WO 2017/118866
`
`PCT/GB2017/050038
`
`CLAIMS
`
`1.
`
`An oncol
`
`5:: W
`E: c:
`.
`i
`.
`ic Virus com Misfit“: (i a Gi‘vi—CSFaeneedini Gene; and ’ii') an imn’inne
`
`co—stiinuiatery pathway activating ineieeuie or an immune comgtimniatmy pathway
`
`activating inoieenie—eneeding gene
`
`2,
`
`The Virus oi‘ciaim l, Wh erein the immune (so—stimulatory path w ay activating
`
`meieenieenceding gene encodes CD40 ligand ('CDéiQL}, ECOS iigand, GITR iigand, 44»
`
`BB iiganth 0X40 ligand, TLiAP CD38 ligand, CD27 or fit?) ligand or a modified version
`
`10
`
`of any of these.
`
`3‘
`
`The virus ei‘eiaim i or 2, wherein the ii‘l’in‘iui’lfi eo~stimuiatory pathway activating
`
`moiecnie—encoding gene encodes CD40 iigand.., GITR iiganth Kiwi—BB iigand.e 0X40 iigand,
`
`EGGS iigand er a inedified version oi’any Qi‘these.
`
`15
`
`4
`
`The virus Oi‘ciaini 1, wherein the immune eo—s‘tiinifla‘tory path w ay activating
`
`molecule—encoding gene encodes a C’i‘LA—ai inhibitor.
`
`5.
`
`The Virus ofeiaiin 4, wherein the {3415A —4 inhibitor is a C'S‘LAA antibody or
`
`20
`
`fragment thereof.
`
`6.
`
`The viii/1S of any one of claims 1 to 5, further comprising a insogenie protein—
`
`eneeriing gene.
`
`25
`
`30
`
`7.
`
`The virus of claim 6 where the t‘nsogenic protein is selected from the group
`
`consisting of vesicular Stoniatitig Virus; (VSV) G-pi'otein, syneitin—i, syneitin—Z, simian
`
`Virus 5 (8V5) F—pi‘otein, ineasies Virus {MV} Eii*pi°01$ifig MV F~pr<.>tein., respiratory
`
`syneytiai Virus (RSV) F—protein anti {1 giycoprotein from gibbon ape ieniieinia virus
`
`(GALV), marine ieukei’nia Virus, (h/ii,i\l’}, Mason—Pfizer monkey Virus: (h’iPh’iV) or equine
`
`infections anaemia Vims (EiAV) front: which the R. peptide has been tieieted.
`
`45
`
`
`
`PCT/GB2017/050038
`
`CLAIMS
`
`1.
`
`An oncol
`
`5:: W
`E: c:
`.
`i
`.
`ic Virus com Misfit“: (i a Gi‘vi—CSFaeneedini Gene; and ’ii') an imn’inne
`
`co—stiinuiatery pathway activating ineieeuie or an immune comgtimniatmy pathway
`
`activating inoieenie—eneeding gene
`
`2,
`
`The Virus oi‘ciaim l, Wh erein the immune (so—stimulatory path w ay activating
`
`meieenieenceding gene encodes CD40 ligand ('CDéiQL}, ECOS iigand, GITR iigand, 44»
`
`BB iiganth 0X40 ligand, TLiAP CD38 ligand, CD27 or fit?) ligand or a modified version
`
`10
`
`of any of these.
`
`3‘
`
`The virus ei‘eiaim i or 2, wherein the ii‘l’in‘iui’lfi eo~stimuiatory pathway activating
`
`moiecnie—encoding gene encodes CD40 iigand.., GITR iiganth Kiwi—BB iigand.e 0X40 iigand,
`
`EGGS iigand er a inedified version oi’any Qi‘these.
`
`15
`
`4
`
`The virus Oi‘ciaini 1, wherein the immune eo—s‘tiinifla‘tory path w ay activating
`
`molecule—encoding gene encodes a C’i‘LA—ai inhibitor.
`
`5.
`
`The Virus ofeiaiin 4, wherein the {3415A —4 inhibitor is a C'S‘LAA antibody or
`
`20
`
`fragment thereof.
`
`6.
`
`The viii/1S of any one of claims 1 to 5, further comprising a insogenie protein—
`
`eneeriing gene.
`
`25
`
`30
`
`7.
`
`The virus of claim 6 where the t‘nsogenic protein is selected from the group
`
`consisting of vesicular Stoniatitig Virus; (VSV) G-pi'otein, syneitin—i, syneitin—Z, simian
`
`Virus 5 (8V5) F—pi‘otein, ineasies Virus {MV} Eii*pi°01$ifig MV F~pr<.>tein., respiratory
`
`syneytiai Virus (RSV) F—protein anti {1 giycoprotein from gibbon ape ieniieinia virus
`
`(GALV), marine ieukei’nia Virus, (h/ii,i\l’}, Mason—Pfizer monkey Virus: (h’iPh’iV) or equine
`
`infections anaemia Vims (EiAV) front: which the R. peptide has been tieieted.
`
`45
`
`
`
`WO 2017/118866
`
`PCT/GB2017/050038
`
`8
`
`The virus oi'clairn (“i or 7, wherein the l‘usogenic protein is the glycoprotein from
`
`gibbon ape leukemia virus (GALV) and has the R transinernhrane peptide initiated or
`
`rerno ved (GALV—R— :3.
`
`5
`
`9.
`
`The virus ol'any one of the preceding claims; which encodes more than one
`
`irnniune co--stinnilatory pathway activating molecule.
`
`l0.
`
`The virus of anyone of the preceding clairns, which is derived from a clinical
`
`isolate of a virus.
`
`10
`
`15
`
`l l .
`
`The virus of any one of the preceding claims; vvl'iich is a niodiliecl clinical isolate of
`
`a virus, wherein the clinical isolate kills two or more turnor cc l lines more rapidly and/or
`
`at a lower dose in vitro than one or tno "e relerenee clinical isolates ol‘ the sarne speei es oi‘
`
`virus.
`
`l2.
`
`The virus oi’clairn 30 or l l, wherein the clinical isolate is
`
`strain RHGl 8A having the provisional accession number ECCAC 16121904;
`
`strain Rlltltlél-A having the provisional, accession nurnber ECCAC lol 21902;
`
`strain RHtB 1A having the provisional accession number ECCAC l6 l 2l907;
`
`20
`
`strain Rl’l0408 l'iaving the provisional accession nntnher ECCAC l ti l 2 i908;
`
`strain RHtll 5A having the provisional accession number 13‘ ‘JCAC l6121903;
`
`strain RH02 lA having the provisional accession number ECCAC loTZl905;
`
`strain l§llt323A having the provisional accession number litiltIAC lol 21906; or
`
`strain RH047A having the provisional accession number ECCAC 16121909.
`
`25
`
`B.
`
`The virus of any one of claims 1 to ll; which is selected from the group consisting
`
`of herpes viruses; pox viruses, adenoviruses, retroviruses, rhabdoviruses, paramyxoviruses
`
`and reoviruses.
`
`30
`
`l4t
`
`The virus or" any one or" the preceding claims? which is a herpes simplex virus
`
`(RSV)
`
`iii.
`
`The virus oi‘cl'tin'i l4 which is a l‘lSV l.
`
`46
`
`
`
`WO 2017/118866
`
`PCT/GB2017/050038
`
`16.
`
`The virus of claim 15, wherein the HSV:
`
`(a) does not express functional ECP345;
`
`(h) does not express functional ECP47; and/or
`
`CF"
`(e) expresses the USll gene as an ii'nrnedia‘te early *ene.
`
`17.
`
`The virus ofany one of claims 14 to 16, wherein the (EM—CSF—encodii‘ig gene and
`
`an innnune era—stimulatory pathway activating molecule—encoding gene are inserted into the
`
`ICP345 encoding locus, either by insertion, or partial or complete deletion, in a hack to
`
`10
`
`back orientation in relation to each other, each under separate regulatory control.
`
`18.
`
`The virus ofany one ot‘the preceding claims, wherein the sequence of a gene
`
`encoding GMmCSF and/or the sequence of the gene encoding an comininmne stimulatory
`
`pathway activating molecule is codon optimized so as to increase expression levels in
`
`15
`
`target cells.
`
`19.
`
`A virus which expresses three heterologous genes, wherein each of the three
`
`heterologous genes is driven by a different promoter selected from the CMV promoter, the
`
`RSV promoter, the SV40 promoter (SEQ ID) and a retroviral LTR promoter.
`
`20
`
`25
`
`30
`
`20.
`
`A Virus according to any one of the preceding claims, which expresses three
`
`heterologous genes, wherein each of the three heterologous genes is driven by a different
`
`promoter selected from the CMV promoter, the RSV promoter, the SV40 promoter and a
`
`retroviral LTR promoter.
`
`21.
`
`The Virus of claim 19 or 20, which expresses four heterologous genes driven by
`
`each of the CMV promoter, the RSV promoter, the SV40 promoter and a retroviral LTR
`
`promoter, respectively.
`
`22.
`
`The Virus of any one of claims 19 to 21, where the retroviral LTR is from MMLV.
`
`47
`
`
`
`WO 2017/118866
`
`PCT/GB2017/050038
`
`23.
`
`A virus which expresses three heterologous genes, wherein each of the three
`
`heterologous genes is terminated by a different poly adenylation sequence selected from
`
`the BGH, SV40, HGH and RBG poly adenylation sequences.
`
`24.
`
`A Virus according to any one of the preceding claims, Which expresses three
`
`hctcrologous gcncs, thrcin each of thc thrcc hctcrologous gcncs is tcrminatcd by a
`
`different poly adenylation sequence selected from the BGH, SV40, HGH and RBG poly
`
`adenylation sequences.
`
`25.
`
`The Virus of claim 23 or 24, which expresses four hctcrologous genes terminated by
`
`each of the BGH, SV40, HGH and RBG poly adenylation sequences, respectively.
`
`26.
`
`The Virus of any one of claims 19 to 25 which is
`
`(a) a HSV;
`
`(b) a HSV]; or
`
`(c) a pox Virus.
`
`27.
`
`A pharmaceutical composition comprising a virus according to any one of claims l
`
`to 26 and a phaimaceut’ically acceptable carrier or diluent,
`
`28
`
`The Virus of any one or” claims l to 25 for use in a, method of treating the human or
`
`animal hotly lay therapy.
`
`29.
`
`The virus of any one of claims 1 to 26 For use in a method oi" treating cance".
`
`30.
`
`The Virus for use according to claim 29; wherein the method comprises
`
`administering a thither anti scancer agent.
`
`Ell.
`
`The virus for use according to claim 30, wherein the tirrther anti —s:ancer agent is
`
`selected from an agent targeting an immune co-inhihitory or immune constimulatory
`
`pathway, radiation and/or chemotherapy, an agent that targets a, specifi c genetic. mutation
`
`which occurs in tumors, an agent intended to induce an immune response to one or more
`
`tnnior antigent’s} or neoantigents). a cellular product derived from T cells or NK cells, an
`
`agent intended to stimulate the S'HN G. CGAS, ’l‘iLR or other innate immune response
`
`48
`
`10
`
`15
`
`20
`
`25
`
`30
`
`
`
`WO 2017/118866
`
`PCT/GB2017/050038
`
`and/or inflammatory pathway, a second virus optionally an oncoiytic virus, and
`
`combinations thereoi:
`
`32‘
`
`The Virus for use according to ciaim 30 or 31, wherein the agent targeting an
`
`immune co—inhibitory path say is a CTLA—ft inhibiton a PD—‘t inhibitor? :3. PDsLt inhibitor,
`
`3 LAG-3 inhibitor, a ’i‘i’M-S inhibitor, 3, V ESTA inhibitor, aCSFi R inhibiton an i130
`
`inhihi‘ton a KER inhibiton a SLAB/[F7 inhibitor, a CEACAMt inhibitor or a CD4?
`
`inhibitor, and/or the agent targeting an immune co~stimuiatorj,r pathway is a GETR agonist,
`
`a 4433B agonisti an 0X40 agonist, a CD48 agonist or an ECGS agonist.
`
`3:3.
`
`The virus for use according to any one oi‘ciaiins 30 to 325 wherein the tiirther anti—
`
`cancer agent is an antibody.
`
`34.
`
`The Virus for use according to any one ot‘ciaiins 30 to 33, wherein the method
`
`comprises administering an inhibitor of the indoieamine 2,3—dioxygenase {:EDO) pathway
`
`and a further antagonist of an immune co-inhibitory pathway, or an agonist of an immune
`
`co-stimulatory pathway.
`
`'35.
`
`The Virus for use according to any one of eiaims 29 to 34, wherein the Virus and the
`
`further antiwancer agentt‘s) are administered separately.
`
`36.
`
`The virus for use according to any one ot‘ciaiins 29 to 34, wherein the Virus and the
`
`tiirther anti—cancer agentfi) are administered concun‘entiy.
`
`37.
`
`The virus for use according to any one ot'eiaims 29 to 36, wherein the cancer is a
`
`solid tumor.
`
`38.
`
`A product ot‘manuiacture comprising a Virus according to any one of claims 1 to
`
`26 in a sterite Via}, amponie or syringe,
`
`39.
`
`A method of treatinv cancer which coin arises adininisterin‘v a theraieutieaii r
`t:
`a
`i
`t:
`i
`3
`
`effective amount. ot‘the Virus ot‘any one ofciairns i to 26' or a phan’nacentioai composition
`
`according to claim 27 to a patient in need thereof.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`49
`
`
`
`WO 2017/118866
`
`PCT/GB2017/050038
`
`40.
`
`A method according to claim 39, which further eon‘iprises administering a
`
`thei‘apenticaiiy effective amount of a further antincaneer agent to a patient in need thereof,
`
`41,
`
`A method according to claim 40,, wherein the further anti—cancer agent is seiected
`
`from the group consisting of an agent targeting an immune co-inhihitow or irnininie co—
`
`stininiatony’ pathway, radiation and/or chemotherapy an agent that targets a specific
`
`genetic mutation which occurs in tumors, an agent intended to induce an immune response
`
`to one or more tninor anti gent s) or iieoaiitigen(s), a cellular product derived from T eeiis or
`
`NE cells, an agent intended to stimulate the STING, cGAS, TLR or other innate immune
`
`response and/or inflammatory pathway, a second Virus optionaiiy an oncoijytic Virus, and
`
`combinations thereotl
`
`42,
`
`A method according to claim 41,, wherein the agent targeting an immune co-
`
`inhibitory pathway is a (Yi‘LA-[t inhibitor, a 1334 inhibitor, a FELL} inhibitor, a LAG-3
`
`inhibitor, a ’i’iivi—3 inhibitor, 3 V iS’i'A inhibitor, aCSFiR inhibitor, an EEO inhibitor, a KER
`
`inhibitor, a SI_,,Ah/ii:'7 inhibitor, a CEACAMi inhihitor or a CD47 inhibitor, and/or the
`
`agent targeting an immune constinniiatory pathway is a Gi’i‘R agonist, a 4—1—33 agonist, an
`
`0X40 agonist, a CD40 agonist or an ECOS agonist.
`
`43.
`
`A method according to claim 4-1 or 42., wherein the further anti~cancer agent
`
`comprises an antibody.
`
`44.
`
`A method according to any one of eiairns 40 to 43., wherein the Virus and the
`
`further anti—cancer agentts) are administered separately.
`
`45.
`
`A method according to any one of eiaiins 4% to 43, wherein the virus and the
`
`fnrti'ier anticancer agentt's) are administered concurrentiy.
`
`10
`
`15
`
`20
`
`25
`
`46.
`
`A method according to any one of claims 4G to 45, wherein the cancer is a soiid
`
`30
`
`tumor.
`
`47.
`
`Use of the Vii’uS of any one of claims '3 to 26 in the manufacture of a medicament
`
`4‘:
`£531” use In 83, nlfiihflii Of treatino cancer,
`
`50
`
`
`
`WO 2017/118866
`
`PCT/GB2017/050038
`
`48.
`
`Use according to atlaim 47‘, whsrein the msthod mmpriscs adn’lii'xistering a further
`
`antiucancer agent.
`
`51
`
`
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