EFTA00596375.pdf

Insulin Opportunity: Technical Presentation PR IUM 3Mr FUNIVDS ac EFTA00596375 Patent Portfolio There is a solid IP Portfolio for the regular insulin process Patent Estate Intellectual Property Portfolio Title Katten Ref. Application / Patent # Filing/ Issue Date Application Data/ ' Status hGh and Methods for Preparation • 343445-00006 • 61.305.451 • 2/17/2010 • Provisional App.; To convert on 2/17/2011 Insulin Production Methods and Pro-Insulin Constructs • 343445-00005 • 7,790.677 • • 5/20/2007(FD) 9/7/2010 (ID) • • Issued 1st Maintenance Fee due 3/7/2014 Insulin Production Methods and Pro-Insulin Constructs • 343445-00013 • 12/658,852 • 2/16/2010 • • Continuation of 11/715.731 Published 8/19/2010 Improved Insulin Aspart Analog Preparations and Methods of Manufacturing and Formulating Same • 343445-00014 • TBD • In progress • In preparation Improved Insulin Glargine Analog Preparations and Methods of Manufacturing and Formulating Same • 343445-00016 • TBD • In progress • In preparation Liquid Insulin Compositions and Improved Methods of Manufacturing Liquid and Crystalline Insulin Preparations and Formulations • 1343445-00015 • TBD • In progress • In preparation 2 ak FUN{ Ppuv UM S EFTA00596376 Physiochemical Properties Technical Data Our generic meets the Doctrine of Equivalence for USP Grade Insulin-Humulin Physiochemical Composition Physiochemical Property Value Amino acid sequence Amino acid composition Peptide map Disulfide bridges Molecular weight Isoform pattern Electrophoretic patterns Liquid chromatographic patterns Potency ♦ Equivalent to insulin hormone, USP ♦ Equivalent to insulin hormone, USP ♦ Equivalent to insulin hormone, USP ♦ Equivalent to insulin hormone, USP ♦ Equivalent to insulin hormone, USP ♦ Equivalent to insulin hormone, USP ♦ Equivalent to insulin hormone, USP ♦ Equivalent to insulin hormone, USP ♦ Equivalent to insulin hormone, USP t Pa' USP Certificate losullin lawman urronly %Wilt arab sm. -5* nos II. ifyitMigil-nt 17 PRIVIUM "‘Wks FUNDS LLC EFTA00596377 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 Criteria Appearance ♦ Visual ♦ Clear, colorless solution with no visible particulates Identity ♦ RP-HPLC USP ♦ Retention time (Rd 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 Weight Proteins ♦ RP-HPLC USP ♦ NMT.1.7% 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 Indentify 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.O 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 7M• r FUNDS [lc EFTA00596378 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 3 QCS-09-155 Filtered - Our Commercial Grade nsulin 16 Standard A - USP Grade Insulin Sample Name: OCS-09-1S5 Filtered Injection Volume: 10.0 Save \erne Standard A Mjechou Volume 20.0 Vial Number. RA7 Channel: UVVISJ Vig Number RAS °enna UV VIS 1 SeiTie Type! unknown Wevaiengeh 314 Sample Two: unknown Weve.ength 214 Coned Pa rte USP related Sub Banchticew As Goad Program: USP related Sub Bandmith Owed. What Insulin ACN PO4 304 Dalton Factor. 1.0000 Outing Alt lraulln ACN POI SO4 (Mace Factor 10000 Recording 717W 1212/2000 7:04 Save Weir 1.0000 Recording Tor 1212/2009 11:05 Semple Wesgta- 14000 Pin Tore fnen): 90.00 Same Amount 1.0000 hem in (awl 60.00 satngue Amount 1.0000 17- 5 Ito 340 4.3 50 VM i4 inessmareseariuss 54 Dan A LIV Vti 1 no 1 4 ( Ar k' 4 rt w . fP 0 ... ... VM.216 re Ps 40, %Ur lab 7.0. esti 5 140 de 240 is is is ' e ' ato s4e eh en IVIUM NDS LLc EFTA00596379 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 F'eak Area Relative Area % Insulin • 21.19 • 884.701 • 99.11 A5/B4 Desamido • • 22.96 26.3 • • 0.842 0.508 • • 0.11 0.07 A21 Desamido • • 27.29 28.65 • • 0.808 0.360 • • 0.10 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 FUNDS LLc EFTA00596380 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 Number USP Reference Standard R&D insulin I Achain gln-eys-cys-thr-scr-ile-eys-ser- Ieu-tyr-gln-leu-glu Banda phe-val-asn-gIn-his-lcu-eys-gly- ser-his-leu-val-glu Achain gin-eys-cys-thr-ser-ile-cys-ser- leu-tyr-gln-leu-glu Bchain phe-val-asn-gln-his-leu-cys-gly- ser-his-leu-val-glu III Achain asn-tyr-cys-asn Bchain ala-leu-tyr-leu-val-cys-gly-glu Achain asn-tyr-cys-asn Bchain ata-leu-tyr-leu-val-cys-gly-glu III Arg-gly-phc-phe-tyr-thr-pro-lys-thr Arg-gly-phe-phe-ty-r-thr-pro-lys-thr IV Gly-ile-val-glu Gly-i le-val-ulu Reduced Peptide Map Using V8 Protease Peptide Fragments Fragment Number USP Reference Standard R&D Insulin 1 Gly-ile-val-glu Gly-ile-val-gl u II Gin-cys-eys-thr-ser-ile-cys-ser-leu-tyr-gln- leu-glu GIncys-cys-tiu--ser-ile-cys-ser-leu-tyr-gln- leu-giu III Asn-tyr-cys-asn Asn-tyr-cys-asn I V Phe-val-asn-gln-his-leu-cys-gly-ser-his- I eu-val-gl u Phe-val-asn-gln-his-leu-eys-gl y-ser-his-I eu- val-gl u V A la-leu-tvr-leu-val-cys-gly-glu A la-leu-tyr-leu-val-eys-gly-glu A rg-gly-phe-phe-tyr-thr-pro-lys-thr VI A rg-gly-phe-phe-tyr-thr-pro-lys-thr 7 FUNDS tic EFTA00596381 Electrophorectic Patterns Technical Data As the graphs illustrate, our generic has the identical electrophoretic patterns as USP grade insulin Figure 3.2.56: Non-Reduced Gel (run on Nupage 4-12% BD TrIs gel with a MES SDS Running Buffer) SNP Human Insulin 2 3 4 5 6 7 Diu* MW marker LISP SID 5P8 R&D Insulin 5uf__ RID twain log USI. STD 51,8 MW market 8 Figure 325.7: Reduced Gel (run on Nupage 4-12% Bis-iris gel with a MES SDS Running Buffer) I 2 3 4 5 6 7 Wok Mug Pits 1 mortar USP STD 5pg R&D Iroulin5ng R&D Insulin lug USP STD 5pg Blue Plus 2 worker ERIVIUM FUNDS lac EFTA00596382