# US 2019/0315835 A1 · Factor viii compositions and methods of making and using same

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- Number: US 2019/0315835 A1
- Document ID: US20190315835A1
- Status: Published application
- Kind: A1
- Application number: 16/369,820
- Filed: 2019-03-29
- Published: 2019-10-17
- Earliest claimed: 2010-08-19
- Assignees: Bioverativ Therapeutics Inc.
- Applicants: Bioverativ Therapeutics Inc.
- Inventors: Volker SCHELLENBERGER; Pei-Yun CHANG; Fatbardha VARFAJ; John KULMAN; Tongyao LIU; Garabet G. TOBY; Haiyan JIANG; Robert PETERS; Deping WANG; Baisong MEI; Joshua SILVERMAN; Chia-Wei WANG; Benjamin SPINK; Nathan GEETHING
- Web page: https://patentgrep.com/patent/US20190315835A1

## CPC

- C07K 14/755: Factors VIII {, e.g. factor VIII C (AHF), factor VIII Ag (VWF)}
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- C07K 14/001: {by chemical synthesis}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07K 2319/00: Fusion polypeptide
- C07K 2319/21: containing a His-tag
- C07K 2319/31: fusions, other than Fc, for prolonged plasma life, e.g. albumin
- C07K 2319/41: containing a Myc-tag
- C07K 2319/50: containing protease site
- C07K 2319/95: containing a motif/fusion for degradation (ubiquitin fusions, PEST sequence)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The present invention relates to compositions comprising factor VIII coagulation factors linked to extended recombinant polypeptide (XTEN), isolated nucleic acids encoding the compositions and vectors and host cells containing the same, and methods of making and using such compositions in treatment of factor VIII-related diseases, disorders, and conditions.

## Claims

### Claim 1

A fusion protein comprising a factor VIII (FVIII) polypeptide fused to an extended recombinant polypeptide (XTEN), wherein the XTEN comprises one or more XTEN sequence motifs, and
wherein the XTEN is further characterized in that (a) the sum of glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) residues constitutes more than about 80% of the total amino acid residues of the XTEN and (b) the XTEN contains no three contiguous amino acids that are identical unless the amino acids are serine.

### Claim 2 (depends on 1)

The fusion protein of claim 1, wherein the one or more XTEN sequence motif is selected from the group consisting of SEQ ID NOs: 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and any combination thereof.

### Claim 3 (depends on 1)

The fusion protein of claim 1, wherein the XTEN comprises at least 36 amino acids.

### Claim 4 (depends on 1)

The fusion protein of claim 1, wherein the XTEN comprises an amino acid sequence at least 90% identical to SEQ ID NOs: 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 384, 386, 388, 404, 406, 408, 410, 412, 414, 416, 418, 420, 422, 424, 426, 428, 430, 432, 434, 436, 438, 440, 442, 444, 446, 448, 450, 452, 454, 456, 458, 460, 462, 464, 466, 468, 470, 472, 474, 476, 478, 480, 482, 484, 486, 488, 490, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564, 566, 568, 570, 572, 574, 576, 578, 580, 582, 584, 586, 588, 590, or 592.

### Claim 5 (depends on 4)

The fusion protein of claim 4, wherein the XTEN comprises an amino acid sequence at least 95% identical to SEQ ID NOs: 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 384, 386, 388, 404, 406, 408, 410, 412, 414, 416, 418, 420, 422, 424, 426, 428, 430, 432, 434, 436, 438, 440, 442, 444, 446, 448, 450, 452, 454, 456, 458, 460, 462, 464, 466, 468, 470, 472, 474, 476, 478, 480, 482, 484, 486, 488, 490, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564, 566, 568, 570, 572, 574, 576, 578, 580, 582, 584, 586, 588, 590, or 592.

### Claim 6 (depends on 4)

The fusion protein of claim 4, wherein the XTEN comprises an amino acid sequence identical to SEQ ID NOs: 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 384, 386, 388, 404, 406, 408, 410, 412, 414, 416, 418, 420, 422, 424, 426, 428, 430, 432, 434, 436, 438, 440, 442, 444, 446, 448, 450, 452, 454, 456, 458, 460, 462, 464, 466, 468, 470, 472, 474, 476, 478, 480, 482, 484, 486, 488, 490, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564, 566, 568, 570, 572, 574, 576, 578, 580, 582, 584, 586, 588, 590, or 592.

### Claim 7 (depends on 1)

The fusion protein of claim 1, wherein the XTEN comprises an amino acid sequence at least 90% identical to SEQ ID NO: 60, SEQ ID NO: 66, SEQ ID NO: 73, SEQ ID NO: 76, SEQ ID NO: 78, or SEQ ID NO: 82.

### Claim 8 (depends on 7)

The fusion protein of claim 7, wherein the XTEN comprises an amino acid sequence at least 95% identical to SEQ ID NO: 60, SEQ ID NO: 66, SEQ ID NO: 73, SEQ ID NO: 76, SEQ ID NO: 78, or SEQ ID NO: 82.

### Claim 9 (depends on 7)

The fusion protein of claim 7, wherein the XTEN comprises an amino acid sequence identical to SEQ ID NO: 60, SEQ ID NO: 66, SEQ ID NO: 73, SEQ ID NO: 76, SEQ ID NO: 78, or SEQ ID NO: 82.

### Claim 10 (depends on 1)

The fusion protein of claim 1, wherein the FVIII polypeptide comprises human FVIII.

### Claim 11 (depends on 1)

The fusion protein of claim 1, wherein the FVIII polypeptide comprises all or a portion of B domain.

### Claim 12 (depends on 1)

The fusion protein of claim 1, which exhibits a prolonged half-life compared to a FVIII polypeptide not linked to the XTEN.

### Claim 13 (depends on 1)

The fusion protein of claim 1, which further comprises a heterologous polypeptide.

### Claim 14 (depends on 1)

The fusion protein of claim 1, which further comprises a cleavage sequence between the FVIII polypeptide and the XTEN.

### Claim 15 (depends on 1)

The fusion protein of claim 1, wherein the cleavage sequence is cleavable by a mammalian protease selected from FXIa, FXIIa, kallikrein, FVIIa, FVIIIa, FXa, FIIa (thrombin), Elastase-2, granzyme B, MMP-12, MMP-13, MMP-17 and MMP-20.

### Claim 16 (depends on 1)

A pharmaceutical composition comprising the fusion protein of claim 1 and a pharmaceutically acceptable carrier.

### Claim 17

A method of treating coagulopathy in a subject, comprising administering to the subject a composition comprising a therapeutically effective amount of a fusion protein comprising a FVIII polypeptide fused to an XTEN.

### Claim 18

A method of controlling or ameliorating a bleeding episode in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a fusion protein comprising a FVIII polypeptide fused to an XTEN.

### Claim 19 (depends on 1)

A nucleic acid molecule encoding the fusion protein of claim 1.

### Claim 20 (depends on 19)

A method of making a fusion protein comprising culturing a host cell comprising the nucleic acid molecule of claim 19 under suitable conditions.