Granted Patent
B2
US 12,630,613 · App. 17/589,519 · Granted May 19, 2026
Method to produce a highly concentrated immunoglobulin preparation for subcutaneous use
Inventors:
Wolfgang Teschner (Vienna, AT); Harald Arno Butterweck (Vienna, AT); Azra Pljevljakovic (Vienna, AT); Theresa Friederike Bauer (Vienna, AT); Bernhard Koelbl (Achau, AT); Hans-Peter Schwarz (Vienna, AT); Nebojsa Nikolic (Vienna, AT); Gerhard Poelsler (Vienna, AT); Johanna Kindermann (Maria Enzersdorf, AT)
Assignee:
Takeda Pharmaceutical Company LImited
C07K16/18A61K39/39591B01D61/145B01D61/146C07K16/00C07K16/065A61K2039/505A61K2039/54B01D2315/16C07K2317/10C07K2317/21
View Patent ↗
Loading inventors, assignments & file history…
Abstract
The present invention relates to a new and improved method for preparing a highly concentrated immunoglobulin composition from pooled plasma for subcutaneous injection. A composition comprising 20% or more immunoglobulin suitable for subcutaneous use is also described.
Claims (32)
1 . A method for preparing a composition of concentrated IgG from plasma, comprising:
a) precipitating a cryo-poor plasma fraction, in a first precipitation step, with about 8% alcohol (v/v) at a pH of from 7.0 to 7.5 to obtain a first precipitate and a first supernatant;
b) precipitating IgG from the first supernatant, in a second precipitation step, with from 20% to 25% alcohol (v/v) at a pH of from 6.8 to 7.2 to form a second precipitate and a second supernatant;
c) suspending the second precipitate to form a suspension;
d) adding fumed silica to the suspension and mixing the fumed silica with the suspension;
e) filtering the suspension after the mixing in step d) to form a third supernatant containing IgG;
f) further purifying IgG from the third supernatant to form an enriched IgG composition, wherein the further purifying comprises ion exchange chromatography;
g) concentrating the enriched IgG composition to a protein concentration of from 2% to 10% (w/v) to form a first ultrafiltrate;
h) diafiltering the first ultrafiltrate against a formulation buffer to form a diafiltrate; and
i) concentrating the diafiltrate to a protein concentration of at least 20%, thereby preparing a composition of concentrated IgG from plasma.
2 . The method of claim 1 , wherein the first precipitation step is performed at a pH of from 7.1 to 7.3.
3 . The method of claim 1 , wherein the second precipitation step is performed with about 20% alcohol (v/v).
4 . The method of claim 1 , wherein the second precipitate is suspended with a buffer having a conductivity of no more than 2.0 mS/cm.
5 . The method of claim 1 , wherein the mixing in step d) is performed for at least 50 minutes.
6 . The method of claim 1 , wherein the mixing in step d) is performed at a pH of from 4 to 5.5 and a conductivity of from 0.5 to 2.0 mS/cm.
7 . The method of claim 1 , wherein the further purifying in step f) comprises contacting a solution comprising IgG from the third supernatant with cation exchange chromatography material to bind IgG from the third supernatant and eluting the bound IgG from the cation exchange chromatography material.
8 . The method of claim 1 , wherein the further purifying in step f) comprises contacting a solution comprising IgG from the third supernatant with an anion exchange chromatography material and collecting IgG from the third supernatant that does not bind to the anion exchange chromatography material.
9 . The method of claim 1 , wherein the further purifying in step f) comprises:
contacting a solution comprising IgG from the third supernatant with a cation exchange chromatography material to bind IgG from the third supernatant and eluting the bound IgG from the cation exchange material to form a first eluate; and
contacting a solution comprising IgG from the first eluate with an anion exchange chromatography material and collecting IgG from the third supernatant that does not bind to the anion exchange chromatography material.
10 . The method of claim 9 , further comprising nanofiltering a solution comprising collected IgG that did not bind to the anion exchange chromatography material.
11 . The method of claim 1 , wherein the first ultrafiltrate has a protein concentration of 5±1% (w/v).
12 . The method of claim 1 , wherein the diafiltrate comprises from 0.2 M to 0.3 M glycine and a pH of from 4.4 to 4.9.
13 . The method of claim 1 , wherein:
a first ultrafiltration system having a first filtration membrane and a second ultrafiltration system having a second filtration membrane are used for the concentrating in step g), diafiltering in step h), and concentrating in step i), and
the second filtration membrane has a smaller surface area than the surface area of the first filtration membrane.
14 . The method of claim 13 , wherein the first filtration membrane and the second filtration membrane each have a nominal molecular weight cut off (NMWCO) of less than 100 kDa.
15 . The method of claim 14 , wherein the first filtration membrane and the second filtration membrane are the same type of filtration membrane.
16 . The method of claim 13 , wherein the first filtration membrane and the second filtration membrane each have a NMWCO of no more than 50 kDa.
17 . The method of claim 13 , wherein the surface area of the second filtration membrane is no more than a tenth of the surface area of the first filtration membrane.
18 . The method of claim 1 , further comprising formulating the composition of concentrated IgG from plasma at a protein concentration of about 20% (w/v).
19 . The method of claim 18 , wherein the composition of concentrated IgG from plasma is formulated at a protein concentration of 20.4%±0.4 (w/v).
Assignments (4)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded May 3, 2022
From: BAXALTA INCORPORATED; BAXALTA GMBH
To: TAKEDA PHARMACEUTICAL COMPANY LIMITED
Reel/Frame 059802/0127 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded May 3, 2022
From: TESCHNER, WOLFGANG; BUTTERWECK, HARALD ARNO; PLJEVLJAKOVIC, AZRA; BAUER, THERESA FRIEDERIKE; KOELBL, BERNHARD; SCHWARZ, HANS-PETER; NIKOLIC, NEBOJSA; POELSLER, GERHARD; KINDERMANN, JOHANNA
To: BAXTER INTERNATIONAL INC.; BAXTER HEALTHCARE SA
Reel/Frame 059849/0754 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded May 3, 2022
From: BAXTER INTERNATIONAL INC.
To: BAXALTA INCORPORATED; BAXALTA GMBH
Reel/Frame 059850/0001 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded May 3, 2022
From: BAXTER HEALTHCARE SA
To: BAXALTA INCORPORATED; BAXALTA GMBH
Reel/Frame 059850/0367 →
Continuity (6)
Provisional Application
61181606
· May 27, 2009
References Cited (184)
US 3998946A
· Condie et al.
· 1976
[cited by applicant]
US 4056614A
· Bonneau et al.
· 1977
[cited by applicant]
US 4136094A
· Condie
· 1979
[cited by applicant]
US 4216205A
· Radowitz
· 1980
[cited by applicant]
US 4228154A
· Fisher et al.
· 1980
[cited by applicant]
US 4272523A
· Kotitschke et al.
· 1981
[cited by applicant]
US 4296027A
· Condie
· 1981
[cited by applicant]
US 4318902A
· Stephan
· 1982
[cited by applicant]
US 4378346A
· Tankersley
· 1983
[cited by applicant]
US 4439358A
· Coan et al.
· 1984
[cited by applicant]
US 4476109A
· Kimura et al.
· 1984
[cited by applicant]
US 4499073A
· Tenold
· 1985
[cited by applicant]
US 4503039A
· Kotitschke et al.
· 1985
[cited by applicant]
US 4550019A
· Polson
· 1985
[cited by applicant]
US 4624780A
· Chang
· 1986
[cited by applicant]
US 5055447A
· Palladino et al.
· 1991
[cited by applicant]
US 5061237A
· Gessler et al.
· 1991
[cited by applicant]
US 5122373A
· Eibl et al.
· 1992
[cited by applicant]
US 5130451A
· Pourreau et al.
· 1992
[cited by applicant]
US 5136094A
· Listemann et al.
· 1992
[cited by applicant]
US 5164487A
· Kothe et al.
· 1992
[cited by applicant]
US 5177194A
· Sarno et al.
· 1993
[cited by applicant]
US 5324425A
· Ellison
· 1994
[cited by applicant]
US 5854403A
· Fischer et al.
· 1998
[cited by applicant]
US 5886154A
· Lebing et al.
· 1999
[cited by applicant]
US 6069236A
· Burnouf-Radosevich et al.
· 2000
[cited by applicant]
US 6093324A
· Bertolini et al.
· 2000
[cited by applicant]
US 6124437A
· Hirao et al.
· 2000
[cited by applicant]
US 6159471A
· Hirao et al.
· 2000
[cited by applicant]
US 6485932B1
· McIntosh et al.
· 2002
[cited by applicant]
US 6835379B2
· Andersson et al.
· 2004
[cited by applicant]
US 7041798B1
· Kothe et al.
· 2006
[cited by applicant]
US 7138120B2
· Laursen et al.
· 2006
[cited by applicant]
US 7186410B2
· Chtourou et al.
· 2007
[cited by applicant]
US 7553938B2
· Buchacher et al.
· 2009
[cited by applicant]
US 7932365B2
· Lim et al.
· 2011
[cited by applicant]
US 8304524B2
· Bairstow et al.
· 2012
[cited by applicant]
US 8546548B2
· Teschner
· 2013
[cited by examiner]
US 8772461B2
· Gonzalez et al.
· 2014
[cited by applicant]
US 8993734B2
· Bruckschwaiger et al.
· 2015
[cited by applicant]
US 9175068B2
· Teschner
· 2015
[cited by examiner]
US 20030190732A1
· Josic
· 2003
[cited by applicant]
US 20080318841A1
· Chtourou et al.
· 2008
[cited by applicant]
US 20090118163A1
· Gronski et al.
· 2009
[cited by applicant]
US 20100099603A1
· Schnecker et al.
· 2010
[cited by applicant]
AU 2010202125B1
· 2010
[cited by applicant]
AU 2010224461A1
· 2010
[cited by applicant]
CN 1157572A
· 1997
[cited by applicant]
CN 1311797A
· 2001
[cited by applicant]
CN 101249265A
· 2008
[cited by applicant]
CN 101279246A
· 2008
[cited by applicant]
CN 201169579Y
· 2008
[cited by applicant]
DE 3523615A1
· 1987
[cited by applicant]
DE 10008619A1
· 2011
[cited by applicant]
EP 0222611A2
· 1987
[cited by applicant]
EP 0363896A2
· 1990
[cited by applicant]
EP 0440509A2
· 1991
[cited by applicant]
EP 0893450A1
· 1999
[cited by applicant]
GB 1344340
· 1972
[cited by applicant]
SE 348942
· 1972
[cited by applicant]
WO WO199511260A1
· 1995
[cited by applicant]
WO WO199732654A1
· 1997
[cited by applicant]
WO WO199805686A1
· 1998
[cited by applicant]
WO WO199943362A1
· 1999
[cited by applicant]
WO WO0067789A1
· 2000
[cited by applicant]
WO WO2003034982A2
· 2003
[cited by applicant]
WO WO2004060528A1
· 2004
[cited by applicant]
WO WO2005012354A1
· 2005
[cited by applicant]
WO WO2005023867A1
· 2005
[cited by applicant]
WO WO2005026197A1
· 2005
[cited by applicant]
WO WO2005046587A2
· 2005
[cited by applicant]
WO WO2005073252A1
· 2005
[cited by applicant]
WO WO2006031560A2
· 2006
[cited by applicant]
WO WO2007038995A1
· 2007
[cited by applicant]
WO WO2007066017A2
· 2007
[cited by applicant]
WO WO2007085626A1
· 2007
[cited by applicant]
WO WO2008113589A1
· 2008
[cited by applicant]
WO WO2009043103A1
· 2009
[cited by applicant]
WO WO2009086400A2
· 2009
[cited by applicant]
WO WO2009005877A2
· 2009
[cited by applicant]
WO WO2009129226A1
· 2009
[cited by applicant]
WO WO2009154695A1
· 2009
[cited by applicant]
WO WO2009156137A1
· 2009
[cited by applicant]
WO WO2010056909A1
· 2010
[cited by applicant]
WO WO2010138736A2
· 2010
[cited by applicant]
WO WO2011011753A1
· 2011
[cited by applicant]
WO WO2011149472A1
· 2011
[cited by applicant]
WO WO2011150284A2
· 2011
[cited by applicant]
WO WO2012006591A1
· 2012
[cited by applicant]
WO WO2012012773A1
· 2012
[cited by applicant]
Barandun, S. et al., “Intravenous Administration of Human γ-Globulin,”
[cited by applicant]
Bee, W.H. et al., “Effects of Recombinant Human Hyaluronidase (rHuPH20) on Subcutaneous Administration of 10% and 20% IgC in Yucatan Mini Pigs,”
[cited by applicant]
Cohn, E.J. et al., “Preparation and Properties of Serum and Plasma Proteins. IV. A System for the Separation into Fractions of the Protein and Lipoprotein Components of Biological Tissues and Fluids,”
[cited by applicant]
Cummins, L.M. et al., “Preparation and Characterization of an Intravenous Solution of IgG From Human Immunodeficiency Virus-Seropostive Donors,”
[cited by applicant]
Deville-Bonne, D. et al., “Ordered Disruption of Subunit Interfaces during the Stepwise Reversible Dissociation of
[cited by applicant]
Falksveden, L.-G. et al., “Ion Exchange and Polyethylene Glycol Precipitation of Immunoglobulin G,” in
[cited by applicant]
Hemming, V.G., “Use of Intravenous Immunoglobulins for Prophylaxis or Treatment of Infectious Diseases,”
[cited by applicant]
Hermann, C. et al., “Analysis of Fc-Receptor-Mediated Activities of New IgG Products Using a Novel THP-1 Cell-based Assay,”
[cited by applicant]
Hofmeister, Y. et al., “Human IgG Subclasses: In Vitro Neutralization of and In Vivo Protection against West Nile Virus,”
[cited by applicant]
Knezevic-Maramica, I. et al., “Intravenous immune globulins: an update for clinicians,”
[cited by applicant]
Koblet, H. et al., “Turnover of Standard-Gammaglobulin, pH-4-Gammaglobulin and Pepsin Desaggregated Gammaglobulin and Clinical Implications,”
[cited by applicant]
International Search Report mailed on Jan. 26, 2011, for International Application No. PCT/US2010/036430 filed on May 27, 2010, 1 page.
[cited by applicant]
Kolarich, D. et al., “Glycoproteomic characterization of butyrylcholinesterase from human plasma,”
[cited by applicant]
Kreil, T.R. et al., “Development of a New 10% Liquid, Triple Virus Reduced Intra-venous Immune-Globulin Product, New Generation IGIV,”
[cited by applicant]
Kreil, T.R. et al., “Pathogen Safety Profile of a New 10% Liquid, Triple Virus Reduced Intravenous Immune Globulin Product, New Generation IGIV (NG IGIV)—Further Studies,”
[cited by applicant]
Kreil, T.R. et al., “Removal of small nonenveloped viruses by antibody-enhanced nanofiltration during the manufacture of plasma derivatives,”
[cited by applicant]
Le Bras, G. et al., “Urea-Induced Inactivation, Dissociation, and Unfolding of the Allosteric Phosphofructokinase from
[cited by applicant]
Lebing, W. et al., “Properties of a new intravenous immunoglobulin (IGIV-C, 10%) produced by virus inactivation with caprylate and column chromatography,”
[cited by applicant]
Leesch, V.W. et al., “30-Day Pharmacokinetic Evaluation of IV versus Subcutaneous Administration of Immunoglobulin with and without Recombinant Human Hyaluronidase in Dogs,”
[cited by applicant]
Muchitsch, E.-M. et al., “In vivo Effect of α
[cited by applicant]
Mumford, H. et al., “Efficacy and physiological effects of human butyrylcholinesterase as a post-exposure therapy against percutaneous poisoning by VX in the guinea-pig,”
[cited by applicant]
Olas, K. et al., “Pro-Inflammatory and Anti-Inflammatory Activities of Human Plasma-Derived Serum IgA,”
[cited by applicant]
Olas, K. et al., “Immunomodulatory properties of human serum immunoglobulin A: anti-inflammatory and pro-inflammatory activities in human monocytes and peripheral blood mononuclear cells,”
[cited by applicant]
Olas, K. et al., “Natural anti-amyloid beta antibodies in intravenous immunoglobulin prevent amyloid beta-induced neurotoxicity in vitro,”
[cited by applicant]
Oncley, J.L et al., “The Separation of the Antibodies, Isoagglutinins, Prothrombin, Plasminogen and ß
[cited by applicant]
Peters, F. et al., “DIADEM—A System For the Interactive Data Acquisition and Processing in an Analytical Laboratory,”
[cited by applicant]
Poelsler, G. et al., “A new liquid intravenous immunoglobulin with three dedicated virus reduction steps: virus and prion reduction capacity,”
[cited by applicant]
Reipert, B.M. et al., “Evaluating the Fc-Function of Intravenous Immunoglobulin Products by Flow Cytometry,”
[cited by applicant]
Reipert, B.M. et al., “Fc function of a new intravenous immunoglobulin product: IGIV 10% triple virally inactivated solution,”
[cited by applicant]
Serre, M-C. et al., “Specific Suppression of Heterotropic Interactions in Phosphofructokinase by the Mutation of Leucine 178 into Tryptophan,”
[cited by applicant]
Tanaka, K. et al., “High quality human immunoglobulin G purified from Cohn fractions by liquid chromatography,”
[cited by applicant]
Teschner, W. et al., “Intermediates on the Folding Pathway of Octopine Dehydrogenease from
[cited by applicant]
Teschner, W. et al., “Intermediates on the Reassociation Pathway of Phosphofructokinase I from
[cited by applicant]
Teschner, W. et al., “A carboxypeptidase Y pulse method to study the accessibility of the C-terminal end during the refolding of ribonuclease A,”
[cited by applicant]
Teschner, W. et al., “Introduction by site-directed mutagenesis of a tryptophan residue as a fluorescent probe for the folding of
[cited by applicant]
Teschner, W. et al., “Enzymatic properties, renaturation and metabolic role of mannitol-1-phosphate dehydrogenease from
[cited by applicant]
Teschner, W. et al., “Fructose-6-phosphate modifies the pathway of the urea-induced dissociated of the allosteric phosphfructokinase from
[cited by applicant]
Teschner, IV, W. et al., “Preclinical Characterization of a New Liquid ‘Immune Globulin Intravenous (Human), 10% Triple Virally Reduced Solution’ (IGIV, 10%TVR),”
[cited by applicant]
Teschner, W. et al., “A new liquid, intravenous immunoglobulin product (IGIV 10%) highly purified by a state-of-the-art process,”
[cited by applicant]
Van Reis, R. et al., “Bioprocess membrane technology,”
[cited by applicant]
Weber, A. et al., “Intravenous Immunoglobulin (IVIG) Gammagard Liquid Contains Anti-Rage IGG and SLRP,”
[cited by applicant]
Weber, A. et al., “Biochemical, molecular and preclinical characterization of a double-virus-reduced human butyrylcholinesterase preparation designed for clinical use,”
[cited by applicant]
Zettlmeissl, G. et al., “Isolation, physicochemical properties, and folding of octopine dehydrogenase from
[cited by applicant]
Ahrer, K. et al., “Effects of ultra-/diafiltration conditions on present aggregates in human immunoglobulin G preparations,” Journal of Membrane Science, 2006, vol. 274, pp. 108-115.
[cited by applicant]
Buchacher, et al., “Purification of intravenous immunoglobulin G from human plasma—aspects of yield and virus safety,” Biotechnol. J., 2006, 1, pp. 148-163.
[cited by applicant]
Cammarata, P.S. et al., “Fractionation and Properties of Glutamic-Oxalacetic Transaminase,” The Journal of Biological Chemistry, Nov. 1951, vol. 193, No. 1, pp. 53-62.
[cited by applicant]
Celite Material Safety Data Sheet, No. 2402, Rev. No. 9, Date Revised Jun. 30, 2012, pp. 1-2.
[cited by applicant]
Cochrane, C.G. et al., “Molecular Assembly in the Contact Phase of the Hageman Factor System,” The American Journal of Medicine, Oct. 1979, vol. 67, pp. 657-664.
[cited by applicant]
Cohn, E.J. et al., “A System for the Separation of the Components of Human Blood: Quantitative Procedures for the Separation of the Protein Components of Human Plasma,” Separation of Protein Components of Human Plasma, …
[cited by applicant]
Curling, J.M. ed., Methods of Plasma Protein Fractionation, 1980, Academic Press, pp. 12-13. 248-249, Table 1.
[cited by applicant]
Fischer, “Recombinant von Willebrand Factor: Potential Therapeutic Use,” Journal of Thrombosis and Thrombolysis, 1999, vol. 8, pp. 197-205.
[cited by applicant]
Fischer, “Structural analysis of recombinant von Willebrand factor produced at industrial scale fermentation of transformed CHO cells co-expressing recombinant furin,” FEBS Letters, 1995, vol. 375, pp. 259262.
[cited by applicant]
Foster, P.R., “Assessment of the potential of plasma fractionation processes to remove causative agents of transmissible spongiform encephalopathy,” Transfusion Medicine, 1999, vol. 9, pp. 3-14.
[cited by applicant]
Goldsmith, et al., “The Activation of Plasminogen by Hageman Factor (Factor XII) and Hageman Factor Fragments,” J. Clin. Invest., 1978, 62,(1), pp. 54-60.
[cited by applicant]
Guerffroy, “A guide for the preparation and use of buffers in biological systems,” © 1975 by Behring Diagnostics, pp. 1-25.
[cited by applicant]
Gun'ko, V.M. et al., “Aqueous Suspensions of Fumed Silica and Adsorption of Proteins,” Journal of Colloid and Interface Science, 1997, vol. 192, pp. 166-178.
[cited by applicant]
Hink, J.H. et al., “Preparation and Properties of a Heat-Treated Human Plamsa Protein Fraction,” Vox Sanguinis, 1957, vol. 2, pp. 174-186.
[cited by applicant]
Jourdain, M. et al., “Effects of Inter-α-inhibitor in Experimental Endotoxic Shock and Disseminated Intravascular Coagulation,” Am J Respir Crit Care Med, 1997, vol. 156, pp. 1825-1833.
[cited by applicant]
Lever, W.F. et al., “Chemical, Clinical, and Immunological Studies on the Products of Human Plasma Fractionation. XL. Quantitative Separation and Determination of the Protein Components in Small Amounts of Normal Human …
[cited by applicant]
Lim, Y-P. et al., “Affinity purification and enzymatic cleavage of inter-alpha inhibitor proteins using antibody and elastase immobilized on CIM monolithic disks,” Journal of Chromatography A, 2005, vol. 1065, pp. 39-43.
[cited by applicant]
Lim, Y-P. et al., “Correlation between Mortality and the Levels of Inter-Alpha Inhibitors in the Plasma of Patients with Severe Sepsis,” The Journal of Infectious Diseases, Sep. 15, 2003, vol. 188, pp. 919-926.
[cited by applicant]
Mccann, K.B. et al., “Evaluation of expanded bed adsorption chromatography for extraction of prothrombin complex from Cohn Supernatant I,” Biologicals, 2008, vol. 36, pp. 227-223.
[cited by applicant]
Michalski, C. et al., “Preparation and Properties of a Therapeutic Inter-Alpha-Trypsin Inhibitor Concentrate from Human Plasma,” Vox Sang, 1994, vol. 67, pp. 329-336.
[cited by applicant]
Mizon, C. et al., “Human pre-α-inhibitor: isolation from a by-product of industrial scale plasma fractionation and structural analysis of its H3 heavy chain,” Journal of Chromatography B, 1997, vol. 692, pp. 281-291.
[cited by applicant]
Nitschmann, et al., “Vereinfachtes Verfahren zur Gewinnung von Humanem Albumin and Gamma-Globulin aus Blutplasma Mittels Alkoholfaellung,” Helvetica Chimica Acta, Verlag Helvetica Chimica Acta, vol. 37, Jan. 1, 1954 (Ja…
[cited by applicant]
Opal, S.M. et al., “Longitudinal studies of inter-alpha inhibitor proteins in severely septic patients: A potential clinical marker and mediator of severe sepsis,” Crit Care Med, 2007, vol. 35, No. 2, pp. 387-392.
[cited by applicant]
Piszkiewicz, D. et al., “Inactivation of Htlv-III/LAV During Plasma Fractionation,” The Lancet, Nov. 23, 1985, pp. 1188-1189.
[cited by applicant]
Radiometer Analytical, “Conductivity Theory and Practice,” Jan. 1, 2004, retrieved from http://www.tau.ac.il/˜chemlaba/Files/Theoryconductivity.pdf, 50 pages.
[cited by applicant]
Radosevich, M. et al., “Intravenous immunoglobulin G; trends in production methods, quality control and quality assurance,” Vox Sanguinis, 2010, vol. 98, pp. 12-28.
[cited by applicant]
Salier, J-P. et al., “The inter-α-inhibitor family: from structure to regulation,” Biochem J., 1996, vol. 315, pp. 1-9.
[cited by applicant]
Schiffman, S. et al, “Partial Purification and Characterization of Contact Activation Cofactor,” The Journal of Clinical Investigation, Nov. 1975, vol. 56, pp. 1082-1092.
[cited by applicant]
Schlokat et al., “Production of highly homogenous and structurally intact recombinant von Willebrand Factor multimers by furin-mediated propeptide removal in vitro,”? Biotechnol. Appl. Biochem., 1996, vol. 24, pp. 257-2…
[cited by applicant]
Schultze, H.E. et al., Molecular Biology of Human Proteins, vol. 1: Nature and Metabolism of Extracellular Proteins, 1966, Elsevier Publishing Company, pp. 236-317.
[cited by applicant]
Turecek et al., “Biochemical and Functional Characterization of a Serum-Free rVWF Durg Candidate,” Blood, 2006, vol. 108, p. 1017.
[cited by applicant]
Turecek et al., “Structure and Function of a Recominant von Willebrand Factor Drug Candidate,” Seminars in Thrombosis and Hemostasis, 2010, vol. 36, No. 5, pp. 510-521.
[cited by applicant]
U.S. Appl. No. 61/227,968, filed Jul. 23, 2009, “Factor H(FH) and FH-Derivative Used to Treat Adult Macular Degeneration and Other Diseases,” Johnson, R. et al., 21 pages.
[cited by applicant]
Wu, R. et al., “Delayed administration of human inter-α inhibitor proteins reduces mortality in sepsis,” Crit Care Med, 2004, vol. 32, No. 8, pp. 1747-1752.
[cited by applicant]
Yang, S. et al., “Administration of human inter-α-inhibitors maintains hemodynamic stability and improves survival during sepsis,” Crit Care Med, 2002, vol. 30, No. 3, pp. 617-622.
[cited by applicant]
Zhuo, L. et al., “Inter-α-trypsin Inhibitor, a Covalent Protein-Glycosaminoglycan-Protein Complex,” The Journal of Biological Chemistry, Sep. 10, 2004, vol. 279, No. 37, pp. 38079-38082.
[cited by applicant]
Anonymous: “Immune globulin (Human) GamaSTAN S/D”, Telecris Biotherapeutics, Inc., Jan. 1, 2005 (Jan. 1, 2005), pp. 1-5, XP093011429, Retrieved from the Internet: URL:https://www.nj.gov/health/cd/documents/topics/hepati…
[cited by applicant]
Misbah S et al.: “Subcutaneous immunoglobulin: opportunities and outlook”, Clinical and Experimental Immunology, Wiley-Blackwell Publishing Ltd, GB, vol. 158, Oct. 30, 2009 (Oct. 30, 2009), pp. 51-59, XP071088450, ISSN:…
[cited by applicant]