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`7b hon),
`TB4 = Ala-TB49] 7B Awe TB4g]
`Lu
`==
`2
`ce
`Wel 7]s
`Oo] THA}
`Ala-TB47} 4]
`
`mW
`xq
`
`“ad
`
`ot
`ai
`
`a
`
`L_
`
`Bne:3Bh
`4b
`El yu Z-zloA Gly-TB4 @ Ala-TB49] AapS
`eS
`ro} 30ere]o] Ut ES] Hs
`by
`ot E]SLAl Gly-TB4, Ala-TB4 HE TB4
`L
`
`ah&
`TB49] S3}Bt+
`©}, Gly-TB4 B Ala-TB49] 48
`EQa YATE 50% TF] 4p
`
`ah
`
`z—_ Te
`TS
`
`°
`
`°
`
`9
`
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`
`=
`
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`AAS
`
`AA
`4
`
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`ray
`xaFAL, 30Rbe] S|}
`JOA] Gly-T B42] Bt
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`8
`ay a
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`2
`IAT.
`Lu
`
`GLA
`2)wy
`a
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`o
`eI
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`
`Gly-TB4 HE TB4
`
`$914
`
`=A] Gly-TB4
`
`/He Ala-TB47} Ba TB4RU}
`
`ao]7] TB4 FEA Gly-TB4
`
`ww
`Rm
`
`/E%S Ala-TB4S °|28KE
`
`3
`
`yw)A
`
`==
`
`(003:
`
`[0033]
`
`[0034]
`
`[0035]
`
`[0036]
`
`[0037]
`
`

`

`[0038]
`
`[00394
`
`{0040}
`
`[0041]
`
`f0042]
`
`[0043]
`
`[0044]
`
`[0045]
`
`[0046]
`
`[0047]
`
`E4= WE PaoMey 23 Ags] Fy se] TB4a B Gly-TB4 FSS) Sze Ue}.
`
`E5E WE Pas] Me 44 He] SAA] TR4 B Ala-TB4 #99 SDS pope.
`
`= 6f HE Bale] WE Ae Hel AS TRA B Ala-TBR4a #92] SHS Yop dey.
`
`ETE RE MaoRES] Es Sale] SS Azo] TBA BW AlaTB4 Foe] ass Ueplcy.
`
`&8f QE wal RES] Es als] Sel Ae] TRA BW AlaTB4 Foe] ass ete.
`
`
`
`
`
`o) HE
`eu
`
`’
`
`Jom,
`
`O90
`Bole of 100ue-5mgo]t}. Best Folate Sx; asa} Hof ubelo] e[J#sh}, BS OF 0. 1ml-5mlolch}.
`
`Be BB] 47] TB4aA] Gly-rB4 B/E Ala-TB4S MSE
`
`ok
`7
`
`Ewe] Zebet AR
`
`mle HE Bae WE Ad He] Pao” TRA B Gly-Tp4 #99] Sas Yep Art.
`
`E22 FE Pao] Me AHe] 84S] TR4 B Gly-TR4 #92] Sas fed.
`
`= 38 HE Baal Bee] Sa Exe] Eo] TR4 WY Gly-TB4 Fels] Sas fede.
`
`
`
`
`
`(0048) 9 Ayl Zech Sete] shee Mol, TB4 2H (C), Ala-TB4 2B (B) 8 PBS 3H (S| Fo 1 Dol
`Ze} Abus] azz] s}4{fo] Fa Avs cpe} Ary,
`
`[00494
`
`[0050]
`
`= lok Hy Ay ate] sey Bao, TB4 1 (C), Ala-TB4 7 (B) R PBS 74% (AS Fo] 5 A
`o] Ze} tule] ezre] set S]Ho] Fe Ass Ue ar}.
`
`aT PVT B4-
`Saad BRS7|S2] Sala Selo] eet Hu WyAEsofo] me}, 2 Baz: Mae
`A/BL21 % PGMT §$4-G/BL21 China General Microbiological Culture Collection Center(CGMCC, Beiyitiao,
`Zhongguancun, Beijing, China)*] 242) 4-= BIS CGMCC 1750 @ CGMCC 17512 Heer}.
`
`fO0S 1]
`
`2 uget Ea 2 elds F242 so FS Bagsclo] Baqze Ao] ofr]e}.
`
`[0052]
`
`[0053]
`
`j00S4]
`
`[0055]
`
`[0056]
`
`[0057]
`
`[0058]
`
`ala] 1. E]SAl B4al] Gly-TB42] aA
`
`1, MHS SzbAvJE pGMTB4Ge] ase
`
`TBAATS HE 1/2] S21 ofa At AVS] pet,
`
`Ser Asp Lys Pro Asp Met Ala Glu Ile Glu Lys Phe Asp Lya Ser Lys Leu Lys Lys
`
`Thr Glu Thr Gln Glu Lys Aso Pro Lew Pro Sor Lys Glu Thr Tis Glu Glo Glu Lys
`
`Gla Ala Gly Glu Ser
`
`(AS U1)
`
`TB42] DNA AAP E. coli] AE AES o]sste Aeo] Pyar. wae} Mae] 24S Sey]
`ae], clo] Ja ASS Wel=s] NA RQ Cao] Asse AS A Bam 1 Y Xho 1S H7}s-z N-
`Bae AA HS 2] Yep Hs} Go] Seal, Gye BID
`
`GGA TCC GAC AAA CCC GAT ATG GCT GAG ATC GAG AAA TTC GAT AAG TCG
`
`BawHI
`
`AAA CTG AAG AAG ACA GAG ACG CAA GAG AAA AAT CCA CTG CCT TCC AAA GAA ACG ATT
`
`GAA CAG GAG AAG CAA GCA GGC GAA TCE TAA CTC GAG
`Xoo (SUS 2);
`
`47> Ae Ao] QBS 2Ac.
`
`

`

`[0059]
`
`ASS ope Yeap Ary:
`
`Gly Ser Asp Lys Pro Asp Met Ala Glu Ile Glu Lys Phe Asp Lys Ser Lys Leu Lys
`
`Lys Thr Glu Thr Gln Glu Lys Aso Pro Leu Pro Ser Lya Glu Thr [le Glu Gin Glu
`
`S251 10-0984635
`
`Lys Gln Ala Gly Glu Ser
`
`(AS WS 6)
`
`SAF GST ofe]aAE AAS] Be}, E.coli AB AES o]-Bspo ee] WES DNA So] WHO] FHA, A
`
`st 29) EcoRI & BamHle] 482} N-Est BZ cee] ASE Bo] Bsa], ojo] cteh, ASA HS Bel] uy
`EPA HS} 2 Ab7] YE] WEES] BWA AWAo) PS RC:
`
`GAATTCATGTCCCCTATACTAGCTTATIGGAAAATTAAGGGCCTIGTGCAACCCA
`HeokI
`
`CTCGACTICTITTOGAATATCTTGAAGAAAAATATGAAGAGCATTTGTATGAGCECGATGAAGGTGATAAATG
`
`GCCAAACAAAAAGTTTGAATTGGGTTTGGAGTTICCCAATCTICCTTATTATATTGATGGTGATGTTAAATTA
`
`ACACAGTCTATGGCCATCATACGTTATATAGCTGACAAGCACAACATGTIGGGTESTTGTCCAAAAGAGCGTG
`
`CAGAGATTTCAATGCTTGAAGGAGCGGTITIGGATATTAGATACGGTOTITCGAGAATIGCATATAGTAAAGA
`
`CTTTGAAACTCTCAAAGTTGATTTTCTTAGCAAGCTACCTGAAATGCTGAAAATGTTCGAAGATCOTITATGT
`
`CATAAAACATATTTAAATGGTGATCATGTAACCCATCCTGACTTCATGTIGTATGACGCTCTIGATGTIGTTT
`
`TATACATGGACCCAATETGCCTOGATGCGTTCCCAAAATTAGTTIGTTTTAAAAAACETATTGAAGCTATCCC
`
`ACAAATTGATAAGTACTTGAAATCCAGCAAGTATATAGCATGGCCTTTGCAGGGCTGGCAAGCCACCTITGOT
`
`GOTCOCGACCATCCTCCAAAATCOGATCTGGTTCCGCGTGGATCE
`
`Raw (AS PS 395
`
`"Molecular Cloning: A Laboratory Manual" a Edition, Cold Spring
`HH HofoA, Stal Ro] apel(4h*,
`Harbor Laboratory Press America, 1992), #7) aJ4#el Bo HEL, Gly-TB4% 2nd SATE pBSK
`(Stratagene, #212205)2 -]G+ SA EcoRI, Xhol, BamHI= 2et3-9 On}, of7]A], EcoRI @ BamHI BL WE
`
`
`HAWe pBKSs Atse FW oSesy, 474 44 ALS SES SA Fo], 1:19] SA)14 tolls
`
`2759 ye Feo ee GAAS TS4H°4, |S pSk-TRe
`
`co]23), EcoRI] B Xhole ABBY S
` BamHI2 Gly-TR4S 2Ashe u]
`S 4Gte F oe54,yoy.
`BUe=
`AZHo] ASATH. aa:lah Ames pol, 27] Gly-TB4 44 AS2] Fa4sshe AAG Se}
`Hoe a2 Bt] Fa Tse] SAAS pat}}e]41 a3 “Asal S]e PPA) Qhe SEPAAS
`paM chee] GST #3 Gass Pas + ow. Beijing Northland Biotech Co., Ltd.o] 2a} Saya
`
`47,
`
`€8 dae Fase Ase We BAER 44 aay,
`
`6B Gee +} Gs Xhol B EcoRIS
`
`[0060]
`
`[0061]
`
`[0062]
`
`[0063]
`
`[0064]
`
`[0065]
`
`[0066]
`
`HS) Bee SE HAS 1809] 4 elo) AAS Ah] BBs Hat SIS ee] qo] Asa] ol
`SII. FSA AAW ISCI VP AMJoR Belge, yey Aad Wat Sareesyaqon,
`pGM TB4-GE We s-grt.
`
`2, MAG SAAS pUNT B4-GS ae 7a by |o bi ZAE] Ur El] Z] Oo} 2] Al
`
`2 the, E. coli BL21@ CaCl, Yel Ue} Ba ASbAlz|aL, 5Oue/me FRtrbo|aS Birshe LB SeelEcd
`
`AZaJader, 37] AY SIA= pANBHoS We ALGAAS Hele] seo] Gy seus
`ASAT,
`
`ODec?] 0.6-0.8°] 2 mt), 7] BAadsal| LK Aes MZ] MSs, HelefobS Uee|e + 4]s}7]
`
`15% SDS-PAGE 417]SoA, ot
`BM LwohH war,
`al 3-44] ZF Bel SES Ms} O.1lmM IPIGE B7- GS,
`30KDS] Sue] GAA Wey} 4042] BS BMS eb}. TB4 BASE Bayo AS44Cimmnoblot) #42
`ey BESS UEC}. ELSA FEA] Gly-Tp4 BYse]) Go) BARBS SSS FAIASE 249 UTS
`PGM2T B 4/BL212=% WY stsrt.
`
`[0068]
`
`mid]
`37] AZ BPM abet, E BeleSa Sa YA FEA Gly-TB4 7} Bo] PASE HACE 244
`
`-8-
`
`

`

`TEE PGMT 8 4-G/BL21 (REF WH: CGMCC No.175) =H BAA.
`
`S251 10-0984635
`
`3. Gly-TB49] Ba BW Aa
`
`1) Aa Sear TSA: A] Pe] AAy HAAS AAS OF PGMT B41-G/BL212 50pue/me 744}
`JAS BSE LB WAZA Bey wee sba2(37C, 200rpm), 50ug/mt FH+Efo] AIS G-F-st= LB Ale] 1:302]
`Fy] H] ASL re, 87CA AI 3A] 7S oF Hi] CFS} aL, O.1lmM IPTG= 2 7} BE OF AA] Zt oO} Friel] ATH. A SES
`stil, SDS-PAGE A7|S9SolR PAsVow, EEA FEA] Gly-Th4 (0K) #2 729 TS Aree] JB
`He Bon, Bea tee] Ge Aa] Aso] 7] Sto] GOEL LEE} SETH.
`¢
`2) Wats Ba R we
`
`ot a
`A. WE HWZ|2] Be
`
`a) AE Hal) HAILED:
`
`EWE:
`
`log/L; SAE 7HE: 5e/L; SS} UES: 10g/L; 7HHOPOIAL: 50ug/me.
`
`b) HHS wR)
`
`(15 eye):
`
`etree: 315g; e4tbolrade: 100g; Sst+Ee: 10.05g; Geos: 50g, EHE 90g.
`
`a) B¢ee Pa g4 Swl7a 4e gee 44 Berd ue, SA Bao] Artsy
`
`SA upay]: 15g) S¥SBLA: 450g; SF (500¢/L): SHAQA.
`
`
`#Fe Bole Seo a S| Sha, 50m] LK (250m) Se}2s=1)e] ASSPAL, 36, 2OOrpme|A] 8AZk “Sek BS
`
`a tS, oO] 50m] AS Aal= 700ml LKZ ol SAl Zl Aral, 36, 200rpme]A wel] aloks-sich.
`
`WSS] YS AA (Dew = 3-4) Bal Broa, VES 36, 150rpm B SH At 10k BHT, URS
`
`FYAAOM; SALE FO, 2]AE Set 2.59] FRM SFMIS SHU, +S Hope] 1g] IPGS A7bsh
`ACH(3 ALE).
`
`3) SEPPey
`
`(i) 23m aer}ecay
`
`
`
`BQA Ar}aay] rye (Pharmacia Inc.)S e]#aMer, Was 2492 25mM Tris-HCl, pH8e]
`a, Baa Way =, B@ae ase] abe ASas SHE] Aseo= ZEA (Pharmacia Inc.)=A
`aAry, Waa So], #e UMASS lomM sel SHES GSH)S Girshe Se]yowR Besar.
`
`(ii) Aa te
`
`“47| Ale] SelSel BSAC NIMU/mL)S B7bso,
`
`387 CoA 2417 Ek BAR AMSA.
`
`
`
`
`
`(iii) Bele Bet Senpeyy
`
`UL
` Source30Q SEr-Eey) A(Pharmacia Inc.)S °]2e9ouy, BAD SAS 20m PB (MARACUER -
`2]
`oe #3] 2] os AAAI 7132, HY
`Ayo] PAUER), pH 79/9 °r, Gal (Hd srzBaqze fey Be
`Aor, WmaA So], S4 she GZ Bz] FAS 20mM PB, pH7, 0-
`
`ok
`
`AA| GaSe PSs Gly-TB49] 2S SDS-PAGE SE BA BD S44 HPLC EA OS 9908 ZzsE Aloe
`
`myox uN ‘a x2, au)
`
`[0069]
`
`[0970]
`
`[0071]
`
`(00724
`
`[0073]
`
`[0074]
`
`[0075]
`
`[0076]
`
`[0077]
`
`[0078]
`
`[00794
`
`fOOR04
`
`foos ty
`
`0082]
`
`[0083]
`
`[0084]
`
`[0085]
`
`fOO86]
`
`[0087]
`
`[0088]
`
`[0089]
`
`[0090]
`
`(00914
`
`f0092]
`
`

`

`[0093]
`
`[0094]
`
`Ala] 2. E]SAl B4 4A) Ala-TB49] AZ
`
`1. FAY Setar] = pOnTp4-Ag] ase
`
`TB4ATS BS Le] S4)S ofr] uAt A) So] opet, TB4 DNA A) Se] WB
`= 983s] Ala-TB1 WA ASS PSSAc; SA, Ast Aso]
`Bam3 Xhol& Se]se|se] Vad 2 Creel asope Bo] F7bsar, Mae AIS ws Aol Yep
`Ho} 4o] Seb, Alak WAAey, ae PH] WSS AA.
`
`S251 10-0984635
`
`
`GGA_TCC CCT CGA GCT TCT GAC AAA CCC GAT ATG GCT GAG ATC GAG AAA
`Bas!
`
`TTC GAT AAG TCG AAA CTG AAG AAG ACA GAG ACG CAA GAG AAA AAT CCA CTG CCT TCC
`
`AAA GAA ACG ATT GAA CAG GAG AAG CAA GCA GGG GAA TCG TAA CTC GAG
`
`thot
`
`(la
`
`rz, tet
`
`4)
`
`ASS os NAS esp ar:
`
`Ata Ser Asp Lys Pro Asp Met Ala Glu Ile Glu Lys Phe Asp Lys Ser Lys Leu Lys
`
`Lye Thr Glu Thr Gla Glu Lys Asa Pro Leu Pro Ser Lys Glu Tht Ile Glu Gln Glu
`Lys Gln Ala Gly Glu Ser
`
`(AS WS 5)
`
`S18 OST ofe|seAL AGA Meh, ae] AES INA AS Bcoli MY HES olSsicl FaIOs Ae]
`AJs+9 Or}, ast 349) EcoRI] @ BamHIS Bese] Es] NB B CBWE] Asse HA] Brea, AS
`#90) Utve. Ge ao} AEE ALVee Psa,
`
`Topo] Sto] BeHo] ab|elCsbs, “Molecular Cloning: A Laboratory Manual :" g* Edition, Cold Spring
`Harbor Laboratory Press America, 1992), 37) AAD Uo AGE, Ala-Te4% 2nd SAqArl= pwKSs
`Ale@+ As EcoRI, Xhol, BamHI @GSYou, FA],
`EcoRI] B BamHI Buy BEES Age gq
`°o]25]7], Xhol & BamHI Gly-TB4S Ase U] ol 25T, EcoRI BF XholS AAA SATE pwKsS 4
`dae A] SS, FA 44 Aes SES Sgt Po], 1:12] SH]E 14 tol Aol a AJA] B-paw
`th. a4 as @ zacSo], 27] AlaTB4 BA ASS] HAAS BRagey AzSeq =} Wo a
`HE $e AAAS +$qVO4, oS pSe-TB2ze BYsge.
`
`3 eo GHA fase sese Wt BAN 44 Adasen, ed daa aa} Bas} Xhol B
`EcoRI2= O)S AA Ado) sla S55 SATE pauehbpol4l 4a 2nays Me 47} VE =
`AYE pGMe vyeke] GST FY Gaas PHS | You, Beijing Northland Biotech Co., Ltd.o] Say 2a]
`AMt)o) eel 2 awe 18cs] M zypoh JAMA Ae] SBAau Sax dws solqolAqe gq
`S8aay. pee ALGAAS 24 RAAGL=S Fels, HS] Soe PSE SASYES PSAWe
`Fy, pM TB4A-AZ YBVsArp.
`
`2. MAY SHAMNES Ze Ayo £28) Bpelelope] ale
`
`2 UU, E. coli BL21S CaCl,He] te} Ys Asl[7)T, 50ue/me Feels See LB Salo]Ea
`
`AMAZHR,
`aaaad.
`
`-Y7] PASAIS pW BAS WE ASWIS Bele] see] GY Feue
`
`[0096]
`
`[0097]
`
`f0098]
`
`[00994
`
`fOL00]
`
`fo10d
`
`[0102]
`
`[0103]
`
`fO104
`
`[0105]
`
`ODeoc] 0.6-0.80]
`
`QL vt, Br] BAAS LK Ad wjxlo| weber, Beles aMakee|e Paleh|
`
`Al 3-44] 2b “eek +r
`
`8i7] 91840] O.1nll IPIGH BPE 4S, al Fulobe wy
`
`S
`
`3
`
`30KD2] Ste]
`Sy BESS LE}
`
`AME} 4009] DA WHS cept}. TR4 BYSE Bale] S88 ACGnmmop1ot) TAS
`
`Has
`
`ch. EMAL EA) Ala-TB4 Pale) Bo] WAYS
`
`SS
`
`

`

`B4/BLI12@ By sarp.
`
`elo&I. ee Le
`
`SAM] a] TS PSA FEA Ala! B47} Bo) PANE FAVOE 249
`7) JAZ Yo] me},
`Pt
`PGMT 6 4-A/BL21 (FE) WS: CGMCC No.1750)% SWaretry.
`
`3. Ala-TB49] 2a B Aaj
`
`1) Ao]a SHAzadA wa: Y7]s Go] ABD AlaTp4 AYA Hayes @Hoe F#Aseoze saa UT
`
`POMT B4-A/BL21& 50pe/ml 74o}o]4l& Bes LB OMZoAL BA HES}(37C, 200rpm), 50p8/mb pie
`
`oS Bs LB Ao 1:309] We PHA GS, 37C4] 34) ese) ASL, O.1mM IPIGH A7bsho} 4
`AT SM HUEAAUY. AMS —PYSta, SDS-PAGE A7NYSOM BHSABPOU, E|MAl Flea Ala-TH4 (30K
`= FEOe? Da tes Gye Jon, Pe ses] SP da] BAe] 7] Ae] Come} yepstry.
`
`AL Wee male] 267d
`
`a) AS Hal wyA|(LE):
`
`BBE: ldg/L; 25 VEE: g/L; AS UER: 1l0g/L; FA+HbO] 4A: S0ne/ me.
`
`b) WAGE HZ]
`
`(15 e]E]):
`
`4peolUE Se: 315g; e4be]-248: 100g; SS+EE: 10.05g; Sate: 50g; EUS 90g.
`
`ay] £3ES Ba te Ala ds aes 44 ate os, Se Bao Arteaga.
`
`SA; pfu) ee: 15g; Bao: 450g; SF (500g/L): SHaer,
`
`Ge Sle SzolEUA Beata, 5oml LK (250ml SAA )o] SB SZSD, 36T, 200rpmaA] 84] ZF Sek Bl
`a 4S, ©] 50m] YE AS 700ml LEE OSA. PEABO, 36, 20rpmo]*] WA we oks-sep,
`
`og
`
`ii) ME RSE wa we
`
`feu
`AE YA Den = 3-4) YA) B51, ES 36C, 150rpm BY SE We low PRU, Was
`
`SYBYOM SAR Fo], QI BSE 2.59] SES of BOOMS SFI, HLS Mh} 1g9]
`ACK Ah),
`
`IPTGH Bre
`
`3) Fares
`
`(i) aE Aerpetay
`
`GSH-9} 7-94 ApeTey) eA (Pharmacia Inc.)& oJSsHor], Weld BAYS 25mM Tris-HCl, pH]
`a 2as) way
`Oz
`1 2, Lael ASS] Alte] ASAS SEES AB222 AA (Pharmacia Inc.)ZY
`|, 3 ABMAS lomM HA SHEE e GSS Bee SzaMou Baye.
`
`4) ae 47| AAl GALE PSS) Ala-TB49] GEE SMS-PAGE GE EA BZ AP HPLC BALE 9848 BSE st |okt
`
`“a7] Gale] Be) eel EUS NIU/mL)S Bz7bSbO], 37°CoA) 2alZb SCr BAe AAtSart,
`
`(iii) S°o]2 WS Serpeaay
`
`Source30Q 2Bes) ofA (Pharmacia Inc.)S ol f2agaeowy, WA 2AS 20mM PB, pH 7°/V24, wal
`
`(24, BATHE FS FS BS Fee] SH *FAy7JD, 2Vs4Aeny, Bas So], S4ehe BHAA
`22] s]Z 20nM PB, pH7, 0-IM NaCl9] TM BelMoe A a-Aep.
`
`FO106]
`
`[0107]
`
`[0108]
`
`fo109]
`
`fO110]
`
`folly
`
`fO112]
`
`fO113]
`
`ford]
`
`fons]
`
`[O11 64
`
`foul7]
`
`fo11s]
`
`FOLEY
`
`fO1204
`
`fo12y
`
`f01294
`
`[0130]
`
`

`

`Syab, > 2
`
`o£
`
`{c az 2 aah we ox a th Jo, Mt kt =z 7 {c rc TH ns oo
`
`S251 10-0984635
`
`cr
`
`& 2 ‘4WH Te ns ye = yWwW Kes} nsfo
`
`2 Ue & 7
`
`c
`
`cy WB Te os 40,
`
`A =
`
`4 eye] de 2 ad Hse] DeoGy-Th4 BW TBA] AAAS Ayer vats] Ase}, Ga a
`on
`AY ©.
`ar
`=Ba - YE 4a tz] as 4 qe LAS FHeaggq.
`
`
`he
`
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`
`APolePAl Smg/keS Folspat; AJEPY] 50me/ke2= BAAlZ]lu, QE Ae SR BS go
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`ASGqu; gas] Ae21 oe, de +e Bas eu, +e PRS LB7
`ae4 tes Pyar. HE <dyh
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`Bh
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`me ar 2S -Sl7|a, WS GS] Su, 44 2¥S do aas Sad. aa aay) At sa
`:
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`
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`
`
`
`
`1) Gly-Tp4 ® Tp42] Bat
`
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`Beijing Northland Biotech Co., Ltd.
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`Thymosin 4 4 derivatives and uses thereof
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`LECOG002Z9PCT
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`200510083894 .6
`2005-07-15
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`200510103293 . 7
`2005-09-23
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`PatentIn version 3.3
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