THOMAS W WAKEFIELD, MD
Radiology in Ann Arbor, MI

5614494, Mar 25, 1997

Sep 8, 1994

8/303025

Thomas W. Wakefield - Ann Arbor MI
James C. Stanley - Ann Arbor MI
Philip C. Andrews - Ann Arbor MI

University of Michigan, The Board of Regents Acting For and on Behalf of - Ann Arbor MI

A61K 3800, C02K 14745

514 12

Less toxic agents for reversal of heparin or low molecular weight heparin anticoagulation which are synthetic protamine-like polycationic peptides having a total cationic charge which is less than that of n-protamine. In preferred embodiments, arginine residues of n-protamine are replaced with lysine residues for ease of manufacture. Selective positively charged arginine residues have been replaced with an uncharged amino acid residue or its analog, such as glycine or glutamine, in order to reduce the total cationic charge on the polycationic peptide to the range of about [+14] to [+18], preferably [+16] to [+18]. In specific embodiments, there are sequences of 29 and 32 amino acid residues wherein 4 to 5 clusters of 2 to 4 positively charged amino acids are separated by 2 to 6 neutral amino acids. The C-terminus and the N-terminus can be modified to mitigate against in vivo degradation by carboxypeptidases and aminopeptidases. Another modification, specifically use of. alpha.

5534619, Jul 9, 1996

Nov 12, 1993

8/152488

Thomas W. Wakefield - Ann Arbor MI
James C. Stanley - Ann Arbor MI
Philip C. Andrews - Ann Arbor MI

The Board of Regents acting on behalf of University of Michigan - Ann Arbor MI

A61K 3800, C07K 1400

530324

Less toxic agents for reversal of heparin or low molecular weight heparin anticoagulation which are synthetic protamine-like polycationic peptides having a total cationic charge which is less than that of n-protamine. In preferred embodiments, arginine residues of n-protamine are replaced with lysine residues for ease of manufacture. Selective positively charged arginine residues have been replaced with an uncharged amino acid residue or its analog, such as glycine or glutamine, in order to reduce the total cationic charge on the polycationic peptide to the range of about [+14] to [+18], preferably [+16]. In specific embodiments, there are sequences of 29 amino acid residues wherein 4 to 5 clusters of 2 to 4 positively charged amino acids are separated by 2 to 6 neutral amino acids. The C-terminus and the N-terminus can be modified to mitigate against in vivo degradation by carboxypeptidases and aminopeptidases.

5721212, Feb 24, 1998

Jul 9, 1996

8/677304

Thomas W. Wakefield - Ann Arbor MI
James C. Stanley - Ann Arbor MI
Philip C. Andrews - Ann Arbor MI

University of Michigan, The Board of Regents . . . et al. - Ann Arbor MI

A61K 3800, C07K 1400

514 12

Less toxic agents for reversal of heparin or low molecular weight heparin anticoagulation which are synthetic protamine-like polycationic peptides having a total cationic charge which is less than that of n-protamine. In preferred embodiments, arginine resides of n-protamine are replaced with lysine residues for ease of manufacture. Selective positively charged arginine residues have been replaced with an uncharged amino acid residue or its analog, such as glycine or glutamine, in order to reduce the total cationic charge on the polycationic peptide to the range of about �+14! to �+18!, preferably �+16!. In specific embodiments, there are sequences of 29 amino acid residues wherein 4 to 5 clusters of 2 to 4 positively charged amino acids are separated by 2 to 6 neutral amino acids. The C-terminus and the N-terminus can be modified to mitigate against in vivo degradation by carboxypeptidases and aminopeptidases.