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WO 2012/142529 A2 O (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2012/142529 A2 18 October 2012 (18.10.2012) P O PCT (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, C12N 7/00 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (21) International Application Number: HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, PCT/US2012/033684 KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (22) International Filing Date: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 13 April 2012 (13.04.2012) OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, (25) Filing Language: English TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 61/5 17,297 15 April 201 1 (15.04.201 1) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, 61/628,684 4 November 201 1 (04. 11.201 1) US UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (71) Applicant (for all designated States except US): GENE- DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LUX CORPORATION [US/US]; 3030 Bunker Hill Road, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Suite 301, San Diego, CA 92109 (US). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (72) Inventors; and (75) Inventors/Applicants (for US only): SZALAY, Aladar, Declarations under Rule 4.17 : A. [US/US]; 7704 North Fork Road, Highland, CA 92364 — as to applicant's entitlement to applyfor and be granted a (US). CHEN, Nanhai, George [US/US]; 9167 Buckwheat patent (Rule 4.1 7(H)) Street, San Diego, CA 92129 (US). YU, Yong, A . [CN/US]; 3830 Elijah Court, Unit 422, San Diego, CA — as to the applicant's entitlement to claim the priority of the 92130 (US). ZHANG, Qian [CN/US]; 5573 Willowmere earlier application (Rule 4.1 7(in)) Ln., San Diego, CA 92130 (US). Published: (74) Agents: SEIDMAN, Stephanie, L. et al; McKENNA — without international search report and to be republished LONG & ALDRIDGE LLP, 4435 Eastgate Mall, Suite upon receipt of that report (Rule 48.2(g)) 400, San Diego, CA 9212 1 (US). — with sequence listing part of description (Rule 5.2(a)) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, < o- (54) Title: CLONAL STRAINS OF ATTENUATED VACCINIA VIRUSES AND METHODS OF USE THEREOF (57) Abstract: Clonal strains of vaccinia viruses are provided. Also provided are methods of identifying and isolating attenuated and oncolytic clonal strains from virus preparations, Modified recombinant forms of the clonal strains also are provided. The clonal strains and virus preparations can be used for diagnostic and therapeutic methods, in particular for therapy and diagnosis or monitor - S ing treatment of proliferative disorders, including neoplastic diseases, such as, but are not limited to, solid tumors and blood cancers. CLONAL STRAINS OF ATTENUATED VACCINIA VIRUSES AND METHODS OF USE THEREOF RELATED APPLICATIONS Benefit of priority is claimed to U.S. Provisional Application Serial No. 61/51 7,297, filed April 15, 201 1, and to U.S. Provisional Application Serial No. 61/628,684, filed November 04, 201 1, each to Aladar A. Szalay, Nanhai Chen, Yong A. Yu and Qian Zhang and each entitled "Clonal Strains of Attenuated Vaccinia Viruses and Methods of Use Thereof." This application is related to U.S. Patent Application Serial No. (Attorney Dkt. No. 333 16.04832.US03/4832), filed the same day herewith, entitled "Clonal Strains of Attenuated Vaccinia Viruses and Methods of Use Thereof," which claims priority to U.S. Provisional Application Serial Nos. 61/517,297 and 61/628,684. Where permitted, the subject matter of each of the above-referenced applications is incorporated by reference in its entirety. Incorporation by reference of Sequence Listing provided electronically An electronic version of the Sequence Listing is filed herewith, the contents of which are incoiporated by reference in their entirety. The electronic file is 4.44 megabytes in size, and titled 4832seqPCl.txt. FIELD OF THE INVENTION Vaccinia viral isolates. BACKGROUND Vaccinia is an oncolytic virus and accumulates in tumors. Attenuated vaccinia virus strains have been developed for therapeutic and diagnostic applications. For example, attenuated viruses include recombinant viruses that are modified in one or more viral genes that results in loss or reduced expression of a viral gene or inactivation of a viral protein. Methods of attenuating viruses, however, can decrease or reduce the oncolytic properties of the virus. Thus, there still exists a need for attenuated oncolytic viruses and methods of identifying attenuated oncolytic viruses. SUMMARY Provided are isolated clonal strains from LIVP preparations. Provided are preparations of substantially homogenous LIVP virus preparations. Also provided are preparations resulting from propagation of an isolated clonal strain. In particular, provided herein are isolated clonal LIVP strains that have a genome containing a sequence of nucleotides other than a clonal strain whose genome contains the sequence of nucleotides set forth in SEQ ID NO: 10. In some examples, the LIVP clonal strains provided herein have a sequence of nucleotides that has at least 85% sequence identity with the sequence of nucleotides set forth in SEQ ID NO: 10 but does not include the sequence of nucleotides set forth in SEQ ID NO: 10. For example, the isolated clonal LIVP strains provided herein have a sequence of nucleotides that has at least 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9% sequence identity with the sequence of nucleotides set forth in SEQ ID NO: 10. In such examples, sequence identity refers to sequence identity that is determined by aligning nucleotide sequences containing nucleotides corresponding to the inverted terminal repetitions (ITRs) (if they are present) and using global alignment with GAP, whereby terminal gaps are not penalized. In particular, the LIVP clonal strains provided herein have greater anti-tumorigenicity and/or reduced toxicity compared to the LIVP strain designated GLV-lh68 having a sequence of nucleotides set forth in SEQ ID NO: 9. In examples of the LIVP clonal strains provided herein, an isolated clonal LIVP strain is one that is present in an LIVP isolate or in a virus preparation propagated from LIVP and the clonal strain has reduced toxicity and/or greater anti- tumorigenicity compared to the virus strain designated GLV-lh68 having a sequence of nucleotides set forth in SEQ ID NO:9. In other examples of the LIVP clonal strains provided herein, an isolated clonal LIVP strain is one that has a genome that does not contain non-viral heterologous nucleic acid that contains an open reading frame encoding a non-viral heterologous protein and exhibits reduced toxicity and/or improved anti- tumorigencity compared to the virus strain designated GLV-lh68 having a sequence of nucleotides set forth in SEQ ID NO:9. LIVP clonal strains provided herein include clonal strains that have reduced toxicity compared to the virus designated GLV-lh68 having a sequence of nucleotides set forth in SEQ ID NO:9. In other examples, LIVP clonal strains provided herein include clonal strains that have greater anti-tumorigencity compared to the virus strain designated GLV-lh68 having a sequence of nucleotides set forth in SEQ ID NO:9. In further examples, LIVP clonal strains provided herein include clonal strains that have reduced toxicity and greater anti-tumorigenicity compared to the virus designated GLV-lh68 having a sequence of nucleotides set forth in SEQ ID NO:9. In any of the the LIVP clonal strains provided herein, the genome of the LIVP clonal strain has a sequence of nucleotides that is at least 85% sequence identity with the sequence of nucleotides set forth in SEQ ID NO: 10 but does not contain the complete sequence of nucleotides set forth in SEQ ID NO: 10. For example, the isolated clonal LIVP strain has a sequence of nucleotides that has at least 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9% sequence identity. In such examples, sequence identity is determined by alignment of nucleotide sequences containing nucleotides corresponding to the inverted terminal repetitions (ITRs) and using global alignment with GAP with the sequence of nucleotides set forth in SEQ ID NO: 10, whereby terminal gaps are not penalized. In any of the provided LIVP clonal strains that exhibit reduced toxicity, reduced toxicity can be manifested upon administration to a subject. For example, the subject can be a human or non-human animal, particularly a domesticated animal. Reduced toxicity can be determined by any method for assessing a toxic effect, such as, but not limited to, a parameter indicative of toxicity such as decreased survival of the subject, decreased body weight, fever, rash, allergy, fatigue, abdominal pain, induction of an immune response in the subject, pock formation and/or lesser accumulation of the virus in non-tumor tissues to a greater extent that LIVP (a virus with the genome set forth in or substantially as set forth in, typically at least 99%, SEQ ID NO: 10) or GLV-lh68 (a virus with the genome set forth in substantially as set forth in typically at least 99%, SEQ ID NO:9).
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