CTNF 18/684,346 CTNF 89123 DETAILED ACTION Disposition of Claims Claims 1-2, 4-8, 11-13, 15-16, 18-23, and 26-28 are pending. Examiner’s Note All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20250144198A1, Published 05/08/2025. 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. Optional Authorization to Initiate Electronic Communications The Applicant’s representative may wish to consider supplying a written authorization in response to this Office action to correspond with the Examiner via electronic mail (e-mail). This authorization is optional on the part of the Applicant’s representative, but it should be noted that the Examiner may not initiate nor respond to communications via electronic mail unless and until Applicant’s representative authorizes such communications in writing within the official record of the patent application. A sample authorization is available at MPEP § 502.03, part II. If Applicant’s representative chooses to provide this authorization, please ensure to include a valid e-mail address along with said authorization. Information Disclosure Statement The information disclosure statement (IDS) submitted on 04/02/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. 06-49-06 AIA 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. 06-55 AIA Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a). Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered. Drawings 06-22 AIA The drawings are objected to because the legend of Fig. 1 at ¶[0015] refers to color (e.g. “Residues that were mutated are indicated in orange.”) Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance. 06-24-01 AIA Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification: The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2). Claim Objections 07-29-01 AIA Claim 4 is objected to because of the following informalities: claim 4 should recite in the preamble “The protein library of claim 1, “ and should delete “any one of” . Appropriate correction is required. 07-29-01 AIA Claim 11 is objected to because of the following informalities: “comprising” at line 2 should be “comprises” . Appropriate correction is required. Claim Rejections - 35 USC § 112(b); Second Paragraph 07-30-02 AIA The following is a quotation of 35 U.S.C. 112(b): (b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention. The following is a quotation of 35 U.S.C. 112 (pre-AIA), second paragraph: The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention. Claims 1, 11, 13, and 15 and dependent claims 2, 4-8, 12, 16, 18-23, and 26 thereof are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. 07-34-03 AIA The term “ protein library ” in claim 1 is a relative term which renders the claim indefinite. The term “ protein library ” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. While a “library”, in general, is understood to be an organized collection of materials, and a skilled artisan would understand what is a “protein”, the use of these two terms together is unclear because it is unclear as to what is, and what is not, considered a “protein library” under the metes and bounds of the claim. For instance, claim 1 does not recite that the library comprises a minimum number of variants, or that the proteins are isolated, purified, or within a host/biological sample. Similarly, it is unclear if the proteins must be recombinant or engineered/synthetic, or how the proteins should be organized or arrayed, or how the library should be generated. As a result, the breadth of the claim and the lack of structural guidance makes the metes and bounds of the claim unclear, because such a claim could read upon an engineered protein library which is isolated and purified into wells of a 96-well microtiter plate, or the “library” could read on naturally occurring populations of antigenic viral protein variants which are present during the natural course of infection . Claim 11 is rejected for similar reasoning and for depending upon claim 1, except that it reads upon “nucleic acid library” instead of a “protein library”. Still, the logic pattern set forth supra can also be applied to a “nucleic acid library”, as the structural limitations of said library have not been set forth. Claims 13 and 15 are also rejected for similar reasoning. Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant claims 1, 11, 13, and 15 are rejected on the grounds of being indefinite. Claims 2, 4-8, 12, 16, 18-23, and 26 are also rejected since they depend from claims 1, 11, 13, or 15, but do(es) not remedy these deficiencies of claims 1, 11, 13, or 15. Claim 1 and dependent claims 2, 4-8, 11-13, 15-16, 18-23, and 26 thereof are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention . 07-34-03 AIA The term “ hypervariable sites ” in claim 1 is a relative term which renders the claim indefinite. The term “ hypervariable sites ” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. While a definition of “hypervariable site” is provided at ¶[0036] of the specification, the definition fails to provide an objective boundary because “frequently” and “infrequently” are relative terms, as is the frame of reference or the number of strains or sequences of a virus that must be compared in order to determine if a site is “hypervariable” versus “variable” versus “conserved”. The claims and specification do not provide any frequency threshold, strain dataset, sequence-alignment method, viral subtype or lineage, host species, geographic population, sampling time period, entropy cutoff, percent identity cutoff, mutation rate cutoff, or any other statistical criterion for determining whether or not a site within a viral sequence is “conserved”, “variable”, or “hypervariable”. This creates further issues as the claims are drawn broadly to any viral antigenic protein from any virus, and amino acid variability may be “hypervariable” in one dataset, yet be “variable” or “conserved” in another dataset . Additionally, the term “different set of mutations” in claim 1 is a relative term which renders the claim indefinite. The term “different set of mutations” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Applicant notes at ¶[0035] that variants” describes a set of related proteins that comprise at least one mutation relative to each other and a “mutation” is a difference in an amino acid sequence relative to a reference sequence. However, the claim does not clearly identify the reference point for determining whether or not a “set of mutations” is “different”. It is unclear whether each variant must comprise a set of mutations that differs from a “base” or specific wild- type sequence, whether each variant must comprise a unique set of mutations relative to every other variant in the library, or whether the mutations at multiple variable sites within a single variant must be different from each other. Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant claim 1 is rejected on the grounds of being indefinite. Claims 2, 4-8, 11-13, 15-16, 18-23, and 26 are also rejected since they depend from claim 1 but does not remedy these deficiencies of claim 1. Claim 5 and dependent claims 6-8 thereof are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 5 recites “hemagglutinin” without expressly tying it to influenza virus hemagglutinin , as there are other types of hemagglutinins in other viruses (e.g. paramyxoviruses, coronaviruses, reoviruses, rotaviruses). It is suggested that claim 5 be amended to clearly recite from which virus the hemagglutinin is derived (e.g. “…wherein the antigenic viral protein is influenza hemagglutinin (HA).”) For at least these reasons, claim 5 is rejected on the grounds of being indefinite. Claims 6-7 are included for depending upon claim 5, but not clarifying the metes and bounds of claim 5 . 07-34-01 Claims 7-8 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claims 7-8 are rejected for not properly incorporating essential subject matter and information into the claim. In the instant case, claims 7-8 reference regions of influenza hemagglutinin (HA) within a figure. MPEP § 2173.05(s) discloses that where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant's convenience.” Ex parte Fressola , 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted). Further, the claim is indefinite because it is improper to import limitations from the specification into the claims, see MPEP §2111.01. Additionally, Figure 11 appears to be data from a passive serum transfer/challenge experiment, so the “regions” referenced are further unclear. Fig. 14 appears to comprise different domains of different subtypes of influenza A HA proteins. Finally, the use of “HA 1” and “HA 3” in parts a) and b) is unclear due to the wording of the claim, as the wording of “a region of HA 1 selected from…” is unclear in that it appears as though Applicant is either referring to a specific influenza A HA subtype (e.g. H1, H2, H3, H4, H5, etc.) or is referring to the HA subunits (e.g. HA1, which is the globular head of HA, or HA2, which is the stalk domain). As there is no HA3 subunit, it appears as though Applicant is referencing a specific type of HA subtype, and should use the appropriate, art-accepted terminology to avoid confusion as to what is being claimed. As the application refers to GenBank wild-type sequences (¶[0090]), and all references are fully incorporated by reference (¶[0087]), one suggestion is to update the sequence deposit to include these full-length influenza HA sequences to utilize as a frame-of-reference to specifically delineate the regions being claimed in instant claims 7-8. For instance, claim 8 refers to mutations that could occur at Sb 192, Sb 193, Sb 196, and Sb 198 or in the 120 loop, 150 loop, 160 loop, and 190 helix; the use of a SEQ ID NO: as a frame-of-reference would provide a skilled artisan with the knowledge as to what the “base” amino acid would be at these positions/loops/helices and therefore would allow that artisan to determine if a mutation has been generated. For at least these reasons, claims 7-8 are rejected on the grounds of being indefinite. 07-34-01 Claim 16 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 15 is drawn to a virus library comprising the nucleic acid library of claim 11, wherein each virus in the virus library comprises one of the nucleic acids of the nucleic acid library, and claim 16 is dependent upon claim 15 and drawn to wherein the virus is selected from the group consisting of influenza virus, HIV, SARS-CoV-2, HCV, RSV, and CMV. First, the use of “a virus library” and “each virus” in claim 15 and “the virus” in claim 16 raise issues as to clear antecedent basis. Claim 15 does not recite a single “a virus” that “the virus” of claim 16 clearly can reference back to; instead, claim 15 recites a plurality of viruses which together make up the virus library. From the wording of claim 15, it is not clear that the “virus library” has to use the same “base” virus for all nucleic acid inserts, making the antecedent basis of claim 16 further unclear, as it is not clear if all of the viruses of claim 15 must be one of those listed in the Markush group or at least one must be a virus from those listed in the Markush group. Further, as the claims depend upon claim 11, which depends upon claim 1, it is unclear if “the virus” in claim 16 refers all the way back to the virus from which the antigenic viral protein is derived. For at least these reasons, claim 16 is rejected on the grounds of being indefinite. Claim 19 and dependent claims 20-23 thereof are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 19 is drawn to “A method of inducing an immune response against the antigenic viral protein in a subject, the method comprising: administering to the subject the protein library of claim 1.” The use of the definite article “the” in the preamble before “antigenic viral protein” is unclear, because it is unclear as to which “antigenic viral protein” is being referenced. Further dependent claims do not aid in clarifying the antecedence, because claims 20-22, for instance, discusses raising an immune response against “the variants of the antigenic viral protein” and “a wild-type antigenic viral protein”. In addition, referencing a “wild-type antigenic viral protein” and a “variant” is unclear without providing a frame-of-reference to determine if the “variant” is indeed a variant or a “wild-type” protein. Finally, the antecedent basis of dependent claim 23 is unclear, as it refers to the immune response being raised against “the virus”, when no “virus” (only antigenic viral proteins) have been recited in the preceding claims. Therefore, the antecedent basis is not only unclear for claim 19, but the dependent claims 20-23 thereof. For at least these reasons, claim 19 is rejected on the grounds of being indefinite. Claims 20-23 are also rejected for depending upon claim 19, but not clarifying the metes and bounds of claim 19. 07-34-01 Claim 21 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. 07-34-03 AIA The term “ distinct ” in claim 21 is a relative term which renders the claim indefinite. The term “ distinct ” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The claim fails to identify what the epitope must be “distinct” from. It is unclear whether the epitopes must be distinct from each other, distinct from epitopes recognized after administration of a wild-type antigenic viral protein, distinct from epitopes present in the wild-type antigenic viral protein, distinct from hypervariable/conserved sites, or distinct from epitopes recognized by antibodies induced by a “control” composition . For at least these reasons, claim 21 is rejected on the grounds of being indefinite . 07-34-01 Claim 23 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. 07-34-03 AIA The term “ highly drifted ” in claim 23 is a relative term which renders the claim indefinite. The term “ highly drifted ” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. While the specification attempts to provide a definition at ¶[0057], it remains that the “base” or “frame of reference” for the parental virus is unclear in both the specification and claim, and the definition uses further relative terminology and does not provide a concrete method or standard as to how to measurably define “highly drifted”, making the term “highly drifted” indefinite . Further, the antecedent basis of “the immune response” is unclear, as claim 23 depends upon claim 22, and claim 22 recites two theoretically distinct immune responses- the immune response against the variants and the immune response against the wild-type protein. For at least these reasons, claim 23 is rejected on the grounds of being indefinite . 07-34-01 Claim 26 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 26 provides the limitation of “the antigenic viral protein”. While claim 26 refers to the vector library of claim 13, and claim 13 refer to the nucleic acid library of claim 11, and claim 11 refers to the protein library of claim 1, the antecedent basis of “the antigenic viral protein” is unclear and indirect. Claim 26 recites performing “saturation mutagenesis on nucleic acids encoding the antigenic viral protein”, “hypervariable sites of the antigenic viral protein”, and “mutated nucleic acids encoding variants of the antigenic viral protein.” Because there are other indefiniteness issues with these claims upon which claim 26 depends, it would be helpful to clarify the metes and bounds of what is being claimed, especially in dependent claims. One suggestion to make the antecedent basis clear and direct is to recite, for example, “performing saturation mutagenesis on nucleic acids encoding the viral protein of the protein library of claim 1” or “performing saturation mutagenesis on the nucleic acids of the nucleic acid library of claim 11”. Additionally, the scope of “mutated nucleic acids” recited in steps a), b) and f) is unclear. Step a) recites performing saturation mutagenesis on nucleic acids encoding the antigenic viral protein at one or more hypervariable sites of the antigenic viral protein to obtain mutated nucleic acids. However, the claim does not make clear whether the “mutated nucleic acids” are full-length nucleic acids encoding the entire antigenic viral protein, shorter mutated fragments comprising the mutated hypervariable sites, amplification products comprising only the mutated regions, or some other nucleic acid species. This ambiguity makes it unclear as to what is being incorporated into the viral vectors of part b) and the expression vector of part f). One suggestion is to clarify that the item being incorporated into the viral vectors/expression vectors are nucleic acids which encode the entire full-length viral protein and which comprise the mutations generation in part a). Further, the issue raised supra regarding “hypervariable sites” is also present here, as the method of claim 26 requires performing the mutation at said “hypervariable sites” without accurately providing how a skilled artisan would determine if said site is, or is not, “hypervariable”. Even further, step e) recites identifying infected cells that express the antigenic viral protein. However, the infected cells are infected with a viral vector, so there is more than one antigenic viral protein present in said infected cell, so it is unclear if one is to detect an antigenic viral protein that is native to the viral vector, or if one is to detect the antigenic viral protein that has been mutated and introduced into said vector in steps a)-b) of the method. Step f) is additionally awkward in that it recites “cloning the mutated nucleic acids encoding variants of the antigenic viral protein found in the infected cells into an expression vector to generate the vector library”, so it is unclear if step f) is introducing an additional mutation step as protein mutants can arise/be selected for depending on the cell type which is infected. It is unclear if the same mutated antigenic viral protein generated in part a) is the same sequence that should be cloned into an expression vector of part f), or if this is an entirely new sequence generated after growth in the infected cell. With respect to “the vector library” of part f), there are two vectors recited in claim 26 – the viral vectors of part b), and the expression vectors of part f). Therefore, it is unclear which vector said vector library generated is meant to comprise. Additionally, the use of “viral vectors” and “viruses” and “transducing the viral vectors” is unclear, because part d) requires “transducing the viral vectors into cells by infecting the cells with the viruses” and it is unclear whether it is required that the cells are transduced with viral particles comprising the viral vectors, introducing viral vector nucleic acids into cells, or infecting cells with viruses generated in step c). The claim should clearly distinguish between the viral vectors cloned in step b), the viruses packaged in step c), and the transduced/infected cells of step d). For at least these reasons, the metes and bounds of claim 26 are unclear. Claim 27 and dependent claim 28 thereof are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 27 in part b) recites “performing a recombination reaction in which the primers are annealed to each other to form a set of recombinant primers that each comprise a different set of mutations at the target sites”. However, the claim does not clearly define what reaction constitutes a “recombination reaction” in this context, what structural product/item is a “recombinant primer”, or how annealing primers to each other forms “recombinant primers” rather than “annealed primer complexes”, extended PCR products, or assembled nucleic acid fragments. Additionally, the phrase “different set of mutations” is indefinite for similar reasons set forth supra . The method does not identify the comparison required to determine whether or not a set of mutations is “different”. It is unclear whether each recombinant primer must comprise mutations that differ from a specific reference nucleic acid sequence, a mutation combination that differs from every other recombinant primer in the set, or different mutations amongst the plurality of target sites within a single recombinant primer. Further, it is unclear how to determine if a vector is “appropriate” or, conversely, “inappropriate” for the amplification reaction product, as such a term is relative. Finally, the phrase “full-length sequences” in part c) lacks a clear reference point. Part c) recites that the step is forming “full-length sequences that span the target site”, but does not identify whether “full-length” means full-length relative to the DNA sequence of interest, the region containing the target sites, a coding sequence, an amplicon, or another defined sequence. For at least these reasons, claim 27 is rejected on the grounds of being indefinite. Claim 28 is also rejected for depending upon claim 27, but not clarifying the metes and bounds of claim 27. 07-34-01 Claim 28 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 28 recites that the mutations of claim 27 comprise “NNK” for the forward primers and/or “MNN” for the reverse primers. However, the meaning of “NNK” and “MNN” is unclear in light of the specification, because at ¶[0072], it states that “N” represents any amino acid, yet these are referencing primers, which are nucleic acid. Further, as per WIPO standard ST.26 and MPEP §2412, at Table 1, “n” is utilized in nucleotide sequences for any nucleotide, while “N” in Table 3 notes that “N” in amino acid sequences stands for asparagine, not “any amino acid”. Any amino acid, per ST.26, is represented by “X”. For at least these reasons, claim 28 is rejected on the grounds of being indefinite. 07-30-03-h AIA Claim Interpretation The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. Claim 1 is drawn to a protein library comprising variants of an antigenic viral protein, wherein each variant of the antigenic viral protein comprises a different set of mutations at one or more hypervariable sites in the antigenic viral protein. Further limitations on the protein library of claim 1, wherein the protein library comprises at least 1x 10⁴ variants of the antigenic viral protein (claim 2); wherein the antigenic viral protein is from influenza virus, human immunodeficiency virus (HIV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), hepatitis C virus (HCV), respiratory syncytial virus (RSV), or human cytomegalovirus (CMV) (claim 4), wherein the antigenic viral protein is influenza hemagglutinin (HA)(claim 5), wherein the antigenic viral protein is a group 1 influenza A HA, a group 2 influenza A HA, or an influenza B HA (claim 6), wherein the one or more hypervariable sites are in: a) a region of HA1 selected from Cb, Sa, Ca2, Ca1, and Sb, as shown in Figure 11; or b) a region of HA3 selected from A, B, C, D, and E, as shown in Figure 11 (claim 7), and wherein the one or more hypervariable sites are: a) selected from positions Sb 192, Sb 193, Sb 196, and Sb 198; or b) in a region of B HA selected from the 120 loop, 150 loop, 160 loop, and 190 helix, as shown in Figure 11 (claim 8). Claim 11 is drawn to a nucleic acid library encoding the protein library of claim 1, wherein each nucleic acid in the nucleic acid library comprises a sequence encoding one of the variants of the antigenic viral protein of the protein library. Further limitations on the nucleic acid library of claim 11 are wherein each nucleic acid in the nucleic acid library further comprises a promoter operably linked to the sequence encoding one of the variants of the antigenic viral protein (claim 12) Claim 13 is drawn to a vector library comprising the nucleic acid library of claim 11, wherein each vector in the vector library comprises one of the nucleic acids of the nucleic acid library. Claim 15 is drawn to a virus library comprising the nucleic acid library of claim 11, wherein each virus in the virus library comprises one of the nucleic acids of the nucleic acid library. Further limitations on the virus library of claim 15 are wherein the virus is selected from the group consisting of influenza virus, HIV, SARS-CoV-2, HCV, RSV, and CMV (claim 16). Claim 18 is drawn to a vaccine comprising the protein library of claim 1 and an adjuvant. Claim 19 is drawn to a method of inducing an immune response against the antigenic viral protein of claim 1 in a subject, the method comprising: administering to the subject an effective amount of the protein library of claim 1. Further limitations on the method of claim 19 are wherein the immune response against the variants of the antigenic viral protein is altered as compared to the immune response against a wild-type antigenic viral protein (claim 20), wherein a greater number of antibodies recognizing distinct epitopes of the antigenic viral protein are generated in response to the variants of the antigenic viral protein as compared to in response to vaccination with a wild-type antigenic viral protein (claim 21), wherein a greater proportion of antibodies are generated against conserved sites as compared to hypervariable sites within the antigenic viral protein in response to the variants of the antigenic viral protein as compared to in response to vaccination with a wild-type antigenic viral protein (claim 22), and wherein the immune response is protective against a highly drifted strain of the virus (claim 23). Claim 26 is drawn to a method of generating the vector library of claim 13, the method comprising: a) performing saturation mutagenesis on nucleic acids encoding the antigenic viral protein at one or more hypervariable sites of the antigenic viral protein to obtain mutated nucleic acids; b) cloning the mutated nucleic acids into viral vectors; c) packaging the viral vectors into viruses; d) transducing the viral vectors into cells by infecting the cells with the viruses; e) identifying infected cells that express the antigenic viral protein; f) cloning the mutated nucleic acids encoding variants of the antigenic viral protein found in the infected cells into an expression vector to generate the vector library. Claim 27 is drawn to a method of performing saturation mutagenesis on a plurality of target sites within a DNA sequence of interest, the method comprising: a) designing a plurality of overlapping primers that are complementary to sequences flanking the target sites and comprise mutations at the target sites; b) performing a recombination reaction in which the primers are annealed to each other to form a set of recombinant primers that each comprise a different set of mutations at the target sites; c) extending the recombinant primers using a DNA polymerase to form full-length sequences that span the target sites; d) amplifying the full-length sequences to form an amplification reaction product; e) purifying the amplification reaction product; and f) cloning the amplification reaction product into an appropriate vector. Further limitations on the method of claim 27 are wherein the mutations comprise NNK for forward primers, and/or MNN for reverse primers (claim 28). Claim Rejections - 35 USC § 101 07-04-01 AIA 07-04 35 U.S.C. 101 reads as follows: Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title. Claims 1-2, 4-8, 11-13, 15-16, and 19-23 are rejected under 35 U.S.C. 101 because the claimed invention is directed to naturally-occurring viral proteins, nucleic acids encoding said proteins, viruses comprising said proteins, compositions comprising said proteins, and methods of natural infection without significantly more. The claims recite a protein library comprising variants of an antigenic viral protein, wherein each variant of the antigenic viral protein comprises a different set of mutations at one or more hypervariable sites in the antigenic viral protein. Further dependent claims provide for nucleic acids which encode said viral proteins, vectors, viruses, and compositions comprising said viral proteins, and methods of inducing an immune response against said viral proteins. This judicial exception is not integrated into a practical application because under one reasonable interpretation of the claims, the claims can be interpreted as being drawn to a population of viruses (e.g. quasispecies, species, mutants, etc.) that are naturally found within a host. Claim 1 encompasses a naturally occurring population of viral antigenic protein variants produced during the natural course of infection, including naturally occurring influenza virus HA or SARS CoV-2 spike protein variants having different mutations at hypervariable sites. Because the claims do not require the proteins, nucleic acids, vectors, or viruses to be synthetic, isolated, purified, formulated, arrayed, encoded by engineered, heterologous vectors, or otherwise structurally or functionally different from naturally occurring viral protein variant populations, the claims are directed to products of nature. For instance, many viruses are utilized as “vectors” in the art, such as adeno-associated virus (AAV) or herpes simplex virus (HSV); said “antigenic viral protein” could be an AAV or HSV protein and within its natural setting which is also a “vector”. Likewise, the methods are recited at such a high level of generality that all that is required is the antigenic viral protein is generically administered to a subject and produces a generic immune response to said viral protein in said subject, which reasonably reads upon natural infection from naturally-occurring viruses such as influenza virus. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the variants do not have to possess markedly different characteristics from naturally occurring viral antigen variants. The claims do not require a non-natural arrangement (e.g. use of a constitutive promoter to express said protein from the nucleic acid which is heterologous to said protein), do not require an artificial expression system (e.g. use of a bacterial/yeast artificial chromosome (BAC/YAC)), do not require that the vector library is engineered (e.g. influenza HA variants within pUC19 or pBR322 plasmids), or do not require any other structural or functional feature that would distinguish the claimed protein library from naturally occurring viral quasispecies or naturally co-existing viral antigenic variants (e.g. see Barbezange C, et. al. Front Microbiol . 2018 Oct 31;9:2596. for a discussion of seasonal genetic drift of influenza A virus and quasispecies which exist in the human host.) The method claims do not require the administration of the protein in a way that does not read upon natural infection (e.g. specific route or dosage of administration, administration of a non-naturally occurring product, administration of a naturally occurring product+adjuvant, etc.) For at least these reasons, the claims read upon natural products and natural methods of infection, and are not patent eligible. Claim Rejections - 35 USC § 112(a); First Paragraph 07-30-01 AIA 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. 07-31-03 AIA Claim s 11-13 and 15-16 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 isolated nucleic acids, vectors, and viruses within a library , does not reasonably provide enablement for any type of nucleic acids, vectors, and/or viruses in any type of library . 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 claims are directed broadly to “a nucleic acid” within a library without limitation as to form, environment, or method of use. While claim 13 is drawn to “a vector” and claim 15 to “a virus”, this also has the same issue as a “nucleic acid” in the context of a library in that (as per 35 USC 101 rejection supra ) the claims can broadly and reasonably read upon a variety of hosts and systems which would comprise said items. As such, the claims encompass the nucleic acid in a wide range of contexts, including incorporation into vectors, plasmids, artificial chromosomes (e.g. bacterial or yeast artificial chromosomes (BACs or YACs)), cosmids, prokaryotic and eukaryotic cells, and organismal systems (e.g. Bacteria and Archaea, Eukaryotes (including vertebrate and invertebrate animals, plants, and fungi), and viruses). The claims also encompass vector library systems which are not enabled across their full scope, including different vector backbones, delivery systems, packaging systems, host-cell contexts, and expression requirements. Finally, the claims encompass different viral platforms, packaging constraints, genome capacity, tropism, host range, replication competence, safety, expression, and recovery. The specification does not provide guidance sufficient to enable the use of the claimed nucleic acid libraries, vector libraries, or virus libraries across this full scope, including in complex biological systems where expression, stability, and functionality may vary depending on the host environment and delivery method. Accordingly, undue experimentation would be required to determine how to make and use the claimed nucleic acid, vector, and viral libraries across the full scope of the claims. It is suggested that the claims be amended to read upon isolated libraries in order to overcome this rejection . 07-31-01 AIA Claim s 1-2, 4-8, 11-13, 15-16, 18-23, and 26 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. The following quotation from section 2163 of the Manual of Patent Examination Procedure is a brief discussion of what is required in a specification to satisfy the 35 U.S.C. 112 written description requirements for a generic claim covering several distinct inventions: 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 .... reduction to drawings .... or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus... See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. Thus, when a claim covers a genus of inventions, the specification must provide written description support for the entire scope of the genus. Support for a genus is generally found where the applicant has provided a number of examples sufficient so that one in the art would recognize from the specification the scope of what is being claimed. Claims 1-2, 4-8, 11-13, 15-16, 18-23, and 26 are rejected as lacking adequate descriptive support for any antigenic viral protein library wherein said viral protein variants within said library are mutated in any hypervariable region. In support of the claimed genera (any antigenic viral protein, any hypervariable region), the application discloses one example in which influenza virus hemagglutinin (HA) protein from A/Puerto Rico/8-MC/1934 (H1N1) influenza virus (commonly known as PR8; GenBank deposit CY083950.1) was utilized to make an HA mutant library. The HA antigenic site Sb, namely four positions in the Sb site of PR8 HA, i.e., Q192, N193, Q196, and E198, were chosen for saturation mutagenesis. The primers generated to perform the saturation mutagenesis according to Fig. 15 were not provided. A fragment of HA (unclear if it was a fragment of the entire HA protein or a fragment of the PR8 genome) was cloned into a lentiviral cloning vector pCMV-IRES-GFP v.3 (pCIG3); viable mutants had their ectodomain further cloned into pDZ mammalian expression vector (¶[0090]). Applicants generated a vaccine comprising variants of these HA-Sb mutants in order to focus on redirecting antibody responses away from the hypervariable regions and towards more conserved HA regions (¶[0102]). While other influenza HA hypervariable sites are noted, the only mutants that appear to have been generated were at the Sb antigenic site with the four noted residues. The disclosed example also specifically selected for variants in a specific conformation through the use of a conformation-dependent HA stalk antibody (¶[0102]). This selection step is notable because “antigenic” seems to be tied to a specific conformation recognized by a specific antibody (6F12) that only recognized HA trimers which were folded and trafficked in a manner which allowed 6F12 to bind to said trimer. Therefore, many of the variants were not selected for even though they might possibly be antigenic; only a subset of mutants that retained the desired expression/folding characteristics were carried forward and tested in further in vitro and in vivo experiments. Those mutants selected for with the 6F12 antibody were inoculated into mice and compared to parental PR8 HA vaccination. The disclosure states that the antibody response elicited by the PR8-Sb mutants was stronger than that for wilt type PR8 HA, and disproportionately boosted responses against conserved, non-antigenic HA domains (¶[0032]; Fig. 16). Applicant further tested protection against matched and drifted influenza strain challenge (¶[0032][0106-0111]) and found that there was improved protection using the PR8-Sb mutant vaccine compared to PR8 wild type vaccine. The working examples focused on influenza A virus HA protein mutants, namely H1 lineage mutants. No other influenza A virus HA subtype mutants were generated; no mutants from any other influenza virus type (e.g. B, C, D, etc.) were generated. No derivatives or variants or mutants thereof are disclosed regarding the generation of any mutant libraries or immunogenic data related thereto with respect to HIV, SARS CoV-2, HCV, RSV, or CMV antigenic proteins. The only viral vector tested appeared to have been the noted lentiviral vector and the only plasmid tested was pDZ; no other viral vectors or plasmids were generated with said mutants, influenza A virus HA or otherwise. While the data provided may support possession of a narrower influenza A virus HA/Sb-region mutant library and related vaccination methods, it fails to demonstrate possession of the broadly claimed antigenic viral protein libraries across unrelated viral antigen families. Thus, the application fails to provide sufficient examples of a representative number of species within the broadly claimed genera. Further, while the claims provide both a structure and a function, the application fails to draw any correlation between the two. In other words, there is no evidence that any mutation to any hypervariable region of any antigenic viral protein can still retain its antigenicity, especially in order to be useful as a vaccine. Moreover, no correlation has been made as to how to assess whether or not a region in any viral antigenic protein is “variable” or “hypervariable”, as the definition of “hypervariable” provided by Applicant provides no reliable metric as to how to perform an assessment of these proteins to determine which regions to target and which regions to avoid. The independent claim is drawn to any viral antigenic protein and narrows to any viral antigenic protein from HIV, SARS-CoV-2, HCV, RSV, and CMV, but each virus has differences in envelope presence, structure, protein folding/glycosylation requirements, expression systems, and available immunological screening reagents/systems. The specification does not describe representative libraries for a sufficient number of examples across the claimed genera, does not identify equivalent hypervariable residues to be mutagenized with sufficient structural particularity, does not show how to select properly folded or antigenically useful variants for those antigens, and does not provide data showing that such libraries redirect antibody responses or protect against drifted strains. Thus, in view of the above, there would have been significant uncertainty as to where antigenic viral proteins could/could not be mutated in order to generate the claimed libraries, and whether said generated mutants would be able confer the claimed improved immunogenicity. In view of this uncertainty and the lack of examples of the claimed genera, the claims are rejected for lack of adequate written description support . 07-31-03 AIA Claim s 1-2, 4-8, 11-13, 15-16, 18-23, and 26 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 specific influenza A virus H1-PR8-Sb mutant library and methods of use thereof , does not reasonably provide enablement for any viral antigenic protein library wherein any hypervariable region is mutated and further results in the ability of said library to be useful as a vaccine in any subject . 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 protein library comprising variants of an antigenic viral protein, wherein each variant of the antigenic viral protein comprises a different set of mutations at one or more hypervariable sites in the antigenic viral protein. Further claims are drawn to nucleic acids encoding said proteins, vectors and viruses comprising said nucleic acids, vaccine compositions comprising said libraries, and methods of delivering said protein libraries in order to elicit a therapeutic immune response in a subject. The breadth of the claims is substantial in that it is drawn to any viral protein or fragment thereof, so long as said protein elicits an immune response in any subject. As set forth supra , the definition of “hypervariable” is unclear, but in general terms is trying to reference a region in said protein which tends to mutate more than other regions. Still, the claimed viral antigens include structurally and antigenically distinct proteins from unrelated viruses, including influenza virus HA, HIV proteins, SARS-CoV-2 proteins, HCV proteins, RSV proteins, and cytomegalovirus proteins. State of the prior art/Predictability of the art. The state of the art reflected that viral antigenic protein vaccine design was unpredictable and highly antigen-specific. Successful immunogen design depends on preserving the antigen’s relevant conformation, glycosylation, oligomeric state, trafficking, and epitope display, and structure-based vaccine design generally attempts to stabilize an antigen in a desired conformation and present epitopes in a manner that focuses the antibody response, but this requires antigen specific structural information and empirical engineering rather than routine substitution of one viral antigen for another. For example, Byrne et. al. (Byrne PO, et. al. Curr Opin Immunol . 2022 Aug;77:102209. Epub 2022 May 19.) provides a review that details how the art typically approaches protein stabilization (e.g. sequence modifications: proline, disulfide, cavity-filling, electrostatic and hydrogen-bond substitution, as well as domain deletion) and outstanding challenges regarding vaccine design. Byrne notes how certain viruses, such as the filoviruses Ebola virus and Marburg virus, have unclear stabilization mechanisms for their viral glycoprotein, and even redirected antigens in influenza virus fail to confer full protection against viral challenge. Caradonna et. al. (Caradonna TM, et. al. NPJ Vaccines . 2021 Dec 17;6(1):154.) reviews that immunogen engineering seeks to alter immunodominance and focus antibody responses on protective/conserved epitopes in rapidly evolving pathogens. Caradonna notes the recent development in strategies to (1) magnify the overall humoral response, (2) prevent or reduce the elicitation of ‘off-target’ antibody responses, and (3) specifically amplify responses targeting preferred epitopes, and notes the challenges with the current strategies, such as the struggle to retain conformationally relevant epitopes with only using fragments of a viral protein, or the struggle to properly stoichiometrically display a multimeric viral protein on nanoparticle surfaces. The influenza virus HA art itself further demonstrates that even with one viral antigen family, antigenic sites and hypervariable regions are subtype-specific and not automatically interchangeable. Wu et. al. (Wu NC, et. al. Cold Spring Harb Perspect Med . 2020 Aug 3;10(8):a038778.) describe distinct major antigenic sites on H1 HA and H3 HA, and Laursen et. al. (Laursen NS, et. al. Antiviral Res . 2013 Jun;98(3):476-83. Epub 2013 Apr 9.) describe five antigenic sites on H1 HA noted as Sa, Sb, Ca1, Ca2, and Cb, while H3 HA antigenic sites are labeled A through E. Laursen further notes that due to the size of HA compared to the larger antibody structure, that antibodies which would theoretically target more conserved areas/residues would inevitably still be tied somewhat structurally to the variable regions of HA in order to access these conserved regions. Influenza B HA uses a different antigenic-site framework, including the 120 loop, 150 loop, 160 loop, and 190 helix in the HA head domain (Sun W, et. al. J Virol . 2019 Jan 4;93(2):e01673-18.) Sun showed that in humans versus other animals, the ability to target non-canonical epitopes in HA increases with age, which is likely due to the effects of seasonal vaccination. These three notable regions all map differently, and can have different effects depending on subtype, lineage, and strain background, meaning that an identified mutation strategy on HA H1 Sb does not readily translate to H3 or influenza B HA. These different nomenclatures and structural regions show that the identification of “hypervariable sites” is not a generic step that can be applied uniformly across all influenza HAs, such less across unrelated viral antigenic proteins. These data also show that there are unpredictable variables which also affect how hosts respond to a viral HA antigen. Accordingly, the state of the art did not support a reasonable expectation that a library-generation strategy demonstrated for a select H1 HA Sb-mutant region would enable, without undue experimentation, antigenic viral protein libraries for other non-H1 influenza A HA proteins, much less non-influenza HA antigenic viral proteins. Working examples. The working example disclosed in the specification was discussed in detail supra in the written description rejection. Briefly, said working example focused on an influenza A virus H1 HA PR8 set of mutants in the Sb region, namely at 4 residues (Q192, N193, Q196, and E198). Saturation mutagenesis was performed at these residues, said mutants were expressed from lentiviral vectors and selected for using a 6F12 conformational antibody against HA trimers. Those selected mutants were then expressed, isolated, and added to a vaccine composition adjuvanted with ADDAVAX™ (squalene oil-in-water nanoemulsion), and then mice were inoculated with said mutants and compared to the immune response generated with the PR8 HA wild type protein. No other influenza subtypes, strains, or isolates were used as the “base”, no other influenza virus antigenic protein (e.g. NA, matrix) had mutants generated in any identified hypervariable region. No other viral proteins had any hypervariable regions mutated and tested. No other viral vectors were tested. No other adjuvants were tested. Guidance in the specification . The specification provides guidance towards the generation of PR8-Sb mutant libraries. The amount of guidance provided for in the specification is not commensurate in scope with the breadth of the instant claims with the examples being limited to only the PR8-Sb mutant library; no other HA hypervariable regions were tested, no other hypervariable regions in other influenza virus proteins were mutated and tested for their immunogenic potential. The specification fails to teach how to select equivalent mutation sites, generate properly folded antigenic libraries, identify appropriate conformation-specific screening reagents, choose relevant adjuvants for vaccine compositions which comprise said libraries, or validate immune redirection for any non-PR8 HA viral antigenic proteins. Amount of experimentation necessary. Additional research is required in order to determine how to generate the claimed genus of any library comprised of variants/mutants of any hypervariable residue or region in any antigenic viral protein, and how effective said library would be in redirecting or strengthening the immune response to said antigenic viral protein in a manner that would be useful as a vaccine. 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 were 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, undue experimentation would be required to identify hypervariable regions in antigenic viral proteins, then generate the appropriate libraries of mutants, and then test said mutants to determine which libraries would be useful in vaccine compositions and therapeutic methods of delivery thereof. For the reasons discussed above, it would require undue experimentation for one skilled in the art to make the claimed libraries and use the claimed methods . Claim Rejections - 35 USC § 102 07-06 AIA 15-10-15 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. 07-07-aia AIA 07-07 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 – 07-08-aia AIA (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. 07-12-aia AIA (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. 07-15 AIA Claim s 27-28 are rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by Hiraga et. al. (Hiraga K, et. al. ACS Synth Biol . 2021 Feb 19;10(2):357-370. Epub 2021 Jan 12.; hereafter “Hiraga”.) The Prior Art Hiraga teaches the program Mutation Maker, an open source mutagenic oligo design software for large-scale protein engineering experiments. Mutation Maker is not only specifically tailored to multi-site random and directed mutagenesis protocols, but also pioneers bespoke mutagenic oligo design for de novo gene synthesis workflows (entire document; see abstract.) Hiraga teaches site scanning saturation mutagenesis (SSSM) of a gene of interest (GOI), with up to 96 amino acids selected as target sites for one library (p. 358, ¶ bridging cols.) Hiraga teaches forward NNK and reverse MNN mutagenic primers designed using the SSSM workflow for target sites in the GOI (p, 359, ¶ bridging cols.; pp. 367-8, ¶ bridging pages; instant claim 28 ). Hiraga also teaches an overlap-extension PCR protocol was used to perform the PCR (“Experimental validation for SSSM”, p. 367, rt. Col.), and teaches that overlapping primers which are complementary to sequences flanking the target sites in the GOI and comprise mutations at said target sites are designed, then said primers are annealed to each other and are allowed to extend using a DNA polymerase to form longer sequences that span the target sites (Fig. 1). Hiraga teaches that the PCR reaction is performed using Q5 Hot Start DNA polymerase and the formation of mutant GOI fragments, wherein said fragments are pooled into a library (p. 360, rt. Col.; p. 367-368, “Experimental Validation for SSSM” to end; Fig. 1). Hiraga teaches creation of N- and C- gene fragments wherein PCR reactions are first conducted separately and in parallel for each site using mutagenic and flanking primer pairs and a gene template. The overlapping N- and C- fragments are then stitched together using flanking primers via a second PCR reaction (SOEing, Splicing by Overlap Extension) that produce full-length gene variants (Fig. 1 legend.) The SOE amplifications were confirmed by purification on a gel system, and then cloned back into a plasmid/vector before transformation into E. coli cells (p. 368, left col.) Hiraga therefore teaches the limitations required within the method of performing saturation mutagenesis on a plurality of target sites within a DNA sequence as required by instant claim 27 . For at least these reasons, Hiraga teaches every limitation of instant claims 27 and 28 , and anticipates the invention encompassed by said claims . 07-15 AIA Claim s 1-2, 4-7, 11-13, 18-23 are rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by Maksyutov et. al. (WO2011138032A2, Pub. 03/08/2012; CITED ART OF RECORD; hereafter “Maksyutov”.) The Prior Art Maksyutov teaches methods for creating universal broad-spectrum influenza vaccines based on influenza virus hemagglutinin protein (HA), including specific examples of seasonal and pandemic influenza vaccines based on peptide libraries or representative peptide panels (RPPs)(entire document; see abstract.) Maksyutov teaches a protein library comprising variants of an antigenic viral protein, wherein each variant of the antigenic viral protein comprises a different set of mutations at one or more hypervariable sites in the antigenic viral protein (p. 5, ¶5; “universal broad-spectrum influenza vaccines based on peptide libraries and RPPs containing a plurality of influenza HA antigenic sites”; p. 20, ¶3 “the regions with the highest variability of dominating amino acids and thus have a high probability to correspond to antigenic sites (see Figure 1)…for HA of H1 influenza, position of the four regions with the highest variability of dominating amino acids determined based on alignment entropy…Visual analysis of HA structure with superimposed positions of glycosylation sites and/or know escape mutations and/or alignment entropy values may be also useful for determination of antigenic sites”; p. 21, ¶2-3, “the use of peptide libraries which adequately represent the diversity of currently existing and potentially emerging variants of antigenic sites. As used herein, the term “peptide library” refers to a combination of different peptides”, p. 2, ¶2 “introduction of amino acid residues into a variable position…After attachment of all residues in the variable position the polymers are combined.”) Maksyutov notes the antigenic sites for H1 HA are Ca, Cb, Sa, and Sb, and for H3 HA, the antigenic sites are designated as A, B, C, D, and E (pp. 19-20, ¶ bridging pages; instant claim 7 ); Maksyutov teaches determination of additional antigenic sites that dominate in evolution of the protein, and provides specific mathematical calculations for determination of these hypervariable sites (p. 20, ¶3). Maksyutov therefore teaches the limitations of instant claims 1 and 4-5 . Maksyutov teaches that the library would include anywhere from 100 to 10000 different peptides (p. 21, ¶3; instant claim 2 ). Maksyutov teaches the HA molecules may be from one of the HA groups, such as Group 1 HAs Subtypes: H1, H2, H5, H6, or H11 (p. 20, ¶2; instant claim 6 ). Maksyutov teaches the peptide library can be used for vaccination, as well as a DNA vaccine (p. 30, ¶4), and teaches that DNA vectors expressing said peptides may be included in such nucleic acid vaccine compositions (p. 36, ¶2-3; instant claims 11, 13 ). Maksyutov teaches the DNA vectors would express the HA proteins from optimized heterologous promoters, such as the CMV promoter (p. 36, ¶2; instant claim 12 ). Maksyutov teaches the vaccine compositions may comprise adjuvants (p. 37, ¶4; instant claim 18 ). Maksyutov teaches the vaccine compositions are administered to the patient at immunologically effective doses (p. 39; ¶5; instant claim 19 ). In regards to claims 20-23 , the recitation that the method of delivering the protein library of claim 1 to induce specific types, strengths, and degrees of an immune response with broad protection against different strains of the virus is not a positive limitation but only requires the ability to so perform. It does not constitute a limitation in any patentable sense. In re Hutchison , 69 USPQ 138 (CCPA 1946); In re Swinehart , 169 USPQ 226 (CCPA 1971); and In re Schreiber , 44 USPQ2d 1429 (Fed. Cir. 1997). A patent applicant is free to recite features of an apparatus either structurally or functionally. See In re Swinehart , 439 F.2d 210, 212, 169 USPQ 226, 228 (CCPA 1971) (“ [T]here is nothing intrinsically wrong with [defining something by what it does rather than what it is] in drafting patent claims.”). Yet, choosing to define an element functionally, i.e., by what it does, carries with it a risk. As our predecessor court stated in In re Swinehart , 439 F.2d at 213, 169 USPQ at 228: where the Patent Office has reason to believe that a functional limitation asserted to be critical for establishing novelty in the claimed subject matter may, in fact, be an inherent characteristic of the prior art, it possesses the authority to require the applicant to prove that the subject matter shown to be in the prior art does not possess the characteristic relied on Therefore, the feature of delivering the protein library of claim 1 to induce specific types, strengths, and degrees of an immune response with broad protection against different strains of the virus would be an inherent characteristic of the methods of Maksyutov since the inoculation methods of Maksyutov meet all the structural limitations of the claimed method. For at least these reasons, Maksyutov teaches the limitations of instant claims 1-2, 4-7, 11-13, 18-23 , and anticipates the invention encompassed by said claims . Claim Rejections - 35 USC § 103 07-06 AIA 15-10-15 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. 07-20-aia AIA 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. 07-23-aia AIA 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. 07-20-02-aia AIA 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. 07-22-aia AIA Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Maksyutov as applied to claim s 1-2, 4-7, 11-13, and 18-23 above, and further in view of Shen et. al. (Shen J, Kirk BD, Ma J, Wang Q. Diversifying selective pressure on influenza B virus hemagglutinin. J Med Virol. 2009 Jan;81(1):114-24.; hereafter “Shen”.) The Prior Art The teachings of Maksyutov have been set forth supra . While Maksyutov teaches known hypervariable regions in different influenza A virus subtypes, Maksyutov is silent as to hypervariable regions known in influenza B virus subtypes as sites for targeted mutation. However, these sites were known in the art, as evidenced by Shen. Shen teaches the hypervariable sites of influenza B virus HA are located in the four major epitopes (120-loop, 150-loop, 160-loop, and 190-helix) of HA identified in previous studies, thus supporting a predominant role of antibody selection in HA evolution (entire document; see abstract; instant claim 8 ). Shen notes the 120-loop was an important epitope under constant positive selection, and it may play an increasingly important role in antigenicity in future field isolates (“Concluding Remarks”, p. 7). It would have been obvious to one of ordinary skill in the art to modify the compositions taught by Maksyutov in order to target known hypervariable sites in influenza B HA. One would have been motivated to do so, given the suggestion by Shen that while influenza B HA was not as highly mutable as influenza A HA, that antigenic sites of B HA were known, and analysis of these sites showed that these regions were hypervariable compared to the rest of the B HA lineages. There would have been a reasonable expectation of success, given the knowledge that Shen suggested analysis of these regions for future epidemic studies, and also given the knowledge that Maksyutov teaches generating mutations in the variable regions of influenza virus HA. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made . 07-22-aia AIA Claim s 15-16 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Maksyutov as applied to claims 1-2, 4-7, 11-13, and 18-23 above, and over Hiraga as applied to claim s 27-28 above, and further in view of Fritsch (US20230203477A1; Priority 05/26/2020; hereafter “Fritsch”.) The Prior Art The teachings of Maksyutov and Hiraga have been set forth supra . While Maksyutov teaches generation of libraries of influenza HA mutant proteins, wherein said proteins are mutated at highly variable regions, and teaches that nucleic acids encoding said proteins can be introduced into vectors, Maksyutov is silent as to teaching that these vectors are viral vectors. However, viral vectors are well known in the art. Further, while Maksyutov teaches methods of generating mutants, they do not appear to follow the specific steps outlined by instant claim 26. However, such a method was known in the art, as evidenced by Hiraga. While Hiraga teaches the general method of making mutants which is required in claim 26, Hiraga fails to use viral vectors in the intermediate steps. Again, viral vectors are known in the art, and the use of said vectors to generate plasmid libraries would be obvious to a skilled artisan, as evidenced by the teachings of Fritsch. Fritsch teaches the generation of nucleic acid artificial mini-proteome libraries, especially for the use in expressing said protein products for vaccine-based applications or transducing mammalian cells so that they may express the proteins of interest (¶[0020-0021]). Fritsch teaches that lentiviral vectors are commonly used vectors, and can include the use of HIV (¶[0149]; instant claims 15-16 ). Given the teachings of Maksyutov and Fritsch, one of skill in the art would be apprised as to the usefulness of generating large libraries capable of expressing antigenic proteins. Given the teachings of Hiraga, one of skill in the art would be apprised as to mutagenesis methods that could be employed to generate the mutants of Maksyutov. Given the teachings of Fritsch, one of skill in the art would be apprised as to the different types of vectors that could be used in the systems of Maksyutov and Hiraga, such as HIV vectors for the mutated viral antigenic proteins. Therefore, arriving at the limitations of instant claims 15-16 and 26 would be obvious to a skilled artisan, given what was known in the prior art. It would have been obvious to one of ordinary skill in the art to modify the compositions and methods taught by Maksyutov in order to utilize different vector systems to house and express the antigenic viral proteins which have mutations in their hypervariable regions. One would have been motivated to do so, given the suggestion by Fritsch that protein-expressing libraries could use viral vectors, such as HIV, as their expression system. There would have been a reasonable expectation of success, given the knowledge that Hiraga teaches a method to generate mutants in a vector system, and also given the knowledge that Maksyutov teaches generating mutations in the variable regions of influenza virus HA. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made . Conclusion No claims are allowed. 07-96 AIA The prior art made of record and not relied upon is considered pertinent to applicant's disclosure and is listed below . Fulton BO, et. al. J Virol . 2018 Jul 31;92(16):e00754-18. Teaches generation of influenza HA library through transposon mutagenesis. Not utilized as rejection would be redundant to those set forth supra . US20220242918A1. Teaches generation of chimeric influenza HA/NA library through selection of protective epitopes and antigenic regions. Not utilized as rejection would be redundant to those set forth supra . Any inquiry concerning this communication or earlier communications from the examiner should be directed to RACHEL B GILL whose telephone number is (571)272-3129. The examiner can normally be reached on M to F 8:00 AM to 5:00 PM Eastern. 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 on 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. /RACHEL B GILL/ Primary Examiner, Art Unit 1671 Application/Control Number: 18/684,346 Page 2 Art Unit: 1671 Application/Control Number: 18/684,346 Page 3 Art Unit: 1671 Application/Control Number: 18/684,346 Page 4 Art Unit: 1671 Application/Control Number: 18/684,346 Page 5 Art Unit: 1671 Application/Control Number: 18/684,346 Page 6 Art Unit: 1671 Application/Control Number: 18/684,346 Page 7 Art Unit: 1671 Application/Control Number: 18/684,346 Page 8 Art Unit: 1671 Application/Control Number: 18/684,346 Page 9 Art Unit: 1671 Application/Control Number: 18/684,346 Page 10 Art Unit: 1671 Application/Control Number: 18/684,346 Page 11 Art Unit: 1671 Application/Control Number: 18/684,346 Page 12 Art Unit: 1671 Application/Control Number: 18/684,346 Page 13 Art Unit: 1671 Application/Control Number: 18/684,346 Page 14 Art Unit: 1671 Application/Control Number: 18/684,346 Page 15 Art Unit: 1671 Application/Control Number: 18/684,346 Page 16 Art Unit: 1671 Application/Control Number: 18/684,346 Page 17 Art Unit: 1671 Application/Control Number: 18/684,346 Page 18 Art Unit: 1671 Application/Control Number: 18/684,346 Page 19 Art Unit: 1671 Application/Control Number: 18/684,346 Page 20 Art Unit: 1671 Application/Control Number: 18/684,346 Page 21 Art Unit: 1671 Application/Control Number: 18/684,346 Page 22 Art Unit: 1671 Application/Control Number: 18/684,346 Page 23 Art Unit: 1671 Application/Control Number: 18/684,346 Page 24 Art Unit: 1671 Application/Control Number: 18/684,346 Page 25 Art Unit: 1671 Application/Control Number: 18/684,346 Page 26 Art Unit: 1671 Application/Control Number: 18/684,346 Page 27 Art Unit: 1671 Application/Control Number: 18/684,346 Page 28 Art Unit: 1671 Application/Control Number: 18/684,346 Page 29 Art Unit: 1671 Application/Control Number: 18/684,346 Page 30 Art Unit: 1671 Application/Control Number: 18/684,346 Page 31 Art Unit: 1671 Application/Control Number: 18/684,346 Page 32 Art Unit: 1671 Application/Control Number: 18/684,346 Page 33 Art Unit: 1671
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