIHTIDGSSGVVNPVMEPIYDEPTTTTSVPL 275
Regarding claim 18: The claim requires the epitopes to linked by a linker sequence. The instant specification is silent on an explicit definition of the term. As evidenced by Priyanka, linkers are short amino acid sequences to separate multiple domains in a single protein (abstract). Thus a linker is broadly interpreted to be an amino acid sequence that separates multiple domains. Epitopes are considered domains.
The combined teaching of Siu and Wu are discussed supra. The vector disclosed by Siu and Wu would encode the ORF3a protein of SARS-CoV-2 in a single peptide sequence and comprises 10 intervening amino acids between the highly networked epitopes “LLYDANYFL” and “IPYNSVTS” (see sequence above). The epitopes are therefore considered to be linked to each other by a linker sequence (the 10 intervening amino acids) as required by the instant claim.
Regarding claim 22: The claim recites “a pharmaceutical composition”. The statement “pharmaceutical composition” is not considered to impose or imply structure on the claimed vector.
Regarding claim 24: The combined teachings of Siu and Wu are discussed supra. Siu further teach THP-1 cells were transfected with the ORF3a expression vector (Fig 7A). This reads on a cell expressing the vector as required by the instant claim.
Claims 13 and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Siu et al (FASEB (2019) 1-13) and Wu et al (Nature (2020) 579;265-284) as applied to claims 7-11, 14, 18, 22 and 24 above, and further in view of Lu et al (Clinical and Vaccine Immunology (2009) 1-5), and Walker et al (WO 2020/186064 A1; provisional application filed 2/12/2019).
Regarding claims 13 and 15-16: The combined teachings of Siu and Wu are discussed supra. Siu and Wu do not teach the vector comprises a furin cleavage site or an endoplasmic reticulum insertion signal sequence (ERISS).
Lu teach a prophylactic vaccine targeting SARS is needed to prevent another SARS epidemic after an outbreak of SARS in 2003 (p3/4 col 2/1 ¶3/1). Lu further teach the ORF 3a gene is found in both SARS-CoV and SL-CoV and that vaccines based on the group-specific ORFs induce specific humoral and cellular immune responses (p4 col1 ¶2). Lu also teach amino acids 15-28 of the 3a protein induce an antibody response (p4 col1 ¶1).
Walker teach a multi-epitope immunogen composition comprising two or more HIV CTL epitopes (claim 1). Walker teach the vector comprises a nucleic acid sequence encoding two or more CTL epitopes (p18 [0066]).
Walker further teach the vector can comprise immune-enhancer elements to increase epitope expression and/or de novo cytotoxic T cell responses (p21 [0076]). Walker teach immune-enhancer elements include an endoplasmic reticulum signal sequence and sequences encoding a furin cleavage site (p21/22 [0076]).
It would have been obvious to one of ordinary skill in the art to adapt the vector as taught by the combination of Shui and Wu drawn to a vector which encodes a multi-epitope T cell immunogen by including a furin cleavage site and endoplasmic reticulum signal sequence as taught by Walker.
One of ordinary skill in the art would have been motivated to modify the vector as taught by Siu and Wu by including a furin cleavage site and endoplasmic reticulum signal sequence as taught by Walker because Walker teach the elements are immune-enhancer elements which increase epitope expression and/or de novo cytotoxic T cell responses. One would also have been motivated because Lu teach a prophylactic vaccine targeting SARS is needed to prevent another SARS epidemic after an outbreak of SARS in 2003 (p3/4 col 2/1 ¶3/1) and one of ordinary skill in the art would have recognized that the vector taught by Siu and Wu could provide insight into vaccine design for disease caused by SARS-CoV and SARS-CoV-2.
One would have had a reasonable expectation of success because Lu teach a part of the ORF3a protein induces neutralizing antibodies and the disclosure of Siu and Wu and the disclosure of Walker are drawn to vectors encoding nucleic acid sequences for expression of amino acid peptides. One of ordinary skill in the art would understand that incorporating functional components of one vector expression system into a different vector expression system comprises standard molecular biology methods that are well known in the art and thus have a reasonable expectation of success.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Siu et al (FASEB (2019) 1-13) and Wu et al (Nature (2020) 579;265-284) as applied to claims 7-11, 14, 18, 22 and 24 above, and further in view of Lu et al (Clinical and Vaccine Immunology (2009) 1-5) and Shey et al (Scientific Reports (2019) 9:4409;1-18).
Regarding claim 19: The combined teachings of Siu and Wu are discussed supra. Siu and Wu do not teach the linker comprises Alanine and Tyrosine.
Shey teach a multi-epitope vaccine candidate peptide which comprises B-cell and T-cell epitopes of proteins predicted to be vaccine candidates (abstract). Shey teach epitope-based vaccines represent a novel approach for generating a specific immune response and avoiding responses against other unfavorable epitopes in the complete antigen (p9 ¶2). Shey further teach epitope-based vaccines may have increased safety and the ability to focus immune responses on conserved epitopes (p0¶2). Shey teach the AAY (alanine/tyrosine) linker is incorporated between epitopes to produce sequences with minimized junctional immunogenicity (p10 ¶1).
Lu teach a prophylactic vaccine targeting SARS is needed to prevent another SARS epidemic after an outbreak of SARS in 2003 (p3/4 col 2/1 ¶3/1). Lu further teach the ORF 3a gene is found in both SARS-CoV and SL-CoV and that vaccines based on the group-specific ORFs induce specific humoral and cellular immune responses (p4 col1 ¶2). Lu also teach amino acids 15-28 of the 3a protein induce an antibody response (p4 col1 ¶1).
It would have been obvious to one of ordinary skill in the art to adapt the vector of Siu and Wu drawn to a vector encoding a multi-epitope T cell immunogen by including a linker comprising alanine and tyrosine as taught by Shey.
One of ordinary skill in the art would have been motivated to modify the vector as taught by Siu by incorporating a linker comprising alanine and tyrosine as taught by Shey because Shey teach the linker incorporated between epitopes produce sequences with minimized junctional immunogenicity, thus one of ordinary skill in the art would understand that the immunogenicity would be more specific to the encoded epitopes. One would also have been motivated to modify the vector of Siu because Lu teach a prophylactic vaccine targeting SARS is needed to prevent another SARS epidemic after an outbreak of SARS in 2003 (p3/4 col 2/1 ¶3/1) and one of ordinary skill in the art would have recognized that the vector taught by Siu could provide insight into vaccine design for SARS-CoV-2 which causes severe respiratory disease in humans.
One would have had a reasonable expectation of success because both the disclosure of Siu and Wu and the disclosure of Shey are drawn to vectors encoding nucleic acid sequences for expression of amino acids comprising multiple epitopes and one of ordinary skill in the art would understand that incorporating functional components, such as linkers, from one vector expression system into a different vector expression system comprises standard molecular biology methods that are well known in the art and thus have a reasonable expectation of success.
Thus the invention as claimed is rendered obvious by the disclosures of Siu, Wu, Walker, Lu and Shey.
Conclusion
No claims are allowed.
Art of relevance not cited in this action:
Grifoni et al (Cell Host & Microbe (2020) 27;671-680; cited in the IDS).
Gaynor et al. US 2023/0141371 A1, which relies upon the priority application 62/992,666, also relied upon by Gaynor et al (US 2023/0083931 A1; cited herein)
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/ANDREA LYNNE MORRIS SPENCER/Examiner, Art Unit 1631
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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