AMENDMENT TO THE CLAIMS
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`The listing of claims will replace all prior versions, and listing of claims in the application.
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`1.
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`(Original) An oncolytic virus comprising: (i) a GM—CSF—enceding gene; and (ii) an
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`immune co-stimulatory pathway activating molecule or an immune co-—stimulatory pathway
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`activating molecule—encoding gene.
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`2.
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`(Currently amended) The virus of claim 1. wherein the immune co~stimulatory pathway
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`activating molecule-encoding gene encodes CD40 ligand (CEMtlL), {COS ligand, GETR ligand,
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`4-—l--BB ligand, OXM) ligand, ’I‘LlA, CD30 ligand, CD27 or flt3 ligand mhameditmdwersienefi
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`3.
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`(Currently amended) The virus of claim 1, wherein the immune (to—stimulatory pathway
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`activating molecule-encoding gene encodes
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`an a onist of CD40. lCOS. GETR. ital-BB, 0X40 or
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`flt3. optionaliy CD40 ligand, GITR ligand. did—BB ligand, 0X40 ligand, ECO-S ligand era
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`4.
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`(Original) The virus of elairn l, wherein the immune rte—stimulatory pathway activating
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`molecule-encoding gene encodes a C'l‘LA-4 inhibitor.
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`5.
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`(Original) The virus of claim 4, wherein the CTLA~4 inhibitor is a C'l‘LA-4 antihotly or
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`fragment thereof.
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`6.
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`(Previously presented) The virus of claim l, further cnmprising a fusogenie protein—
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`eneedin g gene.
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`7.
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`(Original) The virus of claim 6 where the fusngenic protein is selected from the grnup
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`consisting of vesicular stomatitis virus (VSV) (Ll-protein, syncitin-l, syneitin-Q, simian virus 5
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`(3V5) F—protein, measles virus (MV) l-l—protein, MV F—protein, respiratory syncytial virus (RSV)
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`P'--protein and a glycoprotein from gihhon ape leulreinia virus (GALV), murine leukemia virus
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`(MLV), Mason—Pfizer monkey virus (MPMV) or equine infectious ai'iaernia virus (EIAV) from,
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`which the R peptide has been deleted,
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`8.
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`(Previously presented) The virus of claim 6, wherein the fusogenic protein is the
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`glycoprotein from gibbon ape leukemia virus (GALV) and has the R transmenihrane peptide
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`mutated or removed (GALVPJ,
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`9,
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`(Previously presented) The virus of clairn 1, which encodes more than one iinrnune co—
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`stimulatory pathway activating molecule.
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`lti.
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`(Previously presented) The virus of claim 1, which is derived from a clinical isolate of a
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`virus,
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`11.
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`(Previously presented) The virus of clairn 1, which is a modified clinical isolate of a
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`virus, wherein the clinical isolate kills two or more tumor cell lines more rapidly and/or at a
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`lower dose in vitro than one or more reference clinical isolates of the same species of virus.
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`12,
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`(Previously presented) The virus of claim 10, wherein the clinical isolate is
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`strain R110 18A having the accession number ECC AC 16121904;
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`strain RHGOZtA having the accession number ECCAC 16121902;
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`strain Rl-lfifiiA having the accession number ECCAC 16l21907;
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`strain RHOLiOB having the accession number ECCAC 1612l908;
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`strain RHOlSA having the accession number ECCAC 16l21903;
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`strain lit-ltfilA having the accession number ECCAC 16121905;
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`strain RHG’ZBA having the accession number ECCAC 16121906; or
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`strain RH047A having the accession number ECCAC 16121909.
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`13.
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`(Previously presented) The virus of clairn 1, which is selected from the group consisting
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`of herpes viruses, pox viruses, adenoviruses, retroviruses, rhabdoviruses, paramyxoviruses and
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`reoviruses.
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`14.
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`(Previously presented) The virus of claim l, which is a herpes simplex virus (HS V).
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`15.
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`(Griginal) The virus of claim 14 which is a HSVl.
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`16.
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`(Original) The virus of claim 15, wherein the l-lSV:
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`(a) does not express functional lCl’345;
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`(b) does not express l’nnctional lCP47; and/or
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`(c) expresses the USll gene as an immediate early gene.
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`17.
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`(Previously presented) The virus of claim l4, wherein the GM~CSF—encoding gene and
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`an immune co--stimulatory pathway activating molecule-encodin g gene are inserted into the
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`lCPElLl-fi encoding locus, either by ll’lSfil‘llOl’l, or partial or complete deletion, in a hack. to hacl;
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`Orientation in relation to each other, each under separate regulatory control.
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`18.
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`(Previously presented) The virus of claim l, wherein the sequence of a gene encoding
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`Gl‘w’l—CSF and/or the sequence of the gene encoding an eo—immnnc stimulatory pathway
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`activating molecule is codon optimized so as to increase expression levels in target cells.
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`19.
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`(Cancel)
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`20.
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`(Previously presented) The virus of claim 1, which expresses three heterologous genes,
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`wherein each of the three heterologous genes is driven by a different promoter selected from the
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`CMV promoter, the RSV promoter, the SV40 promoter and a retroviral LTR promoter,
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`21.
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`(Currently amended) The virus of claim -1—9 E, which expresses four heterologous genes
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`driven by each of the CMV promoter, the RSV promoter, the SV40 promoter and a retroviral
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`LTR promoter, respectively.
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`22.
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`(Currently amended) The virus of claim -1—9 E, where the retroviral LTR is from MMLV.
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`23.
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`(Cancel)
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`24.
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`(Previously presented) The virus of claim 1, which expresses three heterologous genes,
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`wherein each of the three heterologous genes is terminated by a different poly adenylation
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`sequence selected from the BGH, SV40, HGH and RBG poly adenylation sequences.
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`25.
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`(Currently amended) The virus of claim 2—3 %, which expresses four heterologous genes
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`terminated by each of the BGH, SV40, HGH and RBG poly adenylation sequences, respectively.
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`26.
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`(Currently amended) The virus of claim -l—9 E which is
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`(a) a HSV;
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`(b) a HSVl; or
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`(c) a pox virus.
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`27.
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`(Previously presented) A pharmaceutical composition comprising the virus of claim l
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`and a pliai'inaceutically acceptable carrier or diluent.
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`28. — 3.7. (Cancelled)
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`38.
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`(Previously presented) A product of manufacture comprising a virus according to claim
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`l in a sterile vial, amponle or syringe.
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`39.
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`(Previously presented) A method of treating cancer, which comprises administering a
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`therapeutically effective amount of the virus of claim l to a patient in need thereof.
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`40.
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`(Previously presented) The method of claim 39, which further comprises administering a
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`therapeutically effective amount of a further antivcancer agent to a patient in need thereof.
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`4l.
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`(Previously presented) The method of claim 40, wherein the further anti—cancer agent is
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`selected from the group consisting of an agent targeting an immune co—inhihitory or immune co—
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`stimulatory pathwayt radiation and/or chemotherapy, an agent that targets a specific genetic
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`mutation which occurs in tumors, an agent intended to induce an immune. response to one or
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`more tumor anti gems) or neoantigen(s), a cellular product derived from T cells or NK cells, an
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`agent intended to stimniate the STING, CGAS, TILE or other innate immune response and/or
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`inflammatory pathway, a second Virus optionally an oneoiytic virus, and combinations thereof,
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`42.
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`(Previously presented) The method of ciairn 4i, wherein the. agent targeting an immune
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`(so-inhibitory pathway is a CTLA—4 inhibitor, a PD-i inhibitor, a PD~Li inhibitor, a LAGG
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`inhibitor, a TiM—3 inhibitor, a VISTA inhibitor, aCSFiR inhibitor, an iDO inhibitor, a KER
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`inhibitor, 3. SLA MP? inhibitor, a (:EEEACAMi inhibitor or a CD47 inhibitor, and/or the agent
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`targeting an immune co~stimniatory pathway is a GITR agonist, a 4—i~BB agonist, an 0X40
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`agonist, a CD49 agonist or an 15:08 agonist.
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`43.
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`(Previously presented) The method of ciaint 4i , wherein the further anti—cancer agent
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`comprises an antibody.
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`44.
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`(Previousiy presented) The method of ciaiin 40, wherein the virus and the further anti~
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`cancer agent(s) are administered separateiy.
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`45.
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`(Previously presented) The method of ciaim 40, wherein the Virus and the further anti--
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`cancer agenda) are administered concurrently.
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`46.
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`(Previously presented) The method of ciaint 40, wherein the cancer is a solid tumor.
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`47. - 48. (Canceiied)
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