DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s arguments have overcome the objection to the specification and rejections under 35 USC §§ 112(b) and 112(d).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-6, 12, 13, 15, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over admitted prior art for SEQ ID NO: 1 in paragraph [0051] of the instant published disclosure (USPgPub 2023/0416692), SEQ ID NO 2 alignment with Genseq db access no BJT50159 submitted 3 Feb 2020 isolate Wuhan-Hu-1, SEQ ID NO 3 alignment with Genseq db access no OR240382 isolated 29 January 2020 isolate Wuhan-2020, Yount et al. (PNAS. 2003; 100 (22): 12995-13000, cited in the May 14, 2024 IDS), and Wu et al. (Nature. Available online: 2020 Feb 3; 579 (7798): 265-269). All references cited are of record.
Paragraph [0051] of the instant published disclosure states:
[0051] A SARS-CoV-2 reference sequence can be found in GenBank accession NC 045512.2 as of Mar. 2, 2020 (SEQ ID NO:1). This sequence is a 29903 bp ss-RNA and is referred to as the Wuhan seafood market pneumonia virus isolate Wuhan-Hu-1.
This teaching constitutes admitted prior art for instant SEQ ID NO: 1, recited in instant claims 1-3 and 12.
Genseq db access no BJT50159 submitted 3 Feb 2020 “isolate Wuhan-Hu-1” shares 100% identity with instant SEQ ID NO: 2, see the alignment provided, recited in claims 1-3 and 12.
Genseq db access no OR240382 isolated 29 January 2020 identifies Wuhan/2020 as the genomic source, shares 100% identity with instant SEQ ID NO: 3, see the alignment provided, recited in claims 1-3 and 12.
None of the sequence alignments or descriptions thereof, teach a recombinant cDNA plasmid expression cassette comprising any of the SARS-CoV-2 genome sequences, as required in instant claims 1-4 and 12, operatively linked to a heterologous promoter, recited in claim 5, or a host cell comprising the expression cassette, recited in claim 6. Additionally, none of the sequence alignments or descriptions thereof, teach an assay for SARS-CoV-2 replication by contacting Vero cells with the SARS-CoV-2 genome, contacting the cells with a test agent, and assessing virus replication in the presence of the agent, recited in instant claims 13 and 15, after incubation for hours recited in instant claim 18.
Yount et al. describe a reverse genetics with a full-length infectious cDNA of
severe acute respiratory syndrome coronavirus in the title and abstract. In the “Strategy for Cloning the SARS-CoV cDNAs”, “Systematic Assembly of a Full-Length SARS-CoV cDNA”, and “Assembly of SARS Full-Length cDNAs”, Yount et al. describe assembly of an infectious SARS-CoV cDNA operatively linked to a T7 promoter in a plasmid. In “Virus and cells” and “In Vitro Inhibition of SARS-CoV Replication”, Yount et al. teach propagating SARS-CoV in VeroE6 cell cultures, applying the cysteine protease inhibitor (2S,3S)-transepoxysuccinyl-L-leucylamido-3-methylbutane ethyl ester (E64-d) and observing reduced viral titer and recovered cytopathic effects from viral infection (both measurements meeting the requisite “reporter signal” recited in claim 18) in the following 24 and 48 hours after application.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have incorporated any one of SEQ ID NOs: 1-3 as a full-length cDNA construct in the method of Yount et al. for facile manipulation of the genome and allow rapid development and testing of candidate vaccines and therapeutics. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have incorporated any one of SEQ ID NOs: 1-3 as a full-length cDNA construct in the method of Yount et al. because Wu et al. describe the extensive similarities between SARS and SARS-CoV-2 viruses, see the abstract, Figures 1 and 2, and the paragraph bridging pages 267 to 268 and the last paragraph on page 268.
Claims 7, 8, 9, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over admitted SEQ ID NO: 1 and SEQ ID NOs: 2 and 3 alignments, Yount et al., and Wu et al. as applied to claims 1-6, 12, 13, 15, and 18 above, and further in view of Baric et al. (WO 2005/035712, of record).
See the teachings provided by admitted SEQ ID NO: 1 and SEQ ID NOs: 2 and 3 alignments, Yount et al., Wu et al. above. Yount et al. teach the presence of marker mutations in the SARS cDNA constructs, see the abstract, “Detection of Marker Mutations Inserted in Infectious Clone (ic)SARSCoV”, and “icSARS-CoV Marker Mutations”. However, none of the references teach or suggest a SARS-CoV-2 cDNA recombinant encoding a heterologous reporter protein, presented in claims 7 and 8) that replaces ORF7a (recited in instant claim 19), where the reporter protein is a fluorescent or luminescent protein, recited in claim 9.
In, “Deletion of SARS-Co V Group Specific Genes”, Baric et al. teach replacing ORF7a with luciferase or GFP, see page 38, line 28 to page 39, line 20.
It would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date would have been motivated to have expressed a green fluorescent protein, taught by Baric et al. in any one of SARS-CoV-2 cDNA of SEQ ID NOs: 1-3 alignments, Yount et al., and Wu et al. above, to readily detect recombinant cDNA SARS-CoV-2 infection, discussed in “Rescue of Molecularly Cloned SARS-CoV” and “Stable VRP Single Hit Expression Vectors” on pages 31 and 35, respectively, by Baric et al. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have expressed a green fluorescent protein, taught by Baric et al. in any one of the SARS-CoV-2 cDNA of SEQ ID NOs: 1-3 alignments, Yount et al., and Wu et al. because Baric et al. teach SARS vectors provide for incorporation and expression of multiple heterologous nucleic acids on page 21, lines 1-5 and Yount et al. and Baric et al. teach infectious SARS cDNA, see “Strategy for Cloning the SARS-CoV cDNAs”, “Systematic Assembly of a Full-Length SARS-CoV cDNA”, and “Assembly of SARS Full-Length cDNAs” of Yount et al. and page 2, line 31 to page 3, line 2, page 22, line 30 to page 23, line 3 of Baric et al. (citing Yount et al.) and “Assembly of Coronavirus Full Length cDNAs” on page 30.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have expressed a green fluorescent protein in place of ORF7a, taught by Baric et al. in any one of SARS-CoV-2 cDNA of SEQ ID NOs: 1-3 alignments, Yount et al., and Wu et al. above with a reasonable expectation of success, because Baric et al. teach ORF7a is nonessential for SARS replication in lines 5-7 on page 41.
Claims 10, 14, 16, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over admitted SEQ ID NO: 1 and SEQ ID NOs: 2 and 3 alignments, Yount et al., Wu et al., and Baric et al. as applied to claims 1-9, 12, 13, 15, and 18 above, and further in view of Cao et al. (Scientific Reports. 2019 Nov 4; 9 (1):15899, of record) and Ge et al. (Antiviral Research. 2008; 80: 107-113, of record).
See the teachings of admitted SEQ ID NO: 1 and SEQ ID NOs: 2 and 3 alignments, Yount et al., Wu et al., and Baric et al. above. None of the references teach or suggest mNeonGreen as the fluorescent protein, as recited in instant claims 10 and 14, or assaying for SARS-CoV-2 replication in a 96-well microtiter plate, recited in instant claims 16 and 17.
Cao et al. teach the reporter gene mNeonGreen, see the abstract, “Development and optimization of an all-in-one NP reporter plasmid”, and Preliminary evaluation of the optimized all-in-one reporter for living cell sensing of intracellular NP proteins”.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have incorporated the mNeonGreen reporter gene of Cao et al. into any one of the SARS-CoV-2 cDNA of SEQ ID NO: 1, SEQ ID NOs: 2 and 3 alignments, Yount et al., Wu et al., and Baric et al. because Cao et al. teach that mNeonGreen is up to three times brighter than EGFP in vitro, in “Development and optimization of an all-in-one NP reporter plasmid”. Additional inspiration to the ordinary artisan prior to the instant effective filing date to have incorporated the mNeonGreen reporter gene of Cao et al. into any one of the SARS-CoV-2 cDNA of SEQ ID NO: 1, SEQ ID NOs: 2 and 3 alignments, Yount et al., Wu et al., and Baric et al. would have been to rapidly and conveniently monitor continually emerging virus variants, visualize infections of the variant viruses in living cells, and efficiently evaluate large-scale drug screening for anti-viral agents, see the abstract, Introduction, Figure 3, and the last two paragraphs above “Materials and Methods”. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have incorporated the mNeonGreen reporter gene of Cao et al. into any one of the SARS-CoV-2 cDNA of SEQ ID NO: 1, SEQ ID NOs: 2 and 3 alignments, Yount et al., Wu et al., and Baric et al. because Cao et al. state, “…our study developed a universal reporter system for living cell sensing influenza A virus infection, which does not require any modification on virus” in the first paragraph of the “Materials and methods” section starting with, “Overall, various recombinant fluorescent…” and in the abstract, Cao et al. state that the live-cell biosensors are applicable for other viruses.” In addition, Baric et al. teach SARS vectors provide for incorporation and expression of multiple heterologous nucleic acids on page 21, lines 1-5.
In “Infection” and “Preliminary evaluation of the optimized all-in-one reporter for living cell sensing of intracellular NP proteins”, Cao et al. teach evaluating various viral strains with different neutralizing antibodies at different concentrations in a 96-well microtiter plate.
It would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to have applied a SARS-CoV-2 recombinant or variant comprising mNeonGreen in a 96-well microtiter plate, as taught by Cao et al., to screen for virus inhibitors, as taught by Yount et al. in “In Vitro Inhibition of SARS-CoV Replication”, to simultaneously test and screen 96 antiviral compounds or antibodies against any SARS-CoV-2 recombinant or variant. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success for screening antivirals against live SARS-CoV-2 recombinants or variants with a reporter in a 96-well microtiter plate because Ge et al. teach screening 7035 compounds against SARS in a 96-well microtiter plate comprising Vero cells in the first full paragraph of the first column on page 108 and section 2.3.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over admitted SEQ ID NO: 1 and SEQ ID NOs: 2 and 3 alignments, Yount et al., Wu et al., and Baric et al. as applied to claims 1-9, 12, 13, 15, and 18 above, and further in view of Yan et al. (Biochemistry. 2015; 54: 5589−5604, of record).
See the teachings of admitted SEQ ID NO: 1 and SEQ ID NOs: 2 and 3 alignments, Yount et al., Wu et al., and Baric et al. above. None of the references teach or suggest nanoluciferase as the luminescent protein, as recited in instant claim 11.
Yan et al. teach a replication-competent recombinant influenza harboring nanoluciferase in “Generation of recIAV Reporter Strains”.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have incorporated the nanoluciferase reporter gene of Yan et al. into any one of the SARS-CoV-2 cDNA of SEQ ID NO: 1, SEQ ID NOs: 2 and 3 alignments, Yount et al., Wu et al., and Baric et al. because it produces high signal intensities, see “Generation of a Replication-Competent IAV-WSN PB2-NanoLuc Reporter Strain” and Figures 1C and 1D of Yan et al. One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have incorporated the nanoluciferase reporter gene of Yan et al. into any one of the SARS-CoV-2 cDNA of SEQ ID NO: 1, SEQ ID NOs: 2 and 3 alignments, Yount et al., Wu et al., and Baric et al. because Baric et al. teach SARS vectors provide for incorporation and expression of multiple heterologous nucleic acids on page 21, lines 1-5.
Response to Arguments
Applicant asserts that the motivation provided to have incorporated any one of SEQ ID NOs: 1-3 as a full-length cDNA construct in the method of Yount et al, “lacks articulated reasoning with rational underpinning and is driven by impermissible hindsight” (quoted from the first full paragraph on page 8 of Applicant’s Remarks).
Applicant’s arguments and a review of the references have been fully considered, but are found unpersuasive since the articulated reasoning inspired for generating a full-length infectious cDNA of severe acute respiratory syndrome coronavirus by Yount et al. is provided in at least the last sentence of the abstract:
Availability of a SARS-CoV full-length cDNA provides a template for manipulation of the viral genome, allowing for the rapid and rational development and testing of candidate vaccines and therapeutics against this important human pathogen.
Therefore, motivation to one of ordinary skill in the art prior to the instant effective filing date to have incorporated any one of SEQ ID NOs: 1-3 as a full-length cDNA construct in the method of Yount et al. “for facile manipulation of the genome and allow rapid development and testing of candidate vaccines and therapeutics”, is gleaned directly from Yount et al., published in 2003. Impermissible hindsight reasoning is not applicable.
Applicant details differences made between the Yount et al. cloning system and the instant procedures used to generate a SARS-CoV-2 cDNA, such as PCC1 and BAC-based systems and different junction sites. Applicant asserts that for these reasons, the teachings of Yount et al. and Wu et al. would likely fail if applied to SARS-CoV-2.
Applicant’s arguments and a review of the prior art of record has been considered, but are found unpersuasive. The specific limitations pointed to by applicant as crucial for cloning are not recited elements in the claims. In addition, Yount et al. teach constructing full-length cDNAs of Group I and Group II CoVs in the paragraph bridging the columns on page 12999. Therefore, the reverse genetics used to generate full-length infectious cDNA of coronaviruses even more divergent than genomically and phylogenically closely related SARS and SARS-CoV-2 have been successfully generated as cDNA clones. The specific cloning strategies required to generate full-length infectious cDNA of coronavirus members categorized as Group I and Group II would have been within the purview of the ordinary artisan prior to the instant effective filing date, as evidenced by Yount et al. in the successful construction of full-length cDNAs of Group I and Group II CoVs.
Applicant states that the first SARS-CoV-2 genome shares only approximately 79.6% nucleotide identity with SARS-CoV and summarizes significant structural divergences determined by Wu et al. between SARS-CoV and SARS-CoV-2. Applicant argues that no reference teaches or suggests that the reverse genetics system of Yount et al. can be applied to SARS-CoV-2. Applicant states that the instant specification discloses that full-length coronavirus cDNA is unstable due to genome size and toxic elements.
Applicant’s arguments have been fully considered, but are found unpersuasive. Contrary to applicant’s characterization of teachings of Wu et al., Wu et al. describe the extensive similarities between SARS and SARS-CoV-2 viruses, see the abstract, Figures 1 (genome organization), Figure 2 (closely related phylogeny), the paragraph bridging pages 267 to 268 and the last paragraph on page 268, encompassing high sequence similarities to SARS-CoV RBD, using the human ACE2 receptor for cell entry. In the last paragraph on page 268, Wu et al. conclude (“WHCV”, defined as SARS-CoV-2 in the last paragraph before “Online content”, underlining provided for convenience):
Here we describe a new coronavirus—WHCV—in the BALF from a patient who experienced severe respiratory disease in Wuhan, China. Phylogenetic analysis suggests that WHCV is a member of the genus Betacoronavirus (subgenus Sarbecovirus) that has some genomic and phylogenetic similarities to SARS-CoV1, particularly in the RBD of the spike protein. These genomic and clinical similarities to SARS, as well as its high abundance in clinical samples, provides evidence for an association between WHCV and the ongoing outbreak of respiratory disease in Wuhan and across the world.
The close genomic and structural similarities between SARS and SARS-CoV-2, pointed out by Wu et al., would have provided a reasonable expectation of success to one of ordinary skill in the art prior to the instant effective filing date to have incorporated a SARS-CoV-2 genome as a full-length cDNA construct in the method of Yount et al. In the paragraph bridging the columns on page 12999, Yount et al. teach constructing full-length cDNAs of Group I and Group II CoVs, and removes SARS-CoV toxic domains (in the first paragraph under, “Assembly of SARS Full-Length cDNAs”, that would correspond to SARS-CoV-2 toxic domains, given the extensive similarities between the genomes, as evidenced by Wu et al. Therefore, there is no criticism, discouragement, or disparaging evidence in the art prior to the instant effective filing date that generating genomic cDNAs from other CoVs, such as SARS-CoV-2, in the method of Yount et al. and Wu et al., would not have achieved reasonable success.
Applicant argues that none of Baric et al., Cao et al., Ge et al., and Yan et al. remedy the deficiencies of the combination of SEQ ID NO:1 and SEQ ID NOs:2 and 3 alignments, Yount et al., and Wu et al. However, since there are no deficiencies for the secondary references to cure, the rejections are maintained for reasons of record.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Shanon A. Foley/Primary Examiner, Art Unit 1671
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