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 OM—CSl3i-encoding gene; and (ii) an
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`immune eovstimula'tory 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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`(Original) The Virus of claim l, wherein the immune rte—stimulatory pathway activating
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`molecule-encoding gene encodes CD40 ligand (CD4OL), lCOS ligand, GlTR ligand, 4- l 3.8.8
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`ligand, 0X49 ligand, TLIA, CD30 ligand, C1327 or lltfi ligand or a modified version of any ol
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`these.
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`3.
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`(Currently amended) The virus of claim been}, wherein the immune eta—stimulatory
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`pathway activating molecule—encoding gene encodes CD40 ligand, GlTR ligand, 4~lvBB ligand,
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`0X40 ligand, lCOS ligand or a modified version of any of these.
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`4.
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`(Original) The Virus of claim 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 Vl’l'LlS of claim 4, wherein the CTLA~4 inhibitor is a C'lLA-Zt antibody or
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`fragment thereof.
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`6.
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`(Currently amended.) The Virus of Welaimfisl] l—toé. further comprising a
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`t‘usogenie proteinencoding gene.
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`7.
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`(Original) The Virus of claim 6 where the fusogenic protein is selected from the group
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`consisting of vesicular stomatitis Virus (VSV) (Li-protein, syncitin-l, syneitin-Q, simian Virus 5
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`(SVS) F—protein, measles Virus (MV) varotein. MV prrotein. respiratory syneytial Virus (RSV)
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`F-protein and a glycoprotein from gihhon ape leukemia Virus (GALV), murine leukemia virus
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`(lvlLV), Mason-Pfizer monkey virus (MPMV) or equine infectious anaemia virus (ElAV) from
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`which the R peptide has been deleted.
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`8.
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`(Currently amended) The virus of claim 6e91, wherein the fusogenie protein is the
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`glycoprotein from gibbon ape leukemia virus (GALV) and has the R transmemhrane peptide
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`mutated or removed (GALV—R~),
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`9,
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`(Currently amended) The virus of anyoneeithepreeedingclaimfisfli, which encodes
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`more than one immune (to—stimulatory pathway activating molecule,
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`ll).
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`(Currentlj,i amended) The virus of anyoneohthepeeeedingclaimfisllnl, which is derived
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`from a clinical isolate of a virus.
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`ll.
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`(Currently amended) The virus of any—-one-ei—the—pteee—ding—claiml{s}Ll, which is a
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`modil‘ied clinical isolate of a virus, wherein the clinical isolate kills two or more tumor cell lines
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`more rapidly and/or at a lower dose in vitro than one or more reference clinical isolates of the
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`same species of virus.
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`12,
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`(Currently amended) The virus of claim ides—ll, wherein the clinical isolate is
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`strain RHO 18A having the previsienahaccession number ECCAC lolZlgtlr-i;
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`strain RHGOZlA having the prosaiséenal—accession number ECCAC lolllgllZ;
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`strain Rl-ltlfilA having the WRCCSSSiOH number ECCAC l6l21907;
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`strain RHOL’lOB having the press-isiona-lnaccession number ECCAC lol2l908;
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`strain RHOlSA having the provisional—accession number ECCAC l6l21903;
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`strain RE-ltfilA having the provisienahaccession number ECCAC lbl 2l905;
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`strain RHG’ZBA having the provisienahaeeession number ECCAC 16l2l906; or
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`strain RH047A having the Waccession number EESCCAC 16121909.
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`13.
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`(Currently amended) The virus ot‘Wclaimfisfl l—te—lel, which is selected from,
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`the group consisting of herpes viruses, pox viruses, adenoviruses, retroviruses, rhabdoviruses,
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`paramyxoviruses and reoviruses,
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`14.
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`(Currently amended) The virus ofanyeneeftheepreeedlngclaimllsjj nl_, which is a
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`herpes simplex virus (HSV).
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`l5.
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`(Original) The virus of claim 14 which is a HSVl.
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`l6.
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`(Original) The virus of claim 15, wherein the RSV:
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`(a) does not express functional lCP345;
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`(h) does not express functional lCP47; and/or
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`(e) expresses the US ll gene as an immediate early gene,
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`l7.
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`(Currently amended) The virus of Wclaimflsl] l4 tel-é, wherein the GM-CSF-
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`encoding gene and an immune rte—stimulatory pathway activating molecule—encoding gene are
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`inserted into the £13345 encoding locus, either by insertion, or partial or complete deletion, in a
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`hack to hack orientation in relation to each other, each under separate regulatory control,
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`l8.
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`(Currently amended) The virus of anyeneefthepreeedingclaimflsflg, wherein the
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`sequence of a gene encoding (EM-CSF and/or the sequence of the gene encoding an co~irnrnune
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`stimulatory pathway activating molecule is cedon optimized so as to increase expression levels
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`in target cells.
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`19.
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`(Original) A Virus which expresses three heterologous genes, wherein each of the three
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`heterologous genes is driven by a different promoter selected from the CMV promoter, the RSV
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`promoter, the SV40 promoter (SEQ ID) and a retroviral LTR promoter,
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`'20.
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`(Currently amended) A—T_he Virus ineeeed—ing—te—an—y—oneef—thepeeeed—in—g claim[[s]]_1,
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`which expresses three heterologous genes, wherein each of the three heterologous genes is driven
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`by a different promoter selected from the CMV promoter, the RSV promoter, the SV40 promoter
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`and a retroviral LTR promoter,
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`21.
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`(Currently amended) The Virus of claim l9—er—29, which expresses four heterologous
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`genes driven by each of the CMV promoter, the RSV promoter, the SV40 promoter and a
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`retroviral LTR promoter, respectively.
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`22.
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`(Currently amended) The Virus of an—y—ene—ef—claimflsfl l9 te—2—l-, where the retroviral
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`LTR is from MMLV.
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`23.
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`(Original) A Virus which expresses three heterologous genes, wherein each of the three
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`heterologous genes is terminated by a different poly adenylation sequence selected from the
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`BGH, SV40, HGH and RBG poly adenylation sequences.
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`24.
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`(Currently amended) A—T_he Virus iaeeefd-ing—te—an-y—ene-ef—the—pfeeed-ing claim[[s]]_l,
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`which expresses three heterologous genes, wherein each of the three heterologous genes is
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`terminated by a different poly adenylation sequence selected from the BGH, SV40, HGH and
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`RBG poly adenylation sequences.
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`25.
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`(Currently amended) The Virus of claim 23—or—24, which expresses four heterologous
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`genes terminated by each of the BGH, SV40, HGH and RBG poly adenylation sequences,
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`respectively.
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`26.
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`(Currently amended) The Virus of anyone—ef—claimflsfl l9-te—2é 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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`(Currently amended) A pharmaceutical composition comprising llfillfllfi Virus of
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`aeeerdingteenyeneei elaimflsll lee—2d and a pharmaceutically acceptable carrier or diluent.
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`'28. — 37. (Cancelled)
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`38.
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`(Currently amended) A product of manufacture comprising a Virus according toW
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`e—f-clalnrllsll l-t-euéé in a sterile vial, ampoule or syringe.
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`39.
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`(Currently amended) A method of treating cancer, which comprises administering a
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`therapeuticaiiy effective amount of the virus of anyoneeflciaimfisjj i /
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`e-ompoei—ti—en—nee-ording—te—eiaianE-Tl to a patient in need thereof.
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`40.
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`(Cnrrentiy amended) Am’i'he method tineeerd-ingte ciaim 39, which further comprises
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`administering a therapeutieaiiy effective amount of a fnrti'ier anti—cancer agent to a patient in
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`need thereof.
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`4t.
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`(Currentty amended) Aw'Fhe method Qfieeeeré-ing-te ciaitn 40, wherein the further anti—
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`cancer agent is seiected from the group consisting of an agent targeting an immune rte—inhibitory
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`or immune co—stirnuiatory pathway, radiation and/or chemotherapy, an agent that targets a
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`specific genetic mutation which occurs in tumors, an agent intended to induce an immune
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`response to one or more tumor antigenfs) or neoantigents), a ceiiuiar prod not derived from T
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`cells or NK ceiis, an agent intended to stimniate the STENG, cGAS, TLR or other innate immune
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`response and/or infiamniatory pathway, a second Virus optionaiiy an oncoiytie virus, and
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`combination s thereof.
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`42,.
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`(Currentty amended) Amihe method gfiaeeordingto ciaitn 41, wherein the agent
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`targeting an immune co~inhibitory pathway is a CTLA—4 inhibitor, a PD—i inhibitor, a PD~L1
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`inhibitor, a LAG—3 inhibitor, a TiM-3 inhibitor, a VISTA inhibitor, aCSFiR inhibitor, an [DO
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`inhibitor, a KER inhibitor, a SLAM??? inhibitor, a CEACAMI inhibitor or a CD47 inhibitor,
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`and/or the agent targeting an immune co—stimuiatm‘y pathway is a GETR agonist, a 4—i—BB
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`agonist, an 0X40 agonist, a CD40 agonist or an KISS agonist.
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`43.
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`(Currentij,i amended) hum method ofaeeeidmg-te claim iii—453W, wherein the further
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`anti—cancer agent comprises an antibody,
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`44.
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`(Cnrrentiy amended) Am’i'he method aeeerdi—ng—tewanyene—of ciaimfisfl 4049-43“, wherein
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`the virus and the further anti-cancer agenda) are administered separately,
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`45.
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`(Currently amended) Any methnd; fire-WWf claimflsfi 4043343, wherein
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`the, Virus and {he furthnr gnu—cancer agenu's) are. adnrinrslernd cnncurrenlly.
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`46.
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`(Currently amended) A—Tne rnfiflmdMWfi clairnflsfl 40%, whnmin
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`the, cancar is a sand rurnnr.
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`47. ~ 48. (Cancaiiad)
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