EFTA02726131.pdf

Insulin Opportunity: Technical Presentation PRIVIUM 3alr FUNDS Lic EFTA_R1_02213718 EFTA02726131 Patent Portfolio Patent Estate There is a solid IP Portfolio for the regular insulin process Intellectual Property Portfolio Title Katten Ref. Application / Filing/ Issue Date Application Data/ Patent # Status hGh and Methods for • 343445-00(106 • 61,305,451 • 2,17;2010 • Provisional App.; To Preparation convert on 2/17/2011 Insulin Production Methods and • 343445-00005 • 7,790,677 • 5/20/2007(FD) • Issued Pro-Insulin Constructs • 9/7/2010 (ID) • 1st Maintenance Fee due 3/7/2014 Insulin Production Methods and • 343445-00013 • 12/658,852 • 2/16/2010 • Continuation of Pro-Insulin Constructs 11/715,731 • Published 8/19/2010 Improved Insulin Aspart Analog • 343445-00014 • TBD • In progress • In preparation Preparations and Methods of Manufacturing and Formulating Same Improved Insulin Glargine • 343445-00016 • TBD • In progress • In preparation Analog Preparations and Methods of Manufacturing and Formulating Same Liquid Insulin Compositions • 1343445-00015 • TBD • In progress • In preparation and Improved Methods of Manufacturing Liquid and Crystalline Insulin Preparations and Formulations 2 4 PRIV UM FLJNF S LIC EFTA_R1_02213719 EFTA02726132 Physiochemical Properties Technical Data Our generic meets the Doctrine of Equivalence for USP Grade Insulin-Humulin Physiochemical Property Value Amino acid sequence • Equivalent to insulin hormone, USP Amino acid composition • Equivalent to insulin hormone, USP Peptide map • Equivalent to insulin hormone, USP Disulfide bridges • Equivalent to insulin hormone, USP Molecular weight • Equivalent to insulin hormone, USP Isoform pattern • Equivalent to insulin hormone, USP Electrophoretic patterns • Equivalent to insulin hormone, USP Liquid chromatographic patterns • Equivalent to insulin hormone, USP Potency • Equivalent to insulin hormone, USP I JIM' USP Certificate Illesnan TAT II•TR. r MISISSIO 4•••••• [rm. Ill. istoc i7A 17 PKIVIUM Mir FUNDS ac EFTA_R1_02213720 EFTA02726133 Insulin Specifications Technical Data As the data shows, our generic has specifications that are equivalent to USP Grade Insulin Component Specifications Attribute Analytical Method Acceptance Criteri. Appearance • Visual Clear, colorless solution with no visible particulates Identity • RP-HPLC USP Retention time (RT) of the major peak in the chromatogram of the assay preparation corresponds to that in the chromatogram of the standard preparation, as obtained in the Assay Bacterial Endotoxins • USP <85> NMT 80 USP Endotoxin Units/100 Insulin Human Units Sterility • USP <71> Meets requirements when tested as directed for Membrane Filtration under Test for Sterility of the Products to be Examined Particulate Matter • USP <788> Meets requirements for small volume injections Limit of High Molecular • RP-HPLC USP NMT.1.7% Weight Proteins pH • USP <791> 7.0 to 7.8. determined potentiometrically Zinc • USP<591> 10 to 40 ug/100 USP Insulin Human Units Assay • RP-HPLC USP 3.30 to 3.64 mg/mL Potency 95.0% to 105.0% of label claim expressed in USP Insulin Human Units/mL Degradation Products Report all individual impurities >0.1% - Report Result lndentify all individual impurities >0.5% - Report Result Total degradation products: All peaks above reporting threshold <=3.0% Other • USP<1> Meets requirements for injections APET • USP<51> Bacterix NLT 1.0 log reduction from the initial calculated count at 7 days, NLT 3.0 log reduction from the initial count at 14 days, and no increase from the 14 days' count at 28 days Yeast and molds: no increase from the initial calculated count at 7, 14, and 28 days 18 PRIVIUM lar FUNDS ac EFTA_R1_02213721 EFTA02726134 HPLC Results Technical Data As the graphs illustrate, our generic is able to produce higher purity insulin with less polymeric forms than USP Grade Insulin 13 QCS-09-155 Filtered — Our Commercial Grade 16 Standard A — USP Grade Insulin Insulin SlopM Name: 0CS-09-145 Fatenod tniscbco Volume: 10.0 Semple Nome Mundard A *aim Vain 20.0 KMMints: RA7 IN N71 Val Minder RM Dent •UV San* Two' unknown Wasting", 214 Sample Type: unknown Waal* 214 Can Rogow USP Muted Sub BonoVeitn: ns Canna Ruyan. UV Sim Sub arawl*PIE Gantt Method: IMUln ACM 004 304 Dlulion Fodor. 1.0000 Ounce Mt SUM A014 P04 fat Diction actor. 1.0100 Recording Time: 12/02000 7:04 Sant* ISWont 1.0000 Rscording rent 17M2009 11M Sr* MR* 1.10.0 Run Tent (Si): 6000 Sin* amount 1.0000 Run In (mop OOAO SemplePS Is ell VV VIA I UV VIS 1 VAI.2 4 agI s*45 siliffejlt n aS siwi woo A 1704.214$07 I7 17.Ir 14.0 WS} F A 0} 7.5- I 11 4 4 e t Ii . Y a 0 41 201 ion Ito it) 250 211.0 Teo 3!..1 4o do • Silo it) 4100 5 PR IUM IVDS LLc lar FUN EFTA_R1_02213722 EFTA02726135 R & D Insulin Drug Substances Technical Data As the related substances analysis shows, our generic has the same peaks as USP Insulin, however, it has fewer contaminants Related Substances R & D Insulin Drug Substances Identity Retention Time Peak Area Relative Area Insulin • 21.19 • 884.701 • 99.11 A5/B4 Desamido • 22.96 • 0.842 • 0.11 • 26.3 • 0.508 • 0.07 A21 Desamido • 27.29 • 0.808 • 0.10 • 28.65 • 0.360 • 0.05 Multimer • 46.23 • 2.575 • 0.29 Insulin Human USP Standard Identity Retention Time Peak Area Relative Area % Insulin • 21.06 • 1275.883 • 98.35 A5/B4 Desamido • 23.29 • 3.084 • 0.23 • 25.36 • 0.330 • 0.05 A21 Desamido • 27.26 • 5.746 • 0.49 • 31.93 • 0.350 • 0.05 • 37.87 • 0.330 • 0.05 Multimer • 45.60 • 1.440 • 0.14 Multimer • 46.21 • 1.086 • 0.11 Multimer • 46.75 • 1.155 • 0.13 Multimer • 47.07 • 0.383 • 0.06 Multimer • 47.89 • 0.360 • 0.05 20 PRIVIUM lar FUNDS ac EFTA_R1_02213723 EFTA02726136 Peptide Mapping Technical Data As the data shows, the amino acid bonds in our generic are localized in the identical place as the USP Standard Reference Non-Reduced Peptide Map Using V8 Protease Peptide Fragments Fragment USP Reference Standard R&D Insulin Number Achain gln-cys-cys-thr-ser-ile-cy s-ser- Achain gln-cys-cys-thr-ser-ile-eys-ser- leu-tyr-gln-lcu-glu leu-tyr-gln-leu-glu Bchain phe-val-asn-gln-his-leu-cys-gly- Bchain phe-val-asn-gin-his-leu-cys-gly- ser-his-leu-val-glu ser-his-leu-val-glu I" Achain asn-tyr-cys-asn Achain asn-tyr-cys-asn Bchain ala-leu-tyr-leu-val-cys-gly-glu Bchain ala-leu-tyr-leu-val-cys-gly-glu III Arg-gly-phe-phe-tyr-thr-pro-lys-thr Arg-gly-phe-phe-tyr-thr-pro-lys-thr IV Gly-ile-val-glu Gly-ile-val-glu Reduced Peptide Map Using V8 Protease Peptide Fragments Fragment USP Reference Standard R&D Insulin Number I Gly-ile-val-glu Gly-ile-val-glu II Gln-cys-cys-thr-ser-ile-cys-ser-leu-tyr-gln- Gln-cys-eys-thr-ser-ile-cys-ser-leu-tyr-gln- leu-glu leu-glu III Asn-tyr-cys-asn Asn-tyr-cys-asn IV Phe-val-asn-gln-his-Ieu-cys-gly-ser-his- Phe-val-asn-gln-his-leu-cys-gly-ser-his-leu- leu-val-glu val-glu V Ala-leu-tvr-leu-val-cys-gly-giu Ala-Icu-tyr-Icu-val-cys-gly-glu VI Arg-gly-phe-phe-tyr-thr-pro-lys-thr A rg-gly-phe-phe-tyr-thr-pro-lys-thr 7 PRIVIUM "Mr FUNDS ac EFTA_R1_02213724 EFTA02726137 Electrophorectic Patterns Technical Data As the graphs illustrate, our generic has the identical electrophoretic patterns as USP grade insulin Figure 3.2.S.7: Reduced Gel (run on Nuplata-12% His:Iris gel with a MES SDS Figure 3.2.S.6: Non-Reduced Gel (run os Nupage 4-12% Bis-Tris gel with s MES SDS Running Buffer) Running Buffer) eau I 2 1 4 S 6 7 Blank 1 MW 3 USP SID 4 R&D 3 R&D 6 USP STD 7 MW Mirk Blw3 USP R&D R&D VSP S I 0 Illuc Plus Phs2 STD Spa InsulinSpg Inwlin his 2 nista marker Stag Insulin Insulin in $pg market maw 114 Spa 8 PRIVIUM lar FUNDS LLe EFTA_R1_02213725 EFTA02726138