DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Disposition of Claims
Claims 1-4, 8-9, 15-16, 18, 20-21, 23-26, 28, 30-31, 33, 37-38, 43-44, 46, 48-49, 51-52, 54, 56-57, 64, and 67 are pending.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US 2024/0093234 A1, Published 21 March 2024. Applicant’s amended Specification as presented on 28 July 2023 is acknowledged and entered.
Applicant is encouraged to utilize the new web-based Automated Interview Request (AIR) tool for submitting interview requests; more information can be found at https://www.uspto.gov/patent/laws-and-regulations/interview-practice.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The information disclosure statements (IDSes) submitted on 22 August 2023, 05 August 2024, 04 March 2025, 07 May 2025, and 18 February 2026 have been considered by the examiner. Any individual references with strikethroughs, however have not been considered.
Specification; Sequence Disclosure Requirements
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825 for the reason(s) set forth below or on the attached Notice To Comply With Requirements For Patent Applications Containing Nucleotide Sequence And/Or Amino Acid Sequence Disclosures.
The specification is objected to because Paragraph 0185 comprises a sequence that does not identify said sequence with a corresponding SEQ ID NO. The sequence in question is the T4 fibritin trimerization foldon domain sequence. It contains at least 4 specifically defined and enumerated amino acid residues and therefore should have an accompanying SEQ ID NO. If it corresponds to a sequence in the Sequence Listing, then it should be associated with its corresponding SEQ ID NO each and every time it appears throughout the disclosure. If it does not correspond to a sequence in the Sequence Listing, then it should be assigned a unique SEQ ID NO.
Applicants must comply with sequence rules in order to be considered a complete response to this Office Action.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because it contains language which can be implied as well as legal phraseology. The implied phrase in question is “The present disclosure provides…”. The legal phraseology in question is “e.g.”, which stands for “exempli gratia”. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claims 1, 9, 21, 25, 28, 38, 48-49, and 67 are objected to because of the following informalities: In Claims 1, 9, and 38, all instances of “CoV2” should be replaced with “CoV-2”. There should be a hyphen between the “V” and the “2”.
In Claims 9 and 38, it is suggested that all instances of “SARS-CoV2-N protein” be replaced with “SARS-CoV-2 N protein”.
In Claims 21, 49, and 67, it is suggested that they say “SEQ ID NOs:” instead of “SEQ ID NOS:”.
In Claim 25, it is suggested that it say “…an immune response against an antigenic polypeptide…” instead of “…an immune response towards an antigenic polypeptide…”.
In Claim 28, it is suggested that it say “a club cell[[s]]” instead of “a club cells”. “Cell” should be singular.
In Claim 48, it is suggested that it say “…encoding a toll-like receptor-3 (TLR-3) agonist” instead of “…encoding a a toll-like receptor-3 (TLR-3) agonist”. The “a” has been duplicated.
In Claim 67, it is suggested that it say “…is a CMV promoter[[,]]; and/or…”. The comma should be replaced with a semicolon.
Appropriate correction is required.
Claims 1 and 9 are objected to because of the following informalities: the definitions of the abbreviations SARS-CoV-2 and CMV are not provided. For clarity, it is requested that the first recitation of an abbreviation within a claim set be preceded by its full-length name.
Appropriate correction is required.
Claims are only allowed to have one period, as stated in MPEP § 608.01(m). The claim which does not adhere to this rule is Claim 67. Regarding Claim 67, there is an inadvertent period after the second “and/or”.
Claim Rejections - Judicially Approved Improper Markush Grouping
Claims 4 and 33 are rejected on the basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of the recited antigens in the limitation “wherein the antigenic polypeptide is (i) a cancer antigen; (ii) from a pathogen; (iii) from a virus, bacteria, fungus, or parasite; or (iv) from a human papilloma virus (HPV) antigen, optionally, wherein the polypeptide comprises SEQ ID NO: 22” is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the alternatives are not all members of the same recognized physical or chemical class or the same art-recognized class as the antigens recited all have different structures.
Claim Interpretation
In light of the issues raised above, the claims are being interpreted as reading upon the following:
Claim 1 is drawn to a chimeric adenoviral expression vector, comprising an expression cassette comprising: a nucleic acid encoding an antigenic polypeptide; and a nucleic acid encoding a Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) N protein, wherein the antigenic polypeptide is not a SARS-CoV-2 protein.
Claim 30 is drawn to a chimeric polynucleotide, comprising an expression cassette comprising: a nucleic acid encoding an antigenic polypeptide, with the proviso that the antigenic polypeptide is not a SARS-CoV-2 protein; and a nucleic acid encoding a SARS-CoV-2 N protein.
Claim 56 is drawn to a chimeric adenoviral expression vector, comprising a bicistronic or multicistronic expression construct comprising: a nucleic acid encoding a SARS-CoV-2 S protein; and a nucleic acid encoding a SARS-CoV-2 N protein, wherein the bicistronic construct is operably linked to a promoter.
Further limitations on the chimeric adenoviral expression vector according to Claim 1 are:
2. The chimeric adenoviral expression vector of claim 1, wherein the SARS-CoV-2 N protein comprises an amino acid sequence having at least 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 2.
3. The chimeric adenoviral expression vector of claim 2, wherein the nucleic acid encoding the SARS-CoV-2 N protein comprises a sequence having at least 85%, 90%, 95%, 97%, 99%, or 100% identity to the sequence of SEQ ID NO: 4.
4. The chimeric adenoviral expression vector of claim 1, 2, or-3, wherein the antigenic polypeptide is (i) a cancer antigen; (ii) from a pathogen; (iii) from a virus, bacteria, fungus, or parasite; or (iv) from a human papilloma virus (HPV) antigen, optionally, wherein the antigenic polypeptide comprises SEQ ID NO: 22.
8. The chimeric adenoviral expression vector of claim 1, wherein the expression cassette comprises a bicistronic or multicistronic construct comprising the nucleic acid encoding the antigenic polypeptide and the nucleic acid encoding the SARS-CoV-2 N protein operably linked to a promoter.
9. The chimeric adenoviral expression vector of claim 8, wherein: (a)the nucleic acid encoding the antigenic polypeptide is positioned 5' of the nucleic acid encoding the SARS-CoV-2 N protein; or the nucleic acid encoding the SARS-CoV-2 N protein is positioned 5' of the nucleic acid encoding the antigenic polypeptide; and/or (b) the expression cassette comprises: (i) an internal ribosome entry site (IRES), a ribosomal skipping element, or a furin cleavage site positioned between the nucleic acid encoding the antigenic polypeptide and the nucleic acid encoding the SARS-CoV-2 N protein; or (ii) a ribosomal skipping element, wherein the ribosomal skipping element is a sequence encoding a peptide selected from the group consisting of a 2A peptide (T2A), a porcine teschovirus-1 2A peptide (P2A), a foot-and-mouth disease virus 2A peptide (F2A), equine rhinitis A virus 2A peptide (E2A), a cytoplasmic polyhedrosis virus 2A peptide (BmCPV 2A), and a flacherie virus of B. mori 2A peptide (BmIFV 2A); and/or (c) the promoter is a CMV promoter.
15. The chimeric adenoviral expression vector of claim 1, wherein the nucleic acid encoding the antigenic polypeptide is operably linked to a first promoter and the nucleic acid encoding the SARS-CoV-2 N protein is operably linked to a second promoter.
16. The chimeric adenoviral expression vector of claim 15, wherein the first promoter and the second promoter are each a CMV promoter; or the first promoter is a CMV promoter and the second promoter is a beta-actin promoter; or the first promoter is a beta-actin promoter and the second promoter is a CMV promoter.
18. The chimeric adenoviral expression vector of claim 1, wherein the expression cassette comprises a polyadenylation signal, optionally wherein the polyadenylation signal is a bovine growth hormone polyadenylation signal.
20. The chimeric adenoviral expression vector of claim 1, wherein the chimeric adenoviral expression vector further comprises a nucleic acid encoding a [[a]] toll-like receptor-3 (TLR-3) agonist.
21. The chimeric adenoviral expression vector of claim 20, wherein the TLR-3 agonist comprises a nucleic acid encoding a dsRNA, optionally wherein the nucleic acid encoding the TLR-3 agonist comprises a sequence selected from the group consisting of: SEQ ID NOs: 11-18.
23. A host cell comprising a chimeric adenoviral vector of claim 1.
24. An immunogenic composition comprising the chimeric adenoviral expression vector of claim 1 and a pharmaceutically acceptable carrier.
25. A method for eliciting an immune response against an antigenic polypeptide in a subject, comprising administering to the subject an immunogenically effective amount of the chimeric adenoviral expression vector of claim 1 to a mammalian subject, optionally wherein the mammalian subject is a human.
26. The method of claim 25, wherein the route of administration is oral, intranasal, or mucosal.
28. The method of claim 25, wherein the immune response is elicited in an alveolar cell, an absorptive enterocyte, a ciliated cell, a goblet cell, a club cells, and/or an airway basal cell of the subject.
Further limitations on the chimeric polynucleotide according to Claim 30 are:
31. The chimeric polynucleotide of claim 30, wherein the SARS-CoV-2 N protein comprises an amino acid sequence having at least 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 2, optionally wherein the nucleic acid encoding the SARS-CoV-2 N protein comprises a sequence having at least 85%, 90%, 95%, 97%, 99%, or 100% identity to the sequence of SEQ ID NO: 4.
33. The chimeric polynucleotide of claim 30, 31, or 32, wherein the antigenic polypeptide is (i) a cancer antigen; (ii) from a pathogen; (iii) from a virus, bacteria, fungus, or parasite; or (iv) from a human papilloma virus (HPV) antigen, optionally, wherein the polypeptide comprises SEQ ID NO: 22.
37. The chimeric polynucleotide of claim 30, wherein the expression cassette comprises a bicistronic or multicistronic construct comprising the nucleic acid encoding the antigenic polypeptide and the nucleic acid encoding the SARS-CoV-2 N protein operably linked to a promoter.
38. The chimeric polynucleotide of claim 37, wherein: (a) the nucleic acid encoding the antigenic protein is positioned 5' of the nucleic acid encoding the SARS-CoV-2 N protein; or the nucleic acid encoding the SARS-CoV-2 N protein is positioned 5' of the nucleic acid encoding the antigenic polypeptide; and/or (b) the expression cassette comprises: (i) an internal ribosome entry site (IRES), a ribosomal skipping element, or a furin cleavage site positioned between the nucleic acid encoding the antigenic polypeptide and the nucleic acid encoding the SARS-CoV-2 N protein; or (ii) a ribosomal skipping element and the ribosomal skipping element is a sequence encoding a peptide selected from the group consisting of a 2A peptide (T2A), a porcine teschovirus-1 2A peptide (P2A), a foot-and-mouth disease virus 2A peptide (F2A), equine rhinitis A virus 2A peptide (E2A), a cytoplasmic polyhedrosis virus 2A peptide (BmCPV 2A), and a flacherie virus of B. mori 2A peptide (BmIFV 2A); and/or (c) the promoter is a CV promoter.
43. The chimeric polynucleotide of claim 30, wherein the nucleic acid encoding the antigenic polypeptide is operably linked to a first promoter and the nucleic acid encoding the SARS-CoV-2 N protein is operably linked to a second promoter.
44. The chimeric polynucleotide of claim 43, wherein the first promoter and the second promoter are each a CMV promoter; or the first promoter is a CMV promoter and the second promoter is a beta-actin promoter; or the first promoter is a beta-actin promoter and the second promoter is a CMV promoter.
46. The chimeric polynucleotide of claim 30, wherein the expression cassette comprises a polyadenylation signal, optionally wherein the polyadenylation signal is a bovine growth hormone polyadenylation signal.
48. The chimeric polynucleotide of claim 30, wherein the chimeric polynucleotide further comprises a nucleic acid encoding a toll-like receptor-3 (TLR-3) agonist.
49. The chimeric polynucleotide of claim 48, wherein the TLR-3 agonist comprises a nucleic acid encoding a dsRNA, optionally wherein the nucleic acid encoding the TLR-3 agonist comprises a sequence selected from the group consisting of SEQ ID NOs: 11-18.
51. An expression vector comprising the chimeric polynucleotide of claim 30.
52. A method of inducing an immune response in a subject, the method comprising administering the expression vector of claim 51 to the subject, optionally wherein the subject is a human.
54. A host cell comprising the chimeric polynucleotide of claim 30, optionally wherein the host cell is mammalian.
Further limitations on the chimeric adenoviral expression vector according to Claim 56 are:
57. The chimeric adenoviral expression vector of claim 56, wherein the SARS-CoV-2 N protein comprises an amino acid sequence having at least 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 2, optionally wherein the nucleic acid encoding the SARS-CoV-2 N protein comprises a sequence having at least 85%, 90%, 95%, 97%, 99%, or 100% identity to the sequence of SEQ ID NO: 4; and/or the SARS-CoV-2 S protein comprises a sequence having at least 90% identity to SEQ ID NO: 1, optionally wherein the nucleic acid encoding the SARS-CoV-2 S protein comprises a sequence having at least 85%, 90%, 95%, 97%, 99%, or 100% identity to the sequence of SEQ ID NO: 3.
64. The chimeric adenoviral expression vector of claim 56, wherein the expression cassette comprises an internal ribosome entry site (IRES), a ribosomal skipping element, or a furin cleavage site positioned between the nucleic acid encoding the SARS-CoV-2 S protein and the nucleic acid encoding the SARS-CoV-2 N protein, optionally wherein the expression cassette comprises a ribosomal skipping element and the ribosomal skipping element is a sequence encoding a peptide selected from the group consisting of a 2A peptide (T2A), a porcine teschovirus-1 2A peptide (P2A), a foot-and-mouth disease virus 2A peptide (F2A), equine rhinitis A virus 2A peptide (E2A), a cytoplasmic polyhedrosis virus 2A peptide (BmCPV 2A), and a flacherie virus of B. mori 2A peptide (BmIFV 2A).
67. The chimeric adenoviral vector of claim 56,wherein: the promoter is a CMV promoter; and/or the expression cassette comprises a polyadenylation signal, optionally wherein the polyadenylation signal is a bovine growth hormone polyadenylation signal; and/or the chimeric adenoviral expression vector further comprises a nucleic acid encoding a toll-like receptor-3 (TLR-3) agonist, optionally wherein the nucleic acid encoding the TLR-3 agonist comprises a sequence selected from the group consisting of SEQ ID NOs: 11-18.
Claim Rejections - 35 USC § 112(a); First Paragraph
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-4, 8-9, 15-16, 18, 20-21, 23-26, 28, 30-31, 33, 37-38, 43-44, 46, 48-49, 51-52, 54, 56-57, 64, and 67 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for an isolated chimeric adenovirus expression vector, an isolated chimeric polynucleotide, or an isolated host cell comprising said vector or said polynucleotide, does not reasonably provide enablement for a cell within a transgenic animal or a transgene therein. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). See also MPEP § 2164.01(a) and § 2164.04. Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including: the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
Nature of the invention/Breadth of the claims. Applicant broadly claims a host cell or vector or nucleic acid containing the nucleic acids or expressing the amino acid sequences or antigenic polypeptides of claims 1-4, 8-9, 15-16, 18, 20-21, 30-31, 33, 37-38, 43-44, 46, 48-49, 56-57, 64, and 67. The claims read on a cell within a transgenic animal or a transgene therein given that the term "isolated" is not denoted in describing the host cell, nucleic acid, or vector.
State of the prior art/Predictability of the art. With respect to the unisolated host cells and transgenes as “nucleic acids” or “vectors “of the instant claims discussed above, the state of the art at the time of filing was such that one of skill could not predict the phenotype of transgenics. The art of transgenic animals has for many years stated that the unpredictability lies, in part, with the site or sites of transgene integration into the target genome and that "the position effect" as well as unidentified control elements are recognized to cause aberrant expression of a transgene (Wall et Al., Theriogenology, Vol. 45, Pg. 57-68, 1996).
The elements of the particular construct used to make transgenic animals are also held to be critical, and they must be designed case by case without general rules to obtain good expression of a transgene; e.g., specific promoters, presence or absence of introns, etc. (Houdebine et Al., Journal of Biotechnology, Vol. 34, Pg. 269- 287, 1994). Furthermore, transgenic animals are regarded to have within their cells, cellular mechanisms that prevent expression of the transgene, such as methylation or deletion from the genome (Kappell et Al., Current Opinions in Biotechnology, Vol. 3, Pg. 548-553, 1992). Houdebine (Comparative Immunology, Microbiology, and Infectious Diseases, Vol. 32, Pg. 107-121, 2009) teaches progress has been made in the field of transgenic animals for production of foreign proteins (Abstract); however, constructing an efficient expression vector to produce a therapeutic protein is not a standard operation (Pg. 116, Paragraph, second).
At the time of filing, the phenotype of a transgene and transgenic cell contained within any animal was unpredictable. The claims as written, encompassing a transgene and cell in a transgenic animal, is not adequately described in the specification as to prevent excessive experimentation by the public to generate and use the invention. Applicants can obviate the instant rejection by amending the claim to recite the term "isolated" before the recitation "host cell" and by amending the vector and polynucleotide claims to specify they are not in a transgenic animal. Applicant may consider using purified in such claims if description is appropriate for such a term and it is not redefined away from standard meaning. Method claims using these products should also carry the appropriate adjectives above.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make and use functional polynucleotides that produce the claimed vector and variants thereof, with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed vectors are functional, commensurate in scope with the claimed invention. The same can be said for the transgenes and transgenic animals encompassed by the instant claims. Thus, the claims are rejected here.
Working examples. No working example of a transgenic animal is disclosed in the specification. The working examples disclosed in the Specification describe the chimeric adenoviral expression vector and the chimeric polynucleotide encoding the recited antigenic polypeptides and the host cells comprising said vector and polynucleotide (see Paragraphs 0004, 0052, 0075-0077, at least)
Guidance in the specification. The specification provides guidance towards a chimeric adenoviral expression vector and a chimeric polynucleotide encoding the recited antigenic polypeptides and the host cells comprising said vector and polynucleotide ( see Paragraphs 0004, 0052, 0075-0077, at least).
Amount of experimentation necessary. In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make and use functional polynucleotides that produce the claimed vector and variants thereof, with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed vectors are functional, commensurate in scope with the claimed invention. The same can be said for the transgenes and transgenic animals encompassed by the instant claims. Thus, the claims are rejected here.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to make and/or use the claimed products.
Claims 2-3, 31, and 57 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for amino acid or nucleic acid sequences which are 100% identical to instant SEQ ID NOs: 1-4 , does not reasonably provide enablement for variants of the claimed sequences with less than 100% sequence identity. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). See also MPEP § 2164.01(a) and § 2164.04. Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including: the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
Nature of the invention/Breadth of the claims. The claims are drawn to a chimeric adenoviral expression vector, comprising an expression cassette comprising: a nucleic acid encoding an antigenic polypeptide; and a nucleic acid encoding a SARS-CoV-2 N protein, wherein the antigenic polypeptide is not a SARS-CoV-2 protein, wherein the SARS-CoV-2 N protein comprises an amino acid sequence having at least 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 2, and wherein the nucleic acid encoding the SARS-CoV-2 N protein comprises a sequence having at least 85%, 90%, 95%, 97%, 99%, or 100% identity to the sequence of SEQ ID NO: 4. The instant application also attempts to tie sequence identity to function in the context of a chimeric polynucleotide, comprising an expression cassette comprising: a nucleic acid encoding an antigenic polypeptide, with the proviso that the antigenic polypeptide is not a SARS-CoV-2 protein; and a nucleic acid encoding a SARS-CoV-2 N protein, wherein the SARS-CoV-2 N protein comprises an amino acid sequence having at least 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 2, optionally wherein the nucleic acid encoding the SARS-CoV-2 N protein comprises a sequence having at least 85%, 90%, 95%, 97%, 99%, or 100% identity to the sequence of SEQ ID NO: 4. Additionally, instant application also attempts to tie sequence identity to function in the context of a chimeric adenoviral expression vector, comprising a bicistronic or multicistronic expression construct comprising: a nucleic acid encoding a SARS-CoV-2 S protein; and a nucleic acid encoding a SARS-CoV-2 N protein, wherein the bicistronic construct is operably linked to a promoter, wherein the SARS-CoV-2 N protein comprises an amino acid sequence having at least 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 2, optionally wherein the nucleic acid encoding the SARS-CoV-2 N protein comprises a sequence having at least 85%, 90%, 95%, 97%, 99%, or 100% identity to the sequence of SEQ ID NO: 4; and/or the SARS-CoV-2 S protein comprises a sequence having at least 90% identity to SEQ ID NO: 1, optionally wherein the nucleic acid encoding the SARS-CoV-2 S protein comprises a sequence having at least 85%, 90%, 95%, 97%, 99%, or 100% identity to the sequence of SEQ ID NO: 3.
State of the prior art/Predictability of the art. The art teaches that protein chemistry is probably one of the most unpredictable areas of biotechnology. For example, replacement of a single “lysine” residue at position 118 of acidic fibroblast growth factor by “glutamic acid” led to the substantial loss of heparin binding, receptor binding and biological activity of the protein (Burgess et al., J of Cell Bio. 111:2129-2138, 1990). In transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen (Lazar et al. Molecular and Cellular Biology 8:1247-1252, 1988). As these references illustrate, it is unpredictable that a polypeptide variant of a known target protein binder will also bind said target. It is also unpredictable that they would bind said target in the same way, having the same effect on the target (i.e. inhibit or activate). Ju (Proceedings of the National Academy of Sciences, U.S.A., Vol. 88, Pg. 2658-2662, 1991) teaches that the interleukin 1 receptor (IL-1R) antagonist IL-1ra is a naturally occurring protein with no agonist activity in vitro or in vivo (Abstract). However, substitution of a single amino acid lysine145 to aspartic acid changes the property of this peptide to a partial agonist of IL-1R (Abstract). Thus, even a single substitution can change the biological property of a peptide.
This substitution need not be at a position where said residue would contact the target protein. Baker (Immunity, Vol. 13, Pg. 475-484, 2000) teaches that Tax-peptide is an agonist of the of T cell activity (Abstract). However, mutation of proline at position 6 of this peptide to alanine creates a T cell antagonist (Abstract). Importantly, this residue does not contact the T cell receptor (Abstract).
In another case, Huang (The Journal of Biological Chemistry, Vol. 272, No. 43, Pg. 27155-27159, 1997) teaches that conjugation of peptides to other proteins can change their biological properties. They teach that multiple conjugation of the peptide TGFβ1 (residues 41-65) to carrier proteins enhances its antagonist activity but also confers partial agonist activity as well (Abstract). Thus, the chemical context of a biologically active peptide is also important.
Truncation of proteins can also lead to adverse effects on protein structure and thus protein function. Martindale (Nature Genetics, Vol. 18, Pg. 150-154, 1998) teaches that truncation of huntingtin leads to aggregate development which compromises cell viability (Abstract). Nonaka (Human Molecular Genetics, Vol. 18, No. 18, Pg. 3353-3364, 2009) teaches that truncation of TDP-43 to its C-terminal fragments causes abnormally phosphorylated and ubiquitinated inclusions of the protein (Abstract). Taken together, not just any truncation of a protein will yield a soluble, functional, protein fragment.
In summary, these examples teach that the biological function of peptide variants is unpredictable because even a single mutation can abolish activity or give a different function. For example, agonist and antagonist peptides can be interconverted through conjugation or mutagenesis. Importantly, binding can still occur after mutation or conjugation in the literature examples provided above, illustrating that a simple show of binding is not predictive of the nature of a peptide’s biological activity. This point is underlined by Montrose-Rafizadeh (The Journal of Biological Chemistry, Vol. 272, Pg. 21201-21206, 1997) who teaches that receptor binding does not predict agonist or antagonist activity (Pg. 21205, Column 2, Paragraph, first full, Sentence, first). The prior art additionally teaches that antibody epitopes function as such based in large part on protein primary sequences. Polyak et al. (Blood, Vol. 99, No. 9, Pg. 3256-3262, 2002) teach that mutation of an epitope can have serious consequences on antibody binding. They teach that the sequence AxP at positions 170-172 in human CD20 is critical to the secondary structure of an extracellular loop and its loss causes the loss of binding of three anti-CD20 monoclonal antibodies (Pg. 3261, Column 1, Paragraph, second full). Changes in antigen primary sequences can greatly affect secondary, tertiary, and even quaternary protein structure and in so doing, modify the ability of antibodies to recognize their epitopes. Munodzana et al. (Infection and Immunity, Vol. 66 No. 6, Pg. 2619-2624, 1998) teach that induction of immunity to Anaplasma marginale requires antibodies to conformationally dependent epitopes on the pathogen (Pg. 2622, Column 2, Paragraph, first partial). Epitope mapping on one of the pathogen surface proteins MSP5 revealed antibody dependence on two sets of amino acid sequences 1-91 and 125-161 (Pg. 2622, Column 2, Paragraph, first partial). A dependence on so many amino acids indicates heavy structural requirements for the antibody epitope. Importantly, the N-terminal amino acid sequences include conserved cysteines that participate in intramolecular disulfide bonds (Pg. 2622, Column 2, Paragraph, first partial). Loss of monoclonal antibody ANAF16C1 binding to MSP5 was found after disulfide bond reduction and covalent modification of the reduced sulfhydryl groups (Pg. 2622, Column 2, Paragraph, first partial).
In the context of viruses, more specifically SARS-CoV-2, Li et al. (Li Q, Wu J, Nie J, Zhang L, Hao H, Liu S, Zhao C, Zhang Q, Liu H, Nie L, Qin H, Wang M, Lu Q, Li X, Sun Q, Liu J, Zhang L, Li X, Huang W, Wang Y. The Impact of Mutations in SARS-CoV-2 Spike on Viral Infectivity and Antigenicity. Cell. 2020 Sep 3;182(5):1284-1294.e9. Epub 2020 Jul 17.) teach different mutations in the SARS-CoV-2 S protein and how they affect infectivity, glycosylation, and antigenicity (see Summary). In particular, they found that specific mutations increased or decreased infectivity, increased or decreased sensitivity to neutralizing monoclonal antibodies (mAbs), and/or increased or decreased sensitivity to convalescent sera (see Table 1).
Since the prior art teaches that it is unpredictable if variants of known antigenic polypeptides will fold correctly and if variants of known nucleic acids encoding said polypeptides will function as expected, and the specification does nothing to ameliorate these concerns, one would be burdened with undue experimentation to use the products of the instant claims as broadly as they are currently claimed.
Working examples. No working examples of the claimed variants are disclosed in the specification. The only vectors studied in the working examples were VXA-CoV2-1 and ED107, which comprise SEQ ID NOs: 8 and 23, respectively, at 100% identity.
Guidance in the specification. The specification provides guidance towards constructs shown which are presumably 100% identical to the claimed sequences. The instant Specification fails to disclose the critical or essential amino acids or nucleotides which must be present and any variants of the claimed sequences. The instant Specification does not even provide insight into what kinds of changes can be tolerated.
Amount of experimentation necessary. Since the art teaches that it is unpredictable whether or not peptide and nucleotide variants of known sequences will function as intended, and the Specification does nothing to ameliorate these concerns, one would be burdened with undue experimentation to use the products of the instant claims as broadly as they are currently claimed. In light of the Supreme Court decision in Amgen Inc. et al. v. Sanofi et al., 143 S. Ct. 1243 (2023) (hereafter Amgen), updated guidelines were provided regarding the assessment of enablement (Federal Register, pp. 1563-1566; Pub. Jan. 10, 2024.) In Amgen, the Supreme Court unanimously affirmed that a genus of monoclonal antibodies was not enabled because, when a range within a genus is claimed, there must be reasonable enablement of the scope of the range. The Court found in Amgen that due to the large number of possible candidates within the scope of the claims and the specification's corresponding lack of structural guidance, it would have required undue experimentation to synthesize and screen each candidate to determine which compounds in the claimed class exhibited the claimed functionality. In the instantly claimed invention, the breadth of the claimed sequence variants is extremely broad, especially given the lack of guidance in the Specification regarding the critical or essential amino acids or nucleotides which must be present and what kinds of changes can be tolerated. This wide breadth also extends to each variant and each modality (i.e., nucleic acid versus protein), just to name a few variables.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to make and/or use the claimed products.
Claims 2-3, 31, and 57 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant application attempts to tie sequence identity to function in the context of a chimeric adenoviral expression vector, comprising an expression cassette comprising: a nucleic acid encoding an antigenic polypeptide; and a nucleic acid encoding a SARS-CoV-2 N protein, wherein the antigenic polypeptide is not a SARS-CoV-2 protein, wherein the SARS-CoV-2 N protein comprises an amino acid sequence having at least 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 2, and wherein the nucleic acid encoding the SARS-CoV-2 N protein comprises a sequence having at least 85%, 90%, 95%, 97%, 99%, or 100% identity to the sequence of SEQ ID NO: 4. The instant application also attempts to tie sequence identity to function in the context of a chimeric polynucleotide, comprising an expression cassette comprising: a nucleic acid encoding an antigenic polypeptide, with the proviso that the antigenic polypeptide is not a SARS-CoV-2 protein; and a nucleic acid encoding a SARS-CoV-2 N protein, wherein the SARS-CoV-2 N protein comprises an amino acid sequence having at least 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 2, optionally wherein the nucleic acid encoding the SARS-CoV-2 N protein comprises a sequence having at least 85%, 90%, 95%, 97%, 99%, or 100% identity to the sequence of SEQ ID NO: 4. Additionally, instant application also attempts to tie sequence identity to function in the context of a chimeric adenoviral expression vector, comprising a bicistronic or multicistronic expression construct comprising: a nucleic acid encoding a SARS-CoV-2 S protein; and a nucleic acid encoding a SARS-CoV-2 N protein, wherein the bicistronic construct is operably linked to a promoter, wherein the SARS-CoV-2 N protein comprises an amino acid sequence having at least 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 2, optionally wherein the nucleic acid encoding the SARS-CoV-2 N protein comprises a sequence having at least 85%, 90%, 95%, 97%, 99%, or 100% identity to the sequence of SEQ ID NO: 4; and/or the SARS-CoV-2 S protein comprises a sequence having at least 90% identity to SEQ ID NO: 1, optionally wherein the nucleic acid encoding the SARS-CoV-2 S protein comprises a sequence having at least 85%, 90%, 95%, 97%, 99%, or 100% identity to the sequence of SEQ ID NO: 3. While a percent identity threshold is provided in the claims for the claimed sequences, the instant Specification fails to disclose the critical or essential amino acids or nucleotides which must be present and that therefore cannot be changed. The claim language does not limit how the claimed changes can be interpreted for the instant sequences. The instant Specification does not even provide insight into what kinds of changes can be tolerated. Paragraph 0061 states that unless “otherwise indicated, a particular nucleic acid sequence also encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions) and complementary sequences, as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and/or deoxyinosine residues”. Paragraph 0066 states that the “terms ‘polypeptide’, ‘peptide’, and ‘protein’ are used interchangeably herein to refer to a polymer of amino acid residues” and that the “terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer”. Paragraph 0067 states that the “term ‘amino acid’ refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids”. It then goes on to provide examples of said analogs and mimetics. Paragraphs 0069-0073 describe ways to determine sequence identity and the term “variant” is used throughout the disclosure, although no specific definition is provided. While the information provided in the aforementioned paragraphs is helpful, the claims read on variants of the recited sequences with insertions, deletions, and even non-conservative substitutions present. As such, it would be unclear to a person having ordinary skill in the art to know what to change and what not to change.
Furthermore, while it is not explicitly stated, it is assumed that the constructs shown in the data provided have sequences which are 100% identical to the claimed sequences. Even if that is not the case, the data shown do not explicitly include any claimed variants having as little as 85% sequence identity, or even 90-99% sequence identity, relative to the instant sequences, raising questions about how effective these claimed variants would be in the experiments performed. Thus, it was not clear what was tested, it does not appear that any claimed variants were tested, and the essential characteristics of the genera being claimed by Applicant have not been identified or disclosed. One way to overcome the instant Written Description rejection is for Applicant to show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that Applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
As such, it does not appear Applicant was in possession of the full scope of the claimed invention at the time of filing and thus Claims 2-3, 31, and 57 do not meet the written description requirement.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 4, 8-9, 15-16, 18, 23-26, 30, 33, 37-38, 43-44, 46, 51-52, 54, 56, 64, and 67 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Jooss et al. (WO 2020/243719 A1, Published 03 December 2020) (cited on IDS filed by Applicant on 22 August 2023).
Jooss et al. teach modified Adenoviruses or Adenovirus expression vectors comprising chimeric polynucleotides in the form of antigen cassettes for delivering one or more payload nucleic acid sequences (see Abstract; Paragraphs 0290, 0292), wherein the one or more payload nucleic acid sequences encode one or more antigens, wherein the antigen comprises a MHC class I epitope, a MHC class II epitope, an epitope capable of stimulating a B cell response, or a combination thereof (see Paragraphs 0029, 00290), wherein the antigens can be generated from a coronavirus, such as SARS-CoV-2, and wherein the antigen can be the N protein or Nucleocapsid (see Paragraphs 0248, 0250), which reads on instant Claims 1, 4, 30, 33, 51. The instant claims do not specify that the “antigenic polypeptide” recited in Claims 1 and 30 has to be a heterologous antigenic polypeptide. Claims 30 only specifies that the antigenic polypeptide cannot be another SARS-CoV-2 protein. As such, this claim language is being interpreted as simply reading on a polypeptide naturally expressed by the Adenovirus vector, which also reads on the viral antigen recited in instant Claims 4 and 33. Therefore, Jooss et al. meets these claims limitations.
Jooss et al. also teach a modified Adenovirus expression vector comprising a chimeric polynucleotide in the form of an antigen cassette wherein said cassette comprises a construct expressing multiple payload nucleic acids encoding multiple or a plurality of antigens, including cancer or tumor antigens, antigens from pathogens, antigens from a virus, antigens from a bacteria, antigens from a fungus, and/or antigens from a parasite, wherein the antigens can be generated from a coronavirus, such as SARS-CoV-2, and wherein the antigen can be the N protein or Nucleocapsid (see Paragraphs 0248, 0250), and wherein said nucleic acids are operably linked to a promoter (see Paragraphs 0006-0007, 0032, 00130-00132, 00290-00292, 00296-00297), wherein the promoter is a CMV promoter (see Paragraphs 0009, 0017), which reads on instant Claims 1, 4, 8-9, 30, 33, 37-38, 51.
Additionally, Jooss et al. teach a modified Adenovirus expression vector comprising a chimeric polynucleotide in the form of an antigen cassette wherein the cassette contains multiple payload nucleic acid sequences encoding multiple or a plurality of antigens, including cancer or tumor antigens, antigens from pathogens, antigens from a virus, antigens from a bacteria, antigens from a fungus, and/or antigens from a parasite, wherein the antigens can be generated from a coronavirus, such as SARS-CoV-2, and wherein the antigen can be the N protein or Nucleocapsid (see Paragraphs 0248, 0250), wherein each is independently operably linked to a separate promoter and/or linked together using other multicistronic systems, such as 2A ribosome skipping sequence elements (e.g., E2A, P2A, F2A, or T2A sequences) or Internal Ribosome Entry Site (IRES) sequence elements (see Paragraphs 00290-00291, 00296-00297), wherein said promoters can the beta-actin promoter and the CMV promoter (see Paragraph 00294), wherein said antigens can be in any orientation relative to one another (see Paragraphs 00298), and wherein the antigen cassette comprises a polyadenylation signal, such as the Bovine Growth Hormone (BGH) polyA sequence (see Paragraphs 0006, 0009, 0016, 0041, 00295), which reads on instant Claims 1, 4, 8-9, 15-16, 18, 30, 33, 37-38, 43-44, 46, 51.
Furthermore, Jooss et al. also teach a modified Adenovirus expression vector comprising a chimeric polynucleotide in the form of an antigen cassette wherein the cassette contains multiple payload nucleic acid sequences encoding multiple or a plurality of antigens, wherein the antigens can be generated from a coronavirus, such as SARS-CoV-2, and wherein the antigens can be the N protein or Nucleocapsid and the Spike protein (see Paragraphs 0248, 0250), wherein each is independently operably linked to a separate promoter and/or linked together using other multicistronic systems, such as 2A ribosome skipping sequence elements (e.g., E2A, P2A, F2A, or T2A sequences) or Internal Ribosome Entry Site (IRES) sequence elements (see Paragraphs 00290-00291, 00296-00297), wherein said promoters can the beta-actin promoter and the CMV promoter (see Paragraph 00294), wherein said antigens can be in any orientation relative to one another (see Paragraphs 00298), and wherein the antigen cassette comprises a polyadenylation signal, such as the Bovine Growth Hormone (BGH) polyA sequence (see Paragraphs 0006, 0009, 0016, 0041, 00295-00298), which reads on instant Claims 56, 64, and 67.
Finally, Jooss et al. teach a mammalian host cell comprising the modified Adenovirus expression vector comprising a chimeric polynucleotide in the form of an antigen cassette (see Paragraphs 00345, 00406-00407), which reads on instant Claims 23 and 54. Jooss et al. also teach compositions comprising said modified Adenovirus expression vector and a pharmaceutically acceptable carrier (see Abstract; Paragraphs 0049, 0053) as well as a method for stimulating an immune response against an antigenic polypeptide wherein the method comprises administering said vector or said composition comprising said vector to a subject, wherein said subject is a mammal, including a human (see Paragraphs 0054, 00172-00173, 00269-00270), and wherein the route of administration is oral or intranasal (see Paragraphs 00379-00382, 00395-00397), both of which are types of mucosal administration routes, which reads on instant Claims 24-26 and 52.
For at least these reasons, Jooss et al. teach the limitations of instant 1, 4, 8-9, 15-16, 18, 23-26, 30, 33, 37-38, 43-44, 46, 51-52, 54, 56, 64, and 67 and anticipate the invention encompassed by said claims.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-4, 8-9, 15-16, 18, 20-21, 23-26, 28, 30-31, 33, 37-38, 43-44, 46, 48-49, 51-52, 54, 56-57, 64, and 67 are rejected under 35 U.S.C. 103 as being unpatentable over Jooss et al. (WO 2020/243719 A1, Published 03 December 2020) (cited on IDS filed by Applicant on 22 August 2023), Tucker (US 2013/0164326 A1, Published 27 June 2013), Georges et al. (US 2021/0260180 A1, earliest Priority Date 14 February 2020), and Jennings et al. (US 2025/0195501 A1, earliest Priority Date 07 May 2020).
Jooss et al. teach modified Adenoviruses or Adenovirus expression vectors comprising chimeric polynucleotides in the form of antigen cassettes for delivering one or more payload nucleic acid sequences (see Abstract; Paragraphs 0290, 0292), wherein the one or more payload nucleic acid sequences encode one or more antigens, wherein the antigen comprises a MHC class I epitope, a MHC class II epitope, an epitope capable of stimulating a B cell response, or a combination thereof (see Paragraphs 0029, 00290), wherein the antigens can be generated from a coronavirus, such as SARS-CoV-2, and wherein the antigen can be the N protein or Nucleocapsid (see Paragraphs 0248, 0250). The instant claims do not specify that the “antigenic polypeptide” recited in Claims 1 and 30 has to be a heterologous antigenic polypeptide. Claims 30 only specifies that the antigenic polypeptide cannot be another SARS-CoV-2 protein. As such, this claim language is being interpreted as simply reading on a polypeptide naturally expressed by the Adenovirus vector, which also reads on the viral antigen recited in instant Claims 4 and 33. Therefore, Jooss et al. meets these claims limitations.
Jooss et al. also teach a modified Adenovirus expression vector comprising a chimeric polynucleotide in the form of an antigen cassette wherein said cassette comprises a construct expressing multiple payload nucleic acids encoding multiple or a plurality of antigens, including cancer or tumor antigens, antigens from pathogens, antigens from a virus, antigens from a bacteria, antigens from a fungus, and/or antigens from a parasite, wherein the antigens can be generated from a coronavirus, such as SARS-CoV-2, and wherein the antigen can be the N protein or Nucleocapsid (see Paragraphs 0248, 0250), and wherein said nucleic acids are operably linked to a promoter (see Paragraphs 0006-0007, 0032, 00130-00132, 00290-00292, 00296-00297), wherein the promoter is a CMV promoter (see Paragraphs 0009, 0017).
Additionally, Jooss et al. teach a modified Adenovirus expression vector comprising a chimeric polynucleotide in the form of an antigen cassette wherein the cassette contains multiple payload nucleic acid sequences encoding multiple or a plurality of antigens, including cancer or tumor antigens, antigens from pathogens, antigens from a virus, antigens from a bacteria, antigens from a fungus, and/or antigens from a parasite, wherein the antigens can be generated from a coronavirus, such as SARS-CoV-2, and wherein the antigen can be the N protein or Nucleocapsid (see Paragraphs 0248, 0250), wherein each is independently operably linked to a separate promoter and/or linked together using other multicistronic systems, such as 2A ribosome skipping sequence elements (e.g., E2A, P2A, F2A, or T2A sequences) or Internal Ribosome Entry Site (IRES) sequence elements (see Paragraphs 00290-00291, 00296-00297), wherein said promoters can the beta-actin promoter and the CMV promoter (see Paragraph 00294), wherein said antigens can be in any orientation relative to one another (see Paragraphs 00298), and wherein the antigen cassette comprises a polyadenylation signal, such as the Bovine Growth Hormone (BGH) polyA sequence (see Paragraphs 0006, 0009, 0016, 0041, 00295).
Furthermore, Jooss et al. also teach a modified Adenovirus expression vector comprising a chimeric polynucleotide in the form of an antigen cassette wherein the cassette contains multiple payload nucleic acid sequences encoding multiple or a plurality of antigens, wherein the antigens can be generated from a coronavirus, such as SARS-CoV-2, and wherein the antigens can be the N protein or Nucleocapsid and the Spike protein (see Paragraphs 0248, 0250), wherein each is independently operably linked to a separate promoter and/or linked together using other multicistronic systems, such as 2A ribosome skipping sequence elements (e.g., E2A, P2A, F2A, or T2A sequences) or Internal Ribosome Entry Site (IRES) sequence elements (see Paragraphs 00290-00291, 00296-00297), wherein said promoters can the beta-actin promoter and the CMV promoter (see Paragraph 00294), wherein said antigens can be in any orientation relative to one another (see Paragraphs 00298), and wherein the antigen cassette comprises a polyadenylation signal, such as the Bovine Growth Hormone (BGH) polyA sequence (see Paragraphs 0006, 0009, 0016, 0041, 00295-00298).
Finally, Jooss et al. teach a mammalian host cell comprising the modified Adenovirus expression vector comprising a chimeric polynucleotide in the form of an antigen cassette (see Paragraphs 00345, 00406-00407). Jooss et al. also teach compositions comprising said modified Adenovirus expression vector and a pharmaceutically acceptable carrier (see Abstract; Paragraphs 0049, 0053) as well as a method for stimulating an immune response against an antigenic polypeptide wherein the method comprises administering said vector or said composition comprising said vector to a subject, wherein said subject is a mammal, including a human (see Paragraphs 0054, 00172-00173, 00269-00270), and wherein the route of administration is oral or intranasal (see Paragraphs 00379-00382, 00395-00397), both of which are types of mucosal administration routes.
Jooss et al. does not teach chimeric Adenoviral vectors further comprising a TLR-3 agonist. Jooss et al. al does not teach specific sequences corresponding to instant SEQ ID NOs: 1 and 2. While Jooss et al. does teach codon optimization (see Paragraphs 0048, 00175, 00403), these teachings on their own do not render the instant claims, specifically instant SEQ ID NOs: 3 and 4, obvious. Additionally, Jooss et al. fail to teach a method of eliciting an immune response in an alveolar cell, an absorptive enterocyte, a ciliated cell, a goblet cell, a club cell, and/or an airway basal cell. These deficiencies are remedied by the addition of the supporting references below.
Tucker teaches chimeric Adenoviral vectors comprising a nucleic acid encoding a heterologous polypeptide wherein said polypeptide is a viral, bacterial, cancer, fungal, or parasite antigen (see Abstract; Paragraphs 0083-0089), wherein said vectors further comprise a TLR-3 agonist, wherein said agonist comprises a nucleic acid encoding a dsRNA, wherein the nucleic acid encoding the TLR-3 agonist comprises one of instant SEQ ID NOs: 11-18 (see Paragraphs 0098-0103). Specifically, Tucker teaches SEQ ID NOs: 3-5 and 8-12, which are 100% identical to and the same length as instant SEQ ID NOs: 11-18, respectively (see Sequence Listing). Tucker fails to teach chimeric Adenoviral vectors comprising nucleic acids corresponding to instant SEQ ID NOs: 3 and 4 or nucleic acids encoding sequences which correspond to instant SEQ ID NOs: 1 and 2 as well as a method of eliciting an immune response in an alveolar cell, an absorptive enterocyte, a ciliated cell, a goblet cell, a club cell, and/or an airway basal cell. These deficiencies are remedied by the addition of Georges et al. and Jennings et al. below.
Georges et al. teach immunogenic compositions comprising replication-defective Adenoviral vector comprising an expression cassette encoding one or more SARS-CoV-2 antigens, such as the Spike protein and N protein (see Abstract; Paragraphs 0009-0010, 0020, 0028, 0127, 0179, 0402; Figures 3A, 10). Specifically, Georges et al. teach SEQ ID NOs: 3 and 10, which are 100% identical to and the same length as instant SEQ ID NOs: 1 and 2, respectively (see Sequence Listing). Georges et al. also teach immunogenic compositions wherein the coding sequence of the transgene is codon-optimized for a mammalian subject, such as a human, specifically in the context of the nucleic acids encoding the disclosed SARS-CoV-2 proteins, including prior art SEQ ID NOs: 3 and 10 (see Paragraphs 0013, 0123, 0127, 0296, 0402). As instant SEQ ID NOs: 3 and 4 are nucleic acid sequences encoding the S and N proteins, respectively, that were codon-optimized for expression in human cells (see instant Paragraph 0147), the teachings of Georges et al. render these sequences obvious, as codon optimization is well-known in the art, programs and services for said optimization are widely available, and it would have been obvious to a skilled artisan to optimize the codon usage for the expression system being used. As such, Georges et al. meet these limitations of the instant claims. Georges et al. fail to teach a method of eliciting an immune response in an alveolar cell, an absorptive enterocyte, a ciliated cell, a goblet cell, a club cell, and/or an airway basal cell. These deficiencies are remedied by the addition of Jennings et al. below.
Jennings et al. teach methods for inhibiting the interaction of a coronavirus with an ACE2-expressing cell (see Abstract), wherein the method comprises administering an immunogenic composition comprising an ACE2 polypeptide-interacting peptide compound to a subject, wherein the immunogenic composition elicits an immune response in an ACE2-expressing cell, such as an alveolar cell or an enterocyte, against an ACE2-interacting coronavirus, such as SARS-CoV-2, wherein the peptide compound is administered to the subject orally or intranasally via a vector, such as a viral vector, including an Adenoviral vector (see Paragraphs 0005-0011, 0067, 0100, 0103, 0159, 0163, 0195, 0203, 0206, 0210-0212; Claims 34, 38, 48).
A person having ordinary skill in the art would have been motivated to combine the teachings of Jooss et al., Tucker, Georges et al., and Jennings et al. in order to generate a chimeric Adenoviral expression vector. The TLR-3 agonist taught by Tucker would serve to enhance the immune recognition of the antigen or antigens of interest present, such as the ones taught by Georges et al., which could be incorporated into the chimeric Adenoviral expression vector of Jooss et al. It would have been obvious for a skilled artisan to incorporate specific sequences for the N and/or S proteins, such as those taught by Georges et al., account for any new SARS-CoV-2 variants which have emerged or are emerging in order to protect subjects from the new strains. It would have been obvious for a skilled artisan to try combining the methods of Jennings et al. and Jooss et al. while using the chimeric Adenoviral expression vector of Jooss et al. to more directly elicit an immune response in the cells with which SARS-CoV-2 bind, such as alveolar cells, as taught by Jennings et al., especially in light of the fact that chimeric Adenoviral vectors expressing a heterologous polypeptide elicit strong and effective immune responses specific for said heterologous polypeptide when administered orally, intranasally, or mucosally, as taught by Tucker. As such, the combination of these teachings renders the invention encompassed by said claims obvious and thus render instant Claims 1-4, 8-9, 15-16, 18, 20-21, 23-26, 28, 30-31, 33, 37-38, 43-44, 46, 48-49, 51-52, 54, 56-57, 64, and 67 obvious over the prior art.
Such modifications, combining prior art elements according to known methods in order to yield predictable results, would have had a reasonable expectation of success and arrived at the claimed invention prior to the effective filing date of the instant application. For at least these reasons, instant Claims 1-4, 8-9, 15-16, 18, 20-21, 23-26, 28, 30-31, 33, 37-38, 43-44, 46, 48-49, 51-52, 54, 56-57, 64, and 67 are rejected under 35 U.S.C. 103 as being unpatentable over the prior art.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 30-31, 33, 37-38, 43, and 48-49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 35-36 and 40-41 of copending Application No. 18/000,638 (reference application) (Published as US 2023/0210980 A1). Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are drawn to a chimeric polynucleotide comprising an expression cassette comprising: a nucleic acid encoding an antigenic polypeptide or protein and a nucleic acid encoding a SARS-CoV-2 N protein, wherein the antigenic protein is a cancer antigen, a fungal antigen, a viral antigen, a bacterial antigen, or a parasitic antigen. Both claim sets are also drawn to an expression cassette comprising a bicistronic or multicistronic construct wherein each nucleic acid is operably linked to a respective promoter and wherein the expression cassette further comprises a nucleic acid encoding a TLR-3 agonist, wherein the TLR-3 agonist comprises a nucleic acid encoding a dsRNA. Additionally, both claim sets are drawn to an expression cassette wherein the nucleic acid encoding the antigen protein or polypeptide is positioned 5’ of the nucleic acid encoding the SARS-CoV-2 N protein. Furthermore, instant SEQ ID NO: 2 is 100% identical to and the same length as reference SEQ ID NO: 2 and instant SEQ ID NOs: 11-18 are 100% identical to and the same length as reference SEQ ID NOs: 13-20, respectively.
The main differences between the instant claims and the reference claims are the instant claims are drawn to an antigenic polypeptide with the proviso that the antigenic polypeptide is not a SARS-CoV-2 protein, wherein the nucleic acid encoding the SARS-CoV-2 N protein optionally comprises instant SEQ ID NO: 4, wherein the antigenic polypeptide is, alternatively, an HPV antigen optionally comprising instant SEQ ID NO: 22, wherein the expression cassette alternatively comprises an IRES or ribosomal skipping element and has the CMV promoter, while the reference claims are drawn to a chimeric polynucleotide encoding a generic antigenic protein of any kind, is silent on the specific elements comprising the reference expression cassette, and wherein the expression cassette has the N protein situated between the antigenic protein and the TLR-3 agonist.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 56-57, 64, and 67 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 7-10 of copending Application No. 18/000,638 (Published as US 2023/0210980 A1) in view of Jooss et al. (WO 2020/243719 A1, Published 03 December 2020) (cited on IDS filed by Applicant on 22 August 2023).
Both claim sets are drawn to a chimeric Adenoviral expression vector comprising a bicistronic or multicistronic expression construct comprising a nucleic acid encoding a SARS-CoV-2 S protein, a nucleic acid encoding a SARS-CoV-2 N protein, and a nucleic acid encoding a TLR-3 agonist. Both claim sets are also drawn to an expression construct operably linked to a promoter, wherein said promoter is a CMV promoter. Additionally, instant SEQ ID NOs: 1-4 are 100% identical to and the same length as reference SEQ ID NOs: 1-4, respectively, and instant SEQ ID NOs: 11-18 are 100% identical to and the same length as reference SEQ ID NOs: 13-20, respectively.
The main differences between the instant claims and the reference claims are that the instant claims are drawn an expression cassette comprising an IRES, ribosomal skipping element, or a furin cleavage site positions between the nucleic acids encoding the S and N proteins and wherein the expression cassette comprises a polyadenylation signal, such as the BGH polyadenylation signal, while the reference claims are silent about the presence of such elements in the expression cassette and the reference claims are drawn to an expression cassette wherein the N protein is situated between the S protein and the TLR-3 agonist.
As noted above, Jooss et al. teach a modified Adenovirus expression vector comprising a chimeric polynucleotide in the form of an antigen cassette wherein the cassette contains multiple payload nucleic acid sequences encoding multiple or a plurality of antigens, wherein the antigens can be generated from a coronavirus, such as SARS-CoV-2, and wherein the antigens can be the N protein or Nucleocapsid and the Spike protein (see Paragraphs 0248, 0250), wherein each is independently operably linked to a separate promoter and/or linked together using other multicistronic systems, such as 2A ribosome skipping sequence elements (e.g., E2A, P2A, F2A, or T2A sequences) or Internal Ribosome Entry Site (IRES) sequence elements (see Paragraphs 00290-00291, 00296-00297), wherein said promoter(s) can be the CMV promoter (see Paragraph 00294), wherein said antigens can be in any orientation relative to one another (see Paragraphs 00298), and wherein the antigen cassette comprises a polyadenylation signal, such as the Bovine Growth Hormone (BGH) polyA sequence (see Paragraphs 0006, 0009, 0016, 0041, 00295-00298).
A person having ordinary skill in the art would have been motivated to modify the teachings of the reference claims with those of Jooss et al. in order to generate a chimeric Adenoviral expression vector. The TLR-3 agonist taught by the reference claims would serve to enhance the immune recognition of the reference antigens of interest present. It would have been obvious for a skilled artisan to incorporate specific sequences for the N and/or S proteins, such as those taught by the reference claims in order to target specific SARS-CoV-2 strains. The expression elements included in the expression cassette of Jooss et al. would have allowed for the efficient and regulated expression of the S and N proteins taught by the reference claims so that the proteins are correctly processed and expressed at the appropriate levels, leading to a more effective chimeric Adenoviral expression vector. As such, the combination of these teachings renders the invention encompassed by said claims obvious and thus render instant Claims 56-57, 64, and 67 obvious over the reference claims.
Such modifications, combining prior art elements according to known methods in order to yield predictable results, would have had a reasonable expectation of success and arrived at the claimed invention. For at least these reasons, instant Claims 56-57, 64, and 67 as being unpatentable over the reference application in view of Jooss et al.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
The prior art made of record, but not relied upon, and considered pertinent to applicant's disclosure is listed below:
Tucker (U.S. Patent No. 7,879,602 B2)
Tucker teaches chimeric Adenoviral vectors expressing an antigen of interest and methods for using said vectors to elicit an immune response against said antigen of interest. This reference has not been utilized, as rejection would have been redundant to those set forth above.
Tucker (U.S. Patent No. 8,222,224 B2)
Tucker teaches chimeric Adenoviral vectors expressing an antigen of interest and methods for using said vectors to elicit an immune response against said antigen of interest. This reference has not been utilized, as rejection would have been redundant to those set forth above.
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/CAREY ALEXANDER STUART/Examiner, Art Unit 1671
/RACHEL B GILL/Primary Examiner, Art Unit 1671