Abstract: Bispecific antigen binding molecules (e.g., antibodies) that bind blood clotting factors, factor IXa (FIXa) and factor X (FX), and enhance the FIXa-catalysed activation of FX to FXa. Use of the bispecific antigen binding molecules to control bleeding, by replacing natural cofactor FVIIIa which is deficient in patients with haemophilia A.

Abstract: Bispecific antigen binding molecules (e.g., antibodies) that bind blood clotting factors, factor IXa (FIXa) and factor X (FX), and enhance the FIXa-catalysed activation of FX to FXa. Use of the bispecific antigen binding molecules to control bleeding, by replacing natural cofactor FVIIIa which is deficient in patients with haemophilia A.

Abstract: Provided herein are adeno-associated virus (AAV) compositions that can restore F8 gene function in a cell without co-transducing or co-administering an exogenous nuclease or a nucleotide sequence that encodes an exogenous nuclease. Also provided are methods of using the AAV compositions to correct an F8 gene mutation and/or treat a disease or disorder associated with an F8 gene mutation. Packaging systems for making the adeno-associated virus compositions are also provided.

Abstract: The present invention relates to novel truncated fragments of von Willebrand factor (VWF) and the use of such fragments and nucleic acids encoding such fragments in the treatment of von Willebrand disease (VWD) and haemophilia.

Abstract: The invention relates to a bispecific antibody comprising a first antigen-binding site capable of binding Factor VII(a) and a second antigen-binding site capable of binding TLT-1, pharmaceutical formulations comprising such bispecific antibodies and uses thereof.

Abstract: The present invention provides a chimeric protein comprising a first polypeptide which comprises a FVIII protein and a first Ig constant region or a portion thereof and a second polypeptide which comprises a VWF protein comprising the D? domain and D3 domain of VWF, a XTEN sequence having less than 288 amino acids in length, and a second Ig constant region or a portion thereof, wherein the first polypeptide and the second polypeptide are associated with each other. The invention also includes nucleotides, vectors, host cells, methods of using the chimeric proteins.

Abstract: The present invention relates to a recombinant polypeptide comprising a truncated von Willebrand Factor (VWF) capable of binding to blood coagulation Factor VIII (FVIII) for use in reducing the immunogenicity of Factor VIII (FVIII) wherein said recombinant polypeptide and a blood coagulation Factor VIII (FVIII) protein are co-administered to a subject suffering from a 10 blood coagulation disorder. The invention further relates to pharmaceutical compositions and kits for said use.

Abstract: The present invention relates to a method for treating gastrointestinal bleeding in a subject with severe von Willebrand Disease comprising administering to the subject at least one dose of recombinant von Willebrand Factor (rVWF) ranging from about 40 IU/kg to about 100 IU/kg, wherein the first dose further comprises recombinant Factor VIII (rFVIII).

Abstract: The present invention encompasses engineered meganucleases which recognize and cleave a recognition sequence within an open reading frame (ORF) of the genome of at least two genotypes of the Hepatitis B virus (HBV). The present invention also encompasses methods of using such engineered meganucleases in a pharmaceutical composition and in methods for treating or reducing the symptoms of a HBV infection, or treating hepatocellular carcinoma (HCC). Further, the invention encompasses pharmaceutical compositions comprising engineered meganuclease proteins, nucleic acids encoding engineered meganucleases, and the use of such compositions for treating HBV infections or HCC.

Abstract: The present invention relates to cell lines that are genetically modified to overexpress a ?-galactoside ?-2,3-sialyltransferase 1 (ST3Gal1), preferably human ST3Gal1, which can be used for the production of recombinant glycoproteins having highly or fully sialylated O-linked GalNAc glycans (GalNAc O-glycans), preferably core 1 GalNAc O-glycans, as well as to respective recombinant glycoproteins. Further, the present invention relates to respective methods of expressing recombinant glycoproteins, methods of increasing the degree of sialylation of recombinant glycoproteins, and methods of decreasing the micro-heterogeneity of GalNAc O-glycans. Finally, the present invention relates to respective uses of the above cell lines for the production of recombinant glycoproteins, for increasing the degree of sialylation of recombinant glycoproteins, and for decreasing the micro-heterogeneity of O-linked GalNAc glycans of recombinant glycoproteins.

Abstract: The present invention relates to a method for treating gastrointestinal bleeding in a subject with severe von Willebrand Disease comprising administering to the subject at least one dose of recombinant von Willebrand Factor (rVWF) ranging from about 40 IU/kg to about 100 IU/kg, wherein the first dose further comprises recombinant Factor VIII (rFVIII).

Abstract: The present invention provides chimeric proteins comprising a Factor VIII (FVIII) polypeptide and XTEN polypeptides. The FVIII polypeptide can have a reduced affinity for von Willebrand Factor (VWF). XTEN polypeptides of appropriate sizes are inserted into the FVIII polypeptide at particular locations in order to extend the half-life of the FVIII polypeptide. The invention also includes nucleotides, vectors, host cells, and methods of using the chimeric proteins, e.g., to treat bleeding diseases and disorders.

Abstract: The invention provides stable, aqueous capsaicin injectable formulations, a unit dose containing such injectable formulations, medical kits, and methods for using such injectable formulations and unit doses to treat patients suffering from pain, such as osteoarthritic knee pain. The stable, aqueous capsaicin injectable formulations may contain, for example, capsaicin, a solubilizing agent (e.g., a polyethylene glycol ester of a (C15-C25) hydroxyalkanoic acid), an antioxidant, and water.

Abstract: The invention relates to factor VIII compositions and their use.

Abstract: The present invention relates to cell lines that are genetically modified to overexpress a ?-galactoside ?-2,3-sialyltransferase 1 (ST3Gal1), preferably human ST3Gal1, which can be used for the production of recombinant glycoproteins having highly or fully sialylated O-linked GalNAc glycans (GalNAc O-glycans), preferably core 1 GalNAc O-glycans, as well as to respective recombinant glycoproteins. Further, the present invention relates to respective methods of expressing recombinant glycoproteins, methods of increasing the degree of sialylation of recombinant glycoproteins, and methods of decreasing the micro-heterogeneity of GalNAc O-glycans. Finally, the present invention relates to respective uses of the above cell lines for the production of recombinant glycoproteins, for increasing the degree of sialylation of recombinant glycoproteins, and for decreasing the micro-heterogeneity of O-linked GalNAc glycans of recombinant glycoproteins.

Abstract: Conjugates of a Factor VIII moiety and one or more water-soluble polymers are provided. Typically, the water-soluble polymer is poly(ethylene glycol) or a derivative thereof. Also provided are compositions comprising the conjugates, methods of making the conjugates, and methods of administering compositions comprising the conjugates to a patient.

Abstract: Provided are methods of treating a mammal undergoing sepsis or at risk for sepsis. Also provided are methods of preventing or treating a physiologic effect of sepsis in a mammal. Additionally provided is the use of milk fat globule epidermal growth factor-factor VIII (MFG-E8) for the manufacture of a medicament for preventing or treating a physiologic effect of sepsis in a mammal, and the use of milk fat globule epidermal growth factor-factor VIII (MFG-E8) for the treatment of a mammal having sepsis or at risk for sepsis.

Abstract: The present invention relates to a von Willebrand Factor for use in the treatment and/or prevention of a bleeding event associated with a thrombopathy induced by substances inhibiting thrombocytes. Furthermore, the present invention relates to a method of treating and/or preventing a disorder related to a bleeding event associated with a thrombopathy induced by substances inhibiting thrombocytes comprising administering a pharmaceutically effective amount of a von-Willebrand-Factor (vWF) to a patient in need thereof. The present invention also relates to a composition comprising vWF and a composition comprising FVIII for simultaneous, separate or sequential use for use in the treatment and/or prevention of a bleeding event associated with a thrombopathy induced by substances inhibiting thrombocytes.

Abstract: This document relates to conjugates of a biologically active molecule or a derivative thereof and functionalized (e.g., mono- or bi-functional) polymers (e.g., polyethylene glycol and related polymers) as well as methods and materials for making and using such conjugates.

Abstract: The present invention relates to antibody molecules against anticoagulants, in particular dabigatran, and their use as antidotes of such anticoagulants.

Abstract: The present application relates to novel substituted (aza)pyridopyrazolopyrimidinones and indazolopyrimidinones, to processes for their preparation, the compounds for use alone or in combinations in a method for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of acute and recurrent bleeding in patients with or without underlying hereditary or acquired bleeding disorders, wherein the bleeding is associated with a disease or medical intervention selected from the group consisting of menorrhagia, postpartum hemorrhage, hemorrhagic shock, trauma, surgery, transplantation, stroke, liver diseases, hereditary angioedema, nosebleed, and synovitis and cartilage damage following hemarthrosis.

Abstract: The present invention relates to conjugated Factor VIII variants. The present invention in particular relates to conjugated FVIII variants comprising different polymeric groups as well as use thereof.

Abstract: The present invention provides albumin-binding probes capable of reversibly linking to short-lived amino-containing drugs and non-covalently associating with albumin in-vivo, thereby converting said drugs into inactive reactivable prodrugs having prolonged lifetime in-vivo. The invention further provides conjugates of said probes with amino-containing drugs, as well as pharmaceutical compositions and uses thereof.

Abstract: Methods and dosage formulations are provided for subcutaneous administration in which therapeutic agents are modified to increase the hydrophilicity and molecular dimensions in relation to the native state of the therapeutic agent, in which the Cmax:Caverage ratio is lower than the Cmax:Caverage ratio of the agent when delivered intravenously.

Abstract: The invention describes factor VIII molecules with reduced capacity to elicit activation of NKT cells for use in the treatment of congenital and/or acquired haemophilia A and in bleeding disorders. Said factor VIII molecule is obtainable by: a. identification of at least one NKT cell epitope wherein said epitope comprises hydrophobic aminoacid residues in position P1 and/or P7 b. modification of said epitope(s) by eliminating at least one hydrophobic aminoacid residues in position P1 and/or P7, substituting at least one hydrophobic aminoacid residue in position P1 and/or P7 with a non-hydrophobic residue, or adding a non-hydrophobic residue in position P1 and/or P7.

Abstract: The present invention provides methods of dosing Factor VIII or Factor IX chimeric and hybrid polypeptides.

Abstract: The present invention relates to VWF compounds as well as compositions suitable for treatment of blood clotting diseases.

Abstract: An aqueous composition having increased protein stability is obtained by: a. determining a pH at which the protein has stability at the desired temperature; b. adding to the composition at least one displacement buffer wherein the displacement buffer has a pKa that is at least 1 unit greater or less than the pH of step (a); and c. adjusting the pH of the composition to the pH of step (a); wherein the aqueous composition does not comprise a conventional buffer at a concentration greater than about 2 mM and wherein the conventional buffer has a pKa that is within 1 unit of the pH of step (a).

Abstract: The present invention relates to pharmaceutical compositions suitable for treatment of haemophilia.

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.

Abstract: Conjugates of a Factor VIII moiety and one or more water-soluble polymers are provided. Typically, the water-soluble polymer is poly(ethylene glycol) or a derivative thereof. Also provided are compositions comprising the conjugates, methods of making the conjugates, and methods of administering compositions comprising the conjugates to a patient.

Abstract: The invention relates to a recombinant factor VIII that includes one or more mutations at an interface of A1 and C2 domains of recombinant factor VIII. The one or more mutations include substitution of one or more amino acid residues with either a cysteine or an amino acid residue having a higher hydrophobicity. This results in enhanced stability of factor VIII. Methods for making the recombinant factor VIII, pharmaceutical compositions containing the recombinant factor VIII, and use of the recombinant factor VIII for treating hemophilia A are also disclosed.

Abstract: The present invention provides a VWF fragment comprising the D? domain and D3 domain of VWF, a chimeric protein comprising the VWF fragment and a heterologous moiety, or a chimeric protein comprising the VWF fragment and a FVIII protein and methods of using the same. A polypeptide chain comprising a VWF fragment of the invention binds to or is associated with a polypeptide chain comprising a FVIII protein and the polypeptide chain comprising the VWF fragment can prevent or inhibit binding of endogenous VWF to the FVIII protein. By preventing or inhibiting binding of endogenous VWF to the FVIII, which is a half-life limiting factor for FVIII, the VWF fragment can induce extension of half-life of the FVIII protein. The invention also includes nucleotides, vectors, host cells, methods of using the VWF fragment, or the chimeric proteins.

Abstract: A Factor VIII composition formulated without albumin, comprising the following formulation excipients in addition to Factor VIII: 4% to 10% of a bulking agent selected from the group consisting of mannitol, glycine and alanine; 1% to 4% of a stabilizing agent selected from the group consisting of sucrose, trehalose, raffinose, and arginine; 1 mM to 5 mM calcium salt; 100 mM to 300 mM NaCl; and a buffering agent for maintaining a pH of approximately between 6 and 8. Alternatively, the formulation can comprise 2% to 6% hydroxyethyl starch; 1% to 4% of a stabilizing agent selected from the group consisting of sucrose, trehalose, raffinose, and arginine; 1 mM to 5 mM calcium salt; 100 mM to 300 mM NaCl; and a buffering agent for maintaining a pH of approximately between 6 and 8.

Abstract: A method of preparing an oxidised polysaccharide-protein conjugate by oxidising a polysaccharide with an oxidising agent to form an oxidised polysaccharide and combining such oxidised polysaccharide with a protein. The oxidised polysaccharide is reacted with a protein to form a composition comprising a conjugate wherein the oxidised polysaccharide and the protein are conjugated via one or more imine bonds and wherein the oxidised polysaccharide comprises essentially no alpha-hydroxy aldehyde units. The conjugate may be used to provide sustained or latent activity of the protein.

Abstract: The present invention relates to the use of thrombomodulin analogues for the manufacture of a medicament for the treatment of coagulopathy with hyperfibrinolysis, such as haemophilia disorders. These thrombomodulin analogues exhibit at therapeutically effective dosages an antifibrinolytic effect. Novel protein modifications together with methods for their identification are disclosed.

Abstract: Provided herein are methods and compositions for producing Factor VIII proteins. Such methods include introducing into a cell a nucleic acid molecule encoding a Factor VIII protein operably linked to a promoter, wherein the promoter is characterized by the ability to produce commercially viable Factor VIII protein; and incubating the cell under conditions for producing commercially viable Factor VIII protein. Also provided are nucleic acid molecules which encode a Factor VIII protein operably linked to a Chinese hamster elongation factor 1-a (CHEF1) promoter, which may be used in the methods provided herein.

Abstract: The present invention relates to a polypeptide comprising a modified von Willebrand Factor (VWF) having a higher Factor VIII binding affinity than non-modified VWF, its pharmaceutical use and method of its preparation.

Abstract: Methods for purifying fucoidan in extracts from brown seaweed are disclosed. In particular, methods of purifying fucoidan in the extract to remove heavy metal ions, bacterial and endotoxin contaminants, and other impurities are disclosed. The methods include the use of a chelating agent, selective precipitation, and filtration.

Abstract: The present invention relates to pharmaceutical preparations comprising one or more Factor VIII and a sulfated glycosaminoglycan for increasing the bioavailability of Factor VIII upon non-intravenous administration. The invention further relates to the combined use of Factor VIII and a sulfated glycosaminoglycan for the treatment and prevention of bleeding disorders, whereby the bioavailability of Factor VIII is increased, and to a method for increasing the bioavailability after non-intravenous administration of Factor VIII by coadminstration of a sulfated glycosaminoglycan.

Abstract: The invention relates to a recombinant factor VIII that includes one or more mutations at an interface of A1 and C2 domains of recombinant factor VIII. The one or more mutations include substitution of one or more amino acid residues with either a cysteine or an amino acid residue having a higher hydrophobicity. This results in enhanced stability of factor VIII. Methods for making the recombinant factor VIII, pharmaceutical compositions containing the recombinant factor VIII, and use of the recombinant factor VIII for treating hemophilia A are also disclosed.

Abstract: The present invention provides a formulation of a Factor VIII polypeptide, e.g., FVIII-Fc, and methods of using the same. The FVIII polypeptide can be a recombinant FVIII protein, a short-acting FVIII protein, or a long-acting FVIII protein. The pharmaceutical formulation comprising a FVIII polypeptide can be used for individual prophylaxis, weekly prophylaxis, episodic (on-demand) treatment, or perioperative management of hemophilia.

Abstract: A method of selectively introducing a substituent into a protein proximal to a binding site on the protein for a homing peptide, comprising: (a) contacting the protein with a compound comprising a homing peptide having the ability to bind to the binding site of the protein; and (b) allowing a moiety on the protein proximal to the binding site to react with the compound comprising the homing peptide, thereby to transfer the substituent G onto the protein.

Abstract: Methods for treating bleeding disorders using non-anticoagulant sulfated polysaccharides (NASPs) as procoagulants are disclosed. NASPs can be administered as single agents, or in combination with one another, or with other medications (such as factors VII, VIII and IX) to promote hemostasis. In particular, the use of NASPs in treatment of bleeding disorders, including congenital coagulation disorders, acquired coagulation disorders, and trauma induced hemorrhagic conditions is described.

Abstract: The invention includes methods and compositions for remodeling a peptide molecule, including the addition or deletion of one or more glycosyl groups to a peptide, and/or the addition of a modifying group to a peptide.

Abstract: The present invention provides methods of administering Factor VIII (processed FVIII, single chain FVIII, or a combination thereof); methods of administering chimeric and hybrid polypeptides comprising Factor VIII; chimeric and hybrid polypeptides comprising Factor VIII; polynucleotides encoding such chimeric and hybrid polypeptides; cells comprising such polynucleotides; and methods of producing such chimeric and hybrid polypeptides using such cells

Abstract: Aspects of the invention include methods for enhancing blood coagulation in a subject. In practicing methods according to certain embodiments, an amount of a non-anticoagulant sulfated polysaccharide (NASP) in combination with a gastrointestinal epithelial barrier permeation enhancer is orally administered to a subject in a manner sufficient to enhance blood coagulation in the subject. Compositions and kits for practicing methods of the invention are also described.

Abstract: Method for preparing an oxidized polysaccharide-protein composition, by (a) oxidizing a polysaccharide with an oxidizing agent to form an oxidized polysaccharide where less than 20% of the oxidized units are comprised of alpha-hydroxy aldehyde units, (b) reacting the oxidized polysaccharide with a protein to form a composition comprising an oxidized polysaccharide-protein conjugate, and (c) maintaining the oxidized polysaccharide-protein conjugate composition by placing it in an environment where the temperature is less than 8° C. The oxidized polysaccharide and the protein are conjugated via one or more imine bonds, the oxidized polysaccharide-protein composition is soluble in aqueous solvent, and the composition is capable of releasing the protein.

Abstract: Conjugates of hydroxyalkyl starch and a protein are provided herein. The conjugates are formed by a covalent linkage between the hydroxyalkyl starch or a derivative of the hydroxyalkyl starch and the protein. Methods of producing the conjugates and the use of the conjugates also are provided herein.

Abstract: Methods of treating bleeding disorders, such as bleeding diseases such as hemophilia, by administering adenosine 2a receptor and/or adenosine 2b receptor antagonists to subjects in need thereof are disclosed. In some embodiments, the methods further include administration of the antagonist with one or more of Factor VIII, Factor IX and Factor XI to treat the bleeding disorder.