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(12) STANDARD PATENT (11) Application No. AU 2012328524 B2 (19) AUSTRALIAN PATENT OFFICE

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(12) STANDARD PATENT (11) Application No. AU 2012328524 B2 (19) AUSTRALIAN PATENT OFFICE (12) STANDARD PATENT (11) Application No. AU 2012328524 B2 (19) AUSTRALIAN PATENT OFFICE (54) Title Protein formulations containing amino acids (51) International Patent Classification(s) A61K 47/16 (2006.01) A61K 39/395 (2006.01) A61K 9/08 (2006.01) A61K 47/12 (2006.0 1) (21) Application No: 2012328524 (22) Date of Filing: 2012.10.26 (87) WIPO No: W013/063510 (30) Priority Data (31) Number (32) Date (33) Country 61/552,688 2011.10.28 US (43) Publication Date: 2013.05.02 (44) Accepted Journal Date: 2017.05.18 (71) Applicant(s) Excelse Bio, Inc. (72) Inventor(s) Chang, Byeong Seon (74) Agent / Attorney Pizzeys Patent and Trade Mark Attorneys Pty Ltd, GPO Box 1374, BRISBANE, QLD, 4001, AU (56) Related Art Krishnan et al, Chapter 16; Formulation and Process Development Strategies for Manufacturing Biopharmaceuticals, Ed. Jameel & Hershenson, John Wiley & Sons, Inc., ISBN: 978-0-470-11812-2 Gokarn et al, Chapter 17: "Excipients for Protein Drugs"; Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems, Ed. Katdare & Chaubal, Informa Healthcare USA, Inc., ISBN: 978-0-8493-2706-3 Falconer et al, Journal of Chemical Technology and Biotechnology (2011), Vol. 86, Pages 942-948 US 2009/0291076 Al WO 2011/109365 A2 US 2007/0116700 Al WO 2011/104381 A2 US 2007/0053900 Al Bolli et al, Biologicals (2010), Vol. 38, Pages 150-157 Maeder et al, Biologicals (2011), Vol. 39, Pages 43-49 Kamerzell et al, Advanced Drug Delivery Reviews (2011), Vol. 63, Pages 1118-1159 He et al, Journal of Pharmaceutical Sciences (2011), Vol. 100, Pages 1330-1340 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date W O 2013/063510 Al 2 May 2013 (02.05.2013) W I PO I P CT (51) International Patent Classification: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61K47/16 (2006.01) A61K 9/08 (2006.01) DO, DZ, EC, EE, EG, ES, Fl, GB, GD, GE, GH, GM, GT, A61K 47/12 (2006.01) A61K 39/395 (2006.01) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (21) International Application Number: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, PCT/US2012/062282 NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, (22) International Filing Date: RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, 26 October 2012 (26.10.2012) TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated,for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, 61/552,688 28 October 2011 (28.10.2011) US UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (71) Applicant: INTEGRITYBIO INC. [US/US]; 820 Calle EE, ES, Fl, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Plano, Camarillo, CA 93012 (US). MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (72) Inventor: CHANG, Byeong, Seon; 14735 Sutton Street, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Sherman Oaks, CA 91403 (US). ML, MR, NE, SN, TD, TG). (74) Agent: WEINSTEIN, Peter, D.; One3IP Management, Published: 1560-1 Newbury Rd., #237, Newbury Park, CA 91320 - with internationalsearch report (Art. 21(3)) (US). - before the expiration of the time limit for amending the (81) Designated States (unless otherwise indicated,for every claims and to be republished in the event of receipt of kind of nationalprotection available): AE, AG, AL, AM, amendments (Rule 48.2(h)) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (54) Title: PROTEIN FORMULATIONS CONTAINING AMINO ACIDS 1.4 -L 1 0%4 1~ 29SV-V2rO -- - P 2.0%X 0~~~~~~ 10 4 220 5 0 7 0 0 2.-~4 I- b t- n"I (h r) FIG. 1 (57) Abstract: Provided are stable protein formulations that contain at least one amino acid. In certain embodiments, amino acid O combinations either at least two, or three, or four, or more amino acids are included. By virtue of inclusion of the amino acids, the formulation has low viscosity and a protein in the formulations is physically, chemically, and biological stable even at high concen trations. In further embodiments, by virtue of inclusion of the amino acids, a protein in the formulations is physically, chemically, and biological stable even at high concentrations. PROTEIN FORMULATIONS CONTAINING AMINO ACIDS FIELD OF INVENTION [0001] This invention relates generally to stable protein formulations and their preparation and uses. BACKGROUND [0002] Pharmaceutical proteins and polypeptides, among other biopharmaceuticals, pose formulation challenges that can be intractable. Pharmaceutical proteins often cannot be administered orally, because they are degraded by the digestive process. Transdermal administration also generally is not suitable for proteins, because they are too large to pass through the skin effectively. Pulmonary delivery has been developed to the extent that one insulin product has been introduced to the market, but with limited success. [0003] Consequently, pharmaceutical proteins typically are administered by injection; but, there are problems in formulating proteins for injection as well. Proteins in conventional solutions generally are unstable. They are prone to degradation, such as deamidation, aggregation and precipitation, from both chemical and physical processes. Aggregation, precipitation, and viscosity are particularly problematic for most proteins, especially at high protein concentrations. Proteins generally are more stable when lyophilized than they are in solution. However, inconvenience and patient compliance limit the successful marketing of lyophilized drug products and the preference for liquid formulations. [0004] Proteins often cannot be formulated at sufficiently high concentrations for injection of effective amounts. In cases where the solubility and/or stability of the protein is limited, products are formulated at lower concentrations and delivered by intravenous infusion. However, high concentration protein-based medicines are desired by both patients and manufacturers. One reason is that is allows smaller volumes of liquid to be administered to an individual. Nevertheless, increasing the protein concentration may result in deleterious effects. The goal of high concentration and lyophilization has been elusive, in part because of deleterious viscoelastic and other properties occurring as concentration increases. Increased concentration sometimes, for instance, increases the tendency to aggregate or form gels, as well as increases the difficulty in administering these solutions through standard subcutaneous syringe and needle configurations. [0005] In one example, antibody and antibody-like therapeutics are inherently difficult to concentrate, likely due in part to the nature of their complementarity determining regions ("CDRs," further discussed below). And yet, for therapeutic applications, antibody compositions at concentrations above 100 mg/ml or even 200 mg/ml are desirable. Similarly, high concentrations of other proteins commonly used to treat individuals 1 is also desirable, for instance, for those individuals administered proteins either intravenously or subcutaneously. [0006] Developing acceptable protein formulations is particularly challenging at high concentrations, such as those required for injection. Presently, a variety of proteins cannot be stably formulated at high concentrations in solution. Even for those that have been formulated in solution at relatively high concentrations, the solutions are not stable, suffering from aggregation or precipitation, and are too viscous for injection. Consequently, there are many proteins that suffer from sub-optimal formulations or cannot be formulated advantageously for injection at all. [0007] There is, therefore, a need for methods to make improved protein formulations, and for the formulations themselves. In one aspect, there is a need for protein formulations that are stable and have low viscosity. In another aspect, there is a need for protein formulations that are stable and have low viscosity for a protein therapeutic formulation at a high protein concentration for administration. In a further aspect, there is a need for formulations that are stable and have low viscosity for a liquid protein therapeutic formulation at a high protein concentration for administration by injection. Also, there is a need for better systematic methods to develop such formulations. SUMMARY [0008] It has now been discovered that inclusion of one, two, or more, different amino acids in a protein formulation improves the stability of the protein, even at high concentrations at which the protein is typically not stable in conventional formulations. While not wanting to be bound by any theory, it is believed that the amino acids limit deleterious viscoelastic effects and enhance the stability of the protein. [0009] Again, while not wanting to be bound by any theory, it is contemplated that, when two more amino acids are included in a protein formulation, the amino acid combination may reversibly antagonize or block protein regions that are involved in protein-protein interactions, thereby competitively inhibiting such protein-protein contact and improving protein stability as well as reducing viscosity in the formulation. [0010] The experimental examples below demonstrate that the use of amino acids in protein formulations permits retaining viscoelastic properties found in dilute solution, without resorting to modifying the protein structure itself. Therefore, protein formulations prepared with the present technology are stable even when the protein concentration is greater than about 130 mg/ml, 200 mg/ml or even higher, without deleterious viscoelastic effect or compromised stability. 2 [0011] Also described herein are processes for screening for suitable amino acid and amino acid combinations that improve the stability of protein formulations, using high throughput screening protocol based on relevant physical or biochemical markers.
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