FACTOR VIII CHIMERIC PROTEINS AND USES THEREOF

1 - 149 . (canceled)

150 . A polynucleotide or a set of polynucleotides encoding a chimeric protein, the chimeric protein comprising (i) a first polypeptide which comprises a Factor VIII (“FVIII”) protein fused to a first immunoglobulin (“Ig”) constant region or a portion thereof and (ii) a second polypeptide which comprises a von Willebrand Factor (“VWF”) protein comprising a D′ domain and a D3 domain of VWF fused to a second Ig constant region or a portion thereof by an XTEN sequence in-between, wherein the XTEN sequence contains less than 288 amino acid residues and wherein the first polypeptide is linked to or associated with the second polypeptide.

151 . The polynucleotide or set of polynucleotides claim 150 , wherein the XTEN sequence in the second polypeptide consists of an amino acid sequence having a length of between 12 amino acids and 287 amino acids.

152 - 155 . (canceled)

156 . The polynucleotide or set of polynucleotides of claim 150 , wherein the XTEN sequence of the second polypeptide is selected from AE42, AE72, AE144, AG42, AG72, or AG144.

157 . The polynucleotide or set of polynucleotides of claim 156 , wherein the XTEN sequence of the second polypeptide is selected from SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 14; SEQ ID NO: 60; SEQ ID NO: 61; SEQ ID NO: 62; SEQ ID NO: 63.

158 - 159 . (canceled)

160 . The polynucleotide or set of polynucleotides of claim 150 , wherein the first polypeptide further comprises a second XTEN sequence which is inserted at one or more insertion sites within the FVIII protein.

161 - 164 . (canceled)

165 . The polynucleotide or set of polynucleotides of claim 150 , wherein the XTEN sequence in the second polypeptide is fused to the second Ig constant region or a portion thereof by a cleavable linker.

166 - 171 . (canceled)

172 . The polynucleotide or set of polynucleotides of claim 150 , wherein the first Ig constant region or a portion thereof comprises a first Fc region and/or the second Ig constant region or a portion thereof comprises a second Fc region.

173 - 175 . (canceled)

176 . The polynucleotide or set of polynucleotides of claim 150 , wherein the first Ig constant region or a portion thereof is associated with the second Ig constant region or a portion thereof.

177 . The polynucleotide or set of polynucleotides of claim 176 , wherein the first Ig constant region or a portion thereof is associated with the second Ig constant region or a portion thereof by a covalent bond.

178 - 219 . (canceled)

220 . The polynucleotide or set of polynucleotides of claim 160 , wherein the insertion sites in the FVIII protein are located immediately downstream of amino acid 745 corresponding to the mature FVIII protein (SEQ ID NO: 65).

221 - 227 . (canceled)

228 . The polynucleotide or set of polynucleotides of claim 150 , wherein the FVIII protein comprises a B domain or a portion thereof.

229 - 232 . (canceled)

233 . The polynucleotide or set of polynucleotides of claim 150 , wherein the D′ domain comprises an amino acid sequence at least 90%; identical to amino acids 764 to 866 of SEQ ID NO: 21.

234 . The polynucleotide or set of polynucleotides of claim 150 , wherein the D3 domain comprises an amino acid sequence at least 90% identical to amino acids 867 to 1240 of SEQ ID NO: 21.

235 - 238 . (canceled)

239 . The polynucleotide or set of polynucleotides of claim 150 , wherein the VWF protein contains at least one amino acid substitution at a residue corresponding to residue 1099, residue 1142, or both residues 1099 and 1142 of SEQ ID NO: 21.

240 . (canceled)

241 . The polynucleotide or set of polynucleotides of claim 150 , wherein the VWF protein further comprises the D1 domain, the D2 domain, or the D1 and D2 domains of VWF.

242 - 243 . (canceled)

244 . The polynucleotide or set of polynucleotides of claim 150 , wherein the VWF protein further comprises a signal peptide of VWF or FVIII which is operably linked to the VWF protein.

245 . (canceled)

246 . The polynucleotide or set of polynucleotides of claim 165 , wherein the cleavable linker has a length of about 1 to about 2000 amino acid residues.

247 - 255 . (canceled)

256 . A method of treating a bleeding disease or condition in a subject in need thereof comprising administering to the subject the polynucleotide or the set of polynucleotides of claim 150 .

257 . A method of treating a bleeding disease or condition in a subject in need thereof comprising administering to the subject a chimeric protein, the chimeric protein comprising (i) a first polypeptide which comprises a Factor VIII (“FVIII”) protein fused to a first immunoglobulin (“Ig”) constant region or a portion thereof and (ii) a second polypeptide which comprises a von Willebrand Factor (“VWF”) protein comprising a D′ domain and a D3 domain of VWF fused to a second Ig constant region or a portion thereof by an XTEN sequence in-between, wherein the XTEN sequence contains less than 288 amino acid residues and wherein the first polypeptide is linked to or associated with the second polypeptide.

258 . A chimeric protein comprising (i) a first polypeptide which comprises a Factor VIII (“FVIII”) protein fused to a first immunoglobulin (“Ig”) constant region or a portion thereof and (ii) a second polypeptide which comprises a von Willebrand Factor (“VWF”) protein comprising a D′ domain and a D3 domain of VWF fused to a second Ig constant region or a portion thereof by an XTEN sequence in-between, wherein the XTEN sequence contains less than 288 amino acid residues and wherein the first polypeptide is linked to or associated with the second polypeptide.