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 .
Election/Restrictions
Applicant’s election without traverse of invention II in the reply filed on 3/11/26 is acknowledged.
Claims 12 and 19-28 are examined on the merits.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Allowable Subject Matter
SEQ ID NO: 14 is free of the prior art of record. The closet art of record is Liu et al. (Viruses, 2022, Vol. 14, No 974), which appears to be applicant’s own work about the instant invention. The closest prior art of record is Zhang et al. (see below), which teach a recombinant SARS-2 replicon expressing a luciferase reporter protein operably linked to SARS-2 nucleic acids and testing the expression of luciferase when potential inhibitors are incubated in vitro. However, Zhang et al. do not teach a dual reporter and probe SARS-2 construct.
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 12 and 19-28 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 testing the inhibition of Remdesivir on the expression of different reporter genes operably linked to the SARS-2 non-structural genes expressed by the claimed construct, does not reasonably provide enablement for screening for test compounds with anti-SARS2 activity with reporter genes that are not identified as being distinct and the reporter genes are not operably linked to the SARS-2 non-structural proteins. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Nature of the invention/Breadth of the claims. The claims are drawn to a method for screening a test compound for anti-SARS2 activity, wherein the method comprises:
a) incubating the test compound with a cell line comprising a construct comprising 5' to 3':
i) two or more promoter sequences; ii) a nucleic acid sequence encoding SARS2 non-structural protein 1; iii) a first reporter gene; iv) a nucleic acid sequence encoding SARS2 non-structural proteins 2-16; v) a second reporter gene; and vi) a nucleic acid sequence encoding SARS2 nucleocapsid protein; and
b) assaying for the presence of expression of the first reporter gene or expression of the second reporter gene, wherein a decreased expression of the first reporter gene or a decreased expression of the second reporter gene compared to a control indicates that the test compound comprises anti-SARS2 activity.
The first and second reporter genes are optically detectable or optically distinguishable.
The construct further comprises a 5’ untranslated region (UTR) that is 5’ of the nucleic acid sequence encoding SARS2 non-structural protein 1.
The 5’ UTR is a 5’ nucleic acid sequence encoding SARS2 non-structural protein 1, and is 3’ of the two or more promoter sequences.
The construct further comprises a 3’ untranslated region (UTR) that is 3’ of the nucleic acid sequence encoding SARS2 nucleocapsid protein.
The two or more promoters of the construct comprises a eukaryotic promoter and a prokaryotic promoter. An example of the eukaryotic promoter is HIV-1 long terminal repeat promoter and an example of a prokaryotic promoter is T7 promoter.
A specific example of the construct is SEQ ID NO: 14 or the construct comprises the following structure:HIV-1 promoter sequence, T7 promoter sequence, hammerhead virus ribozyme sequence, a SARS2 5’UTR sequence, a nucleic acid sequence encoding SARS2 non-structural protein 1, a P2A self-cleaving peptide sequence, a first reporter gene, an IRES, a nucleic acid sequence encoding SARS2 non-structural 2-16, a second reporter gene, a nucleic acid sequence encoding SARS2 nucleocapsid protein, a 3’ UTR sequence, a hepatitis delta virus ribozyme sequence, and a poly-A tail.
*However, the claims do not require that the reporter genes be different and the claimed construct does not require that the SARS2 non-structural proteins be operably linked with the reporter genes.
State of the prior art/Predictability of the art. With regard to screening for compounds having anti-SARS activity, Zhang et al. (Journal of General Virology, 2021, Vol. 102) teach the ability of 9 different test compounds, which were believed to have antiviral activity, to interfere with SARS-CoV-2 nucleic acid replication. Zhang et al. used an SARS-CoV-2 replicon that expresses luciferase (reporter) protein to determine if Remdesivir, Brusatol, Bruceine A, Dehydrodiloeugenol, Bufotaline, Bufalin, Tetrandrine, Fangchinoline and Chloroquine will inhibit the expression of the reporter protein. [see figure 1] However, Zhang et al. observed mixed results among these test compounds (see below).
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Therefore, Zhang et al. observed that not all compounds considered to have antiviral activity could achieve interfere with SARS nucleic acid replication.
In addition, Li et al. (Animal Model Exp Med, 2018, Vol. 1, NO. 1) teach that reporter genes that encode similar reporter proteins, such as GFP and YFP, have similar emission spectra and therefore are difficult to visually differentiate. [see left column, on page 30] Presently, the claim does not require that the reporter genes are specifically different from each other.
Working examples. Applicants tested the effect of remdesivir on the expression of reporter genes of a replicon that comprises SARS-CoV-2 non-structural protein sequences and promoters operably linked thereto. The reporter genes employed are fLuc and GFP.
Guidance in the specification. The specification states that test compounds with anti-SARS activity can be identified by incubating the test compound with a cell line possessing the claimed construct. Assessing the reporter gene expression is not specifically claimed, but the specification states that PCR, or luciferase assay systems or western blots can be used, depending on the reporter.
Amount of experimentation necessary. Additional research is required in order to determine how effective the claimed method would be at identifying a generic test compound for possessing an undefined anti-SARS2 activity by using a cell that comprises a nucleic acid construct in which the reporter genes to be monitored are not operably linked to the SARS2 nucleic acid sequences and the reporter genes are potentially the same.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to use the claimed methods.
Claim 23 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of eukaryotic promoters is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: each of these promoters possess different sequences, have different lengths and are from different sources.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim 24 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of prokaryotic promoters is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: each of these promoters possess different sequences, have different lengths and are from different sources.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BENJAMIN P BLUMEL whose telephone number is (571)272-4960. The examiner can normally be reached M-F 8-5 EST.
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/BENJAMIN P BLUMEL/Primary Examiner, Art Unit 1671
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