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
This action is in response to the papers filed September 4, 2026.
Election/Restrictions
Applicant’s reply to the Restriction/Election Requirement mailed 06/26/2026 is acknowledged. See, papers filed 07/21/2026 and 09/04/2026.
Applicant elected without traverse the invention of:
Group 1, drawn to a method of enhancing an immune response in a subject in need thereof by administration of a gene silencing system that decreases expression of at least one endogenous immunosuppressive gene in a target cell of the subject;
A.) a CRISPR-based gene silencing system targeting PD-L1, Galectin-9 (LGALS9), Galectin-3 (LGALS3) and CD47 genes and having an AAV9 vector, a Cas13d endonuclease, PD-L1 gRNAs according to SEQ ID NOs: 4-42 and 333-337, Galectin-9 (LGALS9) gRNAs according to SEQ ID NOs: 43-67 and 918-922, Galectin-3 (LGALS3) gRNAs according to SEQ ID NOs: 83-87 and 913-917, and CD47 gRNAs according to SEQ ID NOs: 88-92 and 353-357; and
B.) treatment of breast cancer.
Claims 5, 7, 18-23 and 34-45 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the replies filed 07/21/2026 and 09/04/2026.
Claim Listing
The instant claim listing was filed on 08/21/2024.
Claims 1-45 are pending.
Claims 5, 7, 18-23 and 34-45 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claims 1-4, 6, 8-17 and 24-33 are under examination.
Priority
The instant application 18/840,303 was filed on 08/21/2024. This application is a national stage of international application PCT/US2023/062809 filed 02/17/2023, claiming priority based on U.S. Provisional Patent Application 63/312,730 filed 02/22/2022.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08/21/2024 and 08/26/2026 have been considered.
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, or by applicant in an information disclosure statement (IDS), they have not been considered.
Improper Markush Grouping
Claims 4 and 6 are 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 SEQ ID NOs: 1-1657 or 1-92, directed to alternative guide RNAs (gRNAs), as claimed in claims 4 and 6, 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:
The compounds represented by the alternative gRNAs, i.e., each member of the Markush grouping of SEQ ID NOs: 1-1657 or 1-92, do not share both a substantial structural feature and a common use that flows from the substantial structural feature. In this case, each alternative gRNA is structurally different and distinct, and therefore each alternative possesses functionally distinct binding activities. In particular, each alternative gRNA possesses a different spacer sequence, and therefore each gRNA hybridizes to a different set of genomic sequences or transcripts thereof, whether on-target or off-target, thereby resulting in different genetic modifications in the host organism when complexed with a CRISPR endonuclease, e.g., Cas13d, as claimed. The members of the Markush grouping of SEQ ID NOs: 1-1657 or 1-92 do not share a substantial structural feature and a common use that flows from the substantial structural feature. Rather, according to Tables 1 and 3 of the specification, the gRNAs according to SEQ ID NOs: 1-1657 or 1-92 are designed to target a vast number of different and distinct genes, including “scramble” (no target), PDL1, Galectin9 (Lgals9), CD73, CD200, CD66a, Galectin3 (Lgals3), CD47, Abl1, Acat1, Adam10, Adam17, Adar, Adipoq, Adora2a, Ager, Ago2, Aire, Alcam, Aoc3, Areg, Arg2, Astl, Atg10, Atg14, Atg9a, Atp13a1, Atp2a3, Aurka, B3gnt3, Bach2, Batf, Bcl11b, Bcl2, Bc12, Bcor, Birc3, Braf, Bst2, Btla, C10orf5, C3ar1, V5ar1, Cad, Casp1, Casp6, Cb1b, Cbx8, Ccl11, Ccl17, Ccnb1, Ccnq, Ccr3, Ccr8, Ccr9, CD160, CD200r1, CD274, CD276, CD3001f, CD38, CD5, CD55, CD51, CD96, Cda, Cdh2, Cdk1, Cdk20, Cdk5, Cebpb, Cep55, Cflar, Chic2, Cish, Cks1b, Clec4e, Cmtm6, Cnot8, Cop1, Creb1, Crp, Csf, Csf1r, Csf3, Cspg4, Ctla4, Cxc11, Cxc15, Cybb, Cyp19a1, Dclk1, Dcp1a, Ddit3, Ddr1, Dgka, Diaph1, Dkk2, Dner, Egf17, Entpd1, Enpt2, Epcam, Epha10, Erbb2, Ern1, Eya3, F11r, F8a, Fabp1, Fabp4, Fcgr2b, Fcrl5, Fgf1, Fitm2, Fos, Fosl1, Foxm1, Fut4, Fyb, Gale, Gch1, Gcnt1, Gdf15, Gls, Gpc2, Gpil, Gpnmb, Gpr68, Havcr2. Hbegf, Hcar1, Hcst, Hdac11, Hdac4, Hgf, Hmox1, Hspa13, Id1, Id3, Ido1, Igflr, Igfbp2, Ikbkg, IL10ra, Il11, Il16, Il18, Il1r1, Il23r, Il34, Il4r, Ippk, Irf9, Isx, Itk, Kdm6b, Kir3dl1, Kit, Klf16, Klrc1, Klrd1, Kmt2a, Krt17, Kynu, L1cam, Lag3, Layn, Lef1, Lgals1, Lif, Lilrb4a, Lipa, Lipt2, Lpar5, Lrrc32, Ly6k, Ly75, Lyn, Maf, Mageh1, Map2k7, Mapk7, Mcl1, Mdm2, Med23, Mertk, Met, Mex3b, Mfge8, Mgat1, Mmp12, Mn1, Mrc1, Msr1, Muc16, Muc5ac, Myc, Mycn, N6amt1, Nanog, Ncf1, Nfatc, Nfkb2, Nfkbia, Nos1, Nos3, Nr4a2, Nras, Nrp1, Nt5e, Ntf3, Otulin, Pced1b, Pcsk1, Pdcd1, Peg10, Pik3ca, Pik3cg, Pik3r5, Pim1, Pkn2, Pla2g2d, Plac1, Plau, Pole, Porcn, Postn, Pou5f1, Prc1, Prkci, Prlr, Pros1, Psmg1, Ptafr, Ptger1, Pteger2, Ptger4, Ptges, Ptgs1, Ptgs2, Ptk2, Ptk7, Ptpn6, Ptprb, Ptx3, Rag2, Rara, Rel, Ret, Rgr, Rgs1, Ric1, Ric8a, Rock1, Rorc, Ros1, S100a8, S100a9, S100pbp, S1pr1, S1pr4, Scarb1, Selplg, Sema4d, Serpinb9, Sh3bp2, Shc1, Shh, Sirpa, Skap1, Snip1, Socs2, Sox2, Sox9, Spn, Sqstm1, Srrt, Susd2, Tacstd2, Tdo2, Tek, Tgfb2, Tgfbr1, Ticam2, Tigit, Tm4sf5, Tnc, Tnfrsf11, Tnfrsf17, Tnfrsf1a, Tnfrsf1b, Tnfrsf8, Tnfrsf11, Trem1, Trex1, Trpm4, Trpm7, Txk, Tymp, Typo3, Usp15, Vangl1, Vdac2, Vps13a, Vps35, Vps4b, Vtcn1, Wdr4, Wdr7, Wdr83, Wfdc2, Wnt2, Xbp1 and Zeb1. Based on this accounting, the claims are directed to targeting at least 314 different genes, which results in a at least about 3.3 × 1094, or 33 trigintillion, different and distinct combinations of genetic modifications to be introduced into the host subject. (Using the combinatorial formula
2
n
-
1
, which counts the number of combinations of any size from 1 to n items).
Even where one or more gRNAs are designed to target the same gene, this is not sufficient to establish a shared substantial structural feature and a common use that flows from the substantial structural feature. In this case, there is no common core structure or sequence shared among alternative gRNAs designed to target the same gene, and each alternative would possess distinct functional activities in terms of the degree of on-target modulation of gene expression and undesired off-target effects. Moreover, knowledge of one functional gRNA possessing an effective on-target activity without an unsuitable degree of off-targeting effects is not sufficient to predict the structure of another, unknown functional gRNA also possessing an effective on-target activity without an unsuitable degree of off-targeting effects a priori. Rather, the on-target activity and degree of off-targeting effects for each alternative gRNA cannot be predicted a priori from knowledge of the structure of each member alone, but the on-target activity and degree of off-targeting effects of each member can only be known through experimentation a posteriori.
There is no evidence of record that the members of the Markush grouping of SEQ ID NOs: 1-1657 or 1-92 were previously recognized in the art, and, considering that no common core structure or sequence can be searched, a complete search and consideration of claims 4 and 6 would necessarily require at least 1657 different searches for each sequence and also at least about 33 trigintillion different combinations of genes.
For the reasons, the Markush grouping of alternative gRNA sequences, as claimed, is improper as the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use. Dependent claims are included in the basis of the rejection because they do not correct the deficiencies of the claim upon which they depend.
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.
The following is a statement of reasons for the indication of allowable subject matter:
In the reply filed 09/04/2026, Applicant elected without traverse to prosecute the invention of Group 1 of CRISPR-based system with the combination of gRNAs according to SEQ ID NOs: 4-67, 83-92, 333-337, 353-357 and 913-922, which targets the combination of genes PD-L1, Galectin-9 (LGALS9), Galectin-3 (LGALS3) and CD47. This elected combination of gRNAs, the combination of SEQ ID NOs: 4-67, 83-92, 333-337, 353-357 and 913-922, is free of the prior art.
MPEP 803.02 instructs:
If the elected species or group of patentably indistinct species is not anticipated by or obvious over the prior art, the examiner should extend the search and examination to a non-elected species or group of species that falls within the scope of a proper Markush grouping that includes the elected species. The search and examination should be continued until either (1) prior art is found that anticipates or renders obvious a species that falls within the scope of a proper Markush grouping that includes the elected species, or (2) it is determined that no prior art rejection of any species that falls within the scope of a proper Markush grouping that includes the elected species can be made. The examiner need not extend the search beyond a proper Markush grouping. In other words, the examiner need not extend the search to any additional species that do not share a single structural similarity and a common use with the elected species (i.e., do not belong to the same recognized physical or chemical class or to the same art-recognized class and/or do not have a common use and/or do not share a substantial structural feature of a chemical compound and a use that flows from the substantial structural feature).
As set forth in the improper Markush grouping rejection, the claimed list of alternative gRNA sequences, as found in claims 4 and 6, is not a proper Markush grouping. The alternative gRNA sequences do not share a single structural similarity, and no common core structure can be identified and searched. The number of searches required for a complete examination of claims 4 and 6 is unfathomably large, necessarily requiring at least 1657 different searches for each sequence and also at least about 33 trigintillion different combinations of genes. The examiner’s search has not been extended beyond the elected combination of gRNA sequences.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 8-17 and 24-33 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2021/0130438 A1 to Jerby-Arnon et al.
Jerby-Arnon teaches methods of modulating genes in vivo for anti-tumor immunity. See, Abstract. The method comprises administering one or more agents capable of decreasing expression, activity and/or function of one or more genes, including PD-L1 (e.g., par. 8, 95, 102, 106); the agent is a CRISPR/Cas system comprising a gRNA and a Cas13d (e.g., par. 102, 106, 182-183, 192); the vector is AAV9 (e.g., par. 80, 138); the target cell is an immune cell, a T cell and a tumor cell (e.g., par. 51, 95, 102, 144, 399); the subject has breast cancer (e.g., par. 63, 399); the composition is administered in doses (e.g., par. 303, 306, 396); compositions are administered intratumorally (e.g., par. 91, 93, 304); additional therapies include checkpoint blockade monotherapy, surgery, chemotherapy and radiation (e.g., par. 12, 144); and the subject is a mammal or human (e.g., par. 47).
Accordingly, Jerby-Arnon anticipates the invention as claimed in claims 1-3, 8-17 and 24-33.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES J GRABER whose telephone number is (571)270-3988. The examiner can normally be reached Monday-Thursday: 9:00 am - 4:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James D Schultz can be reached at (571)272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JAMES JOSEPH GRABER/Examiner, Art Unit 1631
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