Claims for Patent: 10,259,856

Summary for Patent: 10,259,856

Title:	Protease stabilized acylated insulin analogues
Abstract:	Novel acylated insulin analogues exhibiting resistance towards proteases can, effectively, be administered pulmonary or orally. The insulin analogues contain B25H and A14E or A14H.
Inventor(s):	Madsen; Peter (Bagsvaerd, DK), Kjeldsen; Thomas Boerglum (Virum, DK), Hoeg-Jensen; Thomas (Klampenborg, DK), Jakobsen; Palle (Vaerloese, DK), Tagmose; Tina Moeller (Ballerup, DK), Glendorf; Tine (Lyngby, DK), Kodra; Janos Tibor (Koebenhavn, DK), Garibay; Patrick William (Holte, DK), Petersen; Jacob Sten (Charlottenlund, DK)
Assignee:	Novo Nordisk A/S (Bagsvaerd, DK)
Application Number:	14/686,176
Patent Claims:	1. An acylated protease stabilized insulin, wherein said protease stabilized insulin derived from a non-protease stabilized human insulin or human insulin analogue, wherein at least two hydrophobic amino acids have been substituted with hydrophilic amino acids, and wherein said substitutions are situated one amino acid away from or within two or more protease cleavage sites which are selected from positions B14-15, B24-25, B25-26 and A14-15 of the non-protease stabilized insulin and wherein such protease stabilized insulin optionally further comprises one or more additional mutations, with the proviso that there is only one lysine residue in the stabilized insulin, and wherein the acyl moiety is attached to the lysine residue or to a N-terminal position in the protease stabilized insulin and has the general formula Acy-AA1.sub.n-AA2.sub.m-AA3.sub.p- (I), wherein n is 0 or an integer in the range from 1 to 3; m is an integer in the range from 1 to 10; p is 0 or an integer in the range from 1 to 10; Acy is a fatty acid or a fatty diacid comprising from about 8 to about 24 carbon atoms; AA1 is a neutral linear or cyclic amino acid residue; AA2 is an acidic amino acid residue; AA3 is a neutral, alkyleneglycol-containing amino acid residue; the order by which AA1, AA2 and AA3 appears in the formula can be interchanged independently; AA2 can occur several times along the formula; AA2 can occur independently several times along the connections between Acy, AA1, AA2 and/or AA3 are amide bonds which, formally, can be obtained by removal of a hydrogen atom or a hydroxyl group from each of Acy, AA1, AA2 and AA3; and attachment to the protease stabilized insulin can be from the C-terminal end of a AA1, AA2, or AA3 residue in the acyl moiety of the formula (I) or from one of the side chain(s) of an AA2 residue present in the moiety of formula (I). 2. The acylated protease stabilized insulin according to claim 1, wherein the acyl moiety is attached to the lysine residue in the protease stabilized insulin. 3. The acylated protease stabilized insulin according to claim 1, wherein the acyl moiety is attached to the amino group of the A-chain N-terminal residue in the protease stabilized insulin. 4. The acylated protease stabilized insulin according to claim 1, wherein Acy is a fatty diacid, preferably a fatty (.alpha.,.omega.) diacid, more preferred heptadecanedioic acid, hexadecanedioic acid, octadecanedioic acid, nonadecanedioic acid, docosanedioic acid, eicosanedioic acid. 5. The acylated protease stabilized insulin according to claim 1, wherein AA2 is .gamma.Glu, .alpha.Glu, .beta.Asp, .alpha.Asp, .gamma.-D-Glu, .alpha.-D-Glu, .beta.-D-Asp, .alpha.-D-Asp, or an amino acid of the following formula selected from the group consisting of: ##STR00218## wherein the arrows indicate the attachment point to the amino group of AA1, AA2, AA3 or to the .epsilon.-amino group of the B29 lysine residue or to a N-terminal position of the protease stabilised insulin. 6. The acylated protease stabilized insulin according to claim 1, wherein AA3 is selected from the group consisting of: ##STR00219## wherein r is 1, 2, 3, 5, 7, 11, 23 or 27. 7. The acylated protease stabilized insulin according to claim 1, wherein the amino acid in position A12 is Glu or Asp; and/or the amino acid in position A13 is His, Asn, Glu or Asp; and/or the amino acid in position A14 is Tyr, Asn, Gln, Glu, Arg, Asp, Gly or His; and/or the amino acid in position A15 is Glu or Asp; and the amino acid in position B24 is His; and/or the amino acid in position B25 is His or Asn; and/or the amino acid in position B26 is His, Gly, Asp or Thr; and/or the amino acid in position B27 is His, Glu, Asp, Gly or Arg; and/or the amino acid in position B28 is His, Gly, Glu or Asp; and which optionally further comprises one or more additional mutations. 8. The acylated protease stabilized insulin according to claim 1, wherein the amino acid in position A14 is Glu, Asp or His and the amino acid in position B25 is His and the amino acid in position B30 is deleted. 9. The acylated protease stabilized insulin according to claim 1, wherein the one or more additional mutations is selected from a group consisting of: A8His, A18Gln, A21Gln, A21Gly, B1Glu, B1Gln, B3Gln, B10Pro, B14Thr, B16Glu, B17Ser, B26Asp, B27Glu, B27Asp, B28Asp, B28Glu, and desB30. 10. The acylated protease stabilized insulin according to claim 1, wherein the additional mutation is desB30. 11. The acylated protease stabilized insulin according to claim 1, wherein A14 is Glu. 12. The acylated protease stabilized insulin according to claim 1, wherein B25 is His. 13. The acylated protease stabilized insulin according to claim 1, wherein the C terminal amino acid residue in the A chain of the protease stabilized insulin is the A21 amino acid residue. 14. The acylated protease stabilized insulin according to claim 1, comprising an A-chain amino acid sequence of formula 1, i.e.: Xaa.sub.A(-2)-Xaa.sub.A(-1)-Xaa.sub.A0-Gly-Ile-Val-Glu-Gln-Cys-Cys-Xaa.su- b.A8-Ser-Ile-Cys-Xaa.sub.A12-Xaa.sub.A13-Xaa.sub.A14-Xaa.sub.A15-Leu-Glu-X- aa.sub.A18-Tyr-Cys-Xaa.sub.A21 (SEQ ID No:1), and a B-chain amino acid sequence of formula 2, i.e.: Xaa.sub.B(-2)-Xaa.sub.B(-1)-Xaa.sub.B0-Xaa.sub.B1-Xaa.sub.B2-Xaa.sub.B3-X- aa.sub.B4-His-Leu-Cys-Gly-Ser-Xaa.sub.B10-Leu-Val-Glu-Ala-Leu-Xaa.sub.B16-- Leu-Val-Cys-Gly-Glu-Arg-Gly-Xaa.sub.B24-Xaa.sub.B25-Xaa.sub.B26-Xaa.sub.B2- 7-Xaa.sub.B28-Xaa.sub.B29-Xaa.sub.B30-Xaa.sub.B31-Xaa.sub.B32 (SEQ ID No:2), wherein Xaa.sub.A(-2) is absent or Gly; Xaa.sub.A(-1) is absent or Pro; Xaa.sub.A0 is absent or Pro; Xaa.sub.A8 is independently selected from Thr and His; Xaa.sub.A12 is independently selected from Ser, Asp and Glu; Xaa.sub.A13 is independently selected from Leu, Thr, Asn, Asp, Gln, His, Lys, Gly, Arg, Pro, Ser and Glu; Xaa.sub.A14 is independently selected from Tyr, Thr, Asn, Asp, Gln, His, Lys, Gly, Arg, Pro, Ser and Glu; Xaa.sub.A15 is independently selected from Gln, Asp and Glu; Xaa.sub.A18 is independently selected from Asn, Lys and Gln; Xaa.sub.A21 is independently selected from Asn and Gln; Xaa.sub.B(-2) is absent or Gly; Xaa.sub.B(-1) is absent or Pro; Xaa.sub.B0 is absent or Pro; Xaa.sub.B1 is absent or independently selected from Phe and Glu; Xaa.sub.B2 is absent or Val; Xaa.sub.B3 is absent or independently selected from Asn and Gln; Xaa.sub.B4 is independently selected from Gln and Glu; Xaa.sub.B10 is independently selected from His, Asp, Pro and Glu; Xaa.sub.B16 is independently selected from Tyr, Asp, Gln, His, Arg, and Glu; Xaa.sub.B24 is independently selected from Phe and His; Xaa.sub.B25 is independently selected from Phe, Asn and His; Xaa.sub.B26 is absent or independently selected from Tyr, His, Thr, Gly and Asp; Xaa.sub.B27 is absent or independently selected from Thr, Asn, Asp, Gln, His, Gly, Arg, Pro, Ser and Glu; Xaa.sub.B28 is absent or independently selected from Pro, His, Gly and Asp; Xaa.sub.B29 is absent or independently selected from Lys and Gln; Xaa.sub.B30 is absent or Thr; Xaa.sub.B31 is absent or Leu; Xaa.sub.B32 is absent or Glu; the C-terminal may optionally be derivatized as an amide; wherein the A-chain amino acid sequence and the B-chain amino acid sequence are connected by disulphide bridges between the cysteines in position 7 of the A-chain and the cysteine in position 7 of the B-chain, and between the cysteine in position 20 of the A-chain and the cysteine in position 19 of the B-chain and wherein the cysteines in position 6 and 11 of the A-chain are connected by a disulphide bridge; wherein optionally the N-terminal A-chain amino acid sequence is connected to the C-terminal B-chain amino acid sequence by an amino acid sequence comprising 3-7 amino acids to form a single chain insulin molecule, wherein optionally the N-terminal of the B-chain is extended with 1-10 amino acids; wherein if Xaa.sub.A8 is Thr and Xaa.sub.A12 is Ser and Xaa.sub.A13 is Leu and Xaa.sub.A14 is Tyr then Xaa.sub.A15 is Glu or Asp; and wherein if Xaa.sub.B24 is Phe and Xaa.sub.B25 is Phe and Xaa.sub.B26 is Tyr and Xaa.sub.B27 is Thr and Xaa.sub.B28 is Pro then Xaa.sub.B29 Gln. 15. A pharmaceutical composition comprising an acylated protease stabilized insulin according to claim 1 and a pharmaceutically acceptable carrier or excipient. 16. A method of treating hyperglycemia, type 2 diabetes, impaired glucose tolerance or type 1 diabetes in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of the pharmaceutical composition of claim 15. 17. An acylated protease stabilized insulin, wherein the protease stabilized insulin is selected from the group consisting of ASH, B25N, B27E, desB30 human insulin; A14E, A18L, B25H, desB30 human insulin; A14E, A21G, B25H, desB27, desB30 human insulin; A14E, B1E, B25H, B27E, B28E, desB30 human insulin; A14E, B1E, B25H, B28E, desB30 human insulin; A14E, B1E, B27E, B28E, desB30 human insulin; A14E, B1E, B28E, desB30 human insulin; A14E, B16H, B25H, desB30 human insulin; A14E, B25H, desB30 human insulin; A14E, B25H, B26G, B27G, B28G, desB30 human insulin; A14E, B25H, B27E, desB30 human insulin; A14E, B25H, desB27, desB30 human insulin; A14E, B25H, B29R, desB30 human insulin; A14E, B28D, desB30 human insulin; A14E, B28E, desB30 human insulin; B25N, B27E, desB30 human insulin; A14E, A21G, B16H, B25H, desB30 human insulin; A14E, A21G, B25H, B26G, B27G, B28G, desB30 human insulin; B25H, desB30 human insulin; A21G, B25H, desB30 human insulin; A14E, A21G, B25H, desB30 human insulin and A14E, A21G, B25H, desB27, desB30 human insulin, and wherein an acyl moiety is attached to the lysine residue or to a N-terminal position in said protease stabilized insulin and has the general formula Acy-AA1.sub.n-AA2.sub.m-AA3.sub.p- (I), wherein n is 0 or an integer in the range from 1 to 3; m is an integer in the range from 1 to 10; p is 0 or an integer in the range from 1 to 10; Acy is a fatty acid or a fatty diacid comprising from about 8 to about 24 carbon atoms; AA1 is a neutral linear or cyclic amino acid residue; AA2 is an acidic amino acid residue; AA3 is a neutral, alkyleneglycol-containing amino acid residue; the order by which AA1, AA2 and AA3 appears in the formula can be interchanged independently; AA2 can occur several times along the formula; AA2 can occur independently several times along the connections between Acy, AA1, AA2 and/or AA3 are amide bonds which, formally, can be obtained by removal of a hydrogen atom or a hydroxyl group from each of Acy, AA1, AA2 and AA3; and attachment to the protease stabilized insulin can be from the C-terminal end of a AA1, AA2, or AA3 residue in the acyl moiety of the formula (I) or from one of the side chain(s) of an AA2 residue present in the moiety of formula (I). 18. An acylated protease stabilized insulin selected from the group consisting of A14E, B25H, B29K(N.sup..epsilon.-hexadecandioyl), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.3-carboxy-5-octadecanedioylaminobenzoyl), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.--N-octadecandioyl-N-(2-carboxyethyl)glycyl), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon. (N-octadecandioyl-N-carboxymethyl)-beta-alanyl), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.4-([4-({19-carboxynonadecanoylamino}methyl)trans-cycl- ohexanecarbonyl]-.gamma.Glu), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.heptadecanedioyl-.gamma.Glu), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.myristyl), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu-.gamma.Glu), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.4-([4-({19-carboxynonadecanoylamino}methyl)trans-cycl- ohexanecarbonyl]-.gamma.Glu-.gamma.Glu), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.octadecanedioyl-.gamma.Glu-.gamma.Glu), desB30 human insulin; A14E, B28D, B29K(N.sup..epsilon.octadecandioyl-.gamma.Glu), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.octadecandioyl-.gamma.Glu-PEG7), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu-(3-(2-{2-[2-(2-aminoethoxy)e- thoxy]ethoxy}ethoxy)propionyl-.gamma.Glu), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.hexadecanedioyl-.gamma.Glu), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.octadecanedioyl-.gamma.Glu-.gamma.Glu-.gamma.Glu-.gam- ma.Glu), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu-.gamma.Glu-.gamma.Glu), desB30 human insulin; A14E, B25H, B27E, B29K(N.sup..epsilon.octadecanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, B25H, B26G, B27G, B28G, B29K(N.sup..epsilon.octadecanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, B16E, B25H, B29K(N.sup..epsilon.octadecanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, B16H, B25H, B29K(N.sup..epsilon.hexadecanedioyl-.gamma.Glu), desB30 human insulin; A14E, B16E, B25H, B29K(N.sup..epsilon.hexadecandioyl-.gamma.Glu), desB30 human insulin; A14E, B25H, B26G, B27G, B28G, B29K(N.sup..epsilon.hexadecandioyl-.gamma.Glu), desB30 human insulin; A14E, A18L, B25H, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, A18L, B25H, B29K(N.sup..epsilon.octadecanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, B25H, B27E, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A1G(N.sup..alpha.octadecandioyl-.gamma.Glu-OEG-OEG), A14E, B25H, B29R, desB30 human insulin; A14E, B1F(N.sup..alpha.octadecandioyl-.gamma.Glu-OEG-OEG), B25H, B29R, desB30 human insulin; A1G(N.sup..alpha.hexadecandioyl-.gamma.Glu), A14E, B25H, B29R, desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.octadecanedioyl-.gamma.Glu-Abu-Abu-Abu-Abu), desB30 human insulin; A14E, B25H, B29K(N.sup..alpha.eicosanedioyl), desB30 human insulin; A14E, B25H, B29K(N.sup..alpha.4-[16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl]butanoyl)- , desB30 human insulin; A14E, B25H, B26G, B27G, B28G, B29K(N.sup..epsilon.octadecandioyl-.gamma.Glu), desB30 human insulin; A14E, B25H, B26G, B27G, B28G, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu), desB30 human insulin; A14E, B25H, B26G, B27G, B28G, B29K(N.sup..epsilon.octadecandioyl), desB30 human insulin; A14E, B25H, B26G, B27G, B28G, B29K(N.sup..epsilon.eicosanedioyl), desB30 human insulin; A14E, B25H, B26G, B27G, B28G, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.docosanedioyl-.gamma.Glu), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.docosanedioyl-.gamma.Glu-.gamma.Glu), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon. (N-icosanedioyl-N-carboxymethyl)-3Ala), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.3-[2-(2-{2-[2-(17-carboxyheptadecanoylamino)ethoxy]et- hoxy}ethoxy)ethoxy]propionyl-.gamma.Glu), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.3-[2-(2-{2-[2-(19-carboxynonadecanoylamino)-eth- oxy]}ethoxy)ethoxy]propionyl-.gamma.Glu), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.octadecandioyl-.gamma.Glu-(3-(2-{2-[2-(2-aminoe- thoxy)ethoxy]ethoxy}ethoxy)propionyl), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.octadecandioyl-.gamma.Glu-(3-(2-{2-[2-(2-aminoethoxy)- ethoxy]ethoxy}ethoxy)propionyl-.gamma.Glu), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.icosanedioyl-.gamma.Glu-(3-(2-{2-[2-(2-aminoeth- oxy)ethoxy]ethoxy}ethoxy)propionyl), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.4-([4-({17-carboxynonadecanoylamino}methyl)trans-cycl- ohexanecarbonyl]-.gamma.Glu), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.4-([4-({17-carboxyheptadecanoylamino}methyl)trans-cyc- lohexanecarbonyl]-.gamma.Glu-.gamma.Glu), desB30 human insulin; A14E, B28D, B29K(N.sup..epsilon.hexadecandioyl-.gamma.Glu), desB30 human insulin; A14E, B28D, B29K(N.sup..epsilon. eicosanedioyl-.gamma.Glu), desB30 human insulin; A14E, B28D, B29K(N.sup..epsilon. octadecandioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, B28D, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, B28E, B29K(N.sup..epsilon.hexadecandioyl-.gamma.Glu), desB30 human insulin; A14E, B28E, B29K(N.sup..epsilon. octadecandioyl-.gamma.Glu), desB30 human insulin; A14E, B28E, B29K(N.sup..epsilon. eicosanedioyl-.gamma.Glu), desB30 human insulin; A14E, B28E, B29K(N.sup..epsilon.octadecandioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, B28E, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, B1E, B28E, B29K(N.sup..epsilon.hexadecandioyl-.gamma.Glu), desB30 human insulin; A14E, B1E, B28E, B29K(N.sup..epsilon.octadecandioyl-.gamma.Glu), desB30 human insulin; A14E, B1E, B28E, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu), desB30 human insulin; A14E, B1E, B28E, B29K(N.sup..epsilon.hexadecandioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, B1E, B28E, B29K(N.sup..epsilon.octadecandioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, B1E, B28E, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, B1E, B27E, B28E, B29K(N.sup..epsilon.hexadecandioyl-.gamma.Glu), desB30 human insulin; A14E, B1E, B27E, B28E, B29K(N.sup..epsilon.octadecandioyl-.gamma.Glu), desB30 human insulin; A14E, B1E, B27E, B28E, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu), desB30 human insulin; A14E, B1E, B27E, B28E, B29K(N.sup..epsilon.hexadecandioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, B1E, B27E, B28E, B29K(N.sup..epsilon.octadecandioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, B1E, B27E, B28E, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, B1E, B25H, B28E, B29K(N.sup..epsilon.hexadecandioyl-.gamma.Glu), desB30 human insulin; A14E, B1E, B25H, B28E, B29K(N.sup..epsilon.octadecandioyl-.gamma.Glu), desB30 human insulin; A14E, B1E, B25H, B28E, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu), desB30 human insulin; A14E, B1E, B25H, B28E, B29K(N.sup..epsilon.hexadecandioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, B1E, B25H, B28E, B29K(N.sup..epsilon.octadecandioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, B1E, B25H, B28E, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, B1E, B25H, B27E, B28E, B29K(N.sup..epsilon.hexadecandioyl-.gamma.Glu), desB30 human insulin; A14E, B1E, B25H, B27E, B28E, B29K(N.sup..epsilon.octadecandioyl-.gamma.Glu), desB30 human insulin; A14E, B1E, B25H, B27E, B28E, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu), desB30 human insulin; A14E, B1E, B25H, B27E, B28E, B29K(N.sup..epsilon.hexadecandioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, B1E, B25H, B27E, B28E, B29K(N.sup..epsilon.octadecandioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, B1E, B25H, B27E, B28E, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, B28D, B29K(N.sup..epsilon.hexadecanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, B28E, B29K(N.sup..epsilon.hexadecanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; B25N, B27E, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; B25N, B27E, B29K(N.sup..epsilon.octadecanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; B25N, B27E, B29K(N.sup..epsilon.hexadecanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; B25N, B27E, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu), desB30 human insulin; B25N, B27E, B29K(N.sup..epsilon.octadecanedioyl-.gamma.Glu), desB30 human insulin; B25N, B27E, B29K(N.sup..epsilon.hexadecanedioyl-.gamma.Glu), desB30 human insulin; A8H, B25N, B27E, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A8H, B25N, B27E, B29K(N.sup..epsilon.octadecanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A8H, B25N, B27E, B29K(N.sup..epsilon.hexadecanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A8H, B25N, B27E, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu), desB30 human insulin; A8H, B25N, B27E, B29K(N.sup..epsilon.octadecanedioyl-.gamma.Glu), desB30 human insulin; A8H, B25N, B27E, B29K(N.sup..epsilon.hexadecanedioyl-.gamma.Glu), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon. (N-icosanedioyl-N-carboxymethyl)-3Ala-OEG-OEG), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon. (N-octadecanedioyl-N-carboxymethyl)-3Ala-OEG-OEG), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon. (N-hexadecanedioyl-N-carboxymethyl)-3Ala-OEG-OEG), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.octadecanedioyl-.gamma.Glu-2-[(3-{2-[2-(3-aminopropox- y)ethoxy]ethoxy}propyl-carbamoyl)methoxy]acetyl), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu-2-[(3-{2-[2-(3-aminopropoxy)- ethoxy]ethoxy}propylcarbamoyl)methoxy]acetyl), desB30 human insulin; A14E, B16H, B25H, B29K(N.sup..epsilon.octadecanedioyl-.gamma.Glu-2-[(3-{2-[2-(3-amino-propo- xy)ethoxy]ethoxy}propylcarbamoyl)methoxy]acetyl), desB30 human insulin; A14E, B16H, B25H, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu-2-[(3-{2-[2-(3-aminopropoxy)- ethoxy]ethoxy}propyl-carbamoyl)methoxy]acetyl), desB30 human insulin; B25H, B29K(N.sup..epsilon.octadecanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; B25H, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; B25H, B29K(N.sup..epsilon.octadecanedioyl-.gamma.Glu), desB30 human insulin; B25H, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu), desB30 human insulin; B25H, B29K(N.sup..epsilon.octadecanedioyl), desB30 human insulin; B25H, B29K(N.sup..epsilon.eicosanedioyl), desB30 human insulin; B25H, B29K(N.sup..epsilon.octadecanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; B25H, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; B25H, B29K(N.sup..epsilon.octadecanedioyl-.gamma.Glu), desB30 human insulin; B25H, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu), desB30 human insulin; B25H, B29K(N.sup..epsilon.octadecanedioyl), desB30 human insulin; B25H, B29K(N.sup..epsilon.eicosanedioyl), desB30 human insulin; B25H, B29K(N.sup..epsilon.octadecanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; B25H, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; B25H, B29K(N.sup..epsilon.octadecanedioyl-.gamma.Glu), desB30 human insulin; B25H, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu), desB30 human insulin; A14E, B25H, desB27, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu), desB30 human insulin; A14E, A21G, B25H, desB27, B29K(N.sup..epsilon.octadecanedioyl), desB30 human insulin; A14E, A21G, B25H, desB27, B29K(N.sup..epsilon.eicosanedioyl), desB30 human insulin; A14E, A21G, B25H, desB27, B29K(N.sup..epsilon.octadecanedioyl-.gamma.Glu), desB30 human insulin; A14E, B25H, desB27, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu), desB30 human insulin; A14E, A21G, B25H, desB27, B29K(N.sup..epsilon.octadecanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A1G(N.sup..alpha.octadecandioyl-.gamma.Glu-OEG-OEG), A14E, A21G, B25H, desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.eicosanedioyl-OEG), desB30 human insulin; A14E, B25H, B27K(N.sup..epsilon.octadecanedioyl-.gamma.Glu-OEG-OEG), desB28, desB29, desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.(5-cicosancdioylaminoisophthalic acid)), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.octadecanedioyl), desB30 human insulin; A14E, B29K(N.sup..epsilon.octadecanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, B25H, B26G, B27G, B28G, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.octadecanedioyl-.gamma.Glu-OEG), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.eicosanedioyl-OEG-OEG), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.eicosanedioyl-Aoc), desB30 human insulin; A14E, B25H, B26G, B27G, B28G, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu-.gamma.Glu), desB30 human insulin; A14E, B25H, B26G, B27G, B28G, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu-.gamma.Glu), desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.octadecanedioyl-OEG), desB30 human insulin; A14E, B25H, desB27, B29K(N.sup..epsilon.octadecanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A1G(N.sub..epsilon.octadecanedioyl), A14E, B25H, B29R, desB30 human insulin; A14E, B25H, B27K(N.sup..epsilon.eicosanedioyl-.gamma.Glu), desB28, desB29, desB30 human insulin; A14E, B25H, B29K(N.sup..epsilon.octadecanedioyl-.gamma.Glu-.gamma.Glu-.gamma.Glu), desB30 human insulin; A21G, B25H, B29K(N.sup..epsilon.octadecanedioyl), desB30 human insulin; A14E, A21G, B25H, desB27, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, A21G, B25H, B29K(N.sup..epsilon.octadecanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, A21G, B25H, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu-OEG-OEG), desB30 human insulin; A14E, A21G, B25H, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu), desB30 human insulin; A14E, A21G, B25H, B29K(N.sup..epsilon.eicosanedioyl), desB30 human insulin; A14E, A21G, B25H, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu), desB30 human insulin; A14E, A21G, B25H, B29K(N.sup..epsilon.octadecanedioyl), desB30 human insulin; A14E, B25H, B26G, B27G, B28G, B29K(N.sup..epsilon.octadecanedioyl-.gamma.Glu), desB30 human insulin; A14E, B25H, B26G, B27G, B28G, B29K(N.sup..epsilon.octadecanedioyl), desB30 human insulin; A14E, B25H, B26G, B27G, B28G, B29K(N.sup..epsilon.eicosanedioyl-.gamma.Glu), desB30 human insulin; A14E, B25H, B26G, B27G, B28G, B29K(N.sup..epsilon.eicosanedioyl), desB30 human insulin; A1G(N.sup..alpha.octadecandioyl-.gamma.Glu), A14E, B25H, B26G, B27G, B28G, desB30 human insulin; A1G(N.sub..alpha.eicosanedioyl-.gamma.Glu), A14E, B25H, B26G, B27G, B28G, desB30 human insulin; A1G(N.sup..alpha.octadecandioyl-.gamma.Glu), A14E, B25H, B26G, B27G, B28G, B29R, desB30 human insulin; A1G(N.sup..alpha.eicosanedioyl-.gamma.Glu), A14E, B25H, B26G, B27G, B28G, B29R, desB30 human insulin; A1G(N.sup..alpha.octadecandioyl), A14E, B25H, B26G, B27G, B28G, desB30 human insulin; A1G(N.sup..alpha.eicosanedioyl), A14E, B25H, B26G, B27G, B28G, desB30 human insulin; A1G(N.sup..alpha.octadecandioyl), A14E, B25H, B26G, B27G, B28G, B29R, desB30 human insulin and A1G(N.sup..alpha.eicosanedioyl), A14E, B25H, B26G, B27G, B28G, B29R, desB30 human insulin.

Details for Patent 10,259,856

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Eli Lilly And Company	HUMULIN R U-100	insulin human	Injection	018780	October 28, 1982	10,259,856	2028-03-18
Eli Lilly And Company	HUMULIN R U-500	insulin human	Injection	018780	December 29, 2015	10,259,856	2028-03-18
Eli Lilly And Company	HUMULIN R U-100	insulin human	Injection	018780	August 06, 1998	10,259,856	2028-03-18
Eli Lilly And Company	HUMULIN R U-500	insulin human	Injection	018780	March 31, 1994	10,259,856	2028-03-18
Eli Lilly And Company	HUMULIN R U-100	insulin human	Injection	018780	May 25, 2018	10,259,856	2028-03-18
Novo Nordisk Inc.	NOVOLIN R	insulin human	Injection	019938	June 25, 1991	10,259,856	2028-03-18