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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on April 16, 2026 has been entered.
Claim Rejections - 35 USC § 112
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 1-3 and 6-19 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.
Instant claim 1 states that the type IIS restriction enzymes generate “unique cohesive overhangs”. It is unclear what features characterize the cohesive overhangs as “unique”, which is a subjective impression. This rejection affects all depends claims.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3 and 6-19 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. This is a written description rejection.
Instant claim 1 states that the type IIS restriction enzymes generate “unique cohesive overhangs”. Paragraph [0056] of the instant published disclosure (USPgPub 2023/0416692, of record) teaches:
The class IIS endonucleases recognize asymmetric DNA sequences, cleave outside their recognition sequences, and generate unique cohesive overhangs (FIG. 1C). After digestion with BsaI or Esp3I, the seven fragments were directionally ligated to assemble the genome-length cDNA.
Therefore, while the instant disclosure conveys possession of BsaI or Esp3I class IIS endonucleases, there is inadequate written description for the genus of class IIS endonucleases encompassed by the instant claims. The skilled artisan would not recognize a class IIS endonuclease member, as evidenced by Alekseeva et al. (Fermentation. 2023; 9 (10): 874). In section 6.10, “Endonucleases of Subtype IIS”, Alekseeva et al. teach while enzymes of this class share similar functions of DNA cleavage, the domain organization and quaternary architecture vary considerably.
The applicable standard for the written description requirement can be found in MPEP 2163; University of California v. Eli Lilly, 43 USPQ2d 1398 at 1407; PTO Written Description Guidelines; Enzo Biochem Inc. v. Gen-Probe Inc., 63 USPQ2d 1609; Vas- Cath Inc. v. Mahurkar, 19 USPQ2d 1111; and University of Rochester v. G.D. Searle & Co., 69 USPQ2d 1886 (CAFC 2004). To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus of IIS endonucleases. A definition by function alone is not sufficient because it is only an indication of what a thing does, i.e., generating cohesive overhangs, rather than what it is. Eli Lily, 119 F.3 at 1568, 43 USPQ2d at 1406.
The court clearly states in Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not clearly allow persons of ordinary skill in the art to recognize that the inventors invented what is claimed. As discussed above, the skilled artisan cannot envision the distinguishing, identifying characteristics of the encompassed genus of IIS endonucleases claimed. Given that the specification has only described BsaI or Esp3I, the full breadth of the claims does not meet the written description provision of 35 U.S.C. 112, first paragraph.
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 1-3, 6, 12, 13, and 15 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, of record), SEQ ID NO 2 alignment with Genseq db access no BJT50159 submitted 3 Feb 2020 isolate Wuhan-Hu-1, of record, SEQ ID NO 3 alignment with Genseq db access no OR240382 isolated 29 January 2020 isolate Wuhan-2020 , of record, Wu et al. (Nature. Available online: 2020 Feb 3; 579 (7798): 265-269, of record), Spagnolo et al. (“Requirement of the poly(A) tail in coronavirus genome replication”. In The Nidoviruses: Coronaviruses and Arteriviruses; 2001 Jan: 467-474). Boston, MA: Springer US), and Yount et al. (PNAS. 2003; 100 (22): 12995-13000, cited in the May 14, 2024 IDS), as evidenced by Baric et al. (“Development of mouse hepatitis virus and SARS-CoV infectious cDNA constructs.”, In Coronavirus Replication and Reverse Genetics 2005 Oct 25: 229-252). Berlin, Heidelberg: Springer Berlin Heidelberg.
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 DNA “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 RNA 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 DNA plasmid expression cassette comprising any of the infectious SARS-CoV-2 genome segments as cDNA sequences, as required in instant claims 1-3 and 12;
wherein the SARS-CoV-2 genome segment is the product obtained by assembling seven contiguous cDNA fragments by directional ligation using type IIS restriction enzymes that generate unique cohesive overhangs at engineered junction sites, recited in instant claim 1;
wherein each SARS-CoV-2 genome segment is operatively linked to a heterologous promoter in a plasmid backbone, recited in instant claim 1; 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.
Yount et al. describe a reverse genetics with a full-length infectious cDNA of
severe acute respiratory syndrome coronavirus clone (icSARS)in the title and abstract. In the sentence bridging pages 12995-12996 under, “Strategy for Cloning the SARS-CoV cDNAs”, Yount et al. teach (note: “CSs” is an abbreviation for consensus sequences, see the “Abbreviations:” footnote at the bottom right of page 12995), underlining provided for convenience):
All cDNAs were assembled as CSs based on independent sequence analysis of four to seven sibling clones and the reported Urbani sequence (8).
Under, “Assembly of SARS Full-Length cDNAs”, Yount et al. teach:
Our strategy includes a panel of cDNAs spanning the entire CoV genome, which can be systematically and directionally assembled into a genome-length cDNA by in vitro ligation (17, 18). The SARS genome was cloned as six contiguous subclones that could be systematically linked by unique BglI restriction endonuclease sites (Fig. 1). BglI is a class IIS restriction endonuclease that cleaves the symmetrical sequence CCNNNN2NGGC but leaves 64 different asymmetrical ends. Consequently, pairs of contiguous subclones encoded junctions that allow unidirectional assembly of intermediates into a full length cDNA. As shown in Fig. 1A, two BglI junctions were derived from sites encoded within the SARS-CoV genome at nucleotide positions 4373 (A_B junction) and 12065 (C_D junction) (8–10). A third BglI site at nucleotide position 1577 was removed and new BglI sites were inserted by the introduction of silent mutations into the SARS-CoV sequence at nucleotide 8700 (B_C junction), nucleotide 18916 (D_E junction), and at nucleotide 24040 (E_F junction) (Fig. 1B)…. The resulting cDNAs include SARS A (nucleotides 1–4436), SARS B (nucleotides 4344–8712), SARS C (nucleotides 8695–12070), SARS D (nucleotides 12055–18924), SARS E (nucleotides 18907–24051), and SARS F (nucleotides 24030–29736) subclones. The SARS A subclone contains a T7 promoter and the SARS F subclone terminates in 21Ts, allowing for in vitro transcription of capped, polyadenylated transcripts.
Numerous mutations were noted in each of the four to seven sibling subclones encoding a given SARS cDNA fragment (Fig. 1C). To rapidly assemble consensus clones, we used class IIS restriction endonucleases that cut at asymmetric sites and leave asymmetric ends. These enzymes generate strand-specific unique overhangs that allow the seamless ligation of two cDNAs with the concomitant loss of the restriction site (17).
SARS subclones A-F, a total of six contiguous cDNA fragments are clearly depicted in Figure 1. A shaded “21T” section is depicted in Figure 1C:
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Baric et al. points to the teachings of Yount et al. 2003 in the first paragraph under section 5: “SARS-CoV Infectious Clone” on page 245:
A systematic assembly strategy based on the TGEV infectious clone was employed to create an infectious construct of the SARS-CoV, within ~2 months of the identification and isolation of genomic SARS-CoV RNA (Yount et al. 2003).
SARS segments A-F, depicted in Figure 6, and corresponding nucleic acid residue position numbers, described under Figure 6, of Baric et al. are indistinguishable from SARS segments A-F, depicted in Figure 1A of Yount et al., and corresponding nucleic acid residue position numbers, described in the excerpted portion above from: “Assembly of SARS Full-Length cDNAs”) of Yount et al.:
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Fig. 6 of Baric et al. From Fig. 1A of Yount et al.
The description of Figure 6 by Baric et al. identifies a SARS-CoV G fragment (segment 7) as the 21 poly(T) tail, described by Yount et al. under, “Assembly of SARS Full-Length cDNAs”. Therefore, Yount et al. teach assembling seven contiguous cDNA fragments by directional ligation using type IIS restriction enzymes that generate unique cohesive overhangs at engineered junction sites, recited in instant claim 1. Yount et al. describe assembly of an infectious SARS-CoV cDNA operatively linked to a T7 promoter in a plasmid in “Systematic Assembly of a Full-Length SARS-CoV cDNA”, also recited by instant claim 1. In “Virus and cells” and “In Vitro Inhibition of SARS-CoV Replication”, Yount et al. teach propagating SARS-CoV in VeroE6 cell cultures (as required by instant claims 6 and 15), applying the cysteine protease inhibitor (2S,3S)-transepoxysuccinyl-L-leucylamido-3-methylbutane ethyl ester (E64-d) (test agent) and observing reduced viral titer and recovered cytopathic effects from viral infection (meeting the requisite “reporter signal” recited in claim 13).
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., as evidenced by Baric 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.
Further, it is noted that the Urbani sequence, GenBank: AY278741.1, of Yount et al. is published without a poly(A) sequence, see the sequence provided.
Spagnolo et al. (“Requirement of the poly(A) tail in coronavirus genome replication”. In The Nidoviruses: Coronaviruses and Arteriviruses; 2001 Jan: 467-474). Boston, MA: Springer US) teach the poly(A) tail is required for genome replication and infectivity, see Figures 2, 3, and Table 1.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to have supplied the poly(A) tail in a SARS-CoV G fragment (segment 7), as evidenced by Baric et al., and described by Yount et al. under, “Assembly of SARS Full-Length cDNAs”, to generate a replicable, infectious SARS cDNA complete genome with a reasonable expectation of success, absent evidence to the contrary.
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, Wu et al., Spagnolo et al., and Yount et al., as evidenced by Baric et al., as applied to claims 1-3, 6, 12, 13, and 15 above, and further in view of Baric et al. (WO 2005/035712, of record, hereinafter, “Baric ‘712”).
See the teachings provided by admitted SEQ ID NO: 1 and SEQ ID NOs: 2 and 3 alignments, Wu et al., Spagnolo et al., and Yount et al., as evidenced by Baric 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 ‘712 teach replacing ORF7a with luciferase or GFP, see page 39, line 28 to page 40, line 24.
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 ‘712 in any one of SARS-CoV-2 cDNA of SEQ ID NOs: 1-3 alignments, Spagnolo et al., Wu et al., and Yount et al., as evidenced by Baric 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 ‘712. 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 ‘712 in any one of the SARS-CoV-2 cDNA of SEQ ID NOs: 1-3 alignments, Spagnolo et al., Wu et al., and Yount et al., as evidenced by Baric et al. because Baric ‘712 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 ‘712 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 ‘712 (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 ‘712 in any one of SARS-CoV-2 cDNA of SEQ ID NOs: 1-3 alignments, Wu et al., Spagnolo et al., and Yount et al., as evidenced by Baric et al. above with a reasonable expectation of success, because Baric ‘712 teach ORF7a is nonessential for SARS replication in lines 5-7 on page 41.
Claims 10, 14, and 16-18 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, Wu et al., Spagnolo et al., Yount et al., as evidenced by Baric et al., and Baric ‘712 as applied to claims 1-3, 6-9, 12, 13, 15, and 19 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, Wu et al., Spagnolo et al., Yount et al., as evidenced by Baric et al., and Baric ‘712. above. In “In Vitro Inhibition of SARS-CoV Replication” and Figure 4, Yount et al. describe observing reduced viral titer and recovered cytopathic effects from viral infection in the following 24 and 48 hours after application of the E64-d test agent, as required in instant claim 18.
However, 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., as evidenced by Baric et al., and the teachings of Wu et al., Spagnolo et al., and Baric ‘712 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., as evidenced by Baric et al. and the teachings of Wu et al., Spagnolo et al., and Baric ‘712 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., Spagnolo 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 ‘712 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., as evidenced by Baric 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., as evidenced by Baric et al., and the teachings of Spagnolo et al., Wu et al., and Baric ‘712 as applied to claims 1-3, 6-9, 12, 13, 15, and 19 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., as evidenced by Baric et al., and the teachings of Wu et al., Spagnolo et al., and Baric ‘712 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., as evidenced by Baric et al. and the teachings of Wu et al., Spagnolo et al., and Baric ‘712 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., as evidenced by Baric et al., and the teachings of Wu et al., Spagnolo et al., and Baric ‘712 because Baric ‘712 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 no reference teaches or suggests modifying the six-fragment BglI-based framework to employ exactly seven contiguous cDNA fragments assembled exclusively by directional ligation using type IIS restriction enzymes that generate unique cohesive overhangs at silent engineered junction sites for SARS-CoV-2, as instantly claimed.
Applicant’s arguments have been fully considered, but are found unpersuasive because the description of Figure 6 by Baric et al. identifies a SARS-CoV G fragment (segment 7) as the 21 poly(T) tail, described by Yount et al. under, “Assembly of SARS Full-Length cDNAs”. Therefore, Yount et al. teach assembling seven contiguous cDNA fragments by directional ligation using type IIS restriction enzymes that generate unique cohesive overhangs at engineered junction sites, recited in instant claim 1. The procedure taught by Yount et al. produces seamless links between consensus fragment junctions in the infectious full-length SARS-CoV transcripts, see “Strategy for Cloning the SARS-CoV cDNAs”, “Assembly of SARS Full-Length cDNAs”, and Figure 2.
Applicant argues one of ordinary skill would lack a reasonable expectation of success in adapting Yount et al.'s system to SARS-CoV-2 reverse genetics for large RNA viruses are unpredictable due to genome size, bacteriotoxic elements, and sequence-specific differences. Yount's six-fragment BglI design was optimized for SARS-CoV; direct application to SARS-CoV-2 would likely fail.
Applicant’s arguments have been fully considered, but are found unpersuasive because Yount et al. produce a full-length infectious cDNA of SARS coronavirus, see the title, abstract, “Assembly of SARS Full-Length cDNAs”, “Rescue of Molecularly Cloned SARS-CoV”, and Figure 2. 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. The seamless infectious cDNA SARS of Yount et al is assembled from seven SARS fragments, as evidenced by Baric et al.
Applicant argues that the rationale relies on hindsight because the motivation provided, i.e., “facile manipulation... rapid development and testing”, is generic and does not explain why an artisan would specifically choose the claimed seven-fragment assembly with type IIS enzymes that generate unique cohesive overhangs at silent engineered junction sites. The rejection impermissibly reconstructs the invention with knowledge of Applicant's solution (In re Kubin, 561 F.3d 1351 (Fed. Cir. 2009); MPEP § 2145).
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. In addition, Yount et al., as evidenced by Baric et al. teach seven-fragment assembly with type IIS enzymes that generate unique cohesive overhangs at silent engineered junction sites. See “Strategy for Cloning the SARS-CoV cDNAs” and “Assembly of SARS Full-Length cDNAs”. The description of Figure 6 by Baric et al. identifies a SARS-CoV G fragment (segment 7) as the 21 poly(T) tail, described by Yount et al. under, “Assembly of SARS Full-Length cDNAs”. The prior art teaches all requisite limitations recited. Impermissible hindsight reasoning is not applicable.
Conclusion
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/Shanon A. Foley/ Primary Examiner, Art Unit 1671
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