Modified polynucleotides for the production of biologics and proteins associated with human disease
First Claim
Patent Images
1. An isolated polynucleotide comprising;
- (a) a first region of linked nucleosides, said first region encoding a polypeptide of interest, said polypeptide of interest is SEQ ID NO;
1089;
(b) a first flanking region located at the 5′
terminus of said first region comprising at least one 5′
terminal cap;
(c) a second flanking region located at the 3′
terminus of said first region comprising a 3′
tailing sequence of linked nucleosides; and
wherein at least one of said linked nucleosides of (a) comprises at least one modification as compared to the chemical structure of an A, G, U or C ribonucleoside.
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Abstract
The invention relates to compositions and methods for the preparation, manufacture and therapeutic use of polynucleotides, primary transcripts and mmRNA molecules.
942 Citations
16 Claims
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1. An isolated polynucleotide comprising;
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(a) a first region of linked nucleosides, said first region encoding a polypeptide of interest, said polypeptide of interest is SEQ ID NO;
1089;(b) a first flanking region located at the 5′
terminus of said first region comprising at least one 5′
terminal cap;(c) a second flanking region located at the 3′
terminus of said first region comprising a 3′
tailing sequence of linked nucleosides; andwherein at least one of said linked nucleosides of (a) comprises at least one modification as compared to the chemical structure of an A, G, U or C ribonucleoside. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16)
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2. The isolated polynucleotide of claim 1, wherein the 3′
- tailing sequence of linked nucleosides is selected from the group consisting of a poly-A tail of approximately 160 nucleotides and a polyA-G quartet.
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3. The isolated polynucleotide of any one of claim 1 or 2 which is purified.
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4. The isolated polynucleotide of claim 1 or 2, wherein the at least one 5′
- terminal cap is selected from the group consisting of Cap0, Cap 1, ARCA, inosine, N1-methyl-guanosine, 2′
fluoro-guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine and 2-azido-guanosine.
- terminal cap is selected from the group consisting of Cap0, Cap 1, ARCA, inosine, N1-methyl-guanosine, 2′
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5. The isolated polynucleotide of claim 1, wherein the at least one modification does not form the nucleoside pseudouridine (ψ
- ) or 5-methyl-cytidine (m5C).
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6. The isolated polynucleotide of anyone of claim 1 or 2, further comprising a targeting moiety, wherein said targeting moiety is covalently bound to said isolated polynucleotide.
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7. The isolated polynucleotide of claim 6, wherein said targeting moiety is an antibody, thyrotropin, melanotropin, lectin, glycoprotein, surfactant protein A, Mucin carbohydrate, multivalent lactose, multivalent galactose, N-acetyl-galactosamine, N-acetyl-gulucosamine multivalent mannose, multivalent fucose, glycosylated polyaminoacids, multivalent galactose, transferrin, bisphosphonate, polyglutamate, polyaspartate, a lipid, cholesterol, a steroid, bile acid, folate, vitamin B12, biotin, an RGD peptide, an RGD peptide mimetic, or an aptamer.
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8. The isolated polynucleotide of claim 1, wherein the first region is codon optimized.
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9. The isolated polynucleotide of claim 1, wherein the first flanking region comprises a 5′
- untranslated region and the second flanking region comprises a 3′
untranslated region.
- untranslated region and the second flanking region comprises a 3′
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10. The isolated polynucleotide of claim 9, wherein at least one of the 5′
- untranslated region of the 3′
untranslated region is not derived from the native untranslated region of the polypeptide of interest.
- untranslated region of the 3′
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11. The isolated polynucleotide of claim 9, wherein the 5′
- untranslated region and the 3′
untranslated region are not derived from the same species.
- untranslated region and the 3′
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12. The isolated polynucleotide of claim 9, wherein at least one of the 5′
- untranslated region or the 3′
untranslated region is not derived from beta-globin.
- untranslated region or the 3′
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13. The isolated polynucleotide of claim 1, wherein the at least one modification forms the nucleoside N1-methylpseudouridine.
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14. The isolated polynucleotide of claim 13, wherein said isolated polynucleotide further comprises at least one modification to form the nucleoside 5-methyl-cytidine.
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15. The isolated polynucleotide of claim 1, wherein said isolated polynucleotide comprises two modifications and wherein the first modification forms the nucleoside 2-thiouridine and the second modification forms the nucleoside 5-methyl-cytosine.
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16. The isolated polynucleotide of claim 15, wherein 25% of the cytosine residues are 5-methyl-cytosine and 25% of the uridine residues are 2-thiouridine.
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Specification
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Current AssigneeModerna TX, Inc. (Moderna, Inc.)
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Original AssigneeModerna Therapeutics, Inc. (Moderna, Inc.)
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InventorsBancel, Stephane, Chakraborty, Tirtha, de Fougerolles, Antonin, Elbashir, Sayda M., John, Matthias, Roy, Atanu, Whoriskey, Susan, Wood, Kristy M., Hatala, Paul, Schrum, Jason P., Ejebe, Kenechi, Ellsworth, Jeff Lynn, Guild, Justin
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Primary Examiner(s)Ketter, Jim
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Assistant Examiner(s)Galisteo Gonzalez, Antonio
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Application NumberUS13/791,922Publication NumberTime in Patent Office759 DaysField of Search424/450, 435/69.1, 514/1.1, 514/44.R, 530/358, 536/23.5US Class Current424/450CPC Class CodesA61K 31/7115 Nucleic acids or oligonucle...A61K 38/00 Medicinal preparations cont...A61K 38/17 from animals; from humans e...A61K 38/177 Receptors; Cell surface ant...A61K 38/1816 Erythropoietin [EPO]A61K 38/1891 Angiogenesic factors; Angio...A61K 38/191 Tumor necrosis factors [TNF...A61K 38/193 Colony stimulating factors ...A61K 38/212 IFN-alphaA61K 38/45 Transferases (2)A61K 38/4846 Factor VII (3.4.21.21); Fac...A61K 47/543 Lipids, e.g. triglycerides;...A61K 48/0033 the non-active part being n...A61K 48/0041 the non-active part being p...A61K 48/005 characterised by an aspect ...A61K 48/0066 Manipulation of the nucleic...A61K 48/0075 characterised by an aspect ...A61K 9/0019 Injectable compositions; In...A61K 9/1271 Non-conventional liposomes,...A61K 9/145 with organic compoundsA61K 9/5123 : Organic compounds, e.g. fat...A61K 9/5146 : obtained otherwise than by ...A61K 9/5153 : Polyesters, e.g. poly(lacti...A61P 1/00 : Drugs for disorders of the ...A61P 1/04 : for ulcers, gastritis or re...A61P 11/00 : Drugs for disorders of the ...A61P 13/00 : Drugs for disorders of the ...A61P 13/12 : of the kidneysA61P 15/00 : Drugs for genital or sexual...A61P 17/00 : Drugs for dermatological di...A61P 17/02 : for treating wounds, ulcers...A61P 17/04 : AntipruriticsA61P 17/06 : AntipsoriaticsA61P 17/08 : AntiseborrheicsA61P 17/14 : for baldness or alopeciaA61P 19/00 : Drugs for skeletal disordersA61P 19/02 : for joint disorders, e.g. a...A61P 19/10 : for osteoporosisA61P 21/00 : Drugs for disorders of the ...A61P 21/04 : for myasthenia gravisA61P 25/00 : Drugs for disorders of the ...A61P 25/02 : for peripheral neuropathiesA61P 25/14 : for treating abnormal movem...A61P 25/18 : Antipsychotics, i.e. neurol...A61P 25/24 : AntidepressantsA61P 25/28 : for treating neurodegenerat...A61P 25/30 : for treating abuse or depen...A61P 27/02 : Ophthalmic agentsA61P 29/00 : Non-central analgesic, anti...A61P 3/00 : Drugs for disorders of the ...A61P 3/06 : AntihyperlipidemicsA61P 3/10 : for hyperglycaemia, e.g. an...A61P 31/00 : Antiinfectives, i.e. antibi...A61P 31/04 : Antibacterial agentsA61P 31/10 : AntimycoticsA61P 31/12 : AntiviralsA61P 31/14 : for RNA virusesA61P 31/18 : for HIVA61P 35/00 : Antineoplastic agentsA61P 35/02 : specific for leukemiaA61P 35/04 : specific for metastasisA61P 37/00 : Drugs for immunological or ...A61P 37/02 : ImmunomodulatorsA61P 37/06 : Immunosuppressants, e.g. dr...A61P 37/08 : Antiallergic agents antiast...A61P 43/00 : Drugs for specific purposes...A61P 5/00 : Drugs for disorders of the ...A61P 7/00 : Drugs for disorders of the ...A61P 7/02 : Antithrombotic agents; Anti...A61P 7/04 : Antihaemorrhagics; Procoagu...A61P 7/06 : AntianaemicsA61P 9/00 : Drugs for disorders of the ...A61P 9/10 : for treating ischaemic or a...C07H 21/02 : with ribosyl as saccharide ...C07K 14/005 : from virusesC07K 14/435 : from animals; from humansC07K 14/43595 : from coelenteratae, e.g. me...C07K 14/47 : from mammalsC07K 14/4705 : stimulating, promoting or a...C07K 14/4713 : Autoimmune diseases, e.g. I...C07K 14/4723 : Cationic antimicrobial pept...C07K 14/4746 : p53C07K 14/475 : Growth factors; Growth regu...C07K 14/485 : Epidermal growth factor [EG...C07K 14/495 : Transforming growth factor ...C07K 14/505 : Erythropoietin [EPO]C07K 14/515 : Angiogenesic factors; Angio...C07K 14/525 : Tumour necrosis factor [TNF]C07K 14/535 : Granulocyte CSF; Granulocyt...C07K 14/5418 : IL-7C07K 14/56 : IFN-alphaC07K 14/61 : Growth hormone [GH], i.e. s...C07K 14/62 : InsulinsC07K 14/705 : Receptors; Cell surface ant...C07K 14/745 : Blood coagulation or fibrin...C07K 16/00 : Immunoglobulins [IGs], e.g....C07K 16/2863 : against receptors for growt...C07K 16/2887 : against CD20C07K 16/40 : against enzymesC12N 15/11 : DNA or RNA fragments; Modif...C12N 15/52 : Genes encoding for enzymes ...C12N 15/85 : for animal cellsC12N 15/87 : Introduction of foreign gen...C12N 15/88 : using microencapsulation, e...C12N 9/0069 : acting on single donors wit...C12N 9/0091 : oxidizing metal ions (1.16)C12N 9/1051 : Hexosyltransferases (2.4.1)C12N 9/1241 : Nucleotidyltransferases (2....C12N 9/16 : acting on ester bonds (3.1)C12N 9/2402 : hydrolysing O- and S- glyco...C12N 9/2445 : Beta-glucosidase (3.2.1.21)C12N 9/6435 : Plasmin (3.4.21.7), i.e. fi...C12N 9/6437 : Coagulation factor VIIa (3....C12N 9/644 : Coagulation factor IXa (3.4...C12N 9/6443 : Coagulation factor XIa (3.4...C12N 9/6451 : Coagulation factor XIIa (3....C12N 9/88 : Lyases (4.)C12N 9/93 : Ligases (6)C12P 13/04 : Alpha- or beta- amino acids...C12P 21/00 : Preparation of peptides or ...C12P 21/005 : Glycopeptides, glycoproteinsC12Y 113/12007 : Photinus-luciferin 4-monoox...C12Y 116/03001 : Ferroxidase (1.16.3.1), i.e...C12Y 207/07012 : UDP-glucose--hexose-1-phosp...C12Y 304/21007 : Plasmin (3.4.21.7), i.e. fi...C12Y 304/21022 : Coagulation factor IXa (3.4...C12Y 304/21027 : Coagulation factor XIa (3.4...C12Y 403/02001 : Argininosuccinate lyase (4....C12Y 603/02019 : Ubiquitin-protein ligase (6...Y02A 50/30 : Against vector-borne diseas...