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WO2025155923A1 - Aav capsid modifications that enable improved cns-wide gene delivery through interactions with the transferrin receptor - Google Patents

Aav capsid modifications that enable improved cns-wide gene delivery through interactions with the transferrin receptor

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Publication number
WO2025155923A1
WO2025155923A1 PCT/US2025/012207 US2025012207W WO2025155923A1 WO 2025155923 A1 WO2025155923 A1 WO 2025155923A1 US 2025012207 W US2025012207 W US 2025012207W WO 2025155923 A1 WO2025155923 A1 WO 2025155923A1
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eaysr
saaysr
sayyssrr
aaysr
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French (fr)
Inventor
Benjamin DEVERMAN
Ken Chan
Qin Huang
Andrew Barry
Fatmaelzahraa Sobhy Abdelmouty EID
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Broad Institute Inc
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Broad Institute Inc
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    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
    • A61K48/0025—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid
    • A61K48/0041—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid the non-active part being polymeric
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    • G—PHYSICS
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    • G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)

Definitions

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  • EIIYYSSRI EIYRI EMYSRI EMYSR EPYSSR EPYSR E YSR E R E YYSR E YSSR ETYSR E ETYSRR ETYSR ETYSR ETYSR ETTYSR ETYSR ETYSR ETYSR ETYYSR ETYSR ETYSR ETYSR ETYSR ETYSR ETYSR ETYSR E EVYSRR GVYSR GAYSR GAYSR GAAYYSSRR ++ ++ -- -- -- ++++ ++ -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- --

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Abstract

Developing vehicles that efficiently deliver genes throughout the human central nervous system (CNS) will broaden the range of treatable genetic diseases. Applicants engineered an AAV capsid, BI-hTFRl, that binds human Transferrin Receptor (TfRl), a protein expressed on the blood-brain barrier (BBB). BI-hTFRl was actively transported across a human brain endothelial cell layer and, relative to AAV9, provided 40-50 times greater reporter expression in the CNS of human TFRC knock-in mice. The enhanced tropism was CNS-specific and absent in wild type mice. When used to deliver GBA1, mutations of which cause Gaucher disease and are linked to Parkinson's disease, BI-hTFRl substantially increased brain and cerebrospinal fluid glucocerebrosidase activity compared to AAV9.

Description

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. - , 2., on.- -. - - --, ,. , . - - – - -TM .-- . , - , - . ,,, . ,- - . T -,,- . - M ---- .. - . - . , - .., . ,- - . , --, , , ,-- . , , - .- , ., , - -, .,-- -. - . . . ,2 . - .., ., ----, -, --,, - - _ _ ._ _ . . . , , - .-, ,, . , , . . . - .. - - -- -- -- - - . . ,, , - – . – - ,,.°, -, 2 , - , . . , ° , , . , . . ,. ,, . . ,. – . , -- , , , , . , , ,, , . - , --, --,- -. ,,,, , ° , ,° , °. . - - -.- . , , ,, , . - , - -- - - ,,,, - , , , , . , ° 2 , . . , . , . . ° .2 , . - , - . ,-, 2 ° . , .- - , ,, . . , . , 2 -. ,,, , -2,, , .- , , - ° °, , . . , , ,, ° ™ . , . - . -,- - -, , -, , ,, - ,°, . ,- , , , , - - , - , , ., , ,, ,,- , . - -, , , -- ° . ,- . , . °, , . , . - ,--, - ,, , , ,- , , , , , , , , , , , , . - . , , - ,--- -,- -- ™ . , , , , - ., , . , , , ,-,., , , , . - , , , , ,., , - . . , - - - . -.. . ,, . . , , . - ... . , ., , - , -– . ,. , . . , , . . - . - . - - .. – , - - -- . , , - . - , , . - ---- -- - - ,11, ., , .. , −°. ,, , , . , . , . , , . - . . , . , --- - -1-4 12. ., , . , . –– . ,, , . , −°. ..,- −, .°. - - - , ,,. , . ., , - , , , , . , – . - . ,. . , −° , , ,- . . , . , . . . . - , . . . .. ’’. - - : -- -- ::
.. - u enome rouconurcaon are + -+ n m . - . .–. , , . , , , . - –, - - ––, -–, . . --- , -- , - - . ., . ,n r , . , - -,, - . , . , - -. . . , , - . . - - . , , . . “-“ - - “.” - “” “” “--“ - “ ” . “ ” . - - - , . - . - , , . --. -- - . . - - . - . - -- . . . “”. “” “” “ ” “--“ - “-“ “ -” -. . . - .. - --.-- ,--- , , 1 12. - .. . ., . , - ... , - , . , , ,-, -- ,-, .- ,, . - , .,. . , . -.,. ... , - . , - . . , - - -, - .- - . , - - , , . . ., .. ,.,.. ,. ,.,.. ,. .. . -. .. , , – . - . ,.. ,.. , .,– .... -.,.. ,.,.,,.. ,. ,.,... ,,.. ,. ,.. , . ,. ..., – . . .. ,. ,-.. , . ..., ..., – . .-.,. , .,...,,... ,.. ,.. ,. , .,.-. . ,. ,. .,– .. ,. ,. ,. , . ,.-.,. ,..,. , -- - ..-.-,..,..,..,– . ,.... ,,... ,. ,.. ,. - ,.. ,. , ,. ,.,. ,. ,. ,.. ... , . .. ,. , .,– . . ........,–. ... ,.. , .... .,– .....,..., . . ,– . .,.– ,. ,. , - . . .. ,... ,..,.. ,.. ,.. , . .,. , . .,– . . . ,. ,. ,. ,. , ,,. ,.,. ,. ,-. ,-.- ,. ,. . .. ,. ,...,. ,...,.,–, . ,..,.. ,. ,. ,.. ,.. ,. ,. ,..,.. ,. ,.. ,. ,. ,..,., ..,.,...,.. ,.. ,.. ,.. ,.,. ,. ,. ,.,.,.,,... ,,... ,,.... ,.. ,.. , ,.. .... , - . .. ,. ,.,. ,.. . . . ,..,.. ,.. , - ,. ,. , . . , ...... . ,. ,.,...,,...,.,. ,.. ,. ,..,. ,.. ,. ,. ,... ,,...,.,.,.,..,. ,.. ,. ,.,.. ,. . .. ,... . ,.. ,.. , - , . -.. .. .. , . ., ,.... ,. ,. ,. ,. , .. - ,. ,... ,- . ..,. ,... ,.,. . ,.. ,.. ,. ,. -,. ,. - ,. ,. ,.,.,.. . .- . ,.. , ,. ,.,... ,.. , .,..., . . ,. ,.. , .,. ,. , ,.. , . ,. ,.. ,. ,. ,.,.. ,,....,,...,,.,. ,. ,.,. ..-. ,.-. ,. ,. ,...,..,.,,... , ,. ,. ,. - ,. ,. ,...,.. ,. ,. -, ,. , ,. ,. - ,.. ,.. ,,..... ,,..,,... ,.. ,.. , - ,– . ’ .-. . . .. ,..,.. . -,...-., .,... ,...,,...,.,.,,... ,,..,,..,. ,. ,. ,.,.,. ,. , . ,.. , ,. ,. ,. ,.,. . ,. ,. ,. . ,.. ,.. ,. ,.. ,. ,.... ,.. , . ,. ,. ,.,.. , . . ,..-,.,.. ,,.... . . , . ,. ,. , , . ,., -- - , . .- ,.,. ,....,,.– . ,. ,. ,., ,. ,. ,. , ,-. - – .., .,... ,.,...,,...-,.,. ,.. ,. ,. ,.. ,.. ,.. ,.. ,-.,.. ,.. ,. ., -. - . 12 ,,., ,, , 12 4 7, ,, ,,,,,,,.,, ,,,,,,,,12 4, ,,,,,,,, 2,,,,,, 12 , .4, , . , , 12 , , , 12.4 .4 , , , 12 12.4 , , , 12.4 , , , .4 , , , 12 , , , 12.4 .4 , , , 12 12.4 , , , 12.4 , , , .4 , , , 12 , , , 12.4 .4 , , , 12 4 , , , 12. , , , 2.4 1 2.4 , , , 1.4 , , ,,,, 12,,,,,,,,, ,,,, ,,,,,,, 12,,,,,,,, . ,,,, ,,,, ,,.,,, 12,,,,,,, ,,,, ,,,,,,, 12 ,,. ,,, 12 ,, , ,,,, ,,,,,,,,,,,., 1.4 , , ,2 4, ,,,,,,,,,,.12,,. , ,,,,1 2 1 ,,,,,., ,,,, ,, ,,,2 , ,,,, ,,,,,, .,,. , . - , , .. , . , ---.---
aam am am am am am am am am am am am am am am am am am am am am am am am am am am amm . .
aam am am am am am am am am am am am am am am amm .
– - - , ,- - , - - , , , , , ,- , -.- - ----- , . ---- - - . - , , . - ,- ,--,-- , .. ,-, - , ,-,- .-- , .-, ,- ,.- .-, - , , , , . -,. ,. . - , ,- ,- ,- - . , -, - -, - .. , , - - . ,-.-,- ,- - , .-,.-,.-- . , . , . ,- - ,- - .. ,- -....- . . - *** , , ,. . , ,, . , , . . , , , , ,, , ., , . ,, , , . . ,
A SAA_FTull SATLA SDGTLA SDGLA SATLA SAKSV SAKYSV SAYSR AAYSR AAYSR AAYSSR AAYSR AAYSR AAYSR A AAYSRR AA AAYYSSRR AAYSR AAYSR AAYSR AAYSR AAYSR AAAYSR AAYSR AAYSR AAYSR AAYYSR AAYSSRR + + ---- ++ + ----
A AA AAYYSSRR AAYSR AAYSR AAYSR AAYSR AAYSR AAAYSR AAYSR AAYSR AAYSR AAYYSR AAYSR AAYSSR AAYSR A AAYSRR AA AAYYSSRR AAYSR AAYSR AAYSR AAYSR AAYSR AAAYSR AAYSR AAYSR AAYSR AAYYSR AAYSSRR ++ + + +++ +++ ----
A AA AAYYSSRR AAYSR AAYSR AAYSR AAAYSR AAYSR AAYYSR AAYSR AFYSR AFYSR AMYSSR AMYSR APYSRR A APYSR AVYSR AVYSR CYYSR CAYSR CAAYSR CAYSR CAYYSR EAYSR EAYSSR EAYSR EAYSR EAYSR E EAAYYSR SRR ++ ++ ---- +++ +++ --
E EA EAYYSSRR EAYSR EAYSR EAYSR EAAYSR EAYSR EAYYSR EAYSR EAYSR EAYSR EAYSSR EAYSR E EAYSRR EAYSR EAYSR EAYSR EAYSR EAYSR EAAYSR EAYSR EAYYSR EAYSR EAYSSR EAYSR EAYSR EAYSR E EAAYYSR SRR + + ---- +++ +++ ----
E EAYSR EAYSR EAYSR EAAYSR EAYSR EAYYSR EAYSR EAYSSR EAYSR E EAYSRR EAYSR EAYSR EAYSR EAAYSR EAYYSR ECYSSR ECYSR EFYSRR E EF EIYYSSRRI EIMYYSRSRI E EMYSR EPYSR EPYSR ETTYSR EVYSR EVYYSSRR ++ ++ ---- ++++ ++++ ----
F GAYSR GAYSR GAAYSR GAYYSR GAYSR GAYSSR H HAYSRR IAYSR IA IAYYSSRRII IA IAYYSSRRII IAAYYSSRRI IAYSRI IAYSRI IAYSI IAYSRI KAYSRI K KAYSRR KAYSR LAYSR LAAYSR LAYYSR LAYSR LAYSSR L LA LAY AYSR YSR SRR + + ---- ++++ ++++ ----
L LA LAYYSSRR LAYSR LAYSR LAYSR LAYSR LAYSR LPPYSR MAYSR MAYSR MAYSR MAYYSR MAYSR MAYSSR MAYSR M MAYSRR MA MAYYSSRR MAYSR MAYSR MAYSR MAAYSR MAYSR MAYYSR MAYSR MAYSR MAYSR MAYSSR MPYSRR ++ + ---- ++ ++ smar
M NAPYYSSRR N NA NAYYSSRR NA NAYYSSRR NAYSR NAYSR NAYSR NAYSR NAYSR NAYSR NAYSR NAYSR NAYSR NAAYSR NAYSR NFYSR NIYSR NYSRI NMYSR NPYSR NPYSR NVVYSR AYYSR AYSSR AAYSRR AYSR AYYSSRR + + smar ++ + ----
AAY AYSSRR AYSR AYSR AYSR AYYSR AYSR AYSSR AYSR AYSR AYSR AAYSRR AYSR AYSR AYSR AYYSR AYSR AYSR AYSR AYSSR AYSR AAYSRR AYSR MYSR MYSR PYSR APYSR R YYSSRR ++ + ---- +++ +++ -
R SAAAYYSSR SAAYR SAYSSR SAYSR SAYSR SAYSR S SAYSRR SA SAYYSSRR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYYSR SAYSR SAYSR SAYSR SAYSSR SAYSR SAYSR SAYSR S SAYSRR SA SAYYSSRR SAYSR SAYSR SAAYYSSRR + + ---- + + ----
S SA SAYYSSRR SAYSR SAYSR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYSR SAYSR SAYYSR SAYSR SAYSSR SAYSR S SAYSRR SA SAYYSSRR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYYSR SAYSR SAYSR SAYSR SAYSSR SAYSRR +++ +++ -- ++ - ----
S SA SAYYSSRR SAYSR SAYSR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYSR SAYSR SAYYSR SAYSR SAYSSR SAYSR S SAYSRR SA SAYYSSRR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYYSR SAYSR SAYSR SAYSR SAYSSR SAYSRR ++ + ---- +++ + ----
S SA SAYYSSRR SAYSR SAYSR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYSR SAYSR SAYYSR SAYSR SAYSSR SAYSR S SAYSRR SA SAYYSSRR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYYSR SAYSR SAYSR SAYSR SAYSSR SAYSRR + ++ ---- ++ ++ ----
S SA SAYYSSRR SA SAYYSSRR SA SAYYSSRR SAYSR SAYSR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYSR SAYSR SAYYSR SAYSR SAYSR SAYSR SAYSSR SAYSR SAYSR SAYSR S SAYSRR SA SAYYSSRR SAYSR SAYSR SAAYYSSRR ++ ++ smar + + -
S SA SAYYSSRR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYYSR SAYSR SAYSR SAYSR SAYSSR SAYSR S SAYSRR SAYSR SAYSR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYYSR SAYSR SAYSSR SAYSR SAYSR SAYSR S SAAYYSR SRR + + smar +++ +++ smar
S SA SAYYSSRR SAYSR SAYSR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYSR SAYSR SAYYSR SAYSR SAYSR SAYSR SAYSSR SAYSR SAYSR SAYSR S SAYSRR SA SAYYSSRR SAYSR SAYSR SAYSR SAYSR SAYSR SAAYSR SAYYSSRR + + -- ++ +++ ----
S SA SAYYSSRR SAYSR SAYSR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYSR SAYSR SAYYSR SAYSR SAYSSR SAYSR S SAYSRR SA SAYYSSRR SAYSR SAYSR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYSR SAYSR SAYYSR SAYSSRR +++ ++ - ++ ++ ----
S SA SAYYSSRR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYYSR SAYSR SAYSSR SAYSR S SAYSRR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYYSR SAYSR SAYSSR SAYSR S SAYSRR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYYSSRR +++ ++++ ---- ++ ++ ----
S SA SAYYSSRR SAYSR SAYSR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYSR SAYSR SAYYSR SAYSR SAYSR SAYSR SAYSSR SAYSR SAYSR SAYSR S SAYSRR SA SAYYSSRR SAYSR SAYSR SAYSR SAYSR SAYSR SAAYSR SAYYSSRR + + ---- + + ----
S SA SAYYSSRR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYYSR SAYSR SAYSR SAYSR SAYSSR SAYSR S SAYSRR SAYSR SAYSR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYYSR SAYSR SAYSSR SAYSR SAYSR SAYSR S SAAYYSR SRR ++ ++ ---- ++ ++ ----
S SA SAYYSSRR SA SAYYSSRR SA SAYYSSRR SAYSR SAYSR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYSR SAYSR SAYYSR SAYSR SAYSR SAYSR SAYSSR SAYSR SAYSR SAYSR S SAYSRR SA SAYYSSRR SAYSR SAYSR SAAYYSSRR + + - ++ ++ ----
S SA SAYYSSRR SAYSR SAYSR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYSR SAYSR SAYYSR SAYSR SAYSSR SAYSR S SAYSRR SA SAYYSSRR SAYSR SAYSR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYSR SAYSR SAYYSR SAYSSRR ++ ++ ---- + + ----
S SA SAYYSSRR SAYSR SAYSR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYSR SAYSR SAYYSR SAYSR SAYSSR SAYSR S SAYSRR SA SAYYSSRR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYYSR SAYSR SAYSR SAYSR SAYSSR SAYSRR +++ +++ --- ++ ++ --
S SA SAYYSSRR SAYSR SAYSR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYSR SAYSR SAYYSR SAYSR SAYSSR SAYSR S SAYSRR SA SAYYSSRR SAYSR SAYSR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYSR SAYSR SAYYSR SAYSSRR ++ ++ ---- + - ----
S SAYSR SAAYYSR SAYSSR SAR SYSR SAAYSR SAYYSSR SAR SYSR SAAYYSR SAYSSR SAR SYSR SAAYSR SAYYSSR S SAYSRR SAAYSR SAYYSSR SAYSRR
A SE hTFR1ith hTFR1ith Ctl CBA Ctl hS SE hTFR1ith hTFR1ith Ctl CBA Ctl hS SA_sequ SAAYSR AAYYSSR AAYR AASR AAYYSSR AAR AYSR AAAYYSR AASR AYSR AAAYYSR A AAYSSRR AAAYSR A AAYYSSRR AAAYSR AAYYSSR AAR AYSR AAAYYSSR AAR AYSR AAAYYSR A AAYSSRR AAAYYSR AAYSSRR ++++ ++++ -- -- ++ +++ -- --
A AAYSR AAYSR AAYSR AAAYSR AAYSR AAYYSR AAYSR APYSSR APYSR A APYSRR APYSR ATYSR DTYSR DRRYSR EAYYSR EAYSSR EAYSR E E MAYSRR EA MAYYSSRR E EA EAYYSSRR EAYSR EAYSR EAYSR EAAYSR EAYSR EAYYSSRR ++ ++ -- -- ++++ ++++ -- --
E EA EAYYSSRR EAYSR E DAYSR EAYSR DAYSR E EAYSR EAYSR EAAYYSSRR E EAAYSR EAYYSR EAYSR EAYSSR EAYSR E EAYSRR EA EAYYSSRR EAYSR EAYSR EAYSR EAAYSR EAYSR EAYYSR E MAYSR E EAAYS YSRR M SR EAYSR +++ +++ -- -- +++ ++ -- --
E EA EAYYSSRR EAYSR EAYSR EAYSR EAAYSR EAYSR EAYYSR EAYSR EAYSSR EAYSR E EAYSRR EAYSR EAYSR EAYSR EAAYSR EAYSR EAYYSR EAYSR EAYSSR EAYSR E EAYSRR EAYSR EAYSR EAYSR EAAYSR EAYSR EAYYSSRR ++ ++ -- -- +++ ++++ -- --
E EA EAYYSSRR EAYSR EAYSR EAYSR EAYSR EAYSR EAAYSR EAYSR EAYSR EAYSR EAYYSR EAYSR EAYSSR EAYSR E EAYSRR EA EAYYSSRR EAYSR EAYSR EAYSR EAAYSR EAYSR EAYYSR EAYSR EAYSR EFYSR EFYSSR EIYSRRI ++ ++ -- -- + - -- --
E EIIYYSSRI EIYRI EMYSRI EMYSR EPYSSR EPYSR E YSR E R E YYSR E YSSR ETYSR E ETYSRR ETYSR ETYSR ETYSR ETTYSR ETYSR ETYSR ETYSR ETYYSR ETYSR ETYSSR ETYSR E EVYSRR GVYSR GAYSR GAYSR GAAYYSSRR ++ ++ -- -- ++++ ++ -- --
G GAYSR GAYSR GAYSR GAAYSR GAYSR GAYYSR GAYSR GAYSSR GAYSR G GAYSRR GAYSR GAYSR GAYSR GAAYSR GAYSR GAYYSR GAYSR GAYSSR GAYSR G GAYSRR GAYSR GAYSR GAYSR GAAYSR GAYSR GAYYSR GAYSR GAYSSRR ++++ +++ -- -- +++ ++ -- --
G GA GAYYSSRR GAYSR GAYSR GAYSR GAAYSR GAYSR GAYYSR GPYSR GPYSSR GVYSR G HVYSRR HAYSR KAYSR KAYSR KAAYSR KAYSR KAYSR MAYSR MAYYSR MAYSR MAYSSR NAYSR N NAYSRR NAYSR NAYSR NAYSR NAAYYSSRR ++ ++ -- -- ++++ ++ -- --
N NAAYYSSR NAYR NAYSR NA SR AYYSR AYSSR AAYSRR AYSR AYSR AYSR AYYSR AYSR AYSSR AAYSRR AYSR AYSR AYYSR AYSR AYSSR AYSR AAYSRR AYSR AYYSR AYSR AYSSR AYSR AYSRR ++ ++ -- -- +++ +++ -- --
AAYSR AYYSR AYSSR AAYSRR PYSR PYYSR SAYSR SAYSSR SAYSR SAYSR SAYSR SAYSR SAYSR SAYSR SAYSR S SAYSRR SA SAYYSSRR SA SAYYSSRR SA SAYYSSRR SAYSR SAYSR SAYSR SAYSR SA SAY AYS YSR SRR ++ ++ -- -- +++ ++ - --
S SA SAYYSSRR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYYSR SAYSR SAYSR SAYSR SAYSSR SAYSR S SAYSRR SAYSR SAYSR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYYSR SAYSR SAYSSR SAYSR S SAYSRR SA SAY AYS YSR SRR +++ +++ -- -- ++ ++ - --
S SA SAYYSSRR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYYSR SAYSR SAYSSR SAYSR S SAYSRR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYSR SAYSR SAYYSR SAYSR SAYSSR SAYSR S SAYSRR SAYSR SAYSR SAYSR SAAYYSSRR ++++ +++ -- -- ++ + -- --
S SA SAYYSSRR SAYSR SAYSR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYSR SAYSR SAYYSR SAYSR SAYSSR SAYSR S SAYSRR SA SAYYSSRR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYYSR SAYSR SAYSR SAYSR SAYSSR SAYSRR ++ ++ -- -- ++ ++ - --
S SA SAYYSSRR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYYSR SAYSR SAYSR SAYSR SAYSSR SAYSR S SAYSRR SAYSR SAYSR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYYSR SAYSR SAYSSR SAYSR SAYSR SAYSR S SAAYYSR SRR +++ ++ -- -- ++ ++ - --
S SAYSR SAYSR SAYSR SAAYSR SAYSR SAYYSR SAYSR SAYSSR SAYSR S SAYSRR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYYSR SAYSR SAYSSR SAYSR S SAYSRR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYYSR SAYSR SAYSSRR ++++ +++ -- -- +++ +++ + ++
S SA SAYYSSRR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYYSR SAYSR SAYSR SAYSR SAYSSR SAYSR S SAYSRR SAYSR SAYSR SAYSR SAYSR SAYSR SAAYSR SAYSR SAYYSR SAYSR SAYSSR SAYSR S SAYSRR SA SAY AYS YSR SRR +++ +++ -- -- ++ ++ - --
S SAAYYSR SAYSSRR

Claims

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