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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`(Currently Amended) An oncolytic virus comprising: (i) a heterologous GM—CSF—
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`encoding gene; and (ii) a heteroiogous immune co--stimulatory pathway activating molecule--
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`encoding gene wherein both heterologous enes are inserted into the enome of the virus.
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`2.
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`(Previously presented) The virus of claim l, wherein the immune covstimulatory pathway
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`activating molecule-encoding gene encodes C1140 ligand (ClMlll_.), {COS ligand, GETR ligand,
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`4-—l--BB ligand, OX4G ligand, TLlA, CD30 ligand, CD27 or fltii ligand.
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`3.
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`(Previously presented) The virus of claim l, wherein the immune co-stirnulatory pathway
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`activating molecnle-encoding gene encodes an agonist oi CD40, TCOS, GETR, 4—l-BE, 0X40 or
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`tltll, optionally C1340 ligand, GlTR ligand, 4-1433 ligand, (1X40 ligand, or ECUS ligand.
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`4.
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`(Original) The virus of claim l, wherein the imrnune ctr—stimulatory pathway activating
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`molecule—eliteoding gene encodes a CTLA~4 inhibitor.
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`5.
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`(Original) The virus of claim 4, wherein the C'l‘LA--4 inhibitor is a Cl‘lJ’X-élL antibody or
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`fragment thereof.
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`6.
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`(Previously presented) The virus of claim l, further comprising a fusogenic protein~
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`encoding gene.
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`7.
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`(Previously presented) The virus of claim 6 where the l’usogenic protein is selected from
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`the group consisting of vesicular stornatitis virus (VSV) G-protein, syncitin--l, syncitin-Q, simian
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`virus 5 (8V5) F-protein, measles virus (MV) Til—protein, MV F—protein, respiratory syncytial
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`virus (RSV) F-protein and a glycoprotein from gihhon ape leukemia virus (GALV), rnurine
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`leukemia virus (MLV), Mason-Pfizer nionloey virus (MPMV) and equine infectious anaemia
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`virus (ElAV) trom 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 t’usogenic protein is the
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`glycoprotein from gibhon ape leukemia virus (GALV) and has the R transniemhrane peptide
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`mutated, or removed (GALV—R~),
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`9,
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`(Previously presented) The virus of claim l, which encodes more than one immune co—
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`stimnlatory pathwa y activatin g molecule.
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`it).
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`(Previously presented) The virus of claim l, which is derived from a clinical isolate of a
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`virus,
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`ll.
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`(Previously presented) The virus of claim l, 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 viz/'0 than one or more reference clinical isolates of the same species of virus.
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`l2,
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`("Previously presented) The virus of claim ll), wherein the clinical isolate is
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`strain RHOlSA having the accession number ECCAC l612l904;
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`strain RHOtMA having the accession number ECC AC l6l2l902;
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`strain RHG31A having the accession number ECCAC l6121907;
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`strain REM-QB having the accession number ECCAC l6l2l908;
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`strain RHOlSA having the accession number ECCAC l612l 9G3;
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`strain RHOZlA having the accession number ECCAC l612l905;
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`strain Rl-lGZClA having the accession number ECCAC ltil2l906; or
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`strain RH047A having the accession number ECCAC 16121909.
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`l3.
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`(Previously presented) The virus of claim l, 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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`l4.
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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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`16.
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`I,1.
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`:i
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`(Qifiginai) The virus (if claim 14 which is a HSVT.
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`(Original) The Virus of claim, 15, wi'iereih the i-ESV:
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`(a) does not express functional TCP345;
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`(b) does not express functional TCP47; and/er
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`(c) expresses the US$11 gene as an immediate eariy gene.
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`(Previeusiy presented) The virus (if claim, 14, wherein the GM—CSF—ehcedihg gene and
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`an immune ce--stimuiatery pathway activating n10i€cui€--€l‘1€0difl
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`g gene are inserted into the
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`iCPEir-i-fi encnthng teens. either by h’isertinn, er partial or cehipiete deletion, in a hack. tn hack
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`Orientation in reiatien t0 each other, each under separate reguiatory central.
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`18.
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`(Previeusiy presented) The Virus of claim 3, wherein the sequence cf 21 gene enceding
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`(EM—CS}? and/or the sequence at the gene enceding an ce—irnrnunc stiinuiatery pathway
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`activating meiecuie is coden optimized so as to increase expressien ieveis in target cells.
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`19.
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`(Cancel)
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`2Q.
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`21.
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`22.
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`23.
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`24.
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`25.
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`26.
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`(C ancei)
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`(Cancel)
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`(Cancel)
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`(Cancel)
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`(Cancei)
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`(Cancei)
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`(Cancei)
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`27.
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`(Previously presented) A pharniaceutieai composition conipri sing the virus of claim 1
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`and a pharrnaceutieaiiy acceptable carrier or dihient,
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`28. — 37. (Canceiied)
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`2:8.
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`("Previously presented) A product of manufacture comprising a virus according to ciaiin
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`1 in a steriie viai, arnpouie 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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`therapeuticaiiy effective amount of the. virus of ciairn i to a patient in need thereof,
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`40.
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`(Previousiy presented) The method of ciairn 3.9, which further comprises administering a
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`therapeuticaiiy et" Tective amount of a further anti-cancer agent to a patient in need thereof.
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`41.
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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 inunune (to—inhibitory or immune co—
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`stirnuiatory pathway, radiation and/or chemotherapy, an agent that targets a specific genetic
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`mutation which occurs in turnors, an agent intended to induce an irnrnune response to one or
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`more turnor antigents) or neoantigents), a ceiiuiar product derived from T cells or NK ceiis, an
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`agent intended to stiinniate the STING, cGAS, TLR or other innate immune response and/or
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`it’lii?tfilti‘tht0fy pathway, a second virus optionally an oncoiytic virus, and combinations thereof.
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`4-2.
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`(Previously presented) The method of ciairn 4-1, wherein the agent targeting an inunune
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`co--inhibitory pathway is a C’i‘LA—d inhibitor, a FED-i inhibitor, a PD-Li inhibitor, a LAG-3
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`inhibitor, a TIE/iv}: inhibitor, a VISTA inhibitor, aCSFiR inhibitor, an H30 inhibitor, a KER
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`inhibitor, a SLAMF? inhibitor, a CEACAMi inhibitor or a C947 inhibitor, and/or the agent
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`targeting an irnrnune (so—stimulatory pathx 'ay is a GITR agonist, a did—BB agonist, an 0X40
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`agonist, a (31340 agoni st or an BEDS agonist.
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`43.
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`(Previously presented) The method of claim 4i, wherein the. further anti—cancer agent
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`comprises an antibody.
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`44.
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`(Previously pi‘csciiicd) The methcd 0f ciaim 4G, whcrein the Virus and the further anti--
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`cancer agema’S) are. adminisici‘cd scparaiciy.
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`45.
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`(Prcviuusiy prescnted) The mcihud 03? claim 40, wherciri the. virus and the. further ami—
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`cancer agcnfis) are administered ci‘mcurrcmiy.
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`46.
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`("Prcvicusly pmmntcd) The: mathcd of claim 40, whci‘ein thc cancer is, a. sciid tumor.
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`47. — 48. (Cancelled)
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