CTNF 18/549,951 CTNF 98670 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Application Status Applicant’s response filed May 27, 2026 is acknowledged. No amendments to the claims were made. Claims 1-20 are pending. Restriction/Election Applicant’s election without traverse of Group I (claims 1-13) in the reply filed on May 27, 2026 is acknowledged. Claims 14-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1-13 are under consideration hereinafter. Priority Applicant’s priority claims to Application Nos. 63/160,219 and PCT/US2022/019896 are acknowledged. Claims 1-13 find support in Application No. 63/160,219. The effective filing date of the claims under examination is March 12, 2021. Nucleotide and/or Amino Acid Sequence Disclosures REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES Items 1) and 2) provide general guidance related to requirements for sequence disclosures. 37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted: In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying: the name of the ASCII text file; ii) the date of creation; and iii) the size of the ASCII text file in bytes; In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying: the name of the ASCII text file; the date of creation; and the size of the ASCII text file in bytes; In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended). When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824. If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical. If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical. Specific deficiencies and the required response to this Office Action are as follows: Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is defective. See item 1) a) or 1) b) above. USPTO records indicate that the title and size of the sequence listing filed September 11, 2023 is “18549951_1_2.txt,” and “20,670 bytes,” respectively. The title and size of the sequence listing are incorrectly set forth in the amendments to the specification also filed September 11, 2023. Required response – Applicant must provide: A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of: A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version); A copy of the amended specification without markings (clean version); and A statement that the substitute specification contains no new matter. Drawings The drawings are objected to because of the following informalities: The view numbers of Figs. 4, and 7-8 are preceded by the term “Figure.” 37 C.F.R. 1.84(u)(1) states that “view numbers must be preceded by the abbreviation "FIG." Appropriate correction is required. Specification The specification is objected to because of the following informalities: The use of terms which are trade names or marks used in commerce has been noted in this application, e.g., “Veklury” (pg. 30, line 5) and Olumiant (pg. 30, line 14). Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. The terms, including the exemplary terms above, should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Appropriate correction is required. Claim Objections 07-29-01 AIA Claim 1 is objected to because of the following informalities: It is clear that the fusion protein of claim 1 must comprise (i) a protein capable of self-assembling/oligomerizing with a protein of a viral particle, and (ii) an operatively linked molecule capable of inhibiting the function of the viral particle. See for example, Fig. 1B and SEQ ID NOs: 4-5. It would be preferable to amend the claim to recite “the fusion protein comprises (i) a protein capable of self-assembling/oligomerizing with a protein of a viral particle, and (ii) an operatively linked molecule capable of inhibiting a function of the viral particle,” accordingly . Appropriate correction is required. 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. 07-04-03 AIA 07-04-01 Section 33(a) of the America Invents Act reads as follows: Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism. Claim s 10 and 12 are rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability , 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101). Claim 10 is drawn to a “cell comprising the composition of claim 1.” Claim 12 is drawn to a “cell comprising the fusion protein of claim 11.” Neither the specification nor claim expressly excludes cells within a human organism. The specification describes mammalian cells and cells in a subject (“cell is a vertebrate cell, optionally a mammalian cell… the cell is in a subject,” pg. 4). Thus, the term “cell” could reasonably be interpreted as encompassing cells within a human organism, which is non-statutory subject matter. The rejection may be obviated by requiring an in vitro cell, for example, as described in Example 1 of the specification. Claim Rejections - 35 USC § 112(b) 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. 07-34-01 Claim 9 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 9 recites “wherein the operatively linked viral particle protein is not a capsid protein.” As described above, it is clear that the fusion protein comprises (i) a protein capable of self-assembling/oligomerizing with a protein of a viral particle, and (ii) an operatively linked molecule capable of inhibiting the function of the viral particle. The phase “the operatively linked viral particle protein” does not have sufficient antecedent basis, because the term “operatively linked” applies to the “molecule,” and while the protein must be “capable of self-assembling/oligomerizing” with the viral particle protein, it does not require operative linkage thereto. In the interest of compact prosecution, claim 9 will be interpreted as requiring that the viral particle protein, to which the protein must be capable of self-assembling/oligomerizing, is not a capsid protein. Claim Rejections - 35 USC § 112(d) 07-36 AIA The following is a quotation of 35 U.S.C. 112(d): (d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph: Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. 07-36-01 AIA Claim s 11-13 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 11 and 13 recite “a fusion protein encoded by the composition of claim 1,” and “a virus particle comprising the fusion protein encoded by the composition of claim 1,” respectively. The composition of claim 1 recites “a nucleic acid molecule encoding a fusion protein.” Thus, claim 1 requires a nucleic acid molecule comprised of nucleotides. Neither claim 11 nor claim 13 include such a nucleic acid molecule. The claims, instead, substitute the nucleic acid molecule of claim 1, for a protein encoded therefrom comprised of amino acids. The claims fail to include all the limitations of the claim upon which they depend, and are in improper dependent form. Claim 12 is rejected for depending from claim 11 and failing to remedy the aforementioned improper dependency . Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. Claim Rejections - 35 USC § 112(a) – Written Description 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. 07-31-01 Claims 1-13 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 for the reasons that follow. MPEP 2163.II.A3.(a).(i) states the following: “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 inventor was in possession of the claimed genus.” “Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).” Species Encompassed – Claims 1-9 Claim 1 is directed toa composition comprising a nucleic acid molecule encoding a fusion protein comprising (i) a protein capable of self-assembling/oligomerizing with a viral particle protein, wherein the protein capable of self-assembling/oligomerizing is operatively linked to (ii) a molecule capable of inhibiting a function of the viral particle. The claims, therefore, encompass a genus of nucleic acid molecules encoding a genus of fusion proteins, wherein the fusion proteins comprises any one of a genus of “protein[s] capable of self-assembling/oligomerizing with a viral particle protein,” operatively linked to any one of a genus of “molecule[s] capable of inhibiting a function of the viral particle,” e.g., inhibiting reproduction, assembly, release, or packaging of the viral particle (claim 3). The composition is intended to be used for “suppressing a viral infection,” e.g., a RNA, DNA, coronavirus, retroviral, or SARS-CoV-2 infection (claim 2). In view of the indefiniteness described above, claim 9 is interpreted as requiring that the viral particle protein, to which the protein must be capable of self-assembling/oligomerizing, is not a capsid protein. Claim 1-3, and 9 encompass a genus of nucleic acid molecules encoding a genus of fusion proteins defined solely by the function of the constituent elements. The remaining dependent claims impose further limitations on the fusion protein elements. Claim 4 further requires that the protein capable of self-assembling/oligomerizing is “a viral nucleocapsid (N) protein,” optionally a “SARS-CoV-2 N protein.” Claim 5 requires that the nucleic acid molecule comprise a sequence encoding at least one of the recited SEQ ID NOs, which correspond to amino acid sequences encoding a “N-Nuc” fusion protein (SEQ ID NO: 4), various SARS-CoV-2 N protein domains (SEQ ID NOs: 6-12, and 15), and a Staphylococcus “Nuc mut” (SEQ ID NO: 13). Claims 6-8 further require that the molecule capable of inhibiting a function of the viral particle be a “protease, peptide, an antibody, a lipase, or a nuclease” (claim 6), an “RNase, a DNase or a micrococcal nuclease” (claim 7), or a “calcium (Ca2+)-dependent nuclease” (claim 9). The specification has not sufficiently described the genus of fusion proteins, or, therefore, the genus of nucleic acid molecules encoding the fusion proteins. Specifically, the specification fails to describe the structures of “protein[s] capable of self-assembling/oligomerizing with a viral particle protein,” and “molecule[s] capable of inhibiting a function of the viral particle.” As will be further described below, the specification also does not provide sufficient written description for the genus of proteases, peptides, antibodies, lipases, nucleases, RNases, DNases, micrococcal nucleases, or Ca2+-dependent nucleases which “inhibit[] a function of the viral particle,” or the genus of viral nucleocapsid protein, or SARS-CoV-2 N proteins which are “capable of self-assembling/oligomerizing with a viral particle protein.” Finally, the specification does not sufficiently describe fusion proteins comprising a sequence encoding one of SEQ ID NOs: 6, or 9-12 which would achieve functional limitations of the claims. Species Described in the Specification The specification generically describes that a nucleocapsid (N) protein is capable of assembling with a viral particle protein (pg. 25, line 15-16). The specification describes one species of nucleocapsid protein, SEQ ID NO: 1, which corresponds to a SARS-CoV-2 nucleocapsid protein (pg. 8). The specification also describes several truncated variants of the SARS-CoV-2 nucleocapsid protein, i.e., SEQ ID NOs: 6-12, and 15 (pg. 10-11). The specification describes that a protease, a peptide, an antibody, a lipase, or a nuclease is capable of inhibiting a function of a viral particle (pg. 19, line 20-28). The specification generally describes divalent cation-dependent nucleases (pg. 26, line 24 to pg. 27, line 5), DNases, RNAases, and micrococcal nucleases (pg. 27 lines 6-22). The specification structurally describes one species within the genus of molecules, i.e., a Ca2+-dependent Staphylococcus nuclease (SN) corresponding to SEQ ID NO: 3 (pg. 9). The specification also describes a generic fusion protein comprising the structure “N-Nuc,” wherein “N” represents a viral nucleocapsid protein, e.g., a SARS-CoV-2 nucleocapsid protein, and “Nuc” represents a nuclease (Fig. 1A-C; pg. 7, lines 5-21). The specification describes one species of the fusion protein with the claimed function (referred to as “N-Nuc” in the Examples), which appears to correspond to the sequences set forth in SEQ ID NOs: 4-5 (pg. 9; Figs. 3-4, and 6-8, “Antiviral activity,” pg. 42; “Calcium-dependent nuclease activity assays,” pg. 42; “Protein purification,” pg. 43). Based on the sequence listing, the fusion protein comprises the SARS-CoV-2 nucleocapsid protein sequence set forth in SEQ ID NO: 1, and the Ca2+-dependent Staphylococcus nuclease (SN) corresponding to SEQ ID NO: 3. The specification also describes a fusion protein (referred to as “N-Nuc mut”), which is encompassed by the claims based on claim 5 (“the nucleic acid molecule… encoding… SEQ ID NO: 13”), but does not have the functions described in the claim based on the specification, owing to two mutations in the SN fusion partner which reduce its nuclease activity (pg. 40; Figs. 5-7, “Calcium-dependent nuclease activity assays,” pg. 42; “Protein purification,” pg. 43). The specification does not describe the structures of any proteases, peptides, antibodies, lipases, or any nucleases other than the nuclease set forth in SEQ ID NO: 3, which are capable of inhibiting a function of a viral particle. The specification also does not describe any other “molecules,” i.e., virtually any substance, which are capable of inhibiting a function of a viral particle. As evidenced by the specification, at least one species encompassed by the claims (i.e., the nuclease corresponding to SEQ ID NO: 13) does not have the recited function. The specification does not provide any means to predict which of the many structures encompassed by the term “molecules,” or the many structures encompassed by the exemplary terms protease, peptide, antibody, lipase, or nuclease would achieve the recited function. Aside from the specific SARS-CoV-2 nucleocapsid protein set forth in SEQ ID NO: 1, the specification does not describe any other proteins which are capable of self-assembling/oligomerizing with a protein of a viral particle. For example, the specification does not describe any portions of the SARS-CoV-2 nucleocapsid protein (e.g., SEQ ID NOs: 6-12, and 15) which have this function, nor does the specification describe which of the vast genus of “proteins,” i.e., any polypeptide sequence, would be capable of self-assembling/oligomerizing with a protein of a viral particle. Finally, with respect to claim 9, the specification does not appear to describe the structure of any proteins capable of self-assembling/oligomerizing with a protein of a viral particle, wherein the viral particle protein is not a capsid protein. Guidance in the Prior Art The prior art describes fusion proteins with the same purpose (i.e., CTVI) and general structure described in the specification. Several species of fusion proteins are described in Zhang (Zhang et al., 21 September 2016, Viruses, 8, 258, pg. 1-13; of record). The most prevalent species of fusion protein comprise a known viral “capsid” protein which self-assembles/oligomerizes with a protein of the viral particle, fused to a Ca2+-dependent Staphylococcal nuclease (“SN”) which inhibits a function of the viral particle. See Table 1 of Zhang. Zhang describes several other “molecules,” which are proteins, that can inhibit a function of a viral particle (i.e., “scAb,” “RNase HI,” “Ribonuclease,” Table 1). Zhang also describes fusion protein species in which the viral protein which self-assembles/oligomerizes is not a capsid protein (see examples in Table 1 comprising Gag/Gag-Pol or Vpr protein). Zhang provides convincing evidence throughout, that a fusion protein comprising the Ca2+-dependent Staphylococcal nuclease (“SN”) operably linked to a known viral protein (e.g., capsid, Gag/Gag-Pol or Vpr) capable of self-assembly/oligomerization with a viral particle protein, would achieve the functions recited in the claims. However, neither Zhang, nor the prior art related to Zhang reviewed during the search describe any guidance which would allow the skilled artisan to ascertain which of the virtually unlimited “proteins” and “molecules” encompassed by the claims would actually have the recited functions. Zhang suggests that even for nucleases, “issues… remain to be resolved,” including the need to identify which fusion partners are “nontoxic to the host cell but that can also efficiently inactivate the virion from within” (pg. 8). The prior art also provides evidence that the skilled artisan could not predict which structures in the virtually unlimited genus of “proteins” and “molecules” encompassed by the claims would actually have the recited functions. For example, based on Boas (Costa Pereira Vilas Boas, 2019, Cellular and Molecular Life Science (2019) 76:3525-3542), it appears that use of antiviral peptides encompassed by the claims, even while facilitated by rational design choices, would require extensive screening efforts particular to each virus particle, and would be further complicated by the lack of structural information on recently discovered or uncharacterized viruses (“Rationally designed AVPs,” pg. 3532-3535; “Final considerations,” pg. 3535). McManus (McManus, 2016, Current Opinion in Colloid & Interface Science, 22 (106), pg. 73-79) describes that even though capsid proteins self-assemble by design, and capsid assembly involves a relatively small number of molecules, it is not possible to fully predict capsid assembly (“3. Viral capsids… it is not yet possible to fully predict this micelle-like assembly,” pg. 75). McManus states that there are on-going challenges related to predicting viral self-assembly, with respect to protein-protein interactions, protein-genome interactions, and intermediate structures (pg. 75). It is not apparent, therefore, that the skilled artisan could predict, without undertaking extensive screening efforts, which of the structures of the virtually unlimited proteins encompassed by the claims would be capable of self-assembling/oligomerizing with a viral particle protein (e.g., a capsid protein), or which of the virtually unlimited molecules, would be capable of inhibiting a function of a viral particle. Finally, with respect to the sequences set forth in SEQ ID NOs: 6-12, and 15, which are portions of the full-length SARS-CoV-2 nucleocapsid protein, the prior art provides evidence that a fusion protein between a inhibitory molecule, e.g., “SN,” and one of SEQ ID NOs: 6, and 9-12, would not be predicted to self-assemble/oligomerize with a protein of a SARS-CoV-2 viral particle. See teachings of Ye (Ye et al., Protein Science, 2020;29:1890-1901), which define the domains within the N protein which are required for self-assembly; truncated N proteins comprising domains N1a and N1b, or N1a, N1b, and N2a do not self-assemble (i.e., they remain monomeric in solution), truncated N proteins comprising domains N2b or SB/N3 self-assembles into dimers, whereas a truncated N protein comprising domains N2b and SB/N3 self-assembles into tetramers (Fig. 3; pg. 1893, left col.). Conclusion Considering the large variation in the genus, the small percentage of species described in the specification, and the lack of predictability provided by the art for the full scope of the claimed genus, it is reasonable to conclude that Applicant did not possess the invention as claimed at the time of filing. Claims 10-13 do not impose any further structural limitations on the composition of claim 1. The claims are rejected for depending from claim 1 and failing to remedy the lack of sufficient description above. Claim Rejections - 35 USC § 102 - Zhang 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. 07-15 AIA Claim s 1-4, and 6-13 are rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by Zhang (Zhang et al., 21 September 2016, Viruses, 8, 258, pg. 1-13; of record) . Regarding claims 1 and 11, the specification provides that compositions may comprise a vector, e.g., viral vector, encoding the fusion protein (pg. 33, line 24 to pg. 34, line 18). Zhang teaches an antiviral approach, termed “CTVI,” which comprises delivering a composition comprising a viral vector comprising a nucleic acid molecule encoding a fusion protein (i.e., the viral genome “stably expressing a fusion protein…,” see “a,” in Fig. 1B, wherein the viral vector encodes the nucleic acid molecule in black). Zhang teaches the composition is intended to be used to suppress a viral infection (“the CTVI mechanism… the nuclease incorporated into the progeny virion… can degrade the viral nucleic acids,” Fig. 1B). Zhang teaches the fusion protein comprises a viral nucleocapsid protein operatively linked to a nuclease (“nuclease fusion protein”)(“capsid proteins and nucleic acid, is termed the nucleocapsid (Fig. 1Aa)… a fusion protein consisting of a virus nucleocapsid protein and a foreign protein (an effector such as a nuclease, lipase, protease, or single-chain antibody (scab) is generated,” pg. 3; “Capsid protein/nuclease fusion protein,” Fig. 1Ab). Zhang teaches the viral nucleocapsid protein is capable of self-assembling/oligomerizing with a protein of a viral particle (“The mechanism underlying this strategy is based on the fact that viral DNA or RNA is encapsidated into a protein shell… As the protein of the nucleocapsid participates in viral assembly… The fusion protein is then incorporated into the virus particle,” “Capsid virus-like particles are formed by the fusion protein during encapsidation of the viral genome,” pg. 3; “Assembling,” Fig. 1Ab). Zhang teaches the nuclease is capable of inhibiting a function of the viral particle (“the effector molecule of the fusion protein has direct access to the nucleic acid or protein components of the virus ... the fusion protein can degrade DNA/RNA or disrupt the protein composition of the virus, resulting in an antiviral effect," pg. 3). Regarding claim 2, Zhang teaches the viral infection is at least one of RNA, DNA, or retroviral infection (“Application of CTVI for Different Viral Classes,” pg. 5-8; “3.1. Retroviruses,” pg. 5-6; “DENV, an enveloped single-stranded positive-sense RNA virus,” pg. 6-7; “HBV… the relaxed circular DNA (rcDNA) genome,” pg. 7-8). Regarding claim 3, Zhang teaches the inhibited function of the viral particle comprises reproduction of the viral particle within a cell (“thereby interfering with generation of the viral genome and ultimately affecting the viral life cycle,” pg. 3). Regarding claim 4, as stated above, Zhang teaches the protein capable of self-assembling/oligomerizing with the viral particle protein is a viral nucleocapsid protein (The mechanism underlying this strategy is based on the fact that viral DNA or RNA is encapsidated into a protein shell… As the protein of the nucleocapsid participates in viral assembly… The fusion protein is then incorporated into the virus particle,” “Capsid virus-like particles are formed by the fusion protein during encapsidation of the viral genome,” pg. 3; “Assembling,” Fig. 1Ab). Regarding claim 6, as stated above, Zhang teaches the molecule capable of inhibiting a function of the viral particle is a nuclease (“the effector molecule of the fusion protein has direct access to the nucleic acid or protein components of the virus ... the fusion protein can degrade DNA/RNA or disrupt the protein composition of the virus, resulting in an antiviral effect," pg. 3). Regarding claim 7, Zhang teaches the nuclease is an RNase or DNase (“the fusion protein can degrade DNA/RNA,” pg. 3; “When the Ca2+ concentration reaches the millimolar range, the enzyme is activated and digests the viral RNA/DNA,” Fig. 1A). Regarding claim 8, Zhang teaches the nuclease is a calcium (Ca2+)-dependent nuclease (“the nuclease in the virion is inactive due to the intracellular nanomolar Ca2+ concentration… the nuclease incorporated into the progeny virion is active in the extracellular millimolar Ca2+ concentration, where it can degrade the viral nucleic acids,” Fig. 1B). Regarding claim 9, in view of the indefiniteness described above, claim 9 is interpreted as requiring that the viral particle protein to which the protein must be capable of self-assembling/oligomerizing is not a capsid protein. Zhang teaches a nucleic acid molecule (“Plasmid vector, pLR2P”) encoding a fusion protein (“Vpr-SN”) wherein the fusion protein comprises a protein capable of self-assembling/oligomerizing with a protein of a viral particle, wherein the viral particle protein is not a capsid protein (“Vpr”), operatively linked to a nuclease which is capable of inhibiting a function of the viral particle (“SN”)(Table 1; “Vpr-based fusion proteins that can specifically incorporate into the mature virion… Vpr, which plays a distinct and necessary role in viral replication and pathogenesis, is a virion-associated auxiliary protein…,” section 3.1.3, pg. 6). Regarding claim 10, Zhang teaches a cell comprising the composition (“Infection of a cell by a virus stably expressing a fusion protein… The virus enters the host cell through the endocytosis pathway,” Fig. 1B). Regarding claim 12, Zhang teaches a cell comprising the fusion protein (“A schematic representation of the CTVI mechanism. Infection of a cell by a virus stably expressing a fusion protein…” Fig. 1B). Regarding claim 13, Zhang teaches a virus particle comprising the fusion protein (“The assembly process of the virus with the fusion protein composed of a capsid protein and degradative enzyme (e.g., staphylococcal (SN)) that is calcium ion (Ca2+) dependent. The fusion protein is incorporated into the internal virion during viral assembly…,” Fig. 1A). Notice to Joint Inventors 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. Claim Rejections - 35 USC § 103 – Zhang in view of Ye and GenBank 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. 07-21-aia AIA Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang (Zhang et al., 21 September 2016, Viruses, 8, 258, pg. 1-13; of record) as applied to claims 1-4, and 6-13 above, in view of Ye (Ye et al., Protein Science, 2020;29:1890-1901) and GenBank (Severe acute respiratory syndrome coronavirus 2 isolate Wuhan-Hu-1, complete genome, NCBI Reference Sequence: NC_045512.2, available 18 July 2020) The teachings of Zhang are described above and applied as to claims 1-4, and 6-13 hereinafter. Zhang teaches that the CTVI strategy has been “extensively applied” (pg. 8), and has been successfully used to inactivate several different viruses (Table 1). The skilled artisan would understand based on Zhang that the majority of CTVI strategies in the prior art use a nucleic acid encoding a fusion protein comprising the generic structure “Capsid-SN,” wherein the viral protein capable of assembly is a viral capsid protein, and wherein the nuclease fused thereto, which is capable of inactivating the virus once assembled into the viral particle, is a non-cytotoxic Ca2+-dependent Staphylococcus nuclease which can degrade single- and double-stranded DNA and RNA (“SN”)(Table 1; pg. 3; pg. 5). Zhang teaches that “CTVI [] has great potential for the development of preventative vaccines (pg. 3). Zhang also teaches that “[r]esearchers expect that [fusion proteins comprising SN]… may be broadly applicable to other virus families” (section 3.1.1, pg. 5). Indeed, Zhang teaches that a “Capsid-SN” fusion protein is effective to suppress infection of two different RNA viruses, CSFV and Dengue 2 Virus, each of which comprise a capsid protein responsible for packaging the viral nucleic acids (see sections “3.1.2. Classical Swine Fever Virus,” and “3.2.1 Dengue 2 Virus”). Zhang does not teach a nucleic acid molecule encoding a fusion protein comprising SEQ ID NO: 15, which corresponds to the N2b domain and spacer B/N3 domain of a SARS-CoV-2 nucleocapsid (N) protein based on the specification (pg. 11, lines 23-27). Ye teaches that SARS-CoV-2 pandemic is “the most severe acute public health threat of the twenty-first century,” and that the need for therapeutics is “urgent” (Abstract; pg. 1890). In an effort to provide an additional target for the urgently-needed therapeutics, Ye characterizes the architecture and self-assembly properties of the SARS-CoV-2 nucleocapsid protein (Abstract; pg. 1891, left col.; Fig. 2), which Ye teaches is a “critical step” in the viral life cycle which facilitates packaging of the viral RNA into virions (pg. 1891, left col.; pg. 1897, left col.). Ye teaches that the full-length nucleocapsid (N) protein self-assembles into a homotetramer (pg. 1893, right col.; Fig. 3). Ye defines the domains within the N protein which are required for self-assembly; truncated N proteins comprising domains N1a and N1b, or N1a, N1b, and N2a do not self-assemble (i.e., the remain monomeric in solution), truncated N proteins comprising domains N2b or SB/N3 self-assembles into dimers, whereas a truncated N protein comprising domains N2b and SB/N3 self-assembles into tetramers (Fig. 3; pg. 1893, left col.). Ye teaches that residues of the N protein which correspond to each of the aforementioned domains; residues 247-419 correspond to the N2b domain and SB/N3 domain (Fig. 2-3; pg. 1893, left col.).Ye also proposes a mechanism through which self-assembly of the N2b and SB/N3 domains mediates packaging of SARS-CoV-2 viral RNA (pg. 1895; pg. 1897, left col.). Ye does not teach the nucleic acid sequence encoding the SARS-CoV-2 nucleocapsid (N) protein, or the encoded protein sequence. Ye does, however, reference GenBank “YP_009724397” as providing these sequences (“SARS-CoV-2 N protein constructs… were amplified by PCR from the IDT 2019-nCoV N positive control plasmid… NCBI RefSeq YP_009724397,” pg. 1897, right col.). GenBank provides the nucleic acid sequence encoding the SARS-CoV-2 nucleocapsid (N) protein, and the protein sequence corresponding to YP_009724397 (“CDS 28274..29533,” “/gene = “N,” “/product= “nucleocapsid phosphoprotein,” “/protein_id= “YP_009724397.2,” “/translation= “MSDN…,” pg. 9). As shown in the attached alignments in Appendix I, residues 247-419 of GenBank’s protein sequence, which correspond to the N2b domain and SB/N3 domain based on Ye, are 100% identical to instant SEQ ID NO: 15. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have prepared a nucleic acid molecule encoding a fusion protein comprising SEQ ID NO: 15 in view of the prior art. It would have amounted to preparing a nucleic acid molecule encoding a known fusion protein structure suitable for CTVI (i.e., “Capsid-SN”), with a nucleic acid sequence encoding a known SARS-CoV-2 nucleocapsid protein sequence suitable for self-assembly with a protein of the SARS-CoV-2 viral particle, by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success in preparing the nucleic acid molecule encoding a fusion protein comprising SEQ ID NO: 15, because as evidenced by the prior art, means to prepare nucleic acid molecules encoding fusion proteins were well known (see, for example, the many examples of fusion proteins described by Zhang, which are expressed from nucleic acid molecules in the CTVI strategy). Furthermore, the sequence of SEQ ID NO: 15 was known to self-assemble with proteins of the SARS-CoV-2 viral particle. Given the desperate need to develop therapeutics for the SARS-CoV-2 pandemic, the skilled artisan would have been motivated to prepare a nucleic acid molecule encoding a “Capsid-SN” fusion protein comprising SEQ ID NO: 15. The skilled artisan would have had a reasonable expectation that the resulting fusion protein would have functioned for its intended use of inactivating SARS-CoV-2 based on the many successful examples of CTVI fusion proteins taught by Zhang, including successful examples in RNA viruses with similar reliance on capsid proteins to package the viral nucleic acids, as well as the clear teachings in the art regarding the self-assembly properties of the sequence set forth in SEQ ID NO: 15. Conclusion No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNA L PERSONS whose telephone number is (703)756-1334. The examiner can normally be reached M-F: 9-5pm. 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, JENNIFER A DUNSTON can be reached at (571) 272-2916. 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. /JENNA L PERSONS/Examiner, Art Unit 1637 /Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637 Application/Control Number: 18/549,951 Page 2 Art Unit: 1637 Application/Control Number: 18/549,951 Page 3 Art Unit: 1637 Application/Control Number: 18/549,951 Page 4 Art Unit: 1637 Application/Control Number: 18/549,951 Page 5 Art Unit: 1637 Application/Control Number: 18/549,951 Page 6 Art Unit: 1637 Application/Control Number: 18/549,951 Page 7 Art Unit: 1637 Application/Control Number: 18/549,951 Page 8 Art Unit: 1637 Application/Control Number: 18/549,951 Page 9 Art Unit: 1637 Application/Control Number: 18/549,951 Page 10 Art Unit: 1637 Application/Control Number: 18/549,951 Page 11 Art Unit: 1637 Application/Control Number: 18/549,951 Page 12 Art Unit: 1637 Application/Control Number: 18/549,951 Page 13 Art Unit: 1637 Application/Control Number: 18/549,951 Page 14 Art Unit: 1637 Application/Control Number: 18/549,951 Page 15 Art Unit: 1637 Application/Control Number: 18/549,951 Page 19 Art Unit: 1637 Application/Control Number: 18/549,951 Page 20 Art Unit: 1637 Application/Control Number: 18/549,951 Page 21 Art Unit: 1637 Application/Control Number: 18/549,951 Page 22 Art Unit: 1637 Application/Control Number: 18/549,951 Page 23 Art Unit: 1637
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