CHIMERIC ADENOVIRAL VECTORS

§103 §112 §DOUBLEPATENT

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 . Claims Status Applicant’s amendment submitted 5/15/2026 is acknowledged. Claims 1-3, 7-16, 19, 35-36, and 40-41 are canceled. New claims 62-73 are added. Claims 21-22, 27, 29, 30, 34, and 62-73 are pending. Claims 30, 34, and 71 are withdrawn as being drawn to a nonelected invention. Claims 21, 22, and 27 are rejoined and considered. Claims 21, 22, 27, 29, and 62-70, and 72-73 are under examination on the merits. Election/Restrictions Applicant’s election without traverse of Group I, claims 1-3, 7-16, 19, 21-22, 27, 29, 35-36, and 40-41, and the required species: a chimeric adenoviral expression vector, comprising an expression cassette comprising a first, second, and third promoter, as recited in claims 1 and 35 and their dependents, in the reply filed on 11/10/2025 is acknowledged. Claims 30, 34, and 71 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/10/2025. Claims 14-16, 19, 21-22, and 27 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/10/2025. After further consideration, it appears that claims 21 and 22 read on the elected species, therefore they are rejoined and considered. The species election is otherwise still maintained. Claims 21, 22, 27, 29, and 62-70, and 72-73 are under examination on the merits. Withdrawn Objections The previous objections are hereby withdrawn due to Applicant’s amendment submitted on 5/15/2026: Claim objections: Claims 12 and 13 as being dependent upon a rejected base claim. Withdrawn Rejections The previous rejections are hereby withdrawn due to Applicant’s amendment submitted on 5/15/2026: 35 U.S.C. §112(b): claims 36 and 41 35 U.S.C. §112(d): claim 36 35 U.S.C. §103:Claims 1-3, 9-11, 29, 35-36, and 40-41 under 35 U.S.C. 103 as being unpatentable over Tucker (US 20110081375 A1, published 4/7/2011, priority date 2/28/2006; on IDS) in view of Johnson (WO 2017176596 A1, published 10/12/2017, filing date 3/31/2017) and Wu (Nature. 2020 Mar;579(7798):265-269. doi: 10.1038/s41586-020-2008-3. Epub 2020 Feb 3. Erratum in: Nature. 2020 Apr;580(7803):E7. doi: 10.1038/s41586-020-2202-3. PMID: 32015508; on IDS) Double Patenting: Claims 1-3, 7-11, 29, 35-36 and 40-41 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 8-9, 15-16, 20-21, 24, 30-31, 33, 43-44, 48-49, 51, 56-57, 64, and 67 of copending Application No. 18/263,462 (reference application) in view of Tucker, Johnson, and Wu (supra); claims 1-3, 9, 29, 35-36, and 40-41 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 8222224 B2 in view of Johnson and Wu (supra). New Rejections 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. Written Description Claims 21, 22, 27, 29, 62-67, 69, and 72-73 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 claims above are drawn to a genus of chimeric adenoviral expression vectors, comprising an expression cassette comprising the following elements: (a) a first promoter operably linked to a nucleic acid encoding a SARS-CoV-2 S protein, wherein the nucleic acid encoding the SARS-CoV-2 S protein is at least 85% identical to the polynucleotide sequence of SEQ ID NO: 3; and (b) a second promoter operably linked to a nucleic acid encoding a toll-like receptor-e (TLR-3) agonist (claim 21). The claims also encompass the nucleic acid encoding the SARS-CoV-2 S protein is at least 90% (claim 72) or 95% (claim 73) identical to SEQ ID NO: 3. Additionally, the claims encompass the SARS-CoV-S protein has at least 95% identity to any one of SEQ ID NOs: 1, 21, or 22 (claim 22). There is inadequate written support for such genera, which allow for up to 15% variation in the polynucleotide sequence of SEQ ID NO: 3, or 5% amino acid variation of SEQ ID NOs: 1, 21, or 22. Even if the prior art is aware of such SARS-CoV-2 S proteins and respective nucleic acids encoding them, the totality of known proteins would not be representative of each entire genera for the reasons discussed below. Additionally, Claims 22, 27, 29, 62-67, 69, and 72-73 depend from claim 21 but fail to resolve this lack of defined structure. Regarding the claims’ limitation that the chimeric adenoviral expression vector comprises (b) a second promoter operably linked to a nucleic acid encoding a toll-like receptor-3 (TLR-3) agonist, the specification (paras. [0054-0055]) indicates that such agonist may be an antibody, which reads on anti-TLR-3 agonistic antibodies. Thus, “a toll-like receptor-3 (TLR-3) agonist” is being interpreted to encompass antibodies that have TLR-3 agonistic activity. However, antibodies generally require at least 6 CDRs to function, yet the claims fail to provide structural information for the claimed protein having TLR-3 agonistic activity, such as complete sequences of 6 CDRs (and associated numbering scheme), VH, and VL domains. Said another way, the claims encompass an antibody genus recited by function alone. Because such antibodies is not defined by any structure, one must ascertain whether there are sufficient representative species, which there are not in the instant case, because there are no examples in the specification of TLR-3 agonistic antibodies. Notably, in the case of antibodies, there is no structure to function correlation, because CDRs can be completely different but still provide insufficient examples to describe the whole genus. When one goes to the instant specification to identify a representative number of species to define the claimed genera with respect to such an antibody, they do not find any representative species of an antibody with TLR-3 agonistic activity. When one evaluates the specification for representative species of non-antibody TLR-3 agonist activity, they find SEQ ID NOs: 13-20, which are nucleic acids encoding dsRNA (para. [0055]). On 22 February 2018, the USPTO provided a Memorandum clarifying the Written Description Guidelines for claims drawn to antibodies. That Memorandum indicates that, in compliance with recent legal decisions, the disclosure of a fully characterized antigen no longer is sufficient written description of an antibody to that antigen. Even if the instant claims did not implicate the TLR-3 agonist as an antibody, the following analysis is pertinent to demonstrate how there is inadequate written support for the genus defined by function without sufficiently disclosed structure. Accordingly, the instant claims have been evaluated in view of that guidance. “[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04. An applicant may 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. Furthermore, to satisfy the written description requirement for the genera of: (i) nucleic acids encoding SARS-CoV-2 S protein at least 85% (or 90% or 95%) identical to SEQ ID NO: 3, (ii) SARS-CoV-2 S protein at least 95% identical to SEQ ID NOs: 1, 21, or 22, and (iii) antibody TLR-3 agonists, Applicant must adequately describe representative proteins or antibodies to reflect the structural diversity of the claimed genus. See Eli Lilly, 119 F.3d at 1568 (“[N]aming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993) (“Claiming all DNA[s] that achieve a result without defining what means will do so is not in compliance with the description requirement; it is an attempt to preempt the future before it has arrived.”). MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, as here in which (i) nucleic acids encoding SARS-CoV-2 S protein at least 85% (or 90% or 95%) identical to SEQ ID NO: 3, (ii) SARS-CoV-2 S protein at least 95% identical to SEQ ID NOs: 1, 21, or 22, and (iii) antibody TLR-3 agonists not defined by complete CDRs, VH, and VL chains, one must describe a sufficient variety of species to reflect the variation within the genus. Additionally, the TLR-3 agonist is interpreted to read on antibodies, but the disclosure has provided incomplete CDR sets. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615. “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” One of skill in this art cannot envision the structure of SARS-CoV-2 S proteins (up to 15% sequence variation in the nucleic acid encoding the S protein, or 5% sequence variation in the SARS-CoV-2 S protein amino acid sequence) without complete structural information. Therefore, since no species is provided to represent these genera, the claims encompassing the same clearly fail the written description requirement. Additionally, one of ordinary skill in the art cannot envision any antibody comprising zero CDRs that alone specifically has TLR-3 agonist activity. Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. See ABBVIE DEUTSCHLAND GMBH & 2 CO. v. JANSSEN BIOTECH, INC., Appeals from the United States District Court for the District of Massachusetts in Nos. 09-CV-11340-FDS, 10-CV-40003-FDS, and 10-CV-40004-FDS, Judge F. Dennis Saylor, IV. See also Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein). This is particularly pertinent for the genera of SARS-CoV-2 S proteins and TLR-3 agonist antibodies described here, wherein limited (claims 21, 22 and dependents), or no (TLR3 agonist antibodies), structural information is provided. For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding), “[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011). “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species.” Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010). Since the CDR set of each antibody is responsible for antigen binding function of an antibody, and said set varies structurally from antibody to antibody, there is no correlation between structure and function between the members of an antibody genus. One cannot “represent” the entire genus defined only by function with any structural consensus. Thus, functional language should not be used to define an antibody genus. Rather, structure should be used. Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Since each genus recited in the instant claims is large, it would be very challenging to describe sufficient species to cover the structures of the entire genus. While the specification discloses at least four chimeric adenoviral expression vectors encoding SARS-CoV-2 S proteins and a TLR-3 agonist (paras. [0146], [0149], [0156], [0163]), this limited number of species is certainly not adequate. Overall, at the time the invention was made, the level of skill for preparing proteins (or specifically antibodies) and then selecting those proteins (or specifically antibodies) with desired functional properties was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify proteins with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”) Absent the conserved structure provided by full amino acid sequence (or in the case of an antibody, all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences), the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what a protein with a particular set of functional properties would look like structurally. Because limited species of SARS-CoV-2 S proteins having proper activity with associated structural information have been provided, the instant claims above clearly fail the written description requirement. Additionally, since no antibodies possessing no CDRs are shown to be capable of having TLR-3 agonist activity, the instant claims above clearly fail the written description requirement. A representative number of species has not been taught to describe these genera. Given the well-known high level of polymorphism of immunoglobulins / antibodies, the skilled artisan would not have been in possession of the vast repertoire of antibodies and the unlimited number of antibodies encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genera of SARS-CoV-2 S proteins encoded by nucleic acid sequences having at least 85%, 90%, or 95% identical to SEQ ID NO: 3, or amino acid sequences at least 95% identical to SEQ ID NOs: 1, 21, or 22. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genera. Owed to the variation among antibodies with respect to their CDRs, the structure of antibodies that correlates with their function, it is very difficult to provide adequate representation of a functionally defined antibody genus. There is unlikely to be any CDR structure shared by the entire genus, for example. Also, the disclosure of one set of antibody CDRs does not guide one of skill to the next set of CDRs. This is because it is well-known in this art that mutation of CDR residues leads to loss of antigen binding. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proceedings of the National Academy of Sciences USA, Vol., 79, Pg. 1979-1983, 1982). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function (Abstract). Thus, while applicant has described one or a few species within each of the genera recited, and the art may provide more, each genus is very large and would encompass protein structures that cannot be visualized from the prior art or instant disclosure. One of skill in this art cannot determine the protein structures encompassed by the claimed genera only defined by function. Any future protein structure may or may not be encompassed, and if it is, it would not have been represented in Applicant’s disclosed species. Thus, the described species cannot be considered representative of the recited genera of antibodies or proteins defined only by function. E.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, the claims are rejected here. As discussed above, an applicant may 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. Therefore, it is recommended that the instant claims be amended to recite complete structural information of the claimed SARS-CoV-2 S protein and TLR-3 agonist, including full nucleic acid and amino acid sequences of the SARS-CoV-2 S protein and TLR-3 agonist (if applicable; including full CDRs, specific, and full-length heavy and light variable chain domains if the TLR-3 agonist is an antibody). Scope of Enablement Claims 21, 22, 27, 29, 62-70, and 72-73 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 a chimeric adenoviral expression vector, comprising an expression cassette comprising a first promoter operably linked to a nucleic acid encoding a SARS-CoV-2 S protein that has full nucleic acid or protein sequence information, does not reasonably provide enablement for a chimeric adenoviral expression vector, comprising an expression cassette comprising a first promoter operably linked to a nucleic acid encoding a SARS-CoV-2 S protein that is at least 85% (claim 21 and dependents), 90% (claim 72), or 95% (claim 73) identical to the polynucleotide sequence of SEQ ID NO: 3, or wherein the SARS-CoV-2 S protein has at least 95% identity to any one of SEQ ID NOs: 1, 21, or 22 (claim 22). Additionally, the claims encompass a chimeric adenoviral expression vector, wherein elements (a) and (b) together are encoded by a sequence having at least 85% identity to SEQ ID NO: 6 (claim 27). 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 or use the invention commensurate in scope with these claims. The art teaches that protein chemistry is probably one of the most unpredictable areas of biotechnology. For example, conservative 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). 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). Since the art teaches that it is unpredictable whether or not peptide variants will function as such and it is also unpredictable that even a known peptide that functions in vitro will function in vivo, and the specification does nothing to ameliorate these concerns, one would be burdened with undue experimentation to use the products of instant claims as broadly as they are currently claimed. Regarding claims 21, 22, 27, 62-70, and 72-73, Applicant broadly claims chimeric adenoviral expression vector, comprising an expression cassette comprising the following elements: (a) a first promoter operably linked to a nucleic acid encoding a SARS-CoV-2 S protein, wherein the nucleic acid encoding the SARS-CoV-2 S protein is at least 85% identical to the polynucleotide sequence of SEQ ID NO: 3; and (b) a second promoter operably linked to a nucleic acid encoding a toll-like receptor-e (TLR-3) agonist. The claim reads on a cell within a transgenic animal or a transgene therein given that the term "isolated" is not denoted in describing the chimeric adenoviral expression vector. 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). Therefore, undue experimentation is required to make and use a transgene and transgenic animal to produce the nucleic acids and proteins of the instant claims. Examples in the literature aptly demonstrate that even closely related species carrying the same transgene construct can exhibit widely varying phenotypes. Mullins (1993, Hypertension, Vol. 22, No. 4, pp. 630-633) states that not all animals express a transgene sufficiently to provide a model for a disease as the integration of a transgene into different species of animal has been reported to give divergent phenotypes. For example, several animal models of human diseases have relied on transgenic rats when the development of mouse models was not feasible. Mullins (1990, Nature, Vol. 344, 541-544) produced outbred Sprague-Dawley x WKY rats with hypertension caused by expression of a mouse Ren-2 renin transgene. Hammer (1990, Cell, Vol. 63, 1099- 1112) describes spontaneous inflammatory disease in inbred Fischer and Lewis rats expressing human class I major histocompatibility allele HLA-B27 and human 02- microglobulin transgenes. Both investigations were preceded by the failure to develop human disease-like symptoms in transgenic mice expressing the same transgenes that successfully caused the desired symptoms in transgenic rats (Mullins, 1989, EMBO J., Vol. 8, pages 4065-4072). Thus, the use of nonmurine species for transgenesis will continue to reflect the suitability of a particular species for the specific questions being addressed, bearing in mind that a given construct may react very differently from one species to another. 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, "chimeric adenoviral expression vector" and by amending the 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 chimeric adenoviral expression vectors encoding SARS-CoV-2 spike proteins, 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 and proteins they encode 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. Claim Rejections - 35 USC § 103 In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action: A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows: 1. Determining the scope and contents of the prior art. 2. Ascertaining the differences between the prior art and the claims at issue. 3. Resolving the level of ordinary skill in the pertinent art. 4. Considering objective evidence present in the application indicating obviousness or nonobviousness. This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention. Claims 21, 22, 29, 63-67, and 72-73 are rejected under 35 U.S.C. 103 as being unpatentable over Tucker (US 20110081375 A1, published 4/7/2011, priority date 2/28/2006; on IDS) in view of Van Doremalen, et al. (bioRxiv [Preprint]. 2020 May 13:2020.05.13.093195. doi: 10.1101/2020.05.13.093195) as evidenced by NCBI Reference Sequence: YP_009724390.1 (3/13/2020), and Genscript (GenScript Codon Usage Frequency Table Tool, published 4/13/2013 at https://web_archive_org/web/20200413001745/https://www.genscript_com/tools/codon-frequency-table, accessed on 9/20/2026, 3-page printout). The Prior Art Tucker discloses chimeric adenoviral vectors and methods for using the vectors to elicit an immune response to an antigen of interest (Abstract). Tucker also discloses a method for eliciting an immune response, the method comprising an immunogenic composition comprising (a) a chimeric viral vector comprising a first promoter operably linked to a nucleic acid encoding a heterologous polypeptide; (b) a non-specific immune response enhancer; and (c) a pharmaceutically acceptable carrier, wherein the immune response is directed against the heterologous polypeptide (claim 29), wherein the immune response enhancer is a toll-like receptor 3 (TLR3) agonist (claims 30-31). Tucker also teaches the immune response enhancer is encoded on the chimeric viral vector under the control of a second promoter (claim 34), and that the first and second promoters are the same (claim 35) or different (claim 36). Tucker further discloses that the promoters are independently selected from the beta actin promoter and the CMV promoter (paras. [0004] and [0082])). Regarding TLR-3 agonists, expressed TLR-3 agonists (e.g., dsRNA) could also be used with the invention (para. [0111]; claim 32). Tucker discloses a number of TLR-3 agonists (instant SEQ ID NOs: 13-20 are identical to Tucker’s SEQ ID NOs: 3, 4, 5, 8, 9, 10, 11, and 12, respectively; pp. 26-37). Tucker discloses that nucleic acids encoding suitable heterologous polypeptides may be derived from antigens, such as viral antigens, bacterial antigens, cancer antigens, fungal antigens, or parasite antigens (para. [0088]). Tucker also demonstrates that using a TLR-3 agonist along with a chimeric recombinant adenoviral vector can be generally applied to multiple different heterologous antigens, with a 100 fold improvement in antibody titer (para. [0136]). Further, Tucker discloses vector configurations with TLR-3 agonists (expressed dsRNA constructs) which are located downstream of an element expressing a heterologous viral protein (Fig. 5). However, Tucker does not teach a chimeric adenoviral expression vector comprising an expression cassette comprising (a) a first promoter operably linked to a nucleic acid encoding a SARS-CoV-2 S protein, wherein the nucleic acid encoding the SARS-CoV-2 S protein is at least 85% identical to the polynucleotide sequence of SEQ ID NO: 3; and (b) a second promoter operably linked to a nucleic acid encoding a toll-like receptor-3 (TLR-3) agonist. Van Doremalen teaches a ChAdOx1-vectored vaccine encoding a codon-optimized full-length spike protein of SARS-CoV-2 (NCBI Reference Sequence: YP_009724390.1), codon optimized for expression in human cell lines (p. 2, lines 39-40; p. 2, lines 22-24; p. 12, lines 223-225). Genbank accession number YP_009724390.1 is 100% identical in sequence to the instant SEQ ID NO: 1, see alignment summary from ABSS below. Additionally, YP_009724390.1 is 98.9% identical to instant SEQ ID NO: 21, and 99.2% identical to instant SEQ ID NO: 22. PNG media_image1.png 128 606 media_image1.png Greyscale Genscript teaches a Codon Usage Frequence Table Tool, which has frequency information for each codon in expression of host organisms, including human (p. 1). It would have been obvious to one of ordinary skill in the art to modify the chimeric adenoviral expression vector taught by Tucker to comprise an expression cassette comprising the following elements: (a) a first promoter operably linked to a nucleic acid encoding a SARS-CoV-2 S protein, wherein the nucleic acid encoding the SARS-CoV-2 S protein is at least 85% identical to the polynucleotide of SEQ ID NO: 3, and (b) a second promoter operably linked to a nucleic acid encoding a toll-like-3 (TLR-3) agonist, as required by claim 21. Van Doremalen teaches a ChAdOx1-vectored vaccine encoding a codon-optimized full-length spike protein of SARS-CoV-2, which is identical in sequence to the instant SEQ ID NO: 1, 98.9% identical to instant SEQ ID NO: 21, and 99.2% identical to instant SEQ ID NO: 22. The instant SEQ ID NO: 3 nucleotide sequence encodes instant SEQ ID NO: 1, with an additional 12 nucleotides upstream of the start codon, and a stop codon, followed by 6 additional nucleotides 3’ to the spike coding sequence. Accordingly, only 0.47% of SEQ ID NO: 3 does not correspond to a coding sequence that encodes a SARS-CoV-2 spike protein that is 100%, 98.9%, or 99.2% identical to SEQ ID NOs: 1, 21, or 22, respectively. However, as disclosed by van Doremalen, codon optimization, including codon optimization for expression of Adenovirus-vectored genes in human cells, is known in the art. Additionally, Genscript demonstrates that codon usage frequencies for humans were known in the art. Accordingly, it would have been obvious to one of ordinary skill in the art to optimize the SARS-CoV-2 spike protein taught by van Doremalen, and evidenced by YP_009724390.1, for expression in a particular species’ cells, such as human cells, and any possible combination of nucleotides that encode such a protein would be obvious. Therefore, an obvious codon-optimized nucleic acid encoding a SARS-CoV-2 spike protein identical to YP_009724390.1 would be >99% identical to SEQ ID NO: 3 (claims 21, 72, and 73). Similarly, the SARS-CoV-2 S protein having at least 95% identity to any one of SEQ ID NOs: 1, 21, or 22 would also be obvious (claim 22), or comprises the protein sequence of SEQ ID NO: 1 (claim 63). Regarding claim 29, which requires an immunogenic composition comprising the adenoviral expression vector of claim 21 and a pharmaceutically acceptable carrier, that too would be obvious because Tucker discloses compositions comprising adenoviral expression vectors and a pharmaceutically acceptable carrier. Regarding claim 64, which requires the nucleic acid encoding the TLR-3 agonist comprises a nucleic acid encoding a dsRNA, that would have been obvious because Tucker discloses use of expressed TLR-3 agonists (e.g., dsRNA). Claim 65, which requires the TLR-3 agonist comprises a sequence selected from the group consisting of: SEQ ID NOs: 13-20, would also have been obvious because Tucker discloses a number of these TLR-3 agonists (instant SEQ ID NOs: 13-20 are identical to Tucker’s SEQ ID NOs: 3, 4, 5, 8, 9, 10, 11, and 12, respectively). Regarding claims 66 and 67, which require the first promoter and second promoter to be identical, or specifically each a CMV promoter, they would each be obvious because Tucker teaches that the heterologous protein may be expressed by a first promoter and the immune response enhancer, the TLR-3 agonist, may be expressed by a second promoter, which can be identical, and CMV promoters. One of ordinary skill in the art would have been motivated to vaccinate against SARS-CoV-2 infection. There would have been a reasonable expectation of success because Tucker demonstrates that adenoviral vectors encoding transgenes and TLR-3 agonists induce potent immune responses. Therefore, claims 21, 22, 29, 63-67, and 72-73 would have been prima facie obvious to one of ordinary skill in the art before the priority date of the instant application. Applicant’s arguments have been considered but are not completely persuasive: Applicant presents the following arguments: The now claimed subject matter in claim 21 was not recited in any claim rejected under 35 U.S.C. §103 and the Examiner has indicated SEQ ID NO: 3 is allowable subject matter. Moreover, none of the cited references discloses or suggests a nucleic acid encoding a SARS- CoV-2 S protein that is at least 85% identical to the polynucleotide sequence of SEQ ID NO: 3 as recited in amended claim 21. Applicant’s arguments are not completely persuasive because: The Examiner’s previous indication that SEQ ID NO: 3 is free of the prior art of record is now nullified and corrected by the argument presented in the new rejection under 35 U.S.C. §103. 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. The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer. (New Rejection) Claims 21, 22, 29, 63-64, 66, and 72-73 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 8222224 B2 in view of Van Doremalen, et al. (bioRxiv [Preprint]. 2020 May 13:2020.05.13.093195. doi: 10.1101/2020.05.13.093195) as evidenced by NCBI Reference Sequence: YP_009724390.1 (3/13/2020), and Genscript (GenScript Codon Usage Frequency Table Tool, published 4/13/2013 at https://web_archive_org/web/20200413001745/https://www.genscript_com/tools/codon-frequency-table, accessed on 9/20/2026, 3-page printout). Although the claims at issue are not identical, they are not patentably distinct from each other because, while the instant claims are drawn to a chimeric adenoviral expression vector or a composition, and the ‘224 claims are drawn to a method for eliciting an immune response, ‘224’s method comprises administering an immunogenic composition, the immunogenic composition comprising (a) a chimeric viral vector comprising a first promoter operably linked to a nucleic acid encoding a heterologous polypeptide, (b) a non-specific immune response enhancer; and (c) a pharmaceutically acceptable carrier, wherein the immune response is directed against the heterologous polypeptide (claim 1). ‘224 also discloses an immunogenic composition comprising a chimeric adenoviral expression vector comprising a first promoter operably linked to a nucleic acid encoding a TLR-3 agonist that is dsRNA (claim 9). The first and second promoters may be the same (claim 3), or different (claim 4). Additionally, ‘224’s claims encompass the heterologous polypeptide being a viral antigen (claims 5-6). However, Notably, ‘224 does not disclose a chimeric adenoviral expression vector encoding a SARS-CoV-2 S gene. The teachings of Van Doremalen, NCBI Reference Sequence: YP_009724390.1 (3/13/2020), and Genscript are described above in the rejection under 35 U.S.C. §103. It would have been obvious to one of ordinary skill in the art to modify the chimeric adenoviral expression vector taught by ‘224 to comprise a first promoter operably linked to a nucleic acid encoding a SARS-CoV-2 S protein identical to that disclosed by van Doremalen as evidenced by YP_009724390.1, and a second promoter operably linked to a nucleic acid encoding a TLR-3 agonist. As discussed above in the rejection under 35 U.S.C. §103, it would have been obvious to one of ordinary skill in the art to codon optimize a nucleic acid sequence encoding the SARS-CoV-2 S protein sequence represented by YP_009724390.1, for expression in human cells. Accordingly, a sequence >99% identical to SEQ ID NO: 3 would have been obvious to one of ordinary skill in the art. ‘224 discloses that its chimeric adenoviral vectors are suitable for expressing an antigenic protein from a virus. Further, an immunogenic composition comprising the chimeric adenoviral expression vector and a pharmaceutically acceptable carrier would have been obvious to one of ordinary skill in the art, because ‘224 teaches immunogenic compositions that comprise chimeric adenoviral vectors and a pharmaceutically acceptable carrier. Additionally, ‘224 discloses that the gene encoding a heterologous protein can encode an antigenic protein from a virus. One of ordinary skill in the art would have been motivated to vaccinate against SARS-CoV-2. There would be a reasonable expectation of success because ‘224 demonstrates the suitability of chimeric adenoviral vectors and chimeric polynucleotides expressing viral antigens and TLR-3 agonists, and van Doremalen discloses adenoviral vectors encoding SARS-CoV-2 S proteins. Applicant’s arguments have been considered but are not completely persuasive: Applicant presents the following arguments: Claims 1-9 of U.S. Patent No 8,222,224 B2 in view of Johnson and Wu do not disclose or suggest a nucleic acid encoding a SARS-CoV-2 S protein that is at least 85% identical to the polynucleotide sequence of SEQ ID NO: 3 as recited in amended claim 21. For at least these reasons, claim 29 and the remaining pending claims which also depend from claim 21 are patentably distinct from claims 1-9 of U.S. Patent No. 8,222,224 in view of Johnson and Wu. Applicant’s arguments are not completely persuasive because: The examiner agrees and has withdrawn the previous non-statutory double patenting rejection in favor of the new non-statutory double patenting rejection presented above. Conclusion No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEFFREY MARK SIFFORD whose telephone number is (571)272-7289. The examiner can normally be reached 8:30 a.m. - 5:30 p.m. ET with alternating Fridays off. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Allen can be reached at 571-270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /JEFFREY MARK SIFFORD/Examiner, Art Unit 1671 /Michael Allen/Supervisory Patent Examiner, Art Unit 1671