IP Library › Patent Application 13383710

Patent Application

App. No. 13/383,710

PEPTIDE-MEDIATED NON-COVALENT DELIVERY OF ACTIVE AGENTS ACROSS THE BLOOD-BRAIN BARRIER

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App. No.: 13/383,710

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Abstract

The peptides described herein can function as carrier peptides. These peptides can associate with (e.g., non-covalently bind) biologically active molecules or imaging agents to transport the biologically active molecules or imaging across the blood-brain barrier. In some cases, such transport may increase the effectiveness of the biological molecules or imaging agents.

Claims (461)

1 . A carrier peptide comprising the sequence:

X n -[B] m

or a pharmaceutically acceptable salt thereof, wherein:

X is a hydrophilic amino acid;

B is a blood-brain barrier agent;

n is an integer from 4 to 50; and

m is integer from 1 to 3;

wherein the blood-brain barrier agent is not L-R-K-L-R-K-R-L-L-R-L-R-K-L-R-K-R-L-L-R (SEQ ID NO: 141).

2 . The carrier peptide of claim 1 , wherein each X is independently chosen from arginine, asparagine, aspartic acid, glutamic acid, glutamine, histidine, lysine, serine, threonine, and tyrosine.

3 . The carrier peptide of claim 1 , wherein X is lysine.

4 . The carrier peptide of claim 1 , wherein n is chosen from 4, 8, 12, 16, and 20.

5 . The carrier peptide of claim 1 , wherein n is 16.

6 . The carrier peptide of claim 1 , wherein m is 1.

7 . The carrier peptide of claim 1 , wherein B is a receptor binding domain of an apolipoprotein.

8 . The carrier peptide of claim 7 , wherein the a receptor binding domain of an apolipoprotein is chosen from the receptor binding domain of ApoA, ApoB, ApoC, ApoD, ApoE, ApoE2, ApoE3, and ApoE4.

9 . The carrier peptide of claim 8 , wherein the receptor binding domain of an apolipoprotein is chosen from the receptor binding domain of ApoB and ApoE.

10 . The carrier peptide of claim 1 , wherein the blood-brain barrier agent comprises a polypeptide sequence having at least 80% sequence identity to:

(SEQ ID NO: 13)

L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A.

11 . The carrier peptide of claim 1 , wherein the blood-brain barrier agent comprises a polypeptide sequence having at least 80% sequence identity to:

(SEQ ID NO: 14)

S-S-V-I-D-A-L-Q-Y-K-L-E-G-T-T-R-L-T-R-K-R-G-L-

K-L-A-T-A-L-S-L-S-N-K-F-V-E-G-S-H.

12 . The carrier peptide of claim 1 , wherein the blood-brain barrier agent comprises a polypeptide sequence having at least 80% sequence identity to:

(SEQ ID NO: 15)

Y-P-A-K-P-E-A-P-G-E-D-A-S-P-E-E-L-S-R-Y-Y-A-S-

L-R-H-Y-L-N-L-V-T-R-Q-R-Y*;

(SEQ ID NO: 16)

A-K-P-E-A-P-G-E-D-A-S-P-E-E-L-S-R-Y-Y-A-S-L-R-

H-Y-L-N-L-V-T-R-Q-R-Y*;

(SEQ ID NO: 17)

Y-P-S-D-P-D-N-P-G-E-D-A-P-A-E-D-L-A-R-Y-Y-S-A-

L-R-H-Y-I-N-L-I-T-R-Q-R-Y*;

(SEQ ID NO: 18)

A-P-L-E-P-V-Y-P-G-D-D-A-T-P-E-Q-M-A-Q-Y-A-A-E-

L-R-R-Y-I-N-M-L-T-R-P-R-Y*,

wherein Y* is tyrosine or a tyrosine derivative.

13 . The carrier peptide of any one of claims 10 - 12 , wherein the polypeptide is less than 100 amino acids in length.

14 . The carrier peptide of claim 1 , wherein the carrier peptide is chosen from:

(SEQ ID NO: 19)

K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 20)

K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-

L-R-D-A;

(SEQ ID NO: 21)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-

R-K-R-L-L-R-D-A;

(SEQ ID NO: 22)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-

L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 23)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-

L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 24)

K-K-K-K-S-S-V-I-D-A-L-Q-Y-K-L-E-G-T-T-R-L-T-R-K-

R-G-L-K-L-A-T-A-L-S-L-S-N-K-F-V-E-G-S-H;

(SEQ ID NO: 25)

K-K-K-K-K-K-K-K-S-S-V-I-D-A-L-Q-Y-K-L-E-G-T-T-R-

L-T-R-K-R-G-L-K-L-A-T-A-L-S-L-S-N-K-F-V-E-G-S-H;

(SEQ ID NO: 26)

K-K-K-K-K-K-K-K-K-K-K-K-S-S-V-I-D-A-L-Q-Y-K-L-E-

G-T-T-R-L-T-R-K-R-G-L-K-L-A-T-A-L-S-L-S-N-K-F-V-

E-G-S-H;

(SEQ ID NO: 27)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-S-S-V-I-D-A-L-Q-

Y-K-L-E-G-T-T-R-L-T-R-K-R-G-L-K-L-A-T-A-L-S-L-S-

N-K-F-V-E-G-S-H;

and

(SEQ ID NO: 28)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-S-S-V-I-

D-A-L-Q-Y-K-L-E-G-T-T-R-L-T-R-K-R-G-L-K-L-A-T-A-

L-S-L-S-N-K-F-V-E-G-S-H.

15 . A complex, or a pharmaceutically acceptable salt thereof, comprising a biologically active molecule or an imaging agent associated with a carrier peptide, wherein the carrier peptide comprises the sequence:

X n -[B] m

wherein:

X is a hydrophilic amino acid;

B is a blood-brain barrier agent;

n is an integer from 4 to 50; and

m is integer from 1 to 3,

wherein the blood-brain barrier agent is not L-R-K-L-R-K-R-L-L-R-L-R-K-L-R-K-R-L-L-R (SEQ ID NO: 141).

16 .- 28 . (canceled)

29 . The complex of claim 15 , wherein the imaging agent is chosen from: 125 I-IgG and magnevist.

30 . The complex of claim 15 , wherein the biologically active molecule is chosen from a: polypeptide; oligonucleotide; plasmid; small molecule; antibody; antibody fragment; carbohydrate; polysaccharide; lipid; glycolipid; antigen; and antigenic peptide.

31 . The complex of claim 30 , wherein the biologically active molecule is chosen from a: polypeptide; oligonucleotide; and plasmid.

32 . The complex of claim 30 , wherein the oligonucleotide is chosen from a: coding DNA sequence; antisense DNA sequence; mRNA, antisense RNA sequence; RNAi; and siRNA.

33 . The complex of claim 30 , wherein the small molecule is a therapeutic agent.

34 . The complex of claim 15 , wherein the biologically active molecule or imaging agent is non-covalently bound to the carrier peptide.

35 . A method of transporting a biologically active molecule or imaging agent across the blood-brain barrier of a subject, the method comprising administering to the subject a complex, or a pharmaceutically acceptable salt thereof, comprising the biologically active molecule or imaging agent associated with a carrier peptide; wherein the carrier peptide comprises the sequence:

X n -[B] m

or a pharmaceutically acceptable salt thereof, wherein:

X is a hydrophilic amino acid;

B is a blood-brain barrier agent;

n is an integer from 4 to 50; and

m is integer from 1 to 3,

wherein the blood-brain barrier agent is not L-R-K-L-R-K-R-L-L-R-L-R-K-L-R-K-R-L-L-R (SEQ ID NO: 141).

36 . A method of treating a brain disorder in a subject, the method comprising administering to the subject a complex, or a pharmaceutically acceptable salt thereof, comprising a biologically active agent associated with a carrier peptide, wherein the carrier peptide comprises the sequence:

X n -[B] m

wherein:

X is a hydrophilic amino acid;

B is a blood-brain barrier agent;

n is an integer from 4 to 50; and

m is integer from 1 to 3,

wherein the blood-brain barrier agent is not L-R-K-L-R-K-R-L-L-R-L-R-K-L-R-K-R-L-L-R (SEQ ID NO: 141).

37 . The method of claim 36 , wherein the brain disorder is chosen from: meningitis, epilepsy, multiple sclerosis, neuromyelitis optica, late-stage neurological trypanosomiasis, Parkinson's, progressive multifocal leukoencephalopathy, De Vivo disease, Alzheimer's disease, HIV Encephalitis, and cancer.

38 . A method of imaging the central nervous system of a subject, the method comprising administering to the subject a complex, or a pharmaceutically acceptable salt thereof, comprising an imaging agent associated with a carrier peptide, wherein the carrier peptide comprises the sequence:

X n -[B] m

wherein:

X is a hydrophilic amino acid;

B is a blood-brain barrier agent;

n is an integer from 4 to 50; and

m is integer from 1 to 3; and

imaging the central nervous system of the subject,

wherein the blood-brain barrier agent is not L-R-K-L-R-K-R-L-L-R-L-R-K-L-R-K-R-L-L-R (SEQ ID NO: 141).

39 . A pharmaceutical composition comprising a complex, or a pharmaceutically acceptable salt thereof, comprising a biologically active molecule or imaging agent, a carrier peptide, and a pharmaceutically acceptable carrier; wherein the carrier peptide comprises the sequence:

X n -[B] m

wherein:

X is a hydrophilic amino acid;

B is a blood-brain barrier agent;

n is an integer from 4 to 50; and

m is integer from 1 to 3,

wherein the blood-brain barrier agent is not L-R-K-L-R-K-R-L-L-R-L-R-K-L-R-K-R-L-L-R (SEQ ID NO: 141).

40 .- 42 . (canceled)

42 . A blood-brain barrier agent comprising the sequence:

(SEQ ID NO: 29)

L-R-X1-R-X2-X3-X4-H-L-R-X5-X6-X7-K-R-L-X8-R-D-X9

wherein:

X1 is selected from the group consisting of A, L, S, and V;

X2 is selected from the group consisting of L and M;

X3 is selected from the group consisting of A and S;

X4 is selected from the group consisting of N, S, and T;

X5 is selected from the group consisting of K and N;

X6 is selected from the group consisting of L, M, and V;

X7 is selected from the group consisting of R and P;

X8 is selected from the group consisting of L and M; and

X9 is selected from the group consisting of A and L;

wherein the carrier peptide does not comprise:

(SEQ ID NO: 13)

L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A.

43 . The blood-brain barrier agent of claim 42 , wherein the blood-brain barrier agent is selected from the group consisting of:

(SEQ ID NO: 30)

L-R-S-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 31)

L-R-V-R-M-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 32)

L-R-V-R-L-A-T-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 33)

L-R-V-R-L-A-S-H-L-R-K-L-P-K-R-L-L-R-D-A;

(SEQ ID NO: 34)

L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-M-R-D-A;

(SEQ ID NO: 35)

L-R-V-R-L-A-S-H-L-R-N-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 36)

L-R-V-R-L-A-S-H-L-R-K-V-R-K-R-L-L-R-D-A;

(SEQ ID NO: 37)

L-R-V-R-M-S-S-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 38)

L-R-V-R-L-A-S-H-L-R-N-V-R-K-R-L-L-R-D-A;

(SEQ ID NO: 39)

L-R-V-R-L-A-S-H-L-R-N-M-R-K-R-L-L-R-D-A;

(SEQ ID NO: 40)

L-R-A-R-M-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 41)

L-R-V-R-L-S-S-H-L-R-K-L-R-K-R-L-M-R-D-A;

(SEQ ID NO: 42)

L-R-S-R-L-A-S-H-L-R-K-L-R-K-R-L-M-R-D-A;

(SEQ ID NO: 43)

L-R-V-R-L-S-S-H-L-P-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 44)

L-R-V-R-L-A-S-H-L-R-K-M-R-K-R-L-M-R-D-A;

(SEQ ID NO: 45)

L-R-V-R-L-A-S-H-L-R-N-L-P-K-R-L-L-R-D-A;

(SEQ ID NO: 129)

L-R-L-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-L;

and

(SEQ ID NO: 130)

L-R-V-R-L-A-N-H-L-R-K-L-R-K-R-L-L-R-D-L.

44 .- 49 . (canceled)

50 . A complex, or a pharmaceutically acceptable salt thereof, comprising a biologically active molecule or an imaging agent associated with a carrier peptide, wherein the carrier peptide comprises the sequence:

(SEQ ID NO: 143)

[X]n-L-R-X1-R-X2-X3-X4-H-L-R-X5-X6-X7-K-R-L-X8-

R-D-X9

wherein:

X is a hydrophilic amino acid;

n is an integer from 4 to 50;

X1 is selected from the group consisting of A, L, S, and V;

X2 is selected from the group consisting of L and M;

X3 is selected from the group consisting of A and S;

X4 is selected from the group consisting of N, S, and T;

X5 is selected from the group consisting of K and N;

X6 is selected from the group consisting of L, M, and V;

X7 is selected from the group consisting of R and P;

X8 is selected from the group consisting of L and M; and

X9 is selected from the group consisting of A and L.

51 . The complex of claim 50 , wherein the carrier peptide is selected form the group consisting of:

(SEQ ID NO: 19)

K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 20)

K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-

L-R-D-A;

(SEQD NO: 21)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-

R-K-R-L-L-R-D-A;

(SEQ ID NO: 22)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-

L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 23)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-

L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 46)

K-K-K-K-L-R-S-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 47)

K-K-K-K-K-K-K-K-L-R-S-R-L-A-S-H-L-R-K-L-R-K-R-L-

L-R-D-A;

(SEQ ID NO: 48)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-S-R-L-A-S-H-L-R-K-L-

R-K-R-L-L-R-D-A;

(SEQ ID NO: 49)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-S-R-L-A-S-H-

L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 50)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-S-R-

L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 51)

K-K-K-K-L-R-V-R-M-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 52)

K-K-K-K-K-K-K-K-L-R-V-R-M-A-S-H-L-R-K-L-R-K-R-L-

L-R-D-A;

(SEQ ID NO: 53)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-M-A-S-H-L-R-K-L-

R-K-R-L-L-R-D-A;

(SEQ ID NO: 54)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-M-A-S-H-

L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 55)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-

M-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 56)

K-K-K-K-L-R-V-R-L-A-T-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 57)

K-K-K-K-K-K-K-K-L-R-V-R-L-A-T-H-L-R-K-L-R-K-R-L-

L-R-D-A;

(SEQ ID NO: 58)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-T-H-L-R-K-L-

R-K-R-L-L-R-D-A;

(SEQ ID NO: 59)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-T-H-

L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 60)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-

L-A-T-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 61)

K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-P-K-R-L-L-R-D-A;

(SEQ ID NO: 62)

K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-P-K-R-L-

L-R-D-A;

(SEQ ID NO: 63)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-

P-K-R-L-L-R-D-A;

(SEQ ID NO: 64)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-

L-R-K-L-P-K-R-L-L-R-D-A;

(SEQ ID NO: 65)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-

L-A-S-H-L-R-K-L-P-K-R-L-L-R-D-A;

(SEQ ID NO: 66)

K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-M-R-D-A;

(SEQ ID NO: 67)

K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-

M-R-D-A;

(SEQ ID NO: 68)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-

R-K-R-L-M-R-D-A;

(SEQ ID NO: 69)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-

L-R-K-L-R-K-R-L-M-R-D-A;

(SEQ ID NO: 70)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-

L-A-S-H-L-R-K-L-R-K-R-L-M-R-D-A;

(SEQ ID NO: 71)

K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 72)

K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-L-R-K-R-L-

L-R-D-A;

(SEQ ID NO: 73)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-L-

R-K-R-L-L-R-D-A;

(SEQ ID NO: 74)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-

L-R-N-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 75)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-

L-A-S-H-L-R-N-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 76)

K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-V-R-K-R-L-L-R-D-A;

(SEQ ID NO: 77)

K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-V-R-K-R-L-

L-R-D-A;

(SEQ ID NO: 78)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-V-

R-K-R-L-L-R-D-A;

(SEQ ID NO: 79)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-

L-R-K-V-R-K-R-L-L-R-D-A;

(SEQ ID NO: 80)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-

L-A-S-H-L-R-K-V-R-K-R-L-L-R-D-A;

(SEQ ID NO: 81)

K-K-K-K-L-R-V-R-M-S-S-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 82)

K-K-K-K-K-K-K-K-L-R-V-R-M-S-S-H-L-R-K-L-R-K-R-L-

L-R-D-A;

(SEQ ID NO: 83)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-M-S-S-H-L-R-K-L-

R-K-R-L-L-R-D-A;

(SEQ ID NO: 84)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-M-S-S-H-

L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 85)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-

M-S-S-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 86)

K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-V-R-K-R-L-L-R-D-A;

(SEQ ID NO: 87)

K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-V-R-K-R-L-

L-R-D-A;

(SEQ ID NO: 88)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-V-

R-K-R-L-L-R-D-A;

(SEQ ID NO: 89)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-

L-R-N-V-R-K-R-L-L-R-D-A;

(SEQ ID NO: 90)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-

L-A-S-H-L-R-N-V-R-K-R-L-L-R-D-A;

(SEQ ID NO: 91)

K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-M-R-K-R-L-L-R-D-A;

(SEQ ID NO: 92)

K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-M-R-K-R-L-

L-R-D-A;

(SEQ ID NO: 93)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-M-

R-K-R-L-L-R-D-A;

(SEQ ID NO: 94)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-

L-R-N-M-R-K-R-L-L-R-D-A;

(SEQ ID NO: 95)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-

L-A-S-H-L-R-N-M-R-K-R-L-L-R-D-A;

(SEQ ID NO: 96)

K-K-K-K-L-R-A-R-M-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 97)

K-K-K-K-K-K-K-K-L-R-A-R-M-A-S-H-L-R-K-L-R-K-R-L-

L-R-D-A;

(SEQ ID NO: 98)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-A-R-M-A-S-H-L-R-K-L-

R-K-R-L-L-R-D-A;

(SEQ ID NO: 99)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-A-R-M-A-S-H-

L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 100)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-A-R-

M-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 101)

K-K-K-K-L-R-V-R-L-S-S-H-L-R-K-L-R-K-R-L-M-R-D-A;

(SEQ ID NO: 102)

K-K-K-K-K-K-K-K-L-R-V-R-L-S-S-H-L-R-K-L-R-K-R-L-

M-R-D-A;

(SEQ ID NO: 103)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-S-S-H-L-R-K-L-

R-K-R-L-M-R-D-A;

(SEQ ID NO: 104)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-S-S-H-

L-R-K-L-R-K-R-L-M-R-D-A;

(SEQ ID NO: 105)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-

L-S-S-H-L-R-K-L-R-K-R-L-M-R-D-A;

(SEQ ID NO: 106)

K-K-K-K-L-R-S-R-L-A-S-H-L-R-K-L-R-K-R-L-M-R-D-A;

(SEQ ID NO: 107)

K-K-K-K-K-K-K-K-L-R-S-R-L-A-S-H-L-R-K-L-R-K-R-L-

M-R-D-A;

(SEQ ID NO: 108)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-S-R-L-A-S-H-L-R-K-L-

R-K-R-L-M-R-D-A;

(SEQ ID NO: 109)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-S-R-L-A-S-H-

L-R-K-L-R-K-R-L-M-R-D-A;

(SEQ ID NO: 110)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-S-R-

L-A-S-H-L-R-K-L-R-K-R-L-M-R-D-A;

(SEQ ID NO: 111)

K-K-K-K-L-R-V-R-L-S-S-H-L-P-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 112)

K-K-K-K-K-K-K-K-L-R-V-R-L-S-S-H-L-P-K-L-R-K-R-L-

L-R-D-A;

(SEQ ID NO: 113)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-S-S-H-L-P-K-L-

R-K-R-L-L-R-D-A;

(SEQ ID NO: 114)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-S-S-H-

L-P-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 115)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-

L-S-S-H-L-P-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 116)

K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-M-R-K-R-L-M-R-D-A;

(SEQ ID NO: 117)

K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-M-R-K-R-L-

M-R-D-A;

(SEQ ID NO: 118)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-M-

R-K-R-L-M-R-D-A;

(SEQ ID NO: 119)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-

L-R-K-M-R-K-R-L-M-R-D-A;

(SEQ ID NO: 120)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-

L-A-S-H-L-R-K-M-R-K-R-L-M-R-D-A;

(SEQ ID NO: 121)

K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-L-P-K-R-L-L-R-D-A;

(SEQ ID NO: 122)

K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-L-P-K-R-L-

L-R-D-A;

(SEQ ID NO: 123)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-L-

P-K-R-L-L-R-D-A;

(SEQ ID NO: 124)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-

L-R-N-L-P-K-R-L-L-R-D-A;

(SEQ ID NO: 125)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-

L-A-S-H-L-R-N-L-P-K-R-L-L-R-D-A;

(SEQ ID NO: 131)

K-K-K-K-L-R-L-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-L;

(SEQ ID NO: 132)

K-K-K-K-K-K-K-K-L-R-L-R-L-A-S-H-L-R-K-L-R-K-R-L-

L-R-D-L;

(SEQ ID NO: 133)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-L-R-L-A-S-H-L-R-K-L-

R-K-R-L-L-R-D-L;

(SEQ ID NO: 134)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-L-R-L-A-S-H-

L-R-K-L-R-K-R-L-L-R-D-L;

(SEQ ID NO: 135)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-L-R-

L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-L;

(SEQ ID NO: 136)

K-K-K-K-L-R-V-R-L-A-N-H-L-R-K-L-R-K-R-L-L-R-D-L;

(SEQ ID NO: 137)

K-K-K-K-K-K-K-K-L-R-V-R-L-A-N-H-L-R-K-L-R-K-R-L-

L-R-D-L;

(SEQ ID NO: 138)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-N-H-L-R-K-L-

R-K-R-L-L-R-D-L;

(SEQ ID NO: 139)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-N-H-

L-R-K-L-R-K-R-L-L-R-D-L;

(SEQ ID NO: 140)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-

L-A-N-H-L-R-K-L-R-K-R-L-L-R-D-L.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 14, 2012

From: CURRAN, GEOFFRY L.; SARKAR, GOBINDA; PODUSLO, JOSEPH F.; JENKINS, ROBERT B.; LOWE, VAL J.; MAHLUM, ERIC W.

To: MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH

Reel/Frame 027698/0873 →