I 1111111111111111 1111111111 1111111111 1111111111 1111111111111111 IIII IIII IIII
`USO 10155039B2
`
`c12) United States Patent
`Manning et al.
`
`(IO) Patent No.: US 10,155,039 B2
`(45) Date of Patent:
`*Dec. 18, 2018
`
`(54) STABLE AQUEOUS FORMULATIONS OF
`ADALIMUMAB
`
`(71) Applicant: Coherus Biosciences, Inc., Redwood
`City, CA (US)
`
`(72)
`
`Inventors: Mark Manning, Johnstown, CO (US);
`Robert W. Payne, Fort Collins, CO
`(US)
`
`(73) Assignee: Coherus Biosciences, Inc., Redwood
`City, CA (US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by O days.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`(21) Appl. No.: 15/799,851
`
`(22) Filed:
`
`Oct. 31, 2017
`
`(65)
`
`Prior Publication Data
`
`US 2018/0055930 Al Mar. 1, 2018
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 15/360,678, filed on
`Nov. 23, 2016, now Pat. No. 9,861,695, which is a
`continuation of application No. 14/020,733, filed on
`Sep. 6, 2013.
`
`(60) Provisional application No. 61/698,138, filed on Sep.
`7, 2012, provisional application No. 61/769,581, filed
`on Feb. 26, 2013, provisional application No.
`61/770,421, filed on Feb. 28, 2013.
`
`(51)
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`(52)
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`(2006.01)
`(2006.01)
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`(2017.01)
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`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K 39/395
`A61K 47112
`A61K 47118
`A61K 47122
`A61K 47126
`C07K 16124
`A61K 47102
`A61K 47110
`A61K 47114
`A61K 47124
`A61K 9/08
`A61K 39/00
`U.S. Cl.
`CPC .......... A61K 39/39591 (2013.01); A61K 9/08
`(2013.01); A61K 39/3955 (2013.01); A61K
`39/39533 (2013.01); A61K 47102 (2013.01);
`A61K 47110 (2013.01); A61K 47112 (2013.01);
`A61K 47114 (2013.01); A61K 47118 (2013.01);
`A61K 471183 (2013.01); A61K 47122
`(2013.01); A61K 47124 (2013.01); A61K 47126
`(2013.01); C07K 161241 (2013.01); A61K
`2039/505 (2013.01); A61K 2039/542
`(2013.01); A61K 2039/545 (2013.01); C07K
`2317/21 (2013.01); C07K 2317/24 (2013.01);
`C07K 2317/94 (2013.01)
`
`(58) Field of Classification Search
`None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,597,966 A
`5,104,651 A
`5,789,554 A
`5,886,154 A
`5,945,098 A
`6,090,382 A
`6,171,586 Bl
`6,171,686 Bl
`6,238,664 Bl
`6,252,055 Bl
`6,258,562 Bl
`6,281,336 Bl
`6,696,056 Bl
`7,250,165 B2
`7,648,702 B2
`8,216,583 B2
`8,420,081 B2
`8,632,778 B2
`8,802,100 B2
`8,821,865 B2
`8,883,146 B2
`8,889,135 B2
`8,916,157 B2
`9,085,619 B2
`9,114,166 B2
`9,340,611 B2
`9,340,612 B2
`9,346,880 B2
`9,382,317 B2
`9,682,145 B2
`
`7/1986 Zolton et al.
`4/1992 Boone et al.
`8/1998 Leung et al.
`3/1999 Lebing et al.
`8/1999 Sarno et al.
`7/2000 Salfed et al.
`1/2001 Lam et al.
`1/2001 Lam et al.
`5/2001 Hellerbrand et al.
`6/2001 Relton
`6/2001 Salfel d et al.
`8/2001 Laursen et al.
`2/2004 Cheung et al.
`7/2007 Heavner et al.
`1/2010 Gombotz et al.
`7/2012 Krause
`4/2013 Fraunhofer et al.
`1/2014 Kakuta et al.
`8/2014 Krause et al.
`9/2014 Neu et al.
`11/2014 Fraunhofer et al.
`11/2014 Fischkoff et al.
`12/2014 Krause
`7/2015 Fraunhofer
`8/2015 Krause
`5/2016 Manning et al.
`5/2016 Manning et al.
`5/2016 Manning et al.
`7/2016 Manning et al.
`6/2017 Manning et al.
`(Continued)
`
`FOREIGN PATENT DOCUMENTS
`
`CN
`EP
`
`5/2015
`102988984
`9/2009
`1324776
`(Continued)
`
`OTHER PUBLICATIONS
`
`Search Report for corresponding PCT application PCT/US13/
`58618.
`
`(Continued)
`
`Primary Examiner - Yunsoo Kim
`(74) Attorney, Agent, or Firm - Fish & Richardson P.C.
`
`(57)
`
`ABSTRACT
`
`The invention provides aqueous pharmaceutical adalim(cid:173)
`umab compositions suitable for long-term storage of adali(cid:173)
`mumab, methods of manufacture of these compositions,
`methods of administration, and kits containing same.
`
`12 Claims, 28 Drawing Sheets
`(26 of 28 Drawing Sheet(s) Filed in Color)
`
`1 of 77
`
`Fresenius Kabi
`Exhibit 1001
`
`

`

`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`9,707,293 B2
`9,724,414 B2
`9,724,415 B2
`9,731,008 B2
`9,731,009 B2
`9,737,600 B2
`9,757,454 B2
`9,770,507 B2
`9,782,479 B2
`9,782,480 B2
`9,789,185 B2
`9,808,525 B2
`9,861,695 B2
`2002/0004478 Al
`2003/0138417 Al
`2003/0180287 Al
`2003/0206898 Al
`2004/0022792 Al
`2004/0033228 Al
`2004/0033535 Al
`2004/0038878 Al
`2004/0170623 Al
`2006/0149042 Al
`2006/0165733 Al
`2007/0036779 Al
`2007/0184050 Al
`2008/0124326 Al
`2008/0311078 Al
`2009/0291062 Al
`2010/0278822 Al
`2012/0028877 Al
`2013/0195888 Al
`2013/0216522 Al
`2013/0216525 Al
`2013/0243764 Al
`2013/0273066 Al
`2013/0273067 Al
`2013/0336968 Al
`2014/0141007 Al
`2014/0141008 Al
`2014/0186361 Al
`2015/0150982 Al
`2015/0190513 Al
`2015/0191538 Al
`2016/0031982 Al
`2016/0039926 Al
`2016/0256545 Al
`2016/0256547 Al
`2016/0263226 Al
`2016/0303233 Al
`2016/0303234 Al
`2016/0304599 Al
`2016/0304600 Al
`2016/0304601 Al
`2016/0319011 Al
`2016/0339102 Al
`2016/0362484 Al
`2016/0362486 Al
`2017/0143828 Al
`2017/0312361 Al
`2018/0021433 Al
`2018/0028653 Al
`2018/0028654 Al
`2018/0028655 Al
`2018/0028656 Al
`2018/0028657 Al
`2018/0043018 Al
`2018/0043019 Al
`2018/0055929 Al
`2018/0140701 Al
`
`7/2017 Manning et al.
`8/2017 Manning et al.
`8/2017 Manning et al.
`8/2017 Manning et al.
`8/2017 Manning et al.
`8/2017 Manning et al.
`9/2017 Manning et al.
`9/2017 Manning et al.
`10/2017 Manning et al.
`10/2017 Manning et al.
`10/2017 Manning et al.
`11/2017 Manning et al.
`1/2018 Manning et al.
`1/2002 Danko et al.
`7/2003 Kaisheva et al.
`9/2003 Gombotz et al.
`11/2003 F ischkoff et al.
`2/2004 Klinke
`2/2004 Krause et al.
`2/2004 Boyle et al.
`2/2004 Tanikawa et al.
`9/2004 Arvinte et al.
`7/2006 Konstantinov et al.
`7/2006 Betz et al.
`2/2007 Bardat et al.
`8/2007 Ishikawa
`5/2008 Rehder et al.
`12/2008 Gokarn et al.
`11/2009 Fraunhofer
`11/2010 Fraunhofer
`2/2012 Gokam
`8/2013 Wang et al.
`8/2013 Huille et al.
`8/2013 Chen
`9/2013 Ellis et al.
`10/2013 Gokarn et al.
`10/2013 Gokarn et al.
`12/2013 Danek-Bulius et al.
`5/2014 Fraunhofer et al.
`5/2014 Fraunhofer et al.
`7/2014 Manning et al.
`6/2015 Michael et al.
`7/2015 Manning et al.
`7/2015 Manning et al.
`2/2016 Manning et al.
`2/2016 Manning et al.
`9/2016 Manning et al.
`9/2016 Manning et al.
`9/2016 Manning et al.
`10/2016 Manning et al.
`10/2016 Manning et al.
`10/2016 Manning et al.
`10/2016 Manning et al.
`10/2016 Manning et al.
`11/2016 Gokarn et al.
`11/2016 Gokarn et al.
`12/2016 Gokarn et al.
`12/2016 Gokarn et al.
`5/2017 Fraunhofer et al.
`11/2017 Manning et al.
`1/2018 Manning et al.
`2/2018 Manning et al.
`2/2018 Manning et al.
`2/2018 Manning et al.
`2/2018 Manning et al.
`2/2018 Manning et al.
`2/2018 Manning et al.
`2/2018 Manning et al.
`3/2018 Manning et al.
`5/2018 Manning et al.
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`JP
`
`1528933
`2001-503781
`
`5/2012
`3/2001
`
`US 10,155,039 B2
`Page 2
`
`JP
`JP
`JP
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`2010-523493
`2011-509972
`2011-518110
`WO 1997/029131
`WO 1997/45140
`WO 1998/004281
`WO 1998/056418
`WO 1999/037329
`WO 2000/56772
`WO 2000/67789
`WO 2002/013860
`WO 2002/100330
`WO 2006/022599
`2006/138181 A2
`2007 /092772 A2
`WO 2004/091656
`2009/015345 Al
`WO 2009/073569
`WO 2009/073805
`WO 2009/084659
`2010/062896 Al
`WO 2010/066634
`2010/129469 Al
`2011/061712 Al
`WO 2011/080209
`2011/141926 A2
`WO 2012/037534
`2012/065072 A2
`2012/143418 Al
`2012/165917 Al
`2013/006454 Al
`WO 2013/011076
`2013/063510 Al
`2013/096835 Al
`2013/164837 Al
`2013/186230 Al
`214/039903 A2
`2014/099636 Al
`WO 2014/130064
`
`7/2010
`3/2011
`6/2011
`8/1997
`12/1997
`2/1998
`12/1998
`7 /1999
`9/2000
`11/2000
`2/2002
`12/2002
`3/2006
`12/2006
`8/2007
`10/2008
`1/2009
`6/2009
`6/2009
`7/2009
`6/2010
`6/2010
`11/2010
`5/2011
`7/2011
`11/2011
`3/2012
`5/2012
`10/2012
`12/2012
`1/2013
`1/2013
`5/2013
`6/2013
`11/2013
`12/2013
`3/2014
`6/2014
`8/2014
`
`OTHER PUBLICATIONS
`
`"Development Pharmaceutics for Biotechnological and Biological
`Products (Annex to Note for Guidance on Development
`Pharmaceutics)," by Committee for Proprietary Medicinal Products,
`The European Agency for the Evaluation of Medicinal Products
`(Oct. 21, 1999).
`Nozaki & Tanford, "Examination of Titration Behavior," Methods
`Enzymol., 11: 715-734 (1967).
`"Note for Guidance on Development Pharmaceutics," by the Com(cid:173)
`mittee for Proprietary Medicinal Products (CPMP), The European
`Agency for the Evaluation of Medicinal Products (Jan. 28, 1998).
`Akers et al., "Formulation Development of Protein Dosage Forms,"
`Ch. 2 in Development and Manufacture of Protein Pharmaceuticals,
`Kluwer Academic/Plenum Publishers: New York, 47-127 (Nail et
`al., eds., 2002).
`Avastin® Label (Feb. 2004).
`Butler & Hamilton, "Quantitation of Specific Antibodies: Methods
`of Express, Standards, Solid-Phase Considerations, and Specific
`Applications," Ch. 9 in Immunochemistry of Solid-Phase Immunoas(cid:173)
`say, CRC Press (John E. Butler ed. 1991).
`Christensen, "Proteins as buffers," Annals of the New York Acad(cid:173)
`emy of Sciences, 133:34-40 (Apr. 1966).
`Cleland & Langer, "Formulation and Delivery of Proteins and
`Peptides: Design and Development Strategies," Ch. 1 in Formula(cid:173)
`tion and Delivery of Proteins and Peptides, ACS Symposium Series
`567, 1-19 (1994).
`Dean, "Lange's Handbook of Chemistry," McGraw-Hill, p. 8.49,
`8.65 (9th ed. 1999).
`Enbrel® Label (Nov. 1998).
`Enbrel® Label (Sep. 2002).
`Flebogarnma® Label (Jan. 2004).
`Fransson & Espander-Jansson, "Local Tolerance of Subcutaneous
`Injections," J. Pharm. Pharmacol., 48:1012-1015 (1996).
`
`2 of 77
`
`Fresenius Kabi
`Exhibit 1001
`
`

`

`US 10,155,039 B2
`Page 3
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Frenken et al., "Identification of the Component Part in an Epoetin
`Alfa Preparation that Causes Pain after Subcutaneous Injection,"
`American J. of Kidney Diseases, 22(4): 553-556 (1993).
`Gamimune® Label (Oct. 2005).
`Gammagard Liquid Label (Apr. 2005).
`Gamunex® Label (Nov. 2005).
`Hanauer, Gastroenterology, vol. 130 p. 323-333 (Feb. 2006).
`Gokarn et al., "Excipients for Protein Drugs," Ch. 17 in Excipient
`Development for Pharmaceutical, Biotechnology, and Drug Deliv(cid:173)
`ery Systems (Ashok Katdare & Mahesh V. Chaubal eds., 2006).
`Handbook of Pharmaceutical Excipients, Pharmaceutical Press (Ray(cid:173)
`mond C. Rowe, Paul J. Sheskey, & Siiin C. Owen eds., 5th ed.
`2006).
`Humira® Label (Feb. 2007).
`Humira® Label (Feb. 2008).
`Humira® Label (Jan. 2003).
`Humira® Label (Jan. 2008).
`Humira® Label (Nov. 2006).
`Humira® Label (Oct. 2005).
`Humira® Label (Oct. 2016).
`Jefferis et al., "Recognition Sites on Human IgG for Fey Receptors:
`The Role of Glycosylation," Immunology Letters, 44: 111-117
`(1995).
`Laursen et al., "Pain Perception after Subcutaneous Injections of
`Media Containing Different Buffers," Basic & Clinical Pharmacol(cid:173)
`ogy & Toxicology, 98:218-221 (2006).
`Octagam® Label (Mar. 2004).
`Olthuis et al., "Characterization of Proteins by Means of their Buffer
`Capacity, Measured with an ISFET-based Coulometric Sensor(cid:173)
`Actuator System," Biosensors & Bioelectronics, 9:743-751 (1994).
`Parslow, "Immunoglobulins & Immunoglobulin Genes," Ch. 7 in
`Medical Immunology, Appleton & Lange (Daniel P. Stites, Abba I.
`Terr, & Tristram G. Parslow eds., 9th ed. 1997).
`Kempeni, Preliminary results of early clinical trials with the fully
`human anti-TNFa monoclonal antibody D2E7, Ann Rheum Dis,
`58:(Suppl I), 170-172 (1999).
`Remicade® Label (Aug. 1998).
`Stoner et al., "Protein-Solute Interactions Affect the Outcome of
`Ultrafiltration/Diafiltration Operations," J. Pharm. Sci., 93:2332-
`2342 (2004).
`Synagis® Label (Jul. 2004).
`Tysabri® Label (Nov. 2004).
`Van Slyke, "On the Measurement of Buffer Values and on the
`Relationship of Buffer Value to the Dissociation Constant of the
`Buffer and the Concentration and Reaction of the Buffer Solution,"
`J. Biol. Chem., 52:525-570 (1922).
`Vectibix® Label (Sep. 2006).
`Vivaglobin® Label (Jan. 2006).
`AbbVie Filing in Support of Opposition Against EP 1324776 Bl,
`Filed Jun. 16, 2010.
`Arakawa et al., Protection of Bovine Serum Albumin from Aggre(cid:173)
`gation by Tween 80, J. Pharm. Sci., 89(5), 646-651 (May 2000).
`Aulton, ed., Pharmaceutics, The Science of Dosage Form Design,
`2nd ed., Churchill Livingstone: New York, 317-318, 544-553 (2002).
`Barn et al., Tween Protects Recombinant Human Growth Hormone
`against Agitation-Induced Damage via Hydrophobic Interactions, J.
`Pharm. Sci., 87(12), 1554-1559 (Dec. 1998).
`Barrera et al., Effects of treatment with a fully human anti-tumour
`necrosis factor a monoclonal antibody on the local and systemic
`homeostasis of interleukin 1 and TNFa in patients with rheumatoid
`arthritis, Ann. Rheum. Dis., 60, 660-669 (2001).
`Bischoff et al., Deamidation of Asparagine and Glutamine Residues
`in Proteins and Peptides: Structural Determinants and Analytical
`Methodology, J. of Chromatography B, 662, 261-278 (1994).
`Capasso et al., Effect of the Three-Dimensional Structure on the
`Deamidation Reaction of Ribonuclease A, J. Peptide Res., 54,
`377-382 (1999).
`
`Capasso et al., First Evidence of Spontaneous Deamidation of
`Glutamine Residue via Cyclic Imide to a- and y-Glutamic Residue
`under Physiological Conditions, J. Chem. Soc. Chem. Commun.,
`pp. 1667-1668 (1991).
`Carpenter and Manning, eds., Rational Design of Stable Protein
`Formulations. Theory and Practice, Pharmaceutical Biotechnology,
`vol. 13, Kluwer Academic/Plenum Publishers: New York (2002).
`Cleland et al., The Development of Stable protein Formulations: A
`Close Look at Protein Aggregation, Deamidation, and Oxidation,
`Critical Reviews in Therapeutic Drug Carrier Systems, 10(4),
`307-377 (1993).
`Frokjaer et al., eds., Pharmaceutical Formulation development of
`Peptides and Proteins, Taylor & Francis: London (2000).
`Gatlin et al., Formulation and Administration Techniques to Mini(cid:173)
`mize Injection Pain and Tissue Damage Associated with Parenteral
`Products, Injectable Drug Development Techniques to Reduce Pain
`and Irritation, pp. 401-425 (1999).
`Gennaro, ed., Remington: The Science and Practice of Pharmacy,
`20th ed., Solutes, 785-786 (2000).
`Goolcharran et al., The Effects of a Histidine Residue on the
`C-Terminal Side of an Asparaginyl Residue on the Rate ofDeamida(cid:173)
`tion Using Model Pentapeptides, J. of Pharmaceutical Sciences, vol.
`89, Issue 6, 818-825 (2000).
`Jorgensen et al., Pain Assessment of Subcutaneous Injections, Ann.
`Pharma., 30(7/8), 729-732 (Jul./Aug. 1996).
`Krishnamurthy et al., The Stability Factor: Importance in Formu(cid:173)
`lation Development, Curr. Pharm. Biotech, 3, 361-371 (2002).
`Levine et al., The Use of Surface Tension Measurements in the
`Design of Antibody-Based Product Formulations, J. Parenteral Sci.
`& Tech., 45(3), 160-165 (May/Jun. 1991).
`Lorenz, Technology evaluation: Adalimumab, Abbott Laboratories,
`Current Opinion in Molecular Therapeutics, 4(2), 185-190 (2002).
`Manning et al., Stability of Protein Pharmaceuticals, Pharm Res.,
`6(11), 903-918 (1989).
`Nabuchi et al., The Stability and Degradation Pathway of Recom(cid:173)
`binant Human Parathyroid Hormone: Deamidation of Asparaginyl
`Residue and Peptide Bond Cleavage at Aspartyl and Asparaginyl
`Residues, Pharmaceutical Research, vol. 14 Issue 12, 1685-1690
`(1997).
`Nema et al., Excipients and Their Use in Injectable Products, FDA
`J. Pharm. Sci. & Tech, 51(4), 166-171 (Jul./Aug. 1997).
`Paborji et al., Chemical and Physical Stability of Chimeric L6, a
`Mouse-Human Monoclonal Antibody, Pharmaceutical Research,
`vol. 11, Issue 5, 764-771 ( 1994).
`Patel et al., Chemical Pathways of Peptide Degradation. II. Kinetics
`ofDeamidation of an Asparaginyl Residue in a Model Hexapeptide,
`Pharmaceutical Research, vol. 7, Issue 7, 703-711 (1990).
`Santora et al, Characterization of Recombinant human Monoclonal
`Tissue Necrosis Factor-a Antibody Using Cation-Exchange HPLC
`and Capillary Isoelectric Focusing, Analytic Biochem, 275, 98-108
`(1999).
`Schein, Solubility as a Function of Protein Structure and Solvent
`Components, BioTechnology 8, 308-317 (Apr. 1990).
`Scotchler et al., Deamidation ofGlutaminyl Residues: Dependence
`on pH, Temperature, and Ionic Strength, Analytical Biochemistry,
`59, 319-322 (1974).
`Sorbera et al., Adalimumab, Drugs Fut., 26(7), 639-646 (Jul. 2001).
`United States Pharmacopeia and National Formulary (USP 24-NF
`19). vol. 2. Rockville, MD: United States Pharmacopeia Conven(cid:173)
`tion; 1999: 1971-1977, 2011-2021, 2404-2406.
`Wang, Instability, stabilization, and formulation of liquid protein
`pharmaceuticals, Int. J. Pharma., 185, 129-188 (1999).
`Wright et al., Nonenzymatic Deamidation of Asparaginyl and
`Glutaminyl Residues in Protein, Critical Reviews in Biochemistry
`and Molecular Biology, 26: 1, 1-52 (1991).
`Ann L. Daugherty, et al., Formulation and Delivery Issues for
`Monoclonal Antibody Therapeutics, Adv. Drug Deliv. Rev. 58:686
`(2006).
`Branden A. Salinas, et al., Understanding and Modulating Opales(cid:173)
`cence and Viscosity in a Monoclonal Antibody Formulation, 99 J.
`Pharm. Sci. 82 (2010).
`Christine C. Lee, et al., Toward aggregation-resistant antibodies by
`design, 31 Trends in Biotech. 612 (2013).
`
`3 of 77
`
`Fresenius Kabi
`Exhibit 1001
`
`

`

`US 10,155,039 B2
`Page 4
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Douglas D. Banks, et al., Native-State Solubility and Transfer Free
`Energy as Predictive Tools for Selecting Excipients to Include in
`Protein Formulation Development Studies, 101 J. Pharm. Sci. 2720
`(2012).
`Edward C. Keystone, et al., Golimumab, a Human Antibody to
`Tumor Necrosis Factor-a Given by Monthly Subcutaneous Injec(cid:173)
`tions, in Active Rheumatoid Arthritis Despite Methotrexate: The
`Go-Forward Study, 68 Ann. Rheum. Dis. 789 (2009).
`Emily Ha, et al., Peroxide Formation in Polysorbate 80 and Protein
`Stability, 91 J. Pharm. Sci. 2252 (2002).
`Eva Y. Chi, et al., Physical Stability of Proteins in Aqueous
`Solution: Mechanism and Driving Forces in Nonnative Protein
`Aggregation, 20 Pharm. Res. 1325 (2003).
`JennyM. Phillips, Manufacture and Quality Control ofCAMPATH-1
`Antibodies for Clinical Trials, 3 Cytotherapy 233 (2001 ).
`John F. Carpenter, et al., Chapter 7: Freezing- and Drying-Induced
`Perturbations of Protein Structure and Mechanisms of Protein
`Protection by Stabilizing Additives, in Freeze-Drying/
`Lyophilization of Pharmaceutical and Biological Products 167 (2d
`ed. 2004).
`John F. Carpenter, et at., Inhibition of Stress-Induced Aggregation
`of Protein Therapeutics, 309 Methods in Enzymology 236 (1999).
`John F. Carpenter, et al., Rational Design of Stable Lyophilized
`Protein Formulations: Some Practical Advice, Pharm. Res., 14(8):969
`(1997).
`Jose Baselga, et al., Phase II Study of Weekly Intravenous Recom(cid:173)
`binant HumanizedAnti-pl85HER2 Monoclonal Antibody in Patients
`with HER2/neu-overexpressing Metastatic Breast Cancer, 14 J.
`Clin. Oncol. 738 (1996).
`Joseph M. Perchiacca et al., Engineering Aggregation-resistant
`Antibodies, 3 Annu. Rev. Chem. Biomol. Eng. 263 (2012).
`Larry R. Helms, et al., Destabilizing Loop Swaps in the CD Rs of an
`Immunoglobulin VL Domain, 4 Protein Sci. 2073 (1995).
`Lene J0rgensen, et al., Recent Trends in Stabilising Peptides and
`Proteins in Pharmaceutical Formulation----Considerations in the
`Choice of Excipients, 6 Expert Opin. Drug Deliv. 1219 (2009).
`Marco van de Weert & Theodore W. Randolph, Chapter 6: Physical
`Instability of Peptides and Proteins, in Pharmaceutical Formulation
`Development of Peptides and Proteins 107 (2012).
`Masako Ohnishi & Hiromichi Sagitani, The Effect of Nonionic
`Surfactant Structure on Hemolysis, 70 J. Am. Oil Chemists' Soc'Y
`679 (1993).
`Michael J. Treuheit, et al., Inverse Relationship of Protein Concen(cid:173)
`tration and Aggregation, 19 Pharm. Res. 511 (2002).
`Robert G. Hamilton, The Human IGG Subclasses (2001).
`Robert Ritzel, et al., Pharmacokinetic, Insulinotropic, and
`Glucagonostatic Properties of GLP-1 [7-36 amide] after Subcuta(cid:173)
`neous Injection in Healthy Volunteers. Dose-response-relationships,
`38 Diabetologia 720 (1995).
`Sarnpathkumar Krishnan, et al., Chapter 16: Development of For(cid:173)
`mulations for Therapeutic Monoclonal Antibodies and Fe Fusion
`Proteins, in Formulation and Process Development Strategies for
`Manufacturing Biopharmaceuticals 383 (2010).
`Stefan Ewert, et al., Biophysical Properties of Human Antibody
`Variable Domains, 325 J. Mo!. Biol. 531 (2003).
`Theodore W. Randolph & John F. Carpenter, Engineering Chal(cid:173)
`lenges of Protein Formulations, 53 Am. Inst. Chem. Eng. J. 1902
`(2007).
`Tim J. Karnerzell, et al., Increasing IgG Concentration Modulates
`the Conformational Heterogeneity and Bonding Network that Influ(cid:173)
`ence Solution Properties, 113 J. Phys. Chem. B 6109 (2009).
`Enbrel® Summary Basis of Approval (1998).
`Gloff et al., "Pharmacokinetics & Protein Therapeutics," Advanced
`Drug Delivery Reviews, 4 (1990) 359-386.
`Golimumab/Simponi® label (Revised Dec. 2011).
`Guidance for Industry, Clinical Development Programs for Drugs,
`Devices and Biological Products for the Treatment of Rheumatoid
`Arthritis ( 1999).
`Infliximab/Remicade® label (Nov. 1999).
`
`Remicade® Summary Basis of Approval (1999).
`van Gestel et al., "Development and Validation of the European
`League Against Rheumatism Response Criteria for Rheumatoid
`Arthritis," Arthritis & Rheumatism, vol. 39, No. 1, Jan. 1996, pp.
`34-40.
`Wang et al. "Antibody structure, instability, and formulation" Minirevew,
`accepted Jun. 4, 2006.
`U.S. Appl. No. 60/690,582, filed Jun. 14, 2005.
`Australian Examination Report No. 1 in Australian Appln. No.
`2013312300, dated Jul. 28, 2017, 4 pages.
`Carpenter et al., "Overlooking Subvisible Particles in Therapeutic
`Protein Products: Gaps That May Compromise Product Quality," J.
`Pharm Sci, Apr. 2009, 98(4): 1201-1205.
`Chinese Office Action in ChineseAppln. No. 20130058126.8, dated
`Nov. 16, 2015, 14 pages (with machine translation).
`Eurasian Office Action in Eurasion Appln. No. 201590518, dated
`Mar. 10, 2016, 5 pages.
`European Search Report (extended) in EuropeanAppln. No. 13835291,
`dated Mar. 15, 2016, 6 pages.
`Gilbert and Cothran, "SC versus IV delivery: Reducing costs while
`increasing patient satisfaction," Hemotology & Oncology News &
`Issues, Dec. 2005, 25-29.
`Hawe et al., "Taylor Dispersion Analysis Compared to Dynamic
`Light Scattering for the Size Analysis of Therapeutic Peptides and
`Proteins and Their Aggregates," Pharm Res, May 2011, 28: 2302-
`2310.
`Humira, product information sheet, p. 1-16, 2002, Abbott Lab.
`International Preliminary Report on Patentability in International
`Appln. No. PCT/US2013/58618, dated Mar. 10, 2015, 10 pages.
`Israel Office Action in Israeli Appln. No. 2336545, dated Jan. 21,
`2018, 5 pages (w/ English Translation).
`Japanese Office Action in Japanese Appln. No. 2015-531261, dated
`Apr. 25, 2018, 6 pages (with machine translation).
`Japanese Office Action in Japanese Appln. No. 2015-531261, dated
`Jun. 21, 2017, 15 pages (with machine translation).
`Kavanaugh et al., "Treatment with Adalimumab (D2E7) does not
`Affect Normal Immune Responsiveness," Arthritis & Rheumatism,
`Sep. 2002, 46(9): Sl32.
`Kaymakcalan et al., "Development of a Fully Human Anti-TNF
`Monoclonal Antibody," J Interferon & Cytokine Research, Abstact
`6.16, May 1998, 18(5): A-125.
`Keystone et al, "Adalmumab (D2E7), A Fully Human Anti-TNF-a
`Monoclonal Antibody, Inhibits the Progression of Structural Joint
`Damage in Patients with Active RA Despite Doncomitant Methotrex(cid:173)
`ate Therapy," Arthritis & Rheumatism, Sep. 2002, 46(9): S205.
`Maggio, "Use of excipients to control aggregation in peptide and
`protein formulations," J Excipients and Food Chem, Aug. 2010,
`1(2): 40-49.
`Singh and Singh, "Effect of Polyols on the Conformational Stability
`and Biological Activity of a Model Protein Lysozyme," AAPS
`PharmSciTech, Article 42, Jul. 2003, 4(3): 9 pages.
`Taiwanese Office Action in Taiwanese Appln. No. 102132360, dated
`Oct. 25, 2017, 8 pages (with English translation).
`Warne, "Development ofhigh concentration protein biopharmaceuticals:
`The use of platform approaches in formulation development,"
`European J Pharmaceutics and Biopharmaceutics, Mar. 2011 78(2):
`208-212.
`U.S. Appl. No. 61/004,992, filed Nov. 30, 2007, Fraunhofer et al.
`U.S. Appl. No. 16/023,046, filed Jun. 29, 2018, Fraunhofer et al.
`U.S. Appl. No. 16/023,152, filed Jun. 29, 2018, Fraunhofer et al.
`U.S. Appl. No. 16/023,161, filed Jun. 29, 2018, Fraunhofer et al.
`U.S. Appl. No. 16/023,205, filed Jun. 29, 2018, Fraunhofer et al.
`Alon et al., "Lidocaine for the Alleviation of Pain Associated with
`Subcutaneous Erythropoietin Injection," Journal of the American
`Soc. Nephrology, vol. 5, No. 4, 1161-1162, 1994.
`"Annex A Humira Story," Abbive Biotechnology Limited, submit(cid:173)
`ted to European Patent Office by owner ofEP1406656B on Dec. 22,
`2014.
`Atgarn® Label (Nov. 2005).
`Bahrenburg et al., "Buffer-free therapeutic antibody preparations
`provided a viable alternative to conventionally buffered solutions:
`From protein buffer capacity prediction to bioprocess applications,"
`Bio. J. 10:610-622, 2015.
`
`4 of 77
`
`Fresenius Kabi
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`

`US 10,155,039 B2
`Page 5
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Karow et al., "Buffer capacity of biologics-from buffer salts to
`buffering by antibodies," Biotechnol. Prog., vol. 29, No. 2, 480-492,
`2013.
`Brazeau et al., "Current perspectives on pain upon injection of
`drugs," Journal of Pharm. Sci., vol. 87, No. 6, 667-677, 1998.
`Campath (Alemtuzurnab), Genzyme Corporation, 2006.
`Gokarn et al., "Self-buffering antibody formulations," J. of Pharm.
`Sci., vol. 97, No. 8, 3051-3066, 2008.
`Granolleras et al., Experience of pain after subcutaneous adminis(cid:173)
`tration of different preparations of recombinant human erythropoietin:
`a randomized, double-blind crossover study, vol. 36, No. 6, 294-
`298, 1991.
`Harris et al., "Commerical Manufacturing Scale Formulation and
`Analytical Characterization of Therapeutic Recombinant Antibod(cid:173)
`ies," Drug Development Research, 61: 137-154, 2004.
`Humira® Label (Sep. 2007).
`Humira.com [online], "Injection Assistance", Humira®, Mar. 2005,
`[retrieved on Jan. 12, 2017], Retrieved from the Internet URL:
`
`http://web.archive.org/web/200503 l 708333 l/http://www.humira.
`corn/hu/hustore/cgibin/ProdSubEV _ Cat_205043_SubCat_210170_
`NavRoot_205042_NavID_301.htrn, 2 pages.
`McCue et al., "Three Generations of Immunoglobulin G Prepara(cid:173)
`tions for Clinical Use," Reviews of Infectious Diseases, vol. 8,
`Suppl. 4, s374-s381, 1986.
`Napke et al., "Excipients and additives: hidden hazards in drug
`products and in product substitution," Can. Med. Assoc. J., vol. 131,
`1449-1452, 1984.
`Nash et al., "Randomized Crossover Comparison of Injection Site
`Pain with 40mg/0.4 or 0.8mL Formulations of Adalimumab in
`Patients with Rheumatoid Arthritis," Rheu. Ther. 3:257-270, 2016.
`Octagam® Label (Mar. 2007).
`Privigen® Label (Jul. 2007).
`Tindall et al., "Mobile Phase Buffers, Part II," LC, GC Europe, 2-4,
`2003.
`Veys et al., "Pain at the injection site of subcutaneously adminis(cid:173)
`tered erythropoietin: phosphate-buffered epoetin alpha compared to
`cirate-buffered epoetin alpha and epoetin beta," Clin. Nep., vol. 49,
`No. 1, 41-44, 1998.
`
`5 of 77
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`

`

`U.S. Patent
`
`Dec. 18, 2018
`
`Sheet 1 of 28
`
`US 10,155,039 B2
`
`FIGURE 1
`
`LB-140 In pH 5.2 (t2 40 C)
`100.0 . . . . - - - - - - - - - - - - - - - - - - - - - - - - - ,
`
`u
`w
`cr.; 99,5
`
`' -
`CJ
`
`E g 99,0
`
`0
`~
`
`r::.
`(!)
`~ 98,5
`©
`CL
`
`98.83
`-
`
`98.84
`-
`
`98.49
`-
`
`99.19
`-
`
`98,95 -
`
`98.91
`
`~
`
`98.37
`
`~
`
`cit!phos
`
`citrate
`
`phosphate succinate
`
`histidine
`
`tartrate
`
`ma!eate
`
`6 of 77
`
`Fresenius Kabi
`Exhibit 1001
`
`

`

`U.S. Patent
`
`Dec. 18, 2018
`
`Sheet 2 of 28
`
`US 10,155,039 B2
`
`FIGURE 2
`
`LB-140 In pH 5.2 (t2 40 C)
`97.0 - , - - - - - - - - - - - - - - - - - - - - - - - - - ,
`
`96.5
`
`96.0
`
`95.5
`
`CL
`0:::
`>--
`..0
`>.,
`....,
`'-
`:::.;
`CL
`
`-
`96.19
`
`96.12
`-
`
`95.91
`-
`
`96.24
`
`, - - ~ -
`
`96.23
`
`96.21
`
`96.33
`-
`
`cit!phos
`
`citrate
`
`phosphate succinate
`
`histidine
`
`tartrate
`
`maieate
`
`7 of 77
`
`Fresenius Kabi
`Exhibit 1001
`
`

`

`U.S. Patent
`
`Dec. 18, 2018
`
`Sheet 3 of 28
`
`US 10,155,039 B2
`
`FIGURE 3
`
`Effect of Citrate/Phosphate (PLS Model 1)
`
`98.285
`
`98.302
`
`98.319
`
`98,336
`
`98.353
`
`98.370
`
`________ ,:,:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:: ___ _
`
`Response Surface
`
`0
`
`citrate
`
`a
`
`5
`
`phos
`
`8 of 77
`
`Fresenius Kabi
`Exhibit 1001
`
`

`

`U.S. Patent
`
`Dec. 18, 2018
`
`Sheet 4 of 28
`
`US 10,155,039 B2
`
`FIGURE 4
`
`Effect of Citrate/Phosphate (PLS Model 2)
`
`98.882
`
`98.902
`
`98.921
`
`98.941
`
`98.960
`
`98.980
`
`Response Surface
`
`0
`
`citrate
`
`0
`
`phos
`
`9 of 77
`
`Fresenius Kabi
`Exhibit 1001
`
`

`

`U.S. Patent
`
`Dec. 18, 2018
`
`Sheet 5 of 28
`
`US 10,155,039 B2
`
`FIGURE 5
`
`Effect of HIS/GL Y (PLS Model 1)
`
`98.252
`
`98.334
`
`98-417
`
`98.500
`
`98.583
`
`98.666
`
`Response Surface
`
`120
`100
`80
`
`glycine
`
`60
`
`20
`
`hlstidine
`
`10 of 77
`
`Fresenius Kabi
`Exhibit 1001
`
`

`

`U.S. Patent
`
`Dec. 18, 2018
`
`Sheet 6 of 28
`
`US 10,155,039 B2
`
`FIGURE 6
`
`Effect of Arg/sorbitol (PLS Model 1)
`
`98.252
`
`98.340
`
`98.429
`
`98.518
`
`98.607
`
`98.696
`
`--------~:::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: ___ _
`
`Response Surface
`
`arginine
`
`sorbito!
`
`11 of 77
`
`Fresenius Kabi
`Exhibit 1001
`
`

`

`U.S. Patent
`
`Dec. 18, 2018
`
`Sheet 7 of 28
`
`US 10,155,039 B2
`
`FIGURE 7
`
`Effect of pH/His (PLS Model 1)
`
`98.198
`
`98.270
`
`98.341
`
`98.413
`
`98.484
`
`98.556
`
`________ ,:,:::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::,:,:,:,:,:,:,:,:,:,:,:,:,:,:,:,:,:,:,:,:,:,:,:,:,:,:,:,:,:,:,:,:,:,:: ____ __
`
`Response Surface
`
`20
`
`histidine
`
`0
`
`5.1
`
`pH tO
`
`12 of 77
`
`Fresenius Kabi
`Exhibit 1001
`
`

`

`U.S. Patent
`
`Dec. 18, 2018
`
`Sheet 8 of 28
`
`US 10,155,039 B2
`
`FIGURE 8
`
`Effect of pH/His (PLS Model 2)
`
`98.833
`
`98.872
`
`98.911
`
`98.951
`
`98.990
`
`98.029
`
`Response Surface
`
`20
`
`tlistidir.e
`
`13 of 77
`
`Fresenius Kabi
`Exhibit 1001
`
`

`

`U.S. Patent
`
`Dec. 18, 2018
`
`Sheet 9 of 28
`
`US 10,155,039 B2
`
`FIGURE 9
`
`Effect of trehalose/PS 80 (PLS Model 2)
`
`98.879
`
`98.895
`
`98.911
`
`98.927
`
`98.943
`
`98.959
`
`Response Surface
`
`0.10
`0.08
`0.06
`0.04
`
`PS 80
`
`0
`
`trehalose
`
`14 of 77
`
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`Exhibit 1001
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`

`

`U.S. Patent
`
`Dec. 18, 2018
`
`Sheet 10 of 28
`
`US 10,155,039 B2
`
`FIGURE 10
`
`Effect of mannitol/PSSO (pH 5.2) (PLS Model 2)
`
`98.681
`
`98.744
`
`98,806
`
`98.869
`
`98.932
`
`98.995
`
`--------•❖:❖:❖:❖:❖:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:•:••----
`
`Response Surface
`
`0
`
`0
`
`mannitol
`
`PS 80
`
`15 of 77
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`Exhibit 1001
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`

`

`U.S. Patent
`
`Dec. 18, 2018
`
`Sheet 11 of 28
`
`US 10,155,039 B2
`
`FIGURE 11
`
`Effect of mannitol/NaCI (pH 5.2) (PLS Model 1)
`
`98.213
`
`98.254
`
`98,295
`
`98.335
`
`98.376
`
`98.417
`
`Response Surface
`
`0
`
`16 of 77
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`Exhibit 1001
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`

`

`U.S. Patent
`
`Dec. 18, 2018
`
`Sheet 12 of 28
`
`US 10,155,039 B2
`
`FIGURE 12
`
`Effect of EDT A/Met (pH 5.2) {PLS Model 1)
`
`98.287
`
`98.380
`
`98.473
`
`98,566
`
`98.660
`
`98.753
`
`Response Surface
`
`50
`
`17 of 77
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`Fresenius Kabi
`Exhibit 1001
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`

`

`U.S. Patent
`
`Dec. 18, 2018
`
`Sheet 13 of 28
`
`US 10,155,039 B2
`
`FIGURE 13
`
`Effect of citrate and phosphate
`
`................................................................ _,:,:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;: ___ _
`
`0,713
`
`1.008
`
`1.302
`
`Response Surface
`
`i .597
`
`1.892
`
`2.186
`
`30
`
`citrate
`
`18 of 77
`
`Fresenius Kabi
`Exhibit 1001
`
`

`

`U.S. Patent
`
`Dec. 18, 2018
`
`Sheet 14 of 28
`
`US 10,155,039 B2
`
`FIGURE 14
`
`Effect of pH and His
`
`0.481
`
`0,736
`
`Q,991
`
`! .246
`
`1,502
`
`1}57
`
`Response Surface
`
`30
`
`histidine
`
`pH tO
`
`19 of 77
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`Fresenius Kabi
`Exhibit 1001
`
`

`

`U.S. Patent
`
`Dec. 18, 2018
`
`Sheet 15 of 28
`
`US 10,155,039 B2
`
`FIGURE 15
`
`Effect of Gly and Arg
`
`0.190
`
`0.295
`
`0.399
`
`0.504
`
`0.608
`
`0.713
`
`""""""""""""""""'_,n=m-~m=m-~m=~m»>0mo:«~m-~m-n·•·=·=·=·=·=·=·=·=·=·=·=·=·=·=·=·=·=·=·=·=·=·=·=·=·=·=·=·=·=·=·=·=•=❖:❖:❖:❖:❖:❖:❖:❖:❖:❖:❖:❖:❖:❖:❖:❖:❖:nnnnnnnnnnnnnnnnn
`
`Response Surface
`
`0
`
`arginine
`
`0
`
`glycine
`
`20 of 77
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`Fresenius Kabi
`Exhibit 1001
`
`

`

`U.S. Patent
`
`Dec. 18, 2018
`
`Sheet 16 of 28
`
`US 10,155,039 B2
`
`FIGURE 16
`
`Effect o