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 .
Application Status
Applicant’s amendment filed May 19, 2026 amending claims 1, 16, 72-73 and 84-85 is acknowledged. Claims 1, 16, 24, 32-34, 41-42, 62, 64, 66 and 72-92 are pending. Claims 72-92 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected groups, there being no allowable generic or linking claim.
Claims 1, 16, 24, 32-34, 41-42, 62, 64 and 66 are under examination.
Applicant’s amendment to claim 1 overcomes the §102 rejection over Shi; the rejection is withdrawn. The inclusion of functional language “but is noninfectious” overcomes the §103 rejection in the previous office action because the rejection did not address the infectiousness of the coronavirus reporter replicon; the rejections are withdrawn. However, the claims are still obvious over Shi in view of Fernandes for the reasons recited in the new rejections below, which are necessitated by amendment.
The objection to the Specification is maintained. No amendments to the Specification were filed and Applicant did not acknowledge the objection to the Specification in their Remarks.
Specification
The disclosure is objected to because of the following informalities:
First, the nucleic acid sequence of T7 on page 23 needs to be identified with a SEQ ID NO from the sequence listing.
Second, the use of the terms pSMART-BAC®, Gibson Assembly®, mMessage mMachine®, Monarch®, MaxCyte®, and Nucleobond®, which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
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.
Appropriate correction is required.
Claim Interpretation
Claim 1 recites “A coronavirus reporter replicon comprising: (a) SARS-CoV-2 genes… wherein the SARS-CoV-2 genes comprise ORF1ab…, ORF3a…, ORF6…, ORF7a/b…, ORF8…, and ORF 10…, and (b) at least one reporter gene; and wherein the coronavirus reporter replicon does not comprise a spike (S) ORF, an envelope (E) ORF, and a membrane (M) ORF, wherein one or more of the spike (S) ORF, the envelope (E) ORF, and the membrane (M) ORF is replaced with the reporter gene.” Claim 1 is interpreted as a coronavirus reporter replicon that is replication competent, but not infections, and (1) comprises each of ORF1ab, ORF3a, ORF6, ORF7a/b, ORF8, and ORF 10, (2) does not contain the S, E and M ORFs, and (3) requires a reporter gene at the genomic site where the S, E, or M ORF used to be.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 16, 24, 41-42, 62, 64 and 66 are rejected under 35 U.S.C. 103 as being unpatentable over Shi (US 20230416692 A1, priority to US provisional applications 63/000713 filed March 27, 2020 and 63/041667 filed June 19, 2020; of record) in view of Fernandes (Fernandes et al., Viruses (2020), 12:598, pages 1-22, published May 30, 2020; of record). Claim 16 is evidenced by Genbank (NC_045512.2, severe acute respiratory syndrome coronavirus 2 isolate Wuhan-Hu-1, complete genome, https://www.ncbi.nlm.nih.gov/nuccore/NC_0455l2.2, [retrieved January 8, 2026]; of record). This is a new rejection necessitated by amendment.
Shi claims priority to the two US provisional applications recited above. Each of the point citations in the rejection below are fully supported in one or both of the US provisional applications.
Regarding claims 1 and 24, Shi teaches the SARS-CoV2 genome comprises ORF 1a, 1b, S, 3, E, M, 6, 7a/b, 8a/b, N, 9b and 10 (Fig 5A). Shi teaches generating a SARS-CoV-2 replicon by replacing ORF 7a/b with a gene encoding NanoLuc (i.e., a reporter gene, nanoluciferase) (FIG. 5A). Shi teaches the nucleic acid sequence of the SARS-CoV-2 replicon from which the reporter replicon was derived is SEQ ID NO 1 ([0051]), which is 100% identical to SEQ ID NO 1 of the instant application. Therefore, Shi teaches the replicon having each of the genes that are 100% identical with the recited positions from SEQ ID NO 1 of the examined application. Shi teaches the NanoLuc SARS-CoV-2 replicon can form plaques similar to wild type and is therefore replication competent (FIG. 5B-E).
Shi does not teach deletion of each of the spike (S), membrane (M) and envelop (E) ORFs and in place of one of them inserting the reporter gene.
Fernandes teaches the start of the art of developing single-stranded replicon reporters for positive RNA virus, including SARS-CoV-2 (Abstract). Fernandes teaches that replicons are non-infectious, self-replicative subgenomic systems in which the genes encoding viral structural proteins are replaced by a reporter gene (page 2, ¶2). Fernandes teaches the correct 5’ and 3’ ends of the viral genome are crucial to the success of replicon constructs since many viruses have specific structures at their terminals for replication and/or translation (page 2, ¶2). Fernandes teaches a reporter gene is introduced in place of the deleted structural genes to allow luminometric (luciferases) or fluorescent (fluorescent proteins) detection of RNA replication (page 2, ¶3). Fernandes teaches that Coronavirdiae replicons have been developed in which a GFP reporter and a resistance gene replaced the genomic region from the Spike (S) gene through ORF8, including the Envelop (E), and Membrane (M) ORFs (Figure 2c; page 9 ¶4). Fernandes teaches another SARS-CoV replicon system was developed in which the S gene was replaced by a GFP reporter. Fernandes also teaches that replicons can be stably maintained in cells by introducing a drug resistance gene into the system, such as neomycin phosphotransferase (Neo), thereby simplifying high-throughput antiviral screenings (page 2, ¶4). Fernandes teaches other viral replicon reporters that included both a luciferase reporter and a neomycin gene had the transgenes arranged such that they were not adjacent or co-translational with each other (Figure 2a).
Regarding claims 1 and 24, it would have been obvious to one skilled before the effective filing date of the claimed invention to have modified the SARS-CoV-2 reporter of Shi by replacing the Spike ORF with the NanoLuc coding sequence instead of ORF7a/b and 2) included the neomycin resistance coding sequence in place of the Envelope (E) and Membrane (M) ORFs. It would have amounted to the simple combination of known elements by known means to yield predictable results. The skilled artisan would have predicted that a SARS-CoV-2 reporter replicon missing the spike, envelope and membrane ORFs would be replication competent, but noninfectious because Fernandes teaches that the S, E and M genes encoding the structural proteins of coronaviruses can be removed from replicons and be used to assay viral replication but that the S, E and M genes are needed to infect cells. The skilled artisan would have been motivated to include a neomycin resistance gene so that stable cell lines comprising the SARS-CoV-2 replicon reporter could be generated, as taught in Fernandes. It also would have been entirely predictable that separate NanoLuc and Neomycin cassettes could be separated from each other in the viral genome because Fernandes teaches that is a functional arrangement in replicon reporters of other enveloped viruses. Finally, the skilled artisan would have been motivated to retain non-structural ORFS, such as ORF3a, ORF6, ORF7a/b, ORF8 and ORF10 of SARS-CoV-2 so their function in viral replication could be assayed using the reporter replicon.
Regarding claim 16, Shi teaches the ORF nearest the 5’ terminus of the coronavirus (i.e., ORF1a) is translated into a large polyprotein that is cleaved into multiple proteins, and together functions as an RNA-dependent RNA polymerase ([0050]). Shi is silent as to what ORF1a encodes. Genbank teaches the genome sequence of the SARS-CoV-2 isolate Wuhan-Hu-1 (title), which is 100% identical to Shi’s SEQ ID NO 1 and to SEQ ID NO 1 of the present application.
Genbank teaches that ORF1a encodes an ORF1ab polyprotein (page 2), that comprises a sequence that is 100% identical to SEQ ID NO 9 (i.e., an RNA-dependent RNA polymerase) (page 3, highlighted in Genbank reference provided with previous office action). Therefore, Shi’s coronavirus replicon inherently comprises a gene that encodes an RNA-dependent RNA polymerase that is at least 90% identical to SEQ ID NO 9.
Regarding claim 41, Shi teaches the NanoLuc SARS-CoV-2 replicon encoded as cDNA (i.e., a vector) ([0095]).
Regarding claim 42, Shi teaches the NanoLuc SARS-CoV-2 replicon cDNA included a T7 promoter and a poly(A) terminator ([0056])
Regarding claims 62 and 64, the Specification does not provide a limiting definition of “vector”, which is interpreted broadly as any means to provide the sequence to a cell. Shi teaches in vitro transcription of the viral RNA (i.e., a vector) was introduced (i.e., transfected) into a Vero cell ([0095]).
Regarding claim 66, Shi teaches the NanoLuc SARS-CoV-2 replicon can be used to screen therapies ([0067]). Shi teaches combining the Vero cells comprising the NanoLuc SARS-CoV-2 replicon with remdesivir or chlorophane (i.e., a candidate agent for inhibiting SARS-CoV-2) and determining ability of the replicon to replicate based on luciferase activity levels ([0077]; Fig 8C and 8D).
Claims 32 and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Shi (US 20230416692 A1, priority to US provisional applications 63/000713 filed March 27, 2020 and 63/041667 filed June 19, 2020) and Fernandes (Fernandes et al., Viruses (2020), 12:598, pages 1-22, published May 30, 2020), as applied to claims 1, 16, 24, 41, 42, 62, 64 and 66 above, and further in view of Genbank2 (AY909580.1, Synthetic construct neomycin-kanamycin phosphotransferase type II mRNA, complete cds, https://www.ncbi.nlm.nih.gov/nuccore/AY909580.1, available July 5, 2005, [retrieved February 12, 2026]).
Claims 32 and 34 recite a SARS-CoV-2 replicon comprising a sequence that is at least 90% identical to nucleotides 284-26118 of SEQ ID NO 5. According to the Specification, nucleotides 284-26118 of SEQ ID NO 5 comprise the coding sequences for, starting from the 5’ end: ORF1a/b (including all the nsps), nanoLuciferase, ORF3a, Neomycin, ORF6, ORF7a, ORF7b, ORF8, N gene and ends just before ORF10 (Table 5, pages 116-117).
The teachings of Shi and Fernandes are recited above and applied as for claims 1, 16, 24, 41, 42, 62, 64 and 66. Shi also teaches the sequence of the NanoLuc reporter coding sequence is SEQ ID NO 6, which has 100% identity to nucleotide positions 21581-22093 of SEQ ID NO 5 of the examined application (See OA Appendix, page 1).
Shi and Fernandes do not teach the nucleotide sequence of a neomycin resistance gene.
Genbank2 teaches the neomycin-kanamycin phosphotransferase, type II coding sequence for gene targeting in mammalian cells (i.e., a neomycin resistance gene), which is 83% identical (662/796 nucleotides) to positions 22957 - 23751 of SEQ ID NO 5 (See OA appendix, page 2).
Regarding claims 32 and 34, it would have been obvious to one skilled before the effective filing date of the claimed invention to have modified the SARS-CoV-2 reporter rendered obvious above comprising ORF1a/b, nanoLuciferase, ORF3a, Neomycin, ORF6, ORF7a, ORF7b, ORF8, N genes and UTR, by specifically using the nanoluciferase coding sequence taught in Genbank2. Such an arrangement would result in a SARS-CoV-2 reporter replicon having 25701 out of 25835, or 99.5%, identical nucleotides as SEQ ID NO 5. It would have amounted to the simple combination of known elements by known means to yield predictable results. The skilled artisan would have been motivated to include a neomycin resistance gene taught by Genbank2 because Genbank teaches it is the nucleotide sequence of the resistance gene that can be used in mammalian cells, which are the host cells used in Shi.
Claim 33 is rejected under 35 U.S.C. 103 as being unpatentable over Shi (US 20230416692 A1, priority to US provisional applications 63/000713 filed March 27, 2020 and 63/041667 filed June 19, 2020), Fernandes (Fernandes et al., Viruses (2020), 12:598, pages 1-22) and Genbank2 (AY909580.1, Synthetic construct neomycin-kanamycin phosphotransferase type II mRNA, complete cds, https://www.ncbi.nlm.nih.gov/nuccore/AY909580.1, [retrieved February 12, 2026]), as applied to claims 1, 16, 24, 32, 34, 41, 42, 62, 64 and 66 above, and further in view of Nakamura (US 20160281066 A1, published September 29, 2016) and Nakao (US 20170340687 A1, published November 30, 2017).
Claim 33 recites a SARS-CoV-2 replicon comprising a sequence that is at least 90% identical to nucleotides 284-28130 of SEQ ID NO 2. According to the Specification, nucleotides 284-28130 of SEQ ID NO 2 comprise the coding sequences for, starting from the 5’ end: ORF1a/b (including all the nsps), Luciferase-GFP fusion protein, ORF3a, Neomycin, ORF6, ORF7a, ORF7b, ORF8, N gene and ends just before ORF10 (Table 5, pages 116-117).
The teachings of Shi, Fernandes and Genbank2 are recited above as for claims 1, 16, 24, 32, 34, 41, 42, 62, 64 and 66 and are incorporated here. Shi also teaches SARS-CoV-2 replicons having the fluorescent reporter mNeonGreen instead of the NanoLuc reporter ([0008], FIG 3). Fernandes also teaches viral reporters have used the fluorescent proteins GFP and EGFP or the Renilla luciferase and firefly luciferase reporters (Figures 2 and 3; page 5, ¶2). The obviousness of replacing the Spike ORF with NanoLuc coding sequence and the Envelope and Membrane ORFs with the Neomycin resistance gene is recited above as for claims 1, 16, 24, 32, 34, 41, 42, 62, 64 and 66 and incorporated here.
Shi, Fernandes and Genbank2 do not teach using, or the coding sequence for, a Luciferase-GFP fusion gene in a viral replicon reporter.
Nakamura teaches developing vaccinia viral vectors to carry transgenes for the treatment of cancer (Abstract). Nakamura teaches incorporating the coding sequence for a Luciferase-EGFP (Luc-GFP) fusion protein into a vaccinia viral replicon such that the coding sequence for Luc-GFP disrupts the coding sequence for the viral protein VGF (FIG 2B and D). Nakamura teaches the recombinant viral genomes comprising the Luc-GFP cassette were collected from cells infected with the Luc-GFP viral replicons ([0070]), indicating that the viral replicon is replication competent. Nakamura teaches measuring GFP levels in fibroblast cell lines infected with the Luc-GFP viral replicon ([0071]) and measuring luciferase expression levels in mice infected with the Luc-GFP viral replicon ([0074]).
Nakao also teaches the vaccina viral replicon having Luc-GFP fusion protein integrated at and disrupting the VGF gene (FIG 2). Nakamura teaches the sequence of the viral genome having the Luc-GFP coding sequence integrated at the VGF gene is set forth in SEQ ID NO 21 ([0166]). Nakamura teaches the sequence of SEQ ID NO 21 (pages 22-111). SEQ ID NO 21 comprises a sequence that is 97% (2379/2412) identical to positions 21581 – 23992 (i.e., the Luciferase-GFP coding sequence) (See OA Appendix, pages 3-8).
It would have been obvious to one skilled before the effective filing date of the claimed invention to have further modified the SARS-CoV-2 reporter of Shi by substituting the NanoLuc reporter sequence for the Luc-GFP coding sequence taught in Nakamura and Nakao. Such an arrangement using the known sequences of the SARS-CoV-2 genome taught in Shi, the Luc-GFP sequence taught in Nakao, and the sequence of the neomycin resistance gene, as taught in Genbank2 would result in a SARS-CoV-2 reporter replicon having 27680 out of 27847, or 99.4%, identical nucleotides as SEQ ID NO 2. It would have amounted to the simple combination of known elements and the substitution of one reporter for another by known means to yield predictable results. It would have been entirely predictable that a Luc-GFP dual fusion reporter could be used in place of the NanoLuc reporter in the obvious variant of Shi’s coronavirus reporter because 1) Nakamura and Nakao use the Luc-GFP reporter in a different viral replicon reporter, and 2) Shi demonstrates both fluorescent and luminescent reporters in a SARS-CoV-2 reporter. The skilled artisan would have been motivated to use Nakamura and Nakao’s Luc-GFP reporter in order to use both fluorescent and luminometric assays to assess viral replication.
Response to Arguments
Applicant argues that it would not have been obvious to modify Shi’s replicon because Shi replaces ORF7/ab, which is a nonstructural ORF, and Fernandes does not disclose a SARCS-CoV-2 replicon lacking all three structural ORFs in combination with the defined set of retained ORFs in the claims. Applicant argues that the Office did not establish a reasonable expectation of success that removing the S, E, and M ORFs retains replication competence (Remarks, pages 10-11). These arguments have been fully considered but are not persuasive. First, the rejection is a § 103 rejection for obviousness. If either Shi or Fernandes had disclosed “a SARCS-CoV-2 replicon lacking all three structural ORFs in combination with the defined set of retained ORFs in the claims” then the claims should have been rejected under §102. Therefore, the argument does not address the merits of the rejection. Second, Fernandes teaches that reporters in place of structural proteins, which are known to be S, M and E in SARS-CoV2, allow the detection of RNA replication. In fact, Fernandes cites a previous study of a coronavirus replicon in which all three structural proteins, S, E and M were all deleted. Therefore, it would have been highly predictable that the deletion of all three S, M and E would still allow replication of the SARS-CoV2 reporter genome.
Conclusion
No claims are allowable.
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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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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