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Wo 2012/064675 A2 (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 - if 18 May 2012 (18.05.2012) WO 2012/064675 A2 (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12N 15/11 (2006.01) C12Q 1/68 (2006.01) kind of national protection available): AE, AG, AL, AM, C07H 21/00 (2006.01) C12N 15/10 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (21) International Application Number: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US201 1/059656 HN, HR, HU, ID, JL, IN, IS, JP, KE, KG, KM, KN, KP, (22) International Filing Date: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, 7 November 20 11 (07.1 1.201 1) ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, (25) Filing Language: English RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, (26) Publication Language: English TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/41 1,974 10 November 2010 (10.1 1.2010) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (72) Inventor; and GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (71) Applicant : WEBB, Nigel, L. [GB/US]; 1101 Green UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, Valley Road, Bryn Mawr, PA 19010 (US). RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, (72) Inventor; and LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, (75) Inventor/Applicant (for US only): GAMPER, Howard, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, B. [US/US]; Thomas Jefferson University, Department of GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). Biochemistry and Molecular Biology, 233 South 10th Street, Philadelphia, PA 19107 (US). Published: (74) Agents: LEE, H. Janice et al.; Morgan, Lewis & Bockius — without international search report and to be republished LLP, 1111 Pennsylvania Avenue, NW, Washington, DC upon receipt of that report (Rule 48.2(g)) 20004 (US). — with sequence listing part of description (Rule 5.2(a)) < © o (54) Title: NUCLIONS AND RIBOCAPSIDS (57) Abstract: The invention relates to an isolated nuclion having (i) a core nucleic acid, and (ii) one or more nbocapsids each in cluding a polymer of two or more ribocapsid subunits, wherein said ribocapsid subunits include nucleic acid. The invention also relates to a method for manufacturing an isolated nuclion. NUCLIONS AND RIBOCAPSIDS CROSS-REFERENCE TO RELATED APPLICATIONS: The present application claims priority under 35 U.S.C. § 119(e) to U.S. provisional patent application U.S. Ser. No. 61/41 1,974 filed on November 10, 2010. The subject matter in this provisional patent application not disclosed in the present application is hereby expressly abandoned upon the filing of the present application. FEDERALLY SPONSORED RESEARCH: None SEQUENCE LISTING: A computer readable text file, entitled 'SequenceListing.txt,' created on or about October 31, 2011 with a file size of about 1.13 kb contains the sequence listing for this application and is hereby incorporated by reference in its entirety. COPYRIGHT NOTICE. A portion of the disclosure of this patent document contains material which is subject to copyright protection. The owner of the copyright has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure as it appears in the Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever. COLOR DRAWINGS. The file of this patent contains at least one color drawing. Copies of the patent with color drawings will be provided by the PTO upon payment of the necessary fee. BACKGROUND OF THE INVENTION This invention relates to the discovery that certain natural ribonucleic acids form a polymeric shell, called a ribocapsid, around another nucleic acid, forming a biological structure called a nuclion. Transfer RNA ('tRNA') molecules form such nuclions when they bind to each other and messenger RNA ('mRNA') without the participation of a ribosome. These tRNA nuclions qualify and protect the mRNA, flag translation start codons, ensure frame registration, warehouse charged tRNAs, and accelerate protein synthesis. Abnormal nuclions and ribocapsids may cause several human diseases and disorders. For example, mutations in the tRNA sites which bind adjacent tRNAs in a ribocapsid are associated with cellular transformations implicated in certain types of cancer. Retroviruses such as HIV form tRNA primer structures which mimic legal nuclions, presumably to hijack the host cell's protein synthesis machinery. The pharmaceutical and biotechnology industries are in urgent need of new biological targets for the development of novel diagnostic, therapeutic and prophylactic products for the treatment of human diseases and disorders. Several embodiments of this invention directly address this need by providing isolated nuclions for use in pharmaceutical research and development. Nuclions play a key role in all protein synthesis in humans, and, as such, represent prime candidates for medical intervention. Several embodiments define specific nuclion targets for the development of drugs for the treatment of nuclion- mediated diseases and disorders, including but not limited to certain cancers and viral infections. Other embodiments teach methods for the manufacture of isolated nuclions for use by researchers and others in the pharmaceutical and biotechnology industries. SUMMARY OF THE INVENTION The invention relates to an isolated nuclion comprising (i) a core nucleic acid, and (ii) one or more ribocapsids each comprising a polymer of two or more ribocapsid subunits, wherein said ribocapsid subunits comprise nucleic acid. In further embodiments, (a) most of the ribocapsid subunits are bound to at least a part of the core nucleic acid, and (b) most of the ribocapsid subunits are bound to at least a part of one or more adjacent ribocapsid subunits. In further embodiments, the nuclion additionally comprises one or more nuclion envelopes, where at least one of the nuclion envelopes is optionally bound to at least a part of (a) the basic nuclion part of the nuclion, (b) a core nucleic acid, (c) one or more of the ribocapsids, (d) one or more of the ribocapsid subunits, (e) another nuclion envelope of the nuclion, or (f) any combination of the foregoing. In yet further embodiments, one or more of the ribocapsid subunits comprises RNA, for example, transfer RNA. In additional embodiments, one or more of the ribocapsid subunits comprises initiator transfer RNA and one or more of the ribocapsid subunits comprises elongator transfer RNA. In yet additional embodiments, the nuclion is a mimic or counterfeit of a normal nuclion, and said nuclion is a nuclion-like composition associated with a cellular organism, an adventitious agent, a virus, a retrovirus, a retroviral tRNA primer complex, a human immunodeficiency virus tR A primer complex, any other natural source of a nuclion mimic or any non-natural source of a nuclion mimic. In one aspect, the core nucleic acid comprises DNA. In another aspect, the core nucleic acid comprises RNA, for example, messenger RNA. In another aspect, one or more ribocapsid subunits are bound to said mRNA at or near a start codon. In another aspect, one or more ribocapsid subunits are additionally bound to a part of a protein synthesis marker sequence in said mRNA, wherein such marker sequence is optionally a Shine-Dalgarno sequence or a Kozak sequence. In another aspect, one or more nuclion components of the nuclion, such as mRNA, is additionally bound to at least a part of a ribosome. In another aspect, the isolated nuclion is an initiation nuclion, wherein (i) the core nucleic acid comprises mRNA and (ii) at least a part of said mRNA comprises a ribocapsid and/or ribocapsid subunit binding sequence operably linked to the start codon in said mRNA. The invention also relates to a method for manufacturing an isolated nuclion by bringing into association with each other two or more nuclion components. In one aspect, the nuclion is manufactured by bringing into association a combination of nuclion components, wherein such combination is selected from the group consisting of (i) a core nucleic acid and two or more ribocapsid subunits, (ii) a core nucleic acid, two or more ribocapsid subunits, and one or more predefined nuclion envelopes, (iii) a basic nuclion and one or more predefined nuclion envelopes, (iv) a core nucleic acid and two or more tRNA ribocapsid subunits, (v) a core nucleic acid, two or more tRNA ribocapsid subunits, and one or more predefined nuclion envelopes, (vi) a basic tRNA nuclion and one or more predefined nuclion envelopes, (vii) an enveloped nuclion and one or more predefined nuclion envelopes, (viii) a combination of any two or more members of this group, and (ix) a hybrid of two or more members of this group. In another aspect, the method is selected from the group consisting of (1) combining a core nucleic acid preparation with one or more ribocapsid subunit preparations, (2) adding one or more core nucleic acid preparations to a ribocapsid subunit preparation, (3) adding one or more ribocapsid subunit preparations to a core nucleic acid preparation, (4) combining a preparation of core nucleic acid immobilized directly or indirectly
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