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 .
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on June 02, 2023. Claims 1-15 are pending and examined.
Drawing Objection
The drawings are objected to under 37 CFR 1.83(a). The drawings must show every feature of the invention specified in the claims. Therefore, the Fig. 11C must clearly show the deletion location with the amino acid’s sites marked with numbers.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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 1-15 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.
The claims 1, 6 and 10 recite a term “adapted” that render the claims indefinite. It is not clear what the “adapted” referred to.
Accordingly, one of ordinary skill in the art will not know the metes and bounds of the claims.
Claim Rejections - 35 USC § 112 (Scope of Enablement)
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 5 and 15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for stimulating an immune response against SARS-CoV-2 in mice by injecting a specific amount such as 10^5 PFU (See example 19) of the claimed immunogenic composition, does not reasonably provide enablement for making any amount of injection to any subject to induce the immune responses.
The instant specification discloses that the rSARS-CoV-2 Δl3a/Δ7a and Δ3a/Δ7b constructs induce production of antibodies against SARS-CoV-2 WT and emerging variants. Survival of the groups infected with the double ΔORF rSARS-CoV-2 mutants was suggestive of viral attenuation in vivo (See [0138]), and FIGS. 32A-32G are graphical representations of the humoral induced by Double ΔORF rSARS-CoV-2 responses against SARS-CoV-2 variants. K18 hACE2 transgenic female 6-8-week-old mice were mock (PBS)-infected or infected (i.n.) with 10^5 PFU of ORFΔ3a/Δ6, ORFΔ3a/Δ7a, or ORFΔ3a/Δ7b double ΔORF rSARS-CoV-2 (n=4/group) (See [0139]). Based on the instant specification, it provides evidence that the immunogenic composition claimed can induce the immune responses in mice at certain amount injection. However, the claims 5 and 15 require any amount of administration can stimulate an immune response against SARS-CoV-2 in any subject, but the instant specification does not provide evidence to support that any amount of injection can induce immune responses in any subject. Thus, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wriqht, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).1
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:1) the nature of the invention, 2) the state of the prior art, 3) the breadth of the claims, 4) the amount of guidance in the specification, 5) the presence or absence of working examples, 6) the relative skill of those in the art, 7) the predictability or unpredictability of the art, and 8) and the quantity of experimentation necessary. Id. While it is not essential that every factor be examined in detail, those factors deemed most relevant should be considered.
M.P.E.P. §2164.03 [R-2] states: [I]n applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In re Soil, 97 F.2d 623,624, 38 USPQ 189, 191 (CCPA 1938). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833,839, 166 USPQ 18, 24 (CCPA 1970). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488,496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Accordingly, the specification does not provide sufficient guidance to allow one skilled in the art to practice the claimed invention on the full scope with a reasonable expectation of success and without undue experimentation. In the absence of such guidance and evidence of working examples, the specification fails to provide an enabling disclosure commensurate in scope with the claim.
Claim Rejections - 35 USC § 102
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 –
(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.
Claims 1-2, 6 and 9-10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhang et al. (Antiviral Res. 2021 Jan; 185:104974. Epub 2020 Nov 17) as evidenced by Matsugo et al. (Viruses. 2020 Jul 16;12(7):767.) and Wang et al. (J Med Virol. 2022 Jul;94(7):3017-3031).
The base claim 1 is directed to a bacterial artificial chromosome-based construct comprising a replication- competent recombinant severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genome, wherein the SARS-CoV-2 genome contains a deletion of a group-specific open reading frame and a reporter gene adapted to report transcription of the recombinant SARS-CoV- 2 genome.
The base claim 6 is directed to a reverse genetics system for screening and identifying an anti-SARS-CoV-2 agent, the system comprising a bacterial artificial chromosome-based vector containing a replication- competent recombinant SARS-CoV-2 genome and a reporter gene adapted to report transcription of the recombinant SARS-CoV-2 genome.
The base claim 10 is directed to a bacterial artificial chromosome-based vector comprising a replication- competent recombinant SARS-CoV-2 genome, wherein the SARS-CoV-2 genome contains a mutation in the gene encoding for a spike protein and a reporter gene adapted to report transcription of the recombinant SARS-CoV-2 genome.
Zhang et al. teaches a bacterial artificial chromosome (BAC)-vectored noninfectious replicon of SARS-CoV-2 and discloses that they generated a replicon system for SARS-CoV-2, nCoV-SH01 strain with secreted Gaussia luciferase (sGluc) as a reporter gene. The cDNA of viral genome with deletion of S, M, E genes was cloned into a bacterial artificial chromosome (BAC) vector. The reporter gene sGluc was encoded in subgenomic viral RNA. The viral RNA was transcribed in vitro by T7 polymerase. Upon transfection into cells, viral replication was detected, as evidenced by expression of subgenomic viral RNA-encoded sGluc (See Abstract; Bridging pages 1 and 2). Here the description teaches claim 1 at BAC-based replication- competent SARS-COV-2 genome with group-specific open reading frame deletion and a reporter gene. Because the deletion of group-specific open reading frame includes the deletion/mutation of gene encoding the spike protein, Zhang et al. also teaches the base claim 10.
Zhang et al. teaches in order to facilitate antiviral screening against SARS-CoV-2 without requirement for high biosafety level facility, they developed a bacterial artificial chromosome (BAC)-vectored replicon of SARS-CoV-2, nCoV-SH01 strain, in which secreted Gaussia luciferase (sGluc) was encoded in viral subgenomic mRNA as a reporter gene (See Abstract), and discloses that the replicon genome of SARS-COV-2 could also be assembled by in-vitro ligation of four DNA fragments and the RNAs generated by the in-vitro ligated DNA template were capable of replication as the RNAs derived from the BAC-template (See page 2, left column, paragraph 1). Here the description teaches that the replicon is generated by a reverse-genetics technique even though Zhang does not use the term “reverse genetics”, where the four fragments are assembled into bacterial artificial chromosome (BAC) vector, pSMART-BAC v2.0, through restriction enzyme modification (See page 2, paragraph 3), where the pSMART Bac vector series are excellent tools for reverse genetics, especially for large viral genomes. This can be evidenced by both Matsugo and Wang’s studies. Matsugo et al. teaches using a pSMART Bac vector to establish a simple and efficient reverse genetics system for Canine Adenoviruses (See Abstract). Wang et al. teaches a Reverse genetics system for SARS‐CoV‐2 (See Abstract), and discloses that pSMART® BAC vector (Lucigen), is also widely used for cloning large DNA fragments, including the cDNA of SARS‐CoV‐2. pSMART® BAC vector is claimed to be able to protect inserts from the destabilizing influence of transcription by altering the orientation of the chloramphenicol promoter, which faces the cloning sites in pCC1‐BAC vector pBeloBAC11, and thus may drive the transcription of insert and lead to the unexpected influence of transcripts (See page 3021, right column, paragraph 1). Here the descriptions teach the base claim 6 for a reverse genetics system comprising a BAC-based vector containing the SARS-CoV-2 genome and a reporter gene as claimed.
As for the “for screening and identifying an anti-SARS-CoV-2 agent”, this is an intended use claim of the claimed method and cannot be considered as a limitation unless it imposes structure differences. (See MPEP 2111.02, Effect of Preamble [R-07.2022]). The intended use claim is also extended to claim 9, where the “the anti-SARS-CoV-2 agent is a neutralizing antibody”. Thus, claim 9 is interpreted as having the same scope as claim 6 with regard to the method and method steps.
Regarding claim 2, Zhang et al. teaches that the deleted group-specific open reading frames is Spike (S), Membrane (M), Envelope (E) (See Fig. 1, page 3 and below).
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Accordingly, Zhang et al. teaches each and every aspect of the claims 1-2, 6 and 9-10.
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 3-4, 7-8 and 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Antiviral Res. 2021 Jan; 185:104974. Epub 2020 Nov 17) as evidenced by Matsugo et al. (Viruses. 2020 Jul 16;12(7):767.) and Wang et al. (J Med Virol. 2022 Jul;94(7):3017-3031) as applied to claims 1-2, 6 and 9-10 above and in view of Thao et al. (Nature. 2020 Jun;582(7813):561-565. Epub 2020 May 4.).
Claims 3-4, 7-8 and 13-14 require the reporter gene encodes one or more of a fluorescent protein, or one or more of a fluorescent protein and a luciferase, respectively.
Zhang et al. teaches that in fragment D of the BAC-based SARS-COV-2 genome, an expression cassette containing secreted Gaussia luciferase (sGluc), foot-and-mouth disease virus (FMDV) 2 A peptide (NFDLL KLAGD VESNP GP) and blasticidin (BSD) was added upstream the 5′ -position of viral genome (See page 2, left column, paragraph 2). However, Zhang et al. is silent on the reporter gene encodes one or more of a fluorescent protein.
Thao et al. teaches a rapid reconstruction of SARS-CoV-2 by reverse genetics and then reconstructing, rescuing and characterizing of rSARS-CoV-2, rSARS-CoV-2-GFP and synSARS-CoV-2-GFP in a TAR cloning system (See Fig. 3, page 564 and below), where the GFP was inserted in-frame of ORF7a of SARS-COV-2, replacing nucleotides 40–282 (See page 563, right column, paragraph 1; Fig. 3a, page 564 and below).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce the GFP gene into Zhang’s construct based on the need. One of skill in the art would be motivated to do so because the Fluorescent Protein such as GFP can offer a direct visualization to track biological process in live cells. Because Zhang already teaches the luciferase, one of ordinary skill in the art can either insert a GFP gene into Zhang’s construct or can replace the luciferase with GFP. There would be a reasonable expectation of success to include the reporter genes in the BAC-based reverse genetic construct.
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Claims 5 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Antiviral Res. 2021 Jan; 185:104974. Epub 2020 Nov 17) as evidenced by Matsugo et al. (Viruses. 2020 Jul 16;12(7):767.) and Wang et al. (J Med Virol. 2022 Jul;94(7):3017-3031) as applied to claims 1-2, 4, 6, 6, 10 and 14 above and in view of Enjuanes et al. (WO 2006/136448 A2, published on Dec. 28, 2006).
Claims 5 and 15 require stimulating an immune response against SARS-CoV-2 in a subject comprising administering an immunogenic composition containing the bacterial artificial chromosome-based construct of Claims 1 or 10.
Zhang et al. teaches generating recombinant SARS-CoV-2 using BAC-based reverse-genetics system, however, it is silent on stimulating an immune response against SARS-CoV-2 in a subject by administering the immunogenic composition.
Enjuanes et al. teaches that a virus particle in the vaccines of their present invention is preferably prepared starting from a SARS-CoV replicon. Methods to prepare the nucleic acids and the virus particles of the present invention may comprise the preparation of a SARS-CoV derived replicon in a bacterial artificial chromosome (BAC) (See page 18, paragraph 2), and the vaccine may be administered to a mammal to obtain an immune response that reduces or eliminates the disease symptoms caused by infection with the SARS-CoV virus (See page 19, paragraph 2).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Zhang and Enjuanes to arrive at an invention as claimed. One of skill in the art would be motivated to do so because the BAC-based reverse genetics recombinant SARS-COV-2 can be used as vaccine to administer to a subject to induce immune responses. There would be a reasonable expectation of success to stimulate/induce an immune response against SARS-CoV-2 in a subject by administration based on the BAC-vectored noninfectious replicon of SARS-CoV-2 of Zhang and the administration method of Enjuanes.
Claims 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Antiviral Res. 2021 Jan; 185:104974. Epub 2020 Nov 17) as evidenced by Matsugo et al. (Viruses. 2020 Jul 16;12(7):767.) and Wang et al. (J Med Virol. 2022 Jul;94(7):3017-3031) as applied to claims 1-2, 4, 6, 6, 10 and 14 above and in view of Davidson et al. (Genome Med. 2020 Jul 28;12(1):68) as evidenced by Abdoli et al. (Virus Res. 2022 Oct 2;319:198857).
Claims 11-12 require the mutation is a Bristol deletion or Furin deletion, respectively.
Zhang et al. teaches generating recombinant SARS-CoV-2 using BAC-based reverse-genetics system with mutation/deletion, however, it is silent on Bristol deletion and Furin deletion.
Davidson et al. describes the characterization of the transcriptome and proteome of SARS-CoV-2 reveals a cell passage induced in-frame deletion of the furin-like cleavage site from the spike glycoprotein and teaches that detection of an apparently viable deletion in the furin cleavage site of the S glycoprotein, a leading vaccine target, shows that this and other regions of SARS-CoV-2 proteins may readily mutate. The furin site directs cleavage of the S glycoprotein into functional subunits during virus entry or exit and likely contributes strongly to the pathogenesis and zoonosis of this virus (See Abstract). Davidson et al. discloses the furin site is the four amino acid insertion (681-684, PRRA) at the S1/S2 junction (See page 2, right column, paragraph 2) and a Bristol deletion (679-687, NSPRRARSV) (See page 8, Fig. 2). Davidson et al. also teaches that novel SARS-CoV-2 viruses containing deletions or even insertions can arise naturally and successfully propagate. As the virus continues to spread and potentially comes under selective pressure from the host response in humans, vaccines and antiviral drugs in the future, vigilance will be required to detect novel rearrangements/deletions (See page 12, left column, paragraph 2), which indicates that the viral genome sequence should be carefully monitored during the growth of viral stocks for research, animal challenge models and, potentially, in clinical samples. Such variations may result in different levels of virulence, morbidity and mortality (See Abstract). As evidence, Abdoli et al. demonstrates that the furin deletion can result in different levels of virulence. Abdoli et al. teaches that deletion of the furin cleavage site and GTNGTKR motifs in the spike sequence attenuates the virus from the parental strain and can be used as a potent immunogen (See Abstract). Because the Bristol deletion (679-687, NSPRRARSV) of Davidson contains the furin site (681-684, PRRA), it is reasonably considered that making a Bristol deletion can also achieve the same effect as the furin deletion for attenuating the virus. Furthermore, Davidson et al. teaches that the SARS-CoV-2 S glycoprotein deletion identified in their study removes the furin cleavage site, but also Arg685 (corresponding to SARS-CoV Arg667) required for cleavage of the SARS-CoV S glycoprotein (See page 9, right column), and discloses that a pseudoviruses expressing the SARS-CoV-2 S glycoprotein and the corresponding S glycoprotein with the furin cleavage site removed at the S1/S2 boundary (residues 680SPRR683 removed) were made and their ability to mediate entry to Vero E6 and BHK-21 cells expressing hACE2 compared, where the result shows the deletion of the furin cleavage site enhanced the entry of the corresponding pseudovirus into Vero E6 cells but diminished entry into hACE2 BHK-21 cell (See page 11, left column, paragraph 1). Here both the described deletions of Arg685 and 680SPRR683 are included in the Bristol deletion (679-687, NSPRRARSV).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Zhang, Davidson and Abdali to arrive at an invention as claimed. One of skill in the art would be motivated to do so to introduce the deletion of furin or the Bristol deletion into the construct of Zhang and to produce an attenuated vaccine candidate for targeting the SARS-COV-2 virus as well as characterizing other functions played by these deletions. There would be a reasonable expectation of success to develop a BAC-based rSARS-COV-2 construct with the deletion of fruin or Bristol deletions as claimed based on the teachings from Zhang, Davidson and Abdali.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RUIXUE WANG whose telephone number is (571)272-7960. The examiner can normally be reached Monday-Friday 8:00 am..
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/RUIXUE WANG/Examiner, Art Unit 1672
/NICOLE KINSEY WHITE/ Primary Examiner, Art Unit 1672