Granted Patent
B2
US 12,318,447 · App. 18/383,121 · Granted Jun 3, 2025
Lyophilized powder configured for reconstitution as a liquid pharmaceutical formulation with reduced viscosity and method of preparing thereof
Assignee:
AMGEN INC.
View Patent ↗
Loading inventors, assignments & file history…
Abstract
A method for reducing the viscosity of a pharmaceutical formulation is provided that utilizes a viscosity-reducing concentration of an excipient selected from the group consisting of the n-acetyl arginine, n-acetyl lysine, n-acetyl proline and mixtures thereof in combination with a therapeutiv protein. A stable pharmaceutical formulation is also provided.
Claims (13)
1. A lyophilized powder configured for reconstitution as a liquid pharmaceutical formulation comprising at least 70 mg/mL of a therapeutic protein comprising an antibody and an excipient selected from the group consisting of the n-acetyl arginine, n-acetyl lysine, n-acetyl histidine, n-acetyl proline and mixtures thereof, wherein the viscosity of the liquid pharmaceutical formulation is reduced by at least 5% relative to a control.
2. The lyophilized powder of claim 1 wherein the excipient is present at a concentration of between about 100 μg per mg therapeutic protein to about 1 mg per mg therapeutic protein.
3. The lyophilized powder of claim 1 wherein the excipient is present at a concentration between about 200 μg per mg therapeutic protein to about 500 μg per mg therapeutic protein.
4. The lyophilized powder of claim 1 wherein the therapeutic protein is an antibody.
5. The lyophilized powder of claim 1 wherein the antibody is an IgG1 antibody or an IgG2 antibody.
6. The lyophilized powder of claim 1 wherein the excipient is n-acetyl arginine.
7. The lyophilized powder of claim 1 wherein the excipient is n-acetyl lysine.
8. The lyophilized powder of claim 1 wherein the excipient is n-acetyl histidine.
9. The lyophilized powder of claim 1 wherein the excipient is n-acetyl proline.
10. The lyophilized powder of claim 1 , wherein the viscosity of the liquid pharmaceutical formulation is reduced by at least 25% relative to a control.
11. The lyophilized powder of claim 10 , wherein the viscosity of the liquid pharmaceutical formulation is reduced by at least 50% relative to a control.
12. The lyophilized powder of claim 11 , wherein the viscosity of the liquid pharmaceutical formulation is reduced by at least 80% relative to a control.
13. A lyophilized powder prepared by a method of preparing a lyophilized powder comprising lyophilizing a pharmaceutical composition comprising a therapeutic protein comprising an antibody at a concentration of at least 70 mg/ml and an excipient selected from the group consisting of n-acetyl arginine, n-acetyl lysine, n-acetyl histidine, n-acetyl proline and mixtures thereof at a viscosity-reducing concentration, wherein the viscosity is reduced by at least 5% versus a control formulation and the concentration of the excipient is less than about 200 mM.
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jan 24, 2024
From: SLOEY, CHRISTOPHER JAMES; KANAPURAM, SEKHAR
To: AMGEN INC.
Reel/Frame 066234/0397 →
Continuity (3)
Division
15521057
Provisional Application
62067637
· Oct 23, 2014
References Cited (178)
US 6767892B1
· Shirley
· 2004
[cited by examiner]
US 7153507B2
· van de Winkel et al.
· 2006
[cited by applicant]
US 7592429B2
· Paszty et al.
· 2009
[cited by applicant]
US 7648702B2
· Gombotz et al.
· 2010
[cited by applicant]
US 7906625B2
· Shen et al.
· 2011
[cited by applicant]
US 7982016B2
· Comeau et al.
· 2011
[cited by applicant]
US 8030467B2
· Seth et al.
· 2011
[cited by applicant]
US 8062640B2
· Sleeman et al.
· 2011
[cited by applicant]
US 8080243B2
· Liang et al.
· 2011
[cited by applicant]
US 8101182B2
· Dong et al.
· 2012
[cited by applicant]
US 8232372B2
· Presta et al.
· 2012
[cited by applicant]
US 8545849B2
· Borras et al.
· 2013
[cited by applicant]
US 8715663B2
· Paszty et al.
· 2014
[cited by applicant]
US 8961964B2
· Liu et al.
· 2015
[cited by applicant]
US 20040197324A1
· Liu
· 2004
[cited by examiner]
US 20120270782A1
· Gopinath et al.
· 2012
[cited by applicant]
US 20130171128A1
· Huang et al.
· 2013
[cited by applicant]
US 20150004174A1
· Wasserman et al.
· 2015
[cited by applicant]
EP 0804163B1
· 2003
[cited by applicant]
EP 1977763A1
· 2008
[cited by applicant]
EP 2080504A2
· 2009
[cited by applicant]
JP 2011067202A
· 2011
[cited by applicant]
WO 1990000397A1
· 1990
[cited by applicant]
WO 1999024063A1
· 1999
[cited by applicant]
WO 2000024782A2
· 2000
[cited by applicant]
WO 2002038170A2
· 2002
[cited by applicant]
WO 2004055164A2
· 2004
[cited by applicant]
WO 2004066957A2
· 2004
[cited by applicant]
WO 2007074880A1
· 2007
[cited by applicant]
WO 2009026558A1
· 2009
[cited by applicant]
WO 2009073569A2
· 2009
[cited by applicant]
WO 2011095543A1
· 2011
[cited by applicant]
WO 2011104381A2
· 2011
[cited by applicant]
WO 2011139718A1
· 2011
[cited by applicant]
WO 2013166448A1
· 2013
[cited by applicant]
WO 2013186230A1
· 2013
[cited by applicant]
WO 2012154999A1
· 2015
[cited by applicant]
WO 2015173782A1
· 2015
[cited by applicant]
WO 2016065181A1
· 2016
[cited by applicant]
WO 2016087569A1
· 2016
[cited by applicant]
WO 2018064307A2
· 2018
[cited by applicant]
WO 2018067987A1
· 2018
[cited by applicant]
Office Action in Argentinian Patent Application No. P20180100397 dated Sep. 19, 2024 with machine translation.
[cited by applicant]
Office Action in Uruguayan Patent Application No. 37611 dated Sep. 10, 2024 with English translation.
[cited by applicant]
Arakawa et al., “Recombinant Production of Native Proteins from
[cited by applicant]
Arakawa et al., Suppression of Protein Interactions by Arginine: A Proposed Mechanism of the Arginine Effects,
[cited by applicant]
Baynes et al., Rational Design of Solution Additives for the Prevention of Protein Aggregation,
[cited by applicant]
Baynes et al., Role of Arginine in the Stabilization of Proteins Against Aggregation,
[cited by applicant]
Binabaji, Elaheh, Ultrafiltration of Highly Concentrated Monoclonal Antibody Solutions, The Pennsylvania State University, The Graduate School, College of Engineering, Thesis (2015) 1-190.
[cited by applicant]
Binabaji et al., Intermolecular Interactions and the Viscosity of Highly Concentrated Monoclonal Antibody Solutions, Pharm. Res. (2015) 32:3102-3109.
[cited by applicant]
Binabaji et al., Theoretical Analysis of the Ultrafiltration Behavior of Highly Concentrated Protein Solutions, Journal of Membrane Science 494 (2015) 216-223.
[cited by applicant]
Binabaji et al., Ultrafiltration of Highly Concentrated Antibody Solutions: Experiments and Modeling for the Effects of Module and Buffer Conditions, Biotechnol. Prog. (2016), 32(3): 692-701.
[cited by applicant]
Carpenter and Manning, Rational Design of Stable Protein Formulations, Theory and Practice, Pharm. Biotech. (2002), 13:1-222.
[cited by applicant]
Chaudhri et al., The Role of Amino Acid Sequence in the Self-Association of Therapeutic Monoclonal Antibodies: Insights from Coarse-Grained Modeling,
[cited by applicant]
Cheng et al., Linking the Solution Viscosity of an IgG2 Monoclonal Antibody to its Structure as a Function of pH and Temperature,
[cited by applicant]
Chennamsetty et al., Design of Therapeutic Proteins with Enhanced Stability,
[cited by applicant]
Communication in European Patent Application No. 15790759.3 dated Jan. 3, 2020.
[cited by applicant]
Communication in European Patent Application No. 18710193.6 dated Nov. 12, 2019.
[cited by applicant]
Communication in European Patent Application No. 18710193.6 dated Apr. 3, 2023.
[cited by applicant]
Connolly et al., Weak Interactions Govern the Viscosity of Concentrated Antibody Solutions: High-Throughput Analysis Using the Diffusion Interaction Parameter,
[cited by applicant]
Cunningham et al., Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia, Nat Struct Mol Biol (2007), 14(5), 413-419.
[cited by applicant]
Das et al., Inhibition of Protein Aggregation: Supramolecular Assemblies of Arginine Hold the Key,
[cited by applicant]
Examination report No. 1 in Australian Patent Application No. 2015335743 dated Dec. 11, 2019.
[cited by applicant]
Examination report No. 2 in Australian Patent Application No. 2015335743 dated Dec. 3, 2020.
[cited by applicant]
Ferrara et al., “Recombinant renewable polyclonal antibodies”, 2015, mAbs, vol. 7, Issue 1: pp. 32-42, Taylor & Francis Group, LLC.
[cited by applicant]
Guo et al., Structure-Activity Relationship for Hydrophobic Salts as Viscosity-Lowering Excipients for Concentrated Solutions of Monoclonal Antibodies,
[cited by applicant]
Hamada et al., Effect of Additives on Protein Aggregation,
[cited by applicant]
Horton et al., “Molecular biology of PCSK9: its role LDL metabolism,”
[cited by applicant]
Inoue et al., “Arginine and Lysine Reduce the High Viscosity of Serum Albumin Solutions for Pharmaceutical Injection,”
[cited by applicant]
Inoue et al., “Specific Decrease in Solution Viscosity of Antibodies by Arginine for Therapeutic Formulations,”
[cited by applicant]
International Search Report in PCT Application No. PCT/US2015/056972 dated Dec. 16, 2015.
[cited by applicant]
International Search Report in PCT Application No. PCT/US2018/019189 dated May 9, 2018.
[cited by applicant]
Ishibashi et al., “Is Arginine a Protein-Denaturant?,”
[cited by applicant]
Jezek et al., “Viscosity of concentrated therapeutic protein compositions,”
[cited by applicant]
Joshi et al., “Aggregation of Monoclonal Antibody Products: Formation and Removal,”
[cited by applicant]
Jouyban et al., “Review of Pharmaceutical Applications of N-Methyl-2-Pyrrolidone,”
[cited by applicant]
Kamerzell et al., “Polar Solvents Decrease the Viscosity of High Concentration IgG1 Solutions through Hydrophobic Solvation and Interaction: Formulation and Biocompatibility Considerations,”
[cited by applicant]
Ketchem et al., “Mitigation of monoclonal antibody viscosity by modification of protein surface charge,”
[cited by applicant]
Li et al., “Concentration Dependent Viscosity of Monoclonal Antibody Solutions: Explaining Experimental Behavior in Terms of Molecular Properties,”
[cited by applicant]
Lutz et al., “High Concentration Biotherapeutic Formulation and Ultrafiltration: Part 1 Pressure Limits,”
[cited by applicant]
Neergaard et al., “Viscosity of High Concentration Protein Formulations of Monoclonal Antibodies of the IgG1 and IgG4 Subclass—Prediction of Viscosity Through Protein-Protein Interaction Measurements,”
[cited by applicant]
Nichols et al., “Rational Design of Viscosity Reducing Mutants of a Monoclonal Antibody: Hydrophobic Versus Electrostatic Inter-Molecular Interactions,”
[cited by applicant]
Notice of Allowance and Fees Due in U.S. Appl. No. 15/521,057 dated Mar. 17, 2022.
[cited by applicant]
Notice of Allowance and Fees Due in U.S. Appl. No. 15/521,057 dated Nov. 22, 2022.
[cited by applicant]
Notice of Allowance and Fees Due in U.S. Appl. No. 15/521,057 dated Oct. 2, 2023.
[cited by applicant]
Notice of Allowance and Fees Due in U.S. Appl. No. 15/902,775 dated May 18, 2022.
[cited by applicant]
Office Action in Brazilian Patent Application No. 1120170081253 dated Oct. 25, 2022 with machine translation.
[cited by applicant]
Office Action in Brazilian Patent Application No. 1120170081253 dated Feb. 7, 2023 with machine translation.
[cited by applicant]
Office Action in Brazilian Patent Application No. 1120170081253 dated May 16, 2023 with machine translation.
[cited by applicant]
Office Action in Canadian Patent Application No. 2,964,786 dated Nov. 29, 2021.
[cited by applicant]
Office Action in Canadian Patent Application No. 3,053,394 dated Aug. 2, 2023.
[cited by applicant]
Office Action in Chilean Patent Application No. 201700984 dated Jun. 1, 2022 with English translation.
[cited by applicant]
Office Action in Chilean Patent Application No. 201902190 dated Feb. 19, 2021 with English translation.
[cited by applicant]
Office Action in Chilean Patent Application No. 201902362 dated Oct. 22, 2020.
[cited by applicant]
Office Action and Search Report in Chilean Patent Application No. 201902362 dated Oct. 29, 2021 with summary English translation.
[cited by applicant]
Office Action in Chinese Patent Application No. 201580057461.5 dated Mar. 31, 2020 with English translation.
[cited by applicant]
Office Action in Chinese Patent Application No. 201580057461.5 dated Apr. 15, 2021 with English translation.
[cited by applicant]
Office Action in Chinese Patent Application No. 201880025966.7 dated Aug. 16, 2023 with English translation.
[cited by applicant]
Office Action in Chinese Patent Application No. 202210048275.7 dated Jul. 29, 2023 with English translation.
[cited by applicant]
Official Action in Eurasian Patent Application No. 201790787 dated Dec. 18, 2017 with English translation.
[cited by applicant]
Office Action in Eurasian Patent Application No. 201991951 dated Mar. 22, 2021 with English translation.
[cited by applicant]
Office Action in Eurasian Patent Application No. 201991951 dated Dec. 21, 2022 with English translation.
[cited by applicant]
Office Action in Indian Patent Application No. 201717014850 dated Nov. 18, 2019.
[cited by applicant]
Office Action in Israeli Patent Application No. 251726 dated May 6, 2020 with English translation.
[cited by applicant]
Office Action in Israeli Patent Application No. 287947 dated Feb. 16, 2023.
[cited by applicant]
Office Action in Japanese Patent Application No. 2017-522169 dated Apr. 23, 2019 with English translation.
[cited by applicant]
Office Action in Japanese Patent Application No. 2018-023742 dated Dec. 21, 2021 with English translation.
[cited by applicant]
Office Action in Japanese Patent Application No. 2018-023742 dated Oct. 4, 2022 with English translation.
[cited by applicant]
Office Action in Japanese Patent Application No. 2018-023742 dated Jun. 6, 2023 with English translation.
[cited by applicant]
Office Action in Japanese Patent Application No. 2019-191701 dated Nov. 4, 2020 with English translation.
[cited by applicant]
Office Action in Japanese Patent Application No. 2021-170676 dated Dec. 13, 2022 with English translation.
[cited by applicant]
Office Action in Japanese Patent Application No. 2021-170676 dated Jun. 6, 2023 with English translation.
[cited by applicant]
Office Action in Korean Patent Application No. 10-2017-7011706 dated Jul. 26, 2022 with English translation.
[cited by applicant]
Office Action in Korean Patent Application No. 10-2019-7026969 dated Feb. 9, 2023 with English translation.
[cited by applicant]
Office Action in Korean Patent Application No. 10-2019-7026969 dated Aug. 28, 2023 with English translation.
[cited by applicant]
Office Action in Mexican Patent Application No. MX/a/2017/005243 dated Jan. 8, 2021 with English translation.
[cited by applicant]
Office Action in Mexican Patent Application No. MX/a/2017/005243 dated Jun. 15, 2021 with English translation.
[cited by applicant]
Office Action in Mexican Patent Application No. MX/a/2019/009952 dated May 24, 2023 with English translation.
[cited by applicant]
Office Action in U.S. Appl. No. 15/521,057 dated Aug. 31, 2018.
[cited by applicant]
Office Action in U.S. Appl. No. 15/521,057 dated Apr. 2, 2019.
[cited by applicant]
Office Action in U.S. Appl. No. 15/521,057 dated Mar. 13, 2020.
[cited by applicant]
Office Action in U.S. Appl. No. 15/521,057 dated Oct. 23, 2020.
[cited by applicant]
Office Action in U.S. Appl. No. 15/521,057 dated Nov. 30, 2021.
[cited by applicant]
Office Action in U.S. Appl. No. 15/902,775 dated Dec. 26, 2019.
[cited by applicant]
Office Action in U.S. Appl. No. 15/902,775 dated Jul. 31, 2020.
[cited by applicant]
Office Action in U.S. Appl. No. 15/902,775 dated Dec. 20, 2021.
[cited by applicant]
Piper et al., “The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol”,
[cited by applicant]
Rishi et al., “Role of Non-Compatible Osmolytes in the Stabilization of Proteins During Heat Stress,”
[cited by applicant]
Rudikoff et al., “Single Amino Acid Substitution Altering Antigen-Binding Specificity”,
[cited by applicant]
Schneider et al., “Arginine and the Hofmeister Series: The Role of Ion-Ion Interactions in Protein Aggregation Suppression,”
[cited by applicant]
Schneider et al., “Effects of Solute-Solute Interactions on Protein Stability Studied Using Various Counterions and Dendrimers,”
[cited by applicant]
Seidah et al., “The Secretory Proprotein Convertase Neural Apoptosis-Regulated Convertase 1 (NARC-1): Liver Regeneration and Neuronal Differentiation,”
[cited by applicant]
Seidah et al., “The proprotein convertases are potential 2011 targets in the treatment of dyslipidemia,”
[cited by applicant]
Sharma et al., “In silico Selection of Therapeutic Antibodies for Development: Viscosity, Clearance, and Chemical Stability,”
[cited by applicant]
Shukla et al., “Complex Interactions between Molecular Ions in Solution and Their Effect on Protein Stability,”
[cited by applicant]
Shulka et al., “Interaction of Arginine with Proteins and the Mechanism by which it Inhibits Aggregation,”
[cited by applicant]
Shulka et al., “Molecular Level Insight into Intra-Solvent Interaction Effects on Protein Stability and Aggregation,”
[cited by applicant]
Singh et al., “Dipole-Dipole Interaction in Antibody Solutions: Correlation with Viscosity Behavior at High Concentration,”
[cited by applicant]
Srivastava et al., “Viscosity Reduction and Stability Enhancement of Monoclonal Antibody Formulations Using Derivatives of Amino Acids,”
[cited by applicant]
Tsumoto et al., Review: Why is Arginine Effective in Suppressing Aggregation?,
[cited by applicant]
Tsumoto et al., Role of Arginine in Protein Refolding, Solubilization, and Purification,
[cited by applicant]
Voynov et al., Predictive Tools for Stabilization of Therapeutic Proteins,
[cited by applicant]
Wang et al., “Viscosity-Lowering Effect of Amino Acids and Salts on Highly Concentrated Solutions of Two IgG1 Monoclonal Antibodies,”
[cited by applicant]
Written Opinion in PCT Application No. PCT/US2015/056972 dated Dec. 16, 2015.
[cited by applicant]
Written Opinion in PCT Application No. PCT/US2018/019189 dated May 9, 2018.
[cited by applicant]
Written Opinion in Singaporian Patent Application No. 11201703152R dated Jul. 14, 2020.
[cited by applicant]
Written Opinion in Singaporian Patent Application No. 11201907505T dated Jan. 29, 2021.
[cited by applicant]
Yadav et al., “Specific Interactions in High Concentration Antibody Solutions Resulting in High Viscosity,”
[cited by applicant]
Yadav et al., “The Influence of Charge Distribution on Self-Association and Viscosity Behavior of Monoclonal Antibody Solutions,”
[cited by applicant]
Yadav et al., “Viscosity Behavior of High-Concentration Monoclonal Antibody Solutions: Correlation with Interaction Parameter and Electroviscous Effects,”
[cited by applicant]
Examination report No. 1 in Australian Patent Application No. 2021200990 dated Feb. 28, 2022.
[cited by applicant]
Office Action in Brazilian Patent Application No. 1120190173935 dated Jul. 9, 2024 with machine translation.
[cited by applicant]
Office Action in Chinese Patent Application No. 201880025966.7 dated Sep. 15, 2022 with English translation.
[cited by applicant]
Examination report No. 1 in Australian Patent Application No. 2018224095 dated Feb. 16, 2024.
[cited by applicant]
Office Action in Chilean Patent Application No. 201902362 dated Nov. 7, 2023 with English translation.
[cited by applicant]
Office Action in Chinese Patent Application No. 201880025966.7 dated Jan. 16, 2024 with English translation.
[cited by applicant]
Office Action in Eurasian Patent Application No. 202191513 dated Aug. 31, 2023 with English translation.
[cited by applicant]
Office Action in Indian Patent Application No. 201917034377 dated Jan. 17, 2024.
[cited by applicant]
Office Action in Korean Patent Application No. 10-2019-7026969 dated Jan. 30, 2024 with English translation.
[cited by applicant]
Office Action in Chinese Patent Application No. 202210048275.7 dated Oct. 18, 2024 with English translation.
[cited by applicant]
International Preliminary Report on Patentability in PCT Application No. PCT/US2015/056972 dated May 4, 2017.
[cited by applicant]
International Preliminary Report on Patentability in PCT Application No. PCT/US2018/019189 dated Sep. 6, 2019.
[cited by applicant]
Office Action in Chinese Patent Application No. 202210048275.7 dated Jun. 8, 2024 with English translation.
[cited by applicant]
Office Action in Korean Patent Application No. 10-2024-7014122 dated Aug. 30, 2024 with English translation.
[cited by applicant]
Office Action in Mexican Patent Application No. MX/a/2021/015789 dated Jul. 10, 2024 with English translation.
[cited by applicant]
Office Action in Uruguayan Patent Application No. 37611 dated May 10, 2024 with English translation.
[cited by applicant]
Written Opinion in Singaporean Application No. 11201907505T dated Sep. 2, 2022.
[cited by applicant]
Written Opinion in Singaporean Application No. 11201907505T dated May 30, 2024.
[cited by applicant]
Office Action in U.S. Appl. No. 17/893,515 dated Mar. 6, 2025.
[cited by applicant]