# US 2019/0375813 A1 · Insulin analogues with selective signaling properties and reduced mitogenicity > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2019/0375813 A1 - Document ID: US20190375813A1 - Status: Published application - Kind: A1 - Application number: 16/521,969 - Filed: 2019-07-25 - Published: 2019-12-12 - Earliest claimed: 2015-01-20 - Assignees: Case Western Reserve University - Applicants: Case Western Reserve University - Inventors: Michael A. WEISS - Web page: https://patentgrep.com/patent/US20190375813A1 ## CPC - C07K 14/62: Insulins - A61P 3/10: for hyperglycaemia, e.g. antidiabetics - A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) ## Abstract A two-chain insulin analogue contains Aspartic Acid at position B10 and penta-fluoro-Phenylalanine at position B24, optionally Histidine or Glutamic Acid at position A8, optionally additional substitutions or modifications at positions A13 and/or A14 and/or B28 and/or B29. The analogue may be an analogue of a mammalian insulin, such as human insulin, may optionally include (i) N-terminal deletion of one, two or three residues from the B chain, (ii) a mono-peptide or dipeptide C-terminal extension of the B-chain containing at least one acidic residue, and (iii) other modifications known in the art to enhance the stability of insulin. Formulations of the above analogues at successive strengths U-100 to U-1000 in soluble solutions at at least pH value in the range 7.0-8.0 in the absence or presence of zinc ions at a molar ratio of 0.00-0.10 zinc ions per insulin analogue monomer. ## Claims ### Claim 1 An insulin analogue comprising a B-chain polypeptide containing an Asp substitution at position B10 relative to wild type human insulin and a penta-fluoro-Phe substitution at position B24 relative to wild type human insulin. ### Claim 2 (depends on 1) The insulin analogue of claim 1, additionally comprising a Glu substitution at position B29 relative to wild type human insulin. ### Claim 3 (depends on 1) The insulin analogue of claim 1, additionally comprising an Ornithine substitution at position B29 relative to wild type human insulin. ### Claim 4 (depends on 1) The insulin analogue of claim 1, additionally comprising a substitution at position B28 relative to human insulin, selected from the group consisting of Lys, Gln, and Ala. ### Claim 5 (depends on 4) The insulin analogue of claim 4, wherein the substitution at position B28 relative to human insulin is Lys, and additionally comprising a Pro substitution at position B29 relative to human insulin. ### Claim 6 (depends on 1) The insulin analogue of claim 1, additionally comprising an N-terminal deletion of the B-chain polypeptide of one to three amino acids. ### Claim 7 (depends on 6) The insulin analogue of claim 6, additionally comprising an A-chain polypeptide containing one or more of the substitutions, relative to wild type human insulin, selected from the group consisting of: a substitution at position A8 selected from any amino acid other than Val, Leu and Ile; a substitution at position A13 selected from Trp or Tyr; a Tyr substitution at position A14; and a substitution at position A21 selected from the group consisting of Asn, Asp, Ala and Gly. ### Claim 8 (depends on 1) The insulin analogue of claim 1, additionally comprising an A-chain polypeptide containing one or more of the substitutions, relative to wild type human insulin, selected from the group consisting of: a substitution at position A8 selected from any amino acid other than Val, Leu and Ile; a substitution at position A13 selected from Trp or Tyr; a Tyr substitution at position A14; and a substitution at position A21 selected from the group consisting of Asn, Asp, Ala and Gly. ### Claim 9 (depends on 2) The insulin analogue of claim 2, additionally comprising an A-chain polypeptide containing one or more of the substitutions, relative to wild type human insulin, selected from the group consisting of: a substitution at position A8 selected from any amino acid other than Val, Leu and Ile; a substitution at position A13 selected from Trp or Tyr; a Tyr substitution at position A14; and a substitution at position A21 selected from the group consisting of Asn, Asp, Ala and Gly.