US2012107243A1PendingUtilityA1
Peptide-mediated non-covalent delivery of active agents across the blood-brain barrier
Individually held — no corporate assignee on recordPriority: Jul 14, 2009Filed: Jul 14, 2010Published: May 3, 2012
Est. expiryJul 14, 2029(~3 yrs left)· nominal 20-yr term from priority
Inventors:Geoffry L. CurranGobinda SarkarJoseph F. PodusloRobert B. JenkinsVal J. LoweEric W. Mahlum
A61P 31/18A61P 35/00A61P 25/00A61P 25/28A61P 25/16A61P 25/08C12Y 302/01023A61K 47/64A61K 51/1018A61K 38/47A61K 51/12A61K 39/39533C07K 14/775A61K 49/0058A61K 49/0056A61K 51/088Y02A50/30
44
PatentIndex Score
0
Cited by
0
References
0
Claims
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
exact text as granted — not AI-modified1 . 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*;
or
(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.Join the waitlist — get patent alerts
Track US2012107243A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.