W096/12697
`
`PCT/US95/13704
`
`79
`
`propyl)-1-(3-methoxyphenyl)ethylamine, 4Z/SA, as an oil;
`m/z (rel. int.) 283
`(M+, 17), 268
`(71), 164
`(13), 135
`(100) I 121 (21) I 105 (27); 91 (26) t 77 (14) •
`
`5
`
`10
`
`Preparation of 4Y
`In a similar fashion, 2-chloroacetophenone was used
`to prepare 3-methyl-3-:- (2-chlorophenyl) cinnamonitrile. The
`nitrile was catalytically reduced (palladium hydroxide,
`acetic acid, 60 p. s. i. hydrogen 2 hr)
`to generate 3-
`methyl-3- (2-chlorophenyl) propylamine.
`An equal molar
`amount of the amine, 3'-methoxyacetophenone and 1.25 molar
`equivalents titanium (IV) isopropoxide were mixed 4 hr at
`rt and the intermediate imine treated with an ethanolic
`sodium cyanoborohydride (5 ml of 1 M, 5 mmol). Work-up
`and
`chromatography
`afforded N- [3-methyl-3-(2-chloro-
`15 phenyl)propyl)-1-(3-methoxyphenyl)ethylamine, 4Y, as an
`oil; m/z (rel. int.) 283 (M•, 17) 268 (71), 164 (13), 135
`(100) I 121 (21) t 105 (27) I 91 (26) I 77 (14) •
`
`Preparation of 6T
`in
`(30.3 g 100 mmol)
`A solution of NPS R-568
`20 dichloromethane at -78°C was treated dropwise with boron(cid:173)
`tribromide (SO g, 200 mmol). The reaction was stirred l
`hr at rt and poured over ice.
`The hydrobromide was
`extracted from the aqueous phase with chloroform.
`The
`chloroform solubles were then washed (4 x 100 ml) with 50%
`25 HCl.
`The chloroform wash was dried over anhydrous
`magnesium sulfate and concentrated to afford (R)-N-[3-(2-
`chlorophenyl)propyl)-1-(3-hydroxyphenyl)ethylamine hydro(cid:173)
`chloride as a solid. A solution of sodium hydride (0.48
`g, 20 mmol) in dimethylformamide was treated with (R)-N-
`[3-(2-chlorophenyl)propyl)-1-(3-hydroxyphenyl)ethylamine
`hydrochloride (3.25 g, 10 mmol) and the reaction stirred
`1 hr at rt.
`The reaction was treated with iodoethane
`(1.71 g, 11 mmol) and stirred 16 hr at rt. Work-up and
`chromatography
`through silica using
`3% methanol
`in
`35 chloroformafforded (R)-N-[3-(2-chlorophenyl)propyl]-1-(3-
`
`30
`
`SUBSTITUTE SHEET (RULE 26)
`
`776
`
`
`
`PCT/US95/13704
`
`79
`
`propyl)-1-(3-methoxyphenyl)ethylamine, 4Z/SA, as an oil;
`m/z (rel. int.) 283
`(M+, 17), 268
`(71), 164
`(13), 135
`(100) I 121 (21) I 105 (27); 91 (26) t 77 (14) •
`
`5
`
`10
`
`Preparation of 4Y
`In a similar fashion, 2-chloroacetophenone was used
`to prepare 3-methyl-3-:- (2-chlorophenyl) cinnamonitrile. The
`nitrile was catalytically reduced (palladium hydroxide,
`acetic acid, 60 p. s. i. hydrogen 2 hr)
`to generate 3-
`methyl-3- (2-chlorophenyl) propylamine.
`An equal molar
`amount of the amine, 3'-methoxyacetophenone and 1.25 molar
`equivalents titanium (IV) isopropoxide were mixed 4 hr at
`rt and the intermediate imine treated with an ethanolic
`sodium cyanoborohydride (5 ml of 1 M, 5 mmol). Work-up
`and
`chromatography
`afforded N- [3-methyl-3-(2-chloro-
`15 phenyl)propyl)-1-(3-methoxyphenyl)ethylamine, 4Y, as an
`oil; m/z (rel. int.) 283 (M•, 17) 268 (71), 164 (13), 135
`(100) I 121 (21) t 105 (27) I 91 (26) I 77 (14) •
`
`Preparation of 6T
`in
`(30.3 g 100 mmol)
`A solution of NPS R-568
`20 dichloromethane at -78°C was treated dropwise with boron(cid:173)
`tribromide (SO g, 200 mmol). The reaction was stirred l
`hr at rt and poured over ice.
`The hydrobromide was
`extracted from the aqueous phase with chloroform.
`The
`chloroform solubles were then washed (4 x 100 ml) with 50%
`25 HCl.
`The chloroform wash was dried over anhydrous
`magnesium sulfate and concentrated to afford (R)-N-[3-(2-
`chlorophenyl)propyl)-1-(3-hydroxyphenyl)ethylamine hydro(cid:173)
`chloride as a solid. A solution of sodium hydride (0.48
`g, 20 mmol) in dimethylformamide was treated with (R)-N-
`[3-(2-chlorophenyl)propyl)-1-(3-hydroxyphenyl)ethylamine
`hydrochloride (3.25 g, 10 mmol) and the reaction stirred
`1 hr at rt.
`The reaction was treated with iodoethane
`(1.71 g, 11 mmol) and stirred 16 hr at rt. Work-up and
`chromatography
`through silica using
`3% methanol
`in
`35 chloroformafforded (R)-N-[3-(2-chlorophenyl)propyl]-1-(3-
`
`30
`
`SUBSTITUTE SHEET (RULE 26)
`
`776
`
`
`
`W096/12697
`
`PCT/US95/13704
`
`80
`
`ethoxyphenyl)ethylamine, 6T, as an oil; m/z (rel. int.)
`316
`(M+,l), 302
`(100), 282 (11), 196 (5), 178 (7), 149
`(74) r 121 (34) r 103 (25) I 91 (28) I 77 (29) •
`
`5
`
`Preparation of 6R
`NPS R-467 was used in a similar fashion to prepare
`(R)-N-(3-phenylpropyll-1-(3-ethoxyphenyl)ethylamine, GR,
`as an oil; m/z (rel. int.) 283
`(M+,10), 268
`(74), 178
`(ll) I 162 (8) 1 149 (100) I 121 (30) I 103 (16) I 91 (86) I 77
`(29) .
`
`10 Preparation of 3U
`An equal molar mixture of 3, 3 -diphenylpropylamine
`(2.11 g, 10 mmol), l'-acetonaphthone (1.70 g, 10 mmol) and
`1.25 equivalents of titanium (IV)
`isopropoxide (3.55 g,
`12.5 mmol) were stirred 4 hr at rt. The reaction mixture
`15 was then treated with a 1 M solution of ethanolic sodium
`cyanoborohydride (12.5 ml, 12.5 mmol) and stirred 16 hr at
`rt. The reaction was diluted with diethyl ether (50 ml)
`and treated with water (0.72 ml, 40 mmol). After mixing
`thoroughly the mixture was centrifuged and the ether layer
`20 decanted and concentrated to a milky oil. The oil was
`suspended in diethyl ether and filtered through a 0.45 µM
`CR PTFE Acrodisc.
`The diethyl ether filtrate was concen(cid:173)
`N- ( 3, 3 -diphenylpropyl) -1- ( l-naphthyl)
`trated to afford
`ethylamine, 3U, as a clear, colorless oil; m/z (rel. int.)
`25 365 (M+, 17), 350 (19) / 181 (23) / 155 (100) t 141 (25) / 115
`(11), 91 (13), 77 (6).
`
`30
`
`Preparation of 6F
`In a similar fashion equal molar amounts 1-(3-
`methoxyphenyl)ethylamine (1.51 g, 10 mmol), 2'-acetonaph-
`thane (1.70 g, 10 mmol) and 1.25 equivalents of titanium
`{IV)
`isopropoxide
`(3. 55 g, 12. 5 mmol) were treated as
`above.
`Work-up yielded N-(l-(2-naphthyllethyl)-1-(3-
`methoxyphenyl)ethylamine, 6F, as a clear, colorless oil;
`
`SUBSTITUTE SHEET (RULE 26)
`
`777
`
`
`
`W096/12697
`
`PCT/US95/13704
`
`81
`
`m/z (rel. int.) 305 (M+,l), 290 (35), 170 (49), 155 (100),
`135 (55) I 115 (8) I 105 (10) t 91 (9) t 77 (10),
`
`Preparation of 4G
`In a similar fashion equal molar amounts of (R))-1-
`5 phenylethylamine,, 1'-acetonaphthone and 1.25 equivalents
`of titanium (IV) isopropoxide were mixed and the resulting
`intermediate
`imine was
`reduced with ethanolic sodium
`cyanoborohydride. Work-up and chromatography yielded N(cid:173)
`[l- (l-naphthyl) ethyl)-1-phenylethylamine, 4G, as a clear,
`10 colorless oil; m/z (rel. int.) 275 (M+,16), 260 (79), 155
`(100) I 127 (27) I 105 (70) I 77 (32) •
`
`Preparation of 4H
`In a similar fashion equal molar amounts of (R)-1-
`phenylethylamine, 2'-acetonaphthone and 1.25 equivalents
`15 of titanium (IV) isopropoxide were mixed and the resulting
`intermediate
`imine was
`reduced with ethanolic sodium
`cyanoborohydride. Work-up and chromatography yielded N(cid:173)
`[l- (2-naphthyl) ethyl) -1-phenylethylamine, 4H, as a clear,
`colorless oil; m/z (rel. int.) 275 (M+,l), 260 (61), 155
`(100), 120 (36) I 105 (SS) I 77 (15).
`
`20
`
`25
`
`Preparation of 6E
`In a similar fashion equal molar amounts· of 1- (3-
`methoxyphenyl) ethylamine,
`l'-acetonaphthone
`and
`1.25
`equivalents of titanium (IV) isopropoxide were mixed and
`the resulting intermediate imine was reduced with ethan(cid:173)
`olic sodium cyanoborohydride. Work-up and chromatography
`yielded N-l-(l-naphthyl)ethyl-1-(3-methoxyphenyl)ethyl(cid:173)
`amine, 6E, as a clear, colorless oil; m/z (rel. int.) 305
`(M+,10), 290 (30), 170 (43), 155 (100), 135 (69), 115 (9),
`30 105 (15) I 91 (14) I 77 {18) •
`
`SUBSTITUTE SHEET (RULE 26)
`
`778
`
`
`
`W096/12697
`
`PCT/US95/13704
`
`82
`
`Example 19: Pharmaceutical Formulation
`Preparation of a pharmaceutical formulation suitable
`for administering a calcimimetic into a human patient is
`shown in Table 3.
`
`5
`
`10
`
`g/representative
`batch of 5,000
`capsules
`280.0
`
`670.0
`
`170.0
`
`5.0
`
`TABLE 3
`
`Ingredient
`
`mg/capsule
`
`NPS R-568
`Pregelatinized
`Starch NF
`Microcrystalline
`Cellulose NF
`Colloidal Silicon
`Dioxide
`Total
`
`56.0
`
`134.0
`
`34.0
`
`1. 0
`
`225 mg
`
`1125 g
`
`(R)-568 hydrochloride formulations
`15 Other examples of NPS
`and dosage forms include those suitable for sustained or
`extended release, using standard techniques.
`Proper dosing can also be carried out using standard
`techniques. For example, in one set of experiments, 10 -
`20 400 mg oral doses of NPS
`(R) -568 hydrochloride showed
`pharmacological activity in human subjects. Significant
`levels of the 0-glucuronide conjugate of 17Q, a principal
`metabolite of NPS
`(R)-568, was observed in human plasma
`following oral administration of NPS
`(R)-568 hydro-
`25 chloride. Thus, the glucuronide conjugate of 17Q may be
`exerting some beneficial effect.
`Using standard
`techniques other suitable dosage
`ranges for NPS (R)-568 can be determined.
`Suitable dosage
`ranges,
`formulations, and dosage
`forms for other compounds described herein can also be
`determined by one skilled in art based on the teachings
`provided in the application.
`
`3 o
`
`SUBSTITUTE SHEET (RULE 26)
`
`779
`
`
`
`W096/12697
`
`PCT/US95/13704
`
`83
`
`Other embodiments are within the following claims.
`Thus, while several embodiments have been shown and de(cid:173)
`scribed, various modifications may be made, without
`departing from the spirit and scope of the present inven-
`tion.
`
`5
`
`SUBSTITUTE SHEET (RULE 26)
`
`780
`
`
`
`WO 96/12697
`
`PCT/US95/l3704
`
`84
`
`SEQUENCE LISTING
`
`(1) GENERAL INFORMATION:
`
`(i) APPLICANT:
`
`NPS Pharmaceuticals, Inc.
`
`(ii) TITLE OF INVENTION: CALCIUM
`COMPOUNDS
`
`RECEPTOR-ACTIVE
`
`(iii) NUMBER OF SEQUENCES: 2
`
`(iv) CORRESPONDENCE ADDRESS:
`(A) ADDRESSEE:
`Lyon & Lyon
`(B) STREET:
`First
`Interstate World
`Center, Suite 4700
`633 West Fifth Street
`Los Angeles
`California
`USA
`90017
`
`(C) CITY:
`(D) STATE:
`(E) COUNTRY:
`(F) ZIP:
`
`(v) COMPUTER READABLE FORM:
`(A) MEDIUM TYPE:
`
`(B) COMPUTER:
`(C) OPERATING SYSTEM:
`(D) SOFTWARE:
`
`3. 5" Diskette, 1. 44 Mb
`storage
`IBM PC compatible
`PC-DOS/MS-DOS
`Fast Seq
`
`(vi) CURRENT APPLICATION DATA:
`(A) APPLICATION NUMBER:
`(B) FILING DATE:
`(C) CLASSIFICATION:
`
`(vii) PRIOR APPLICATION DATA:
`
`Prior applications total,
`including application
`described below:
`2
`
`(A) APPLICATION NUMBER: U.S; 08/353,784
`(B)
`FILING DATE:
`8 December, 1994
`
`(A) APPLICATION NUMBER: PCT/US/94/12117
`(B)
`FILING DATE:
`21 October, 1994
`
`(viii) ATTORNEY/AGENT INFORMATION:
`
`SUBSTITUTE SHEET (RULE 26)
`
`781
`
`
`
`W096/11697
`
`PCT/US95/l3704
`
`85
`
`(A) NAME:
`(B) REGISTRATION NUMBER:
`(C) REFERENCE/DOCKET NUMBER:
`
`Heber, Sheldon o.
`38,179
`215/304
`
`(ix) TELECOMMUNICATION INFORMATION:
`
`(A) TELEPHONE:
`(B) TELEFAX:
`(C) TELEX:
`
`(213) 489-1600
`(213) 955-0440
`67-3510
`
`(2)
`
`INFORMATION FOR SEQ ID NO: l:
`
`(i) SEQUENCE CHARACTERISTICS:
`(A) LENGTH:
`5006 base pairs
`(B) TYPE:
`nucleic acid
`(C) STRANDEDNESS:
`single
`(D) TOPOLOGY:
`linear
`
`(ii) MOLECULE TYPE: cDNA to mRNA
`
`(ix) FEATURE:
`CDS
`(A) NAME/KEY:
`436 .. 3699
`(B) LOCATION:
`(D) OTHER INFORMATION:
`
`(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1:
`
`GCTGCTGTGG CCGGACCCGA AGGCGGGCGC CGGGAGCGCA
`
`GCGAGCCAGA CGCGCCTCTC CAAGACCGTG ACCTTGGCAT
`
`AGGGAGCGGG GCTGCGCGCA GTCCTGAGAT CAGACCAGAG
`
`CTCATCCTCG TGGAGACCCA CGGCCGAGGG GCCGGAGCTG
`
`CCTCTGTGCG AGGGAGCCCT GGCCGCGGCG CAGAAGGCAT
`
`CACAGGAGGC CTCTGCATGA TGTGGCTTCC AAAGACTCAA
`
`GGACCACCCA CATTACAAGT CTGGATTGAG GAAGGCAGAA
`
`ATGGAGATTC AAACACCACG TCTTCTATTA TTTTATTAAT
`
`CAATCTGTAG ACATGTGTCC CCACTGCAGG GAGTGAACTG
`
`CTCCAAGGGA GAAACTTCTG GGAGCCTCCA AACTCCTAGC
`
`TGTCTCATCC CTTGCCCTGG AGAGACGGCA GAACC
`
`ATG GCA TTT TAT AGC TGC TGC TGG GTC CTC TTG GCA
`Met Ala Phe Tyr Ser Cys Cys Trp Val Leu Leu Ala
`s
`1
`10
`
`SUBSTITUTE SHEET (RULE 26)
`
`40
`
`80
`
`120
`
`160
`
`200
`
`240
`
`280
`
`320
`
`360
`
`400
`
`435
`
`471
`
`782
`
`
`
`W096/12697
`
`PCT/US95/13704
`
`86
`
`CTC ACC TGG CAC ACC TCT GCC TAC GGG CCA GAC CAG
`Leu Thr Trp His Thr Ser Ala Tyr Gly Pro Asp Gln
`15
`20
`
`CGA GCC CAA AAG AAG GGG GAC ATT ATC CTT GGG GGG
`Arg Ala Gln Lys Lys Gly Asp Ile Ile Leu Gly Gly
`25
`30
`3S
`
`CTC TTT CCT ATT CAT TTT GGA GTA GCA GCT AAA GAT
`Leu Phe Pro Ile His Phe Gly Val Ala Ala Lys Asp
`40
`45
`
`CAA GAT CTC AAA TCA AGG CCG GAG TCT GTG GAA TGT
`Gln Asp Leu Lys Ser Arg Pro Glu Ser Val Glu Cys
`50
`60
`SS
`
`ATC AGG TAT AAT TTC CGT GGG TTT CGC TGG TTA CAG
`Ile Arg Tyr Asn Phe Arg Gly Phe Arg Trp Leu Gln
`70
`65
`
`GCT ATG ATA TTT GCC ATA GAG GAG ATA AAC AGC AGC
`Ala Met Ile Phe Ala Ile Glu Glu Ile Asn Ser Ser
`75
`80
`
`CCA GCC CTT CTT CCC AAC TTG ACG CTG GGA TAC AGG
`Pro Ala Leu Leu Pro Asn Leu Thr Leu Gly Tyr Arg
`90
`95
`BS
`
`ATA TTT GAC ACT TGC AAC ACC GTT TCT AAG GCC TTG
`Ile Phe Asp Thr Cys Asn Thr Val Ser Lys Ala Leu
`105
`100
`
`GAA GCC ACC CTG AGT TTT GTT GCT CAA AAC AAA ATT
`Glu Ala Thr Leu Ser Phe Val Ala Gln Asn Lys Ile
`110
`115
`120
`
`GAT TCT TTG AAC CTT GAT GAG TTC TGC AAC TGC TCA
`Asp Ser Leu Asn Leu Asp Glu Phe Cys Asn Cys Ser
`125
`130
`
`GAG CAC ATT CCC TCT ACG ATT GCT GTG GTG GGA GCA
`Glu His Ile Pro Ser Thr Ile Ala Val Val Gly Ala
`135
`140
`
`ACT GGC TCA GGC GTC TCC ACG GCA GTG GCA AAT CTG
`Thr Gly Ser Gly Val Ser Thr Ala Val Ala Asn Leu
`14S
`150
`1S5
`
`CTG GGG CTC TTC TAC ATT CCC CAG GTC AGT TAT GCC
`Leu Gly Leu Phe Tyr Ile Pro Gln Val Ser Tyr Ala
`160
`165
`
`TCC TCC AGC AGA CTC CTC AGC AAC AAG AAT CAA TTC
`Ser Ser Ser Arg Leu Leu Ser Asn Lys Asn Gln Phe
`170
`17S
`180
`
`SUBSTITUTE SHEET (RULE 26)
`
`507
`
`543
`
`579
`
`615
`
`651
`
`687
`
`723
`
`759
`
`795
`
`831
`
`867
`
`903
`
`939
`
`975
`
`783
`
`
`
`W096/12697
`
`PCT/US95/13704
`
`87
`
`AAG TCT TTC CTC CGA ACC ATC CCC AAT GAT GAG CAC
`Lys Ser Phe Leu Arg Thr Ile Pro Asn Asp Glu His
`185
`190
`
`CAG GCC ACT GCC ATG GCA GAC ATC ATC GAG TAT TTC
`Gln Ala Thr Ala Met Ala Asp Ile Ile Glu Tyr Phe
`195
`200
`
`CGC TGG AAC TGG GTG GGC ACA ATT GCA GCT GAT GAC
`Arg Trp Asn Trp Val Gly Thr Ile Ala Ala Asp Asp
`205
`210
`215
`
`GAC TAT GGG CGG CCG GGG ATT GAG AAA TTC CGA GAG
`Asp Tyr Gly Arg Pro Gly Ile Glu Lys Phe Arg Glu
`220
`225
`
`GAA GCT GAG GAA AGG GAT ATC TGC ATC GAC TTC AGT
`Glu Ala Glu Glu Arg Asp Ile Cys Ile Asp Phe Ser
`235
`240
`230
`
`GAA CTC ATC TCC CAG TAC TCT GAT GAG GAA GAG ATC
`Glu Leu Ile Ser Gln Tyr Ser Asp Glu Glu Glu Ile
`245
`250
`
`CAG CAT GTG GTA GAG GTG ATT CAA AAT TCC ACG GCC
`Gln His Val Val Glu Val Ile Gln Asn Ser Thr Ala
`260
`255
`
`AAA GTC ATC GTG GTT TTC TCC AGT GGC CCA GAT CTT
`Lys Val Ile Val Val Phe Ser Ser Gly Pro Asp Leu
`270
`275
`265
`
`GAG CCC CTC ATC AAG GAG ATT GTC CGG CGC AAT ATC
`Glu Pro Leu Ile Lye Glu Ile Val Arg Arg Asn Ile
`285
`280
`
`ACG GGC AAG ATC TGG CTG GCC AGC GAG GCC TGG GCC
`Thr Gly Lys Ile Trp Leu Ala Ser Glu Ala Trp Ala
`300
`295
`290
`
`AGC TCC TCC CTG ATC GCC ATG CCT CAG TAC TTC CAC
`Ser Ser Ser Leu Ile Ala Met Pro Gln Tyr Phe His
`310
`305
`
`GTG GTT GGC GGC ACC ATT GGA TTC GCT CTG AAG GCT
`Val Val Gly Gly Thr Ile Gly Phe Ala Leu Lys Ala
`315
`320
`
`GGG CAG ATC CCA GGC TTC CGG GAA TTC CTG AAG AAG
`Gly Gln Ile Pro Gly Phe Arg Glu Phe Leu Lys Lye
`325
`330
`335
`
`GTC CAT CCC AGG AAG TCT GTC CAC AAT GGT TTT GCC
`Val His Pro Arg Lys Ser Val His Asn Gly Phe Ala
`340
`345
`
`SUBSTITUTE SHEET (RULE 26)
`
`1011
`
`1047
`
`1083
`
`1119
`
`1155
`
`1191
`
`1227
`
`1263
`
`1299
`
`1335
`
`1371
`
`1407
`
`1443
`
`1479
`
`784
`
`
`
`W096/ll697
`
`PCl'/US95/13704
`
`88
`
`AAG GAG TTT TGG GAA GAA ACA TTT AAC TGC CAC CTC
`Lys Glu Phe Trp Glu Glu Thr Phe Asn Cys His Leu
`350
`355
`360
`
`CAA GAA GGT GCA AAA GGA CCT TTA CCT GTG GAC ACC
`Gln Glu Gly Ala Lys Gly Pro Leu Pro Val Asp Thr
`365
`370
`
`TTT CTG AGA GGT CAC GAA GAA AGT GGC GAC AGG TTT
`Phe Leu Arg Gly His Glu Glu Ser Gly Asp Arg Phe
`375
`380
`
`AGC AAC AGC TCG ACA GCC TTC CGA CCC CTC TGT ACA
`Ser Asn Ser Ser Thr Ala Phe Arg Pro Leu Cys Thr
`385
`390
`395
`
`GGG GAT GAG AAC ATC AGC AGT GTC GAG ACC CCT TAC
`Gly Asp Glu Asn Ile Ser Ser Val Glu Thr Pro Tyr
`400
`405
`
`ATA GAT TAC ACG CAT TTA CGG ATA TCC TAC AAT GTG
`Ile Asp Tyr Thr His Leu Arg Ile Ser Tyr Asn Val
`420
`410
`415
`
`TAC TTA GCA GTC TAC TCC ATT GCC CAC GCC TTG CAA
`Tyr Leu Ala Val Tyr Ser Ile Ala His Ala Leu Gln
`425
`430
`
`GAT ATA TAT ACC TGC TTA CCT GGG AGA GGG CTC TTC
`Asp Ile Tyr Thr Cys Leu Pro Gly Arg Gly Leu Phe
`435
`440
`
`ACC AAT GGC TCC TGT GCA GAC ATC AAG AAA GTT GAG
`Thr Asn Gly Ser Cys Ala Asp Ile Lys Lys Val Glu
`445
`450
`455
`
`GCG TGG CAG GTC CTG AAG CAC CTA CGG CAT CTA AAC
`Ala Trp Gln Val Leu Lys His Leu Arg His Leu Asn
`460
`465
`
`TTT ACA AAC AAT ATG GGG GAG CAG GTG ACC TTT GAT
`Phe Thr Asn Asn Met Gly Glu Gln Val Thr Phe Asp
`480
`470
`475
`
`GAG TGT GGT GAC CTG GTG GGG AAC TAT TCC ATC ATC
`Glu Cys Gly Asp Leu Val Gly Asn Tyr Ser Ile Ile
`485
`490
`
`AAC TGG CAC CTC TCC CCA GAG GAT GGC TCC ATC GTG
`Asn Trp His Leu Ser Pro Glu Asp Gly Ser Ile Val
`500
`495
`
`TTT AAG GAA GTC GGG TAT TAC AAC GTC TAT GCC AAG
`Phe Lys Glu Val Gly Tyr Tyr Asn Val Tyr Ala Lys
`sos
`510
`515
`
`SUBSTITUTE SHEET (RULE 26)
`
`1515
`
`1551
`
`1587
`
`1623
`
`1659
`
`1695
`
`1731
`
`1767
`
`1803
`
`1839
`
`1875
`
`1911
`
`1947
`
`1983
`
`785
`
`
`
`W096/12697
`
`PCf/US95/13704
`
`89
`
`AAG GGA GAA AGA CTC TTC ATC AAC GAG GAG AAA ATC
`Lys Gly Glu Arg Leu Phe Ile Asn Glu Glu Lys Ile
`520
`525
`
`CTG TGG AGT GGG TTC TCC AGG GAG CCA CTC ACC TTT
`Leu Trp Ser Gly Phe Ser Arg Glu Pro Leu Thr Phe
`530
`535
`540
`
`GTG CTG TCT GTC CTC CAG GTG CCC TTC TCC AAC TGC
`Val Leu Ser Val Leu Gln Val Pro Phe Ser Asn Cys
`545
`550
`
`AGC CGA GAC TGC CTG GCA GGG ACC AGG AAA GGG ATC
`Ser Arg Asp Cys Leu Ala Gly Thr Arg Lys Gly Ile
`SSS
`560
`
`ATT GAG GGG GAG CCC ACC TGC TGC TTT GAG TGT GTG
`Ile Glu Gly Glu Pro Thr Cys Cys Phe Glu Cys Val
`565
`570
`575
`
`GAG TGT CCT GAT GGG GAG TAT AGT GAT GAG ACA GAT
`Glu Cys Pro Asp Gly Glu Tyr Ser Asp Glu Thr Asp
`580.
`585
`
`GCC AGT GCC TGT AAC AAG TGC CCA GAT GAC TTC TGG
`Ala Ser Ala Cys Asn Lys Cys Pro Asp Asp Phe Trp
`S90
`595
`600
`
`TCC AAT GAG AAC CAC ACC TCC TGC ATT GCC AAG GAG
`Ser Asn Glu Asn His Thr Ser Cys Ile Ala Lys Glu
`605
`610
`
`ATC GAG TTT CTG TCG TGG ACG GAG CCC TTT GGG ATC
`Ile Glu Phe Leu Ser Trp Thr Glu Pro Phe Gly Ile
`620
`615
`
`GCA CTC ACC CTC TTT GCC GTG CTG GGC ATT TTC CTG
`Ala Leu Thr Leu Phe Ala Val Leu Gly Ile Phe Leu
`630
`635
`625
`
`ACA GCC TTT GTG CTG GGT GTG TTT ATC AAG TTC CGC
`Thr Ala Phe Val Leu Gly Val Phe Ile Lys Phe Arg
`640
`645
`
`AAC ACA CCC ATT GTC AAG GCC ACC AAC CGA GAG CTC
`Asn Thr Pro Ile Val Lys Ala Thr Asn Arg Glu Leu
`660
`655
`650
`
`TCC TAC CTC CTC CTC TTC TCC CTG CTC TGC TGC TTC
`Ser Tyr Leu Leu Leu Phe Ser Leu Leu Cys Cys Phe
`665
`670
`
`TCC AGC TCC CTG TTC TTC ATC GGG GAG CCC CAG GAC
`Ser Ser Ser Leu Phe Phe Ile Gly Glu Pro Gln Asp
`675
`680
`
`SUBSTITUTE SHEET (RULE 26)
`
`2019
`
`2055
`
`2091
`
`2127
`
`2163
`
`2199
`
`2235
`
`2271
`
`2307
`
`2343
`
`2379
`
`2415
`
`2451
`
`2487
`
`786
`
`
`
`W096/12697
`
`PCT/US95/13704
`
`90
`
`TGG ACG TGC CGC CTG CGC CAG CCG GCC TTT GGC ATC
`Trp Thr Cys Arg Leu Arg Gln Pro Ala Phe Gly Ile
`685
`690
`695
`
`AGC TTC GTG CTC TGC ATC TCA TGC ATC CTG GTG AAA
`Ser Phe Val Leu Cys Ile Ser Cys Ile Leu Val Lys
`700
`705
`
`ACC AAC CGT GTC CTC CTG GTG TTT GAG GCC AAG ATC
`Thr Asn Arg Val Leu Leu Val Phe Glu Ala Lys Ile
`710
`715
`720
`
`CCC ACC AGC TTC CAC CGC AAG TGG TGG GGG CTC AAC
`Pro Thr Ser Phe His Arg Lys Trp Trp Gly Leu Asn
`725
`730
`
`CTG CAG TTC CTG CTG GTT TTC CTC TGC ACC TTC ATG
`Leu Gln Phe Leu Leu Val Phe Leu Cys Thr Phe Met
`735
`740
`
`CAG ATT GTC ATC TGT GTG ATC TGG CTC TAC ACC GCG
`Gln Ile Val Ile Cys Val Ile Trp Leu Tyr Thr Ala
`750
`745
`755
`
`CCC CCC TCA AGC TAC CGC AAC CAG GAG CTG GAG GAT
`Pro Pro Ser Ser Tyr Arg Asn Gln Glu Leu Glu Asp
`760
`765
`
`GAG ATC ATC TTC ATC ACG TGC CAC GAG GGC TCC CTC
`Glu Ile Ile Phe Ile Thr Cys His Glu Gly Ser Leu
`77Cj
`775
`780
`
`ATG GCC CTG GGC TTC CTG ATC GGC TAC ACC TGC CTG
`Met Ala Leu Gly Phe Leu Ile Gly Tyr Thr Cys Leu
`785
`790
`
`CTG GCT GCC ATC TGC TTC TTC TTT GCC TTC AAG TCC
`Leu Ala Ala Ile Cys Phe Phe Phe Ala Phe Lys Ser
`600
`795
`
`CGG AAG CTG CCG GAG AAC TTC AAT GAA GCC AAG TTC
`Arg Lys Leu Pro Glu Asn Phe Asn Glu Ala Lys Phe
`805
`610
`815
`
`ATC ACC TTC AGC ATG CTC ATC TTC TTC ATC GTC TGG
`Ile Thr Phe Ser Met Leu Ile Phe Phe Ile Val Trp
`820
`825
`
`ATC TCC TTC ATT CCA GCC TAT GCC AGC ACC TAT GGC
`Ile Ser Phe Ile Pro Ala Tyr Ala Ser Thr Tyr Gly
`830
`835
`840
`
`AAG TTT GTC TCT GCC GTA GAG GTG ATT GCC ATC CTG
`Lys Phe Val Ser Ala Val Glu Val Ile Ala Ile Leu
`845
`850
`
`SUBSTITUTE-SHEET {RULE 26)
`
`2523
`
`2559
`
`2595
`
`2631
`
`2667
`
`2703
`
`2739
`
`2775
`
`2811
`
`2647
`
`2683
`
`2919
`
`2955
`
`2991
`
`787
`
`
`
`W096/ll697
`
`PCT/US95/13704
`
`91
`
`GCA GCC AGC TTT GGC TTG CTG GCG TGC ATC TTC TTC
`Ala Ala Ser Phe Gly Leu Leu Ala Cys Ile Phe Phe
`855
`860
`
`AAC AAG ATC TAC ATC ATT CTC TTC AAG CCA TCC CGC
`Asn Lys Ile Tyr Ile Ile Leu Phe Lys Pro Ser Arg
`870
`865
`875
`
`AAC ACC ATC GAG GAG GTG CGT TGC AGC ACC GCA GCT
`Asn Thr Ile Glu Glu Val Arg Cys Ser Thr Ala Ala
`880
`885
`
`CAC GCT TTC AAG GTG GCT GCC CGG GCC ACG CTG CGC
`His Ala Phe Lys Val Ala Ala Arg Ala Thr Leu Arg
`895
`900
`890
`
`CGC AGC AAC GTC TCC CGC AAG CGG TCC AGC AGC CTT
`Arg Ser Asn Val Ser Arg Lys Arg Ser Ser Ser Leu
`905
`910
`
`GGA GGC TCC ACG GGA TCC ACC CCC TCC TCC TCC ATC
`Gly Gly Ser Thr Gly Ser Thr Pro Ser Ser Ser Ile
`915
`920
`
`AGC AGC AAG AGC AAC AGC GAA GAC CCA TTC CCA CGG
`Ser Ser Lys Ser Asn Ser Glu Asp Pro Phe Pro Arg
`925
`930
`935
`
`CCC GAG AGG CAG AAG CAG CAG CAG CCG CTG GCC CTA
`Pro Glu Arg Gln Lys Gln Gln Gln Pro Leu Ala Leu
`945
`940
`
`ACC CAG CAA GAG CAG CAG CAG CAG CCC CTG ACC CTC
`Thr Gln Gln Glu Gln Gln Gln Gln Pro Leu Thr Leu
`960
`955
`950
`
`CCA CAG CAG CAA CGA TCT CAG CAG CAG CCC AGA TGC
`Pro Gln Gln Gln Arg Ser Gln Gln'Gln Pro Arg Cys
`965
`970
`
`AAG CAG AAG GTC ATC TTT GGC AGC GGC ACG GTC ACC
`Lys Gln Lys Val Ile Phe Gly Ser Gly Thr Val Thr
`975
`980
`
`TTC TCA CTG AGC TTT GAT GAG CCT CAG AAG AAC GCC
`Phe Ser Leu Ser Phe Asp Glu Pro Gln Lys Asn Ala
`985
`990
`995
`
`ATG GCC CAC AGG AAT TCT ACG CAC CAG AAC TCC CTG
`Met Ala His Arg Asn Ser Thr His Gln Asn Ser Leu
`1000
`1005
`
`GAG GCC CAG AAA AGC AGC GAT ACG CTG ACC CGA CAC
`Glu Ala Gln Lys Ser Ser Asp Thr Leu Thr Arg His
`1010
`1015
`1020
`
`SUBSTITUTE SHEET (RULE 26)
`
`3027
`
`3063
`
`3099
`
`3135
`
`3171
`
`3207
`
`3243
`
`3279
`
`3315
`
`3351
`
`3387
`
`3423
`
`3459
`
`3495
`
`788
`
`
`
`W096/12697
`
`PCT/US95/13704
`
`92
`
`CAG CCA TTA CTC CCG CTG CAG TGC GGG GAA ACG GAC
`Gln.Pro Leu Leu Pro Leu Gln Cys Gly Glu Thr Asp
`1025
`1030
`
`TTA GAT CTG ACC GTC CAG GAA ACA GGT CTG CAA GGA
`Leu Asp Leu Thr Val Gln Glu Thr Gly Leu Gln Gly
`1035
`1040
`
`CCT GTG GGT GGA GAC CAG CGG CCA GAG GTG GAG GAC
`Pro Val Gly Gly Asp Gln Arg Pro Glu Val Glu Asp
`1045
`1050
`1055
`
`CCT GAA GAG TTG TCC CCA GCA CTT GTA GTG TCC AGT
`Pro Glu Glu Leu Ser Pro Ala Leu Val Val Ser Ser
`1060
`1065
`
`TCA CAG AGC TTT GTC ATC AGT GGT GGA GGC AGC ACT
`Ser Gln Ser Phe Val Ile Ser Gly Gly Gly Ser Thr
`1070
`1075
`1080
`
`GTT ACA GAA AAC GTA GTG AAT TCA TAAAATGGAA
`Val Thr Glu Asn Val Val Asn Ser
`1085
`
`GGAGAAGACT GGGCTAGGGA GAATGCAGAG AGGTTTCTTG
`
`GGGTCCCAGG GATGAGGAAT CGCCCCAGAC TCCTTTCCTC
`
`TGAGGAAGAA GGGATAATAG ACACATCAAA TGCCCCGAAT
`
`TTAGTCACAC CATCTTAAAT GACAGTGAAT TGACCCATGT
`
`TCCCTTTAAA ATTAAAAAAA AGAAGAGCCT TGTGTTTCTG
`
`TGGTTGCATT TGTCAAAGCA TTGAGATCTC CACGGTCAGA
`
`TTTGCTGTTC ACCCACATCT AATGTCTCTT CCTCTGTTCT
`
`ATCCCACCCA ACAGCTCAGA GATGAAACTA TGGCTTTAAA
`
`CTACCCTCCA GAGTGTGCAG ACTGATGGGA CATCAAATTT
`
`GCCACCACTA GAGCTGAGAG TCTGAAAGAC AGAATGTCAC
`
`CAGTCCTGCC CAATGCCTTG ACAACAGACT GAATTTTAAA
`
`TGTTCACAAC ATAAGGAGAA TGTATCTCCT CCTATTTATG
`
`AAAACCATAT GATATTTTGT CTCCTACCTG CTGCTGCTAT
`
`TATGTAACAT CCAGAAGGTT TGCACCCCTC CTATACCATA
`
`TGTCTGGTTC TGTCCAGGAC ATGATACTGA TGCCATGTTT
`
`AGATTCCAGG ATCACAAGAA TCACCTCAAA TTGTTAGGAA
`
`SUBSTITUTE SHEET (RULE 26)
`
`3531
`
`3567
`
`3603
`
`3639
`
`3675
`
`3709
`
`3749
`
`3789
`
`3829
`
`3869
`
`3909
`
`3949
`
`3989
`
`4029
`
`4069
`
`4109
`
`4149
`
`4189·
`
`4229
`
`4269
`
`4309
`
`4349
`
`789
`
`
`
`W096/l2697
`
`PCT/US95/13704
`
`4389
`
`4429
`
`4469
`
`4509
`
`4549
`
`4589
`
`4629
`
`4669
`
`4709
`
`4749
`
`4789
`
`4829
`
`4869
`
`4909
`
`4949
`
`4989
`
`5006
`
`93
`
`GGGACTGCAT AAACCAATGA GCTGTATCTG TAATTAATAT
`
`TCCTATATGT AGCTTTATCC TTAGGAAAAT GCTTCTGTTG
`
`TAATAGTCCA TGGACAATAT AAACTGAAAA ATGTCAGTCT
`
`GGTTTATATA AGGCAGTATT ATTGAGCTCT ATTTCCCCAC
`
`CCCACTATCC TCACTCCCAT AAGCTAAGCC TTATGTGAGC
`
`CCCTTCAGGG ACTCAAGGGT CCAGAAGTCC CTCCCATCTC
`
`TACCCCAAAG AATTCCTGAA GCCAGATCCA CCCTATCCCT
`
`GTACAGAGTA AGTTCTCAAT TATTGGCCTG CTAATAGCTG
`
`CTAGGGTAGG AAAGCGTGGT TCCAAGAAAG ATCCACCCTC
`
`AAATGTCGGA GCTATGTTCC CTCCAGCAGT GGTATTAATA
`
`CTGCCGGTCA CCCAGGCTCT GGAGCCAGAG AGACAGACCG
`
`GGGTTCAAGC CATGGCTTCG TCATTTGCAA GCTGAGTGAC
`
`TGTAGGCAGG GAACCTTAAC CTCTCTAAGC CACAGCTTCT
`
`TCATCTTTAA AATAAGGATA ATAATCATTC CTTCCCCTCA
`
`GAGCTCTTAT GTGGATTAAA CGAGATAATG TATATAAAGT
`
`ACTTTAGCCT GGTACCTAGC ACACAATAAG CATTCAATAA
`
`ATATTAGTTA ATATTAT.
`
`(2)
`
`INFORMATION FOR SEQ ID NO: 2:
`
`(i) SEQUENCE CHARACTERISTICS:
`(A) LENGTH:
`3809 base pairs
`(B) TYPE:
`nucleic acid
`(C) STRANDEDNESS:
`single
`(D) TOPOLOGY:
`linear
`
`(ii) MOLECULE TYPE:
`
`cDNA to mRNA
`
`(ix) FEATURE:
`CDS
`(A) NAME/KEY:
`373 .. 3606
`(B) LOCATION:
`(D) OTHER INFORMATION:
`
`(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2:
`
`CAACAGGCAC CTGGCTGCAG CCAGGAAGGA CCGCACGCCC
`
`40
`
`SUBSTITUTE SHEET (RULE 26)
`
`790
`
`
`
`W096/12697
`
`PCT/US95/13704
`
`94
`
`TTTCGCGCAG GAGAGTGGAA GGAGGGAGCT GTTTGCCAGC
`
`ACCGAGGTCT TGCGGCACAG GCAACGCTTG ACCTGAGTCT
`
`TGCAGAATGA AAGGCATCAC AGGAGGCCTC TGCATGATGT
`
`GGCTTCCAAA GACTCAAGGA CCACCCACAT TACAAGTCTG
`
`GATTGAGGAA GGCAGAAATG GAGATTCAAA CACCACGTCT
`
`TCTATTATTT TATTAATCAA TCTGTAGACA TGTGTCCCCA
`
`CTGCAGGGAG TGAACTGCTC CAAGGGAGAA ACTTCTGGGA
`
`GCCTCCAAAC TCCTAGCTGT CTCATCCCTT GCCCTGGAGA
`
`GACGGCAGAA CC ATG GCA TTT TAT AGC TGC TGC TGG
`Met Ala Phe Tyr Ser Cys Cys Trp
`1
`5
`
`GTC CTC TTG GCA CTC ACC TGG CAC ACC TCT GCC TAC
`Val Leu Leu Ala Leu Thr Trp His Thr Ser Ala Tyr
`10
`15
`20
`
`GGG CCA GAC CAG CGA GCC CAA AAG AAG GGG GAC ATT
`Gly Pro Asp Gln Arg Ala Gln Lys Lys Gly Asp Ile
`25
`30
`
`ATC CTT GGG GGG CTC TTT CCT ATT CAT.TTT GGA GTA
`Ile Leu Gly Gly Leu Phe Pro Ile His Phe Gly Val
`35
`40
`
`GCA GCT AAA GAT CAA GAT CTC AAA TCA AGG CCG GAG
`Ala Ala Lys Asp Gln Asp Leu Lys Ser Arg Pro Glu
`so
`45
`55
`TCT GTG GAA TGT ATC AGG TAT AAT TTC CGT GGG TTT
`Ser Val Glu cys Ile Arg Tyr Asn Phe Arg Gly Phe
`60
`65
`
`CGC TGG TTA CAG GCT ATG ATA TTT GCC ATA GAG GAG
`Arg Trp Leu Gln Ala Met Ile Phe Ala Ile Glu Glu
`70
`75
`80
`
`ATA AAC AGC AGC CCA GCC CTT CTT CCC AAC TTG ACG
`Ile Asn Ser Ser Pro Ala Leu Leu Pro Asn Leu Thr
`85
`90
`
`CTG GGA TAC AGG ATA TTT GAC ACT TGC AAC ACC GTT
`Leu Gly Tyr Arg Ile Phe Asp Thr Cys Asn Thr Val
`95
`100
`
`TCT AAG GCC TTG GAA GCC ACC CTG AGT TTT GTT GCT
`Ser Lys Ala Leu Glu Ala Thr Leu Ser Phe Val Ala
`105
`110
`115
`
`SUBSTITUTE SHEET (RULE 26)
`
`80
`
`120
`
`160
`
`200
`
`240
`
`280
`
`320
`
`360
`
`396
`
`432
`
`468
`
`504
`
`540
`
`576
`
`612
`
`648
`
`684
`
`720
`
`791
`
`
`
`W096/12697
`
`PCT/US9S/l3704
`
`95
`
`CAA AAC AAA ATT GAT TCT TTG AAC CTT GAT GAG TTC
`Gln Asn Lys Ile Asp Ser Leu Asn Leu Asp Glu Phe
`120
`125
`
`TGC AAC TGC TCA GAG CAC ATT CCC TCT ACG ATT GCT
`Cys Asn Cys Ser Glu His Ile Pro Ser Thr Ile Ala
`130
`135
`140
`
`GTG GTG GGA GCA ACT GGC TCA GGC GTC TCC ACG GCA
`Val Val Gly Ala Thr Gly Ser Gly Val Ser Thr Ala
`145
`150
`
`GTG GCA AAT CTG CTG GGG CTC TTC TAC ATT CCC CAG
`Val Ala Asn Leu Leu Gly Leu Phe Tyr Ile Pro Gln
`155
`160
`
`GTC AGT TAT GCC TCC TCC AGC AGA CTC CTC AGC AAC
`val Ser Tyr Ala Ser Ser Ser Arg Leu Leu Ser Asn
`170
`175
`165
`
`AAG AAT CAA TTC AAG TCT TTC CTC CGA ACC ATC CCC
`Lys Asn Gln Phe Lys Ser Phe Leu Arg Thr Ile Pro
`180
`185
`
`AAT GAT GAG CAC CAG GCC ACT GCC ATG GCA GAC ATC
`Asn Asp Glu His Gln Ala Thr Ala Met Ala Asp Ile
`190
`195
`200
`
`ATC GAG TAT TTC CGC TGG AAC TGG GTG GGC ACA ATT
`Ile Glu Tyr Phe Arg Trp Asn Trp Val Gly Thr Ile
`205
`210
`
`GCA GCT GAT GAC GAC TAT GGG CGG CCG GGG ATT GAG
`Ala Ala Asp Asp Asp Tyr Gly Arg Pro Gly Ile Glu
`215
`220
`
`AAA TTC CGA GAG GAA GCT GAG GAA AGG GAT ATC TGC
`Lys Phe Arg Glu Glu Ala Glu Glu Arg Asp Ile Cys
`225
`230
`235
`
`ATC GAC TTC AGT GAA CTC ATC TCC CAG TAC TCT GAT
`Ile Asp Phe Ser Glu Leu Ile Ser Gln Tyr Ser Asp
`240
`245
`
`GAG GAA GAG ATC CAG CAT GTG GTA GAG GTG ATT CAA
`Glu Glu Glu Ile Gln His Val Val Glu Val Ile Gln
`250
`255
`260
`
`AAT TCC ACG GCC AAA GTC ATC GTG GTT TTC TCC AGT
`Asn Ser Thr Ala Lys Val Ile Val Val Phe Ser Ser
`265
`270
`
`GGC CCA GAT CTT GAG CCC CTC ATC AAG GAG ATT GTC
`Gly Pro Asp Leu Glu Pro Leu Ile Lys Glu Ile Val
`275
`280
`
`SUBSTITUTE SHEET (RULE 26)
`
`756
`
`792
`
`828
`
`864
`
`900
`
`936
`
`972
`
`1008
`
`1044
`
`1080
`
`1116
`
`1152
`
`1188
`
`1224
`
`792
`
`
`
`W096/12697
`
`PCT/US95/13704
`
`96
`
`CGG CGC AAT ATC ACG GGC AAG ATC TGG CTG GCC AGC
`Arg Arg Asn Ile Thr Gly Lys Ile Trp Leu Ala Ser
`285
`290
`295
`
`GAG GCC TGG GCC AGC TCC TCC CTG ATC GCC ATG CCT
`Glu Ala Trp Ala Ser Ser Ser Leu Ile Ala Met Pro
`300
`305
`
`CAG TAC TTC CAC GTG GTT GGC GGC ACC ATT GGA TTC
`Gln Tyr Phe His Val Val Gly Gly Thr Ile Gly Phe
`315
`320
`310
`
`GCT CTG AAG GCT GGG CAG ATC CCA GGC TTC CGG GAA
`Ala Leu Lys Ala Gly Gln Ile Pro Gly Phe Arg Glu
`330
`325
`
`TTC CTG AAG AAG GTC CAT CCC AGG AAG TCT GTC CAC
`Phe Leu Lys Lys Val His Pro Arg Lys Ser Val His
`335
`340
`
`AAT GGT TTT GCC AAG GAG TTT TGG GAA GAA ACA TTT
`Asn Gly Phe Ala Lys Glu Phe Trp Glu Glu Thr Phe
`345
`350
`355
`
`AAC TGC CAC CTC CAA GAA GGT GCA AAA GGA CCT TTA
`Asn Cys His Leu Gln Glu Gly Ala Lys Gly Pro Leu
`360
`365
`
`CCT GTG GAC ACC TTT CTG AGA GGT CAC GAA GAA AGT
`Pro Val Asp Thr Phe Leu Arg Gly His Glu Glu Ser
`370
`375
`380
`
`GGC GAC AGG TTT AGC AAC AGC TCG ACA GCC TTC CGA
`Gly Asp Arg Phe Ser Asn Ser Ser Thr Ala Phe Arg
`385
`390
`
`CCC CTC TGT ACA GGG GAT GAG AAC ATC AGC AGT GTC
`Pro Leu Cys Thr Gly Asp Glu Asn Ile Ser Ser Val
`395
`400
`
`GAG ACC CCT TAC ATA GAT TAC ACG CAT TTA CGG ATA
`Glu Thr Pro Tyr Ile Asp Tyr Thr His Leu Arg Ile
`405
`410
`415
`
`TCC TAC AAT GTG TAC TTA GCA GTC TAC TCC ATT GCC
`Ser Tyr Asn Val Tyr Leu Ala Val Tyr Ser Ile Ala
`420
`425
`
`CAC GCC TTG CAA GAT ATA TAT ACC TGC TTA CCT GGG
`His Ala Leu Gln Asp Ile Tyr Thr Cys Leu Pro Gly
`430
`435
`440
`
`AGA GGG CTC TTC ACC AAT GGC TCC TGT GCA GAC ATC
`Arg Gly Leu Phe Thr Asn Gly Ser Cys Ala Asp Ile
`445
`450
`
`SUBSTITUTE SHEET (RULE 26)
`
`1260
`
`1296
`
`1332
`
`1368
`
`1404
`
`1440
`
`1476
`
`1512
`
`1548
`
`1584
`
`1620
`
`1656
`
`1692
`
`1728
`
`793
`
`
`
`W096/12697
`
`PCT/US95/13704
`
`97
`
`AAG AAA GTT GAG GCG TGG CAG GTC CTG AAG CAC CTA
`Lys Lys Val Glu Ala Trp Gln Val Leu Lys His Leu
`455
`460
`
`CGG CAT CTA AAC TTT ACA AAC AAT ATG GGG GAG CAG
`Arg His Leu Asn Phe Thr Asn Asn Met Gly Glu Gln
`470
`465
`475
`
`GTG ACC TTT GAT GAG TGT GGT GAC CTG GTG GGG AAC
`Val Thr Phe Asp Glu Cys Gly Asp Leu Val Gly Asn
`480
`485
`
`TAT TCC ATC ATC AAC TGG CAC CTC TCC CCA GAG GAT
`Tyr Ser Ile Ile Asn Trp His Leu Ser Pro Glu Asp
`490
`495
`500
`
`GGC TCC ATC GTG TTT AAG GAA GTC GGG TAT TAC AAC
`Gly Ser Ile Val Phe Lys Glu Val Gly Tyr Tyr Asn
`505
`510
`
`GTC TAT GCC AAG AAG GGA GAA AGA CTC TTC ATC AAC
`Val Tyr Ala Lys Lys Gly Glu Arg Leu Phe Ile Asn
`515
`520
`
`GAG GAG AAA ATC CTG TGG AGT GGG TTC TCC AGG GAG
`Glu Glu Lys Ile Leu Trp Ser Gly Phe Ser Arg Glu
`525
`530
`535
`
`GTG CCC TTC TCC AAC TGC AGC CGA GAC TGC CTG GCA
`Val Pro Phe Ser Asn Cys Ser Arg Asp Cys Leu Ala
`540
`545
`
`GGG ACC AGG AAA GGG ATC ATT GAG GGG GAG CCC ACC
`Gly Thr Arg Lys Gly Ile Ile Glu Gly Glu Pro Thr
`550
`560
`555
`
`TGC TGC TTT GAG TGT GTG GAG TGT CCT GAT GGG GAG
`Cys Cys Phe Glu Cys Val Glu Cys Pro Asp Gly Glu
`570
`565
`
`TAT AGT GAT GAG ACA GAT GCC AGT GCC TGT AAC AAG
`Tyr Ser Asp Glu Thr Asp Ala Ser Ala Cys Asn Lys
`575
`580
`
`TGC CCA GAT GAC TTC TGG TCC AAT GAG AAC CAC ACC
`Cys Pro Asp Asp Phe Trp Ser Asn Glu Asn His Thr
`SSS
`590
`595
`
`TCC TGC ATT GCC AAG GAG ATC GAG TTT CTG TCG TGG
`Ser cys Ile Ala Lys Glu Ile Glu Phe Leu Ser Trp
`600
`605
`
`ACG GAG CCC TTT GGG ATC GCA CTC ACC CTC TTT GCC
`Thr Glu Pro Phe Gly Ile Ala Leu Thr Leu Phe Ala
`610
`615
`620
`
`SUBSTITUTE SHEET (RULE 26)
`
`1764
`
`1800
`
`1836
`
`1872
`
`1908
`
`1944
`
`1980
`
`2016
`
`2052
`
`2088
`
`2124
`
`2160
`
`2196
`
`2232
`
`794
`
`
`
`W096/12697
`
`PCT/US95113704
`
`98
`
`GTG CTG GGC ATT TTC CTG ACA GCC TTT GTG CTG GGT
`Val Leu Gly Ile Phe Leu Thr Ala Phe Val Leu Gly
`630
`625
`
`GTG TTT ATC AAG TTC CGC AAC ACA CCC ATT GTC AAG
`Val Phe Ile Lys Phe Arg Asn Thr Pro Ile Val Lys
`640
`635
`
`GCC ACC AAC CGA GAG CTC TCC TAC CTC CTC CTC TTC
`Ala Thr Asn Arg Glu Leu Ser Tyr Leu Leu Leu Phe
`645
`650
`655
`
`TCC CTG CTC TGC TGC TTC TCC AGC TCC CTG TTC TTC
`Ser Leu Leu Cys Cys Phe Ser Ser Ser Leu Phe Phe
`660
`665
`
`ATC GGG GAG CCC CAG GAC TGG ACG TGC CGC CTG CGC
`Ile Gly Glu Pro Gln Asp Trp Thr Cys Arg Leu Arg
`670
`675
`680
`
`CAG CCG GCC TTT GGC ATC AGC TTC GTG CTC TGC ATC
`Gln Pro Ala Phe Gly Ile Ser Phe Val Leu Cys Ile
`690
`685
`
`TCA TGC ATC CTG GTG AAA ACC AAC CGT GTC CTC CTG
`Ser Cys Ile Leu Val Lys Thr Asn Arg Val Leu Leu
`700
`695
`
`GTG TTT GAG GCC AAG ATC CCC ACC AGC TTC CAC CGC
`Val Phe Glu Ala Lys Ile Pro Thr Ser Phe His Arg
`715
`705
`710
`
`AAG TGG TGG GGG CTC AAC CTG CAG TTC CTG CTG GTT
`Lys Trp Trp Gly Leu Asn Leu Gln Phe Leu Leu Val
`720
`725
`
`TTC CTC TGC ACC TTC ATG CAG ATT GTC ATC TGT GTG
`Phe Leu Cys Thr Phe Met Gln Ile Val Ile Cys Val
`735
`740
`730
`
`ATC TGG CTC TAC ACC GCG CCC CCC TCA AGC TAC CGC
`Ile Trp Leu Tyr Thr Ala Pro Pro Ser Ser Tyr Arg
`750
`745
`
`AAC CAG GAG CTG GAG GAT GAG ATC ATC TTC ATC ACG
`Asn Gln Glu Leu Glu Asp Glu Ile Ile Phe Ile Thr
`760
`755
`
`TGC CAC GAG GGC TCC CTC ATG GCC CTG GGC TTC CTG
`Cys His Glu Gly Ser Leu Met Ala Leu Gly Phe Leu
`770
`775
`765
`
`ATC GGC TAC ACC TGC CTG CTG GCT GCC ATC TGC TTC
`Ile Gly Tyr Thr Cys Leu Leu Ala Ala Ile Cys Phe
`780
`785
`
`SUBSTITUTE SHEET (RULE 26)
`
`2268
`
`2304
`
`2340
`
`2376
`
`2412
`
`2448
`
`2484
`
`2520
`
`2556
`
`2592
`
`2628
`
`2664
`
`2700
`
`2736
`
`795
`
`
`
`W096/12697
`
`PCT/US95/13704
`
`99
`
`TTC TTT GCC TTC AAG TCC CGG AAG CTG CCG GAG AAC
`Phe Phe Ala Phe Lys Ser Arg Lys Leu Pro Glu Asn
`790
`795
`800
`
`TTC AAT GAA GCC AAG TTC ATC ACC TTC AGC ATG CTC
`Phe Asn Glu Ala Lys Phe Ile Thr Phe Ser Met Leu
`805
`810
`
`ATC TTC TTC ATC GTC TGG ATC TCC TTC ATT CCA GCC
`Ile Phe Phe Ile Val Trp Ile Ser Phe Ile Pro Ala
`815
`820
`
`TAT GCC AGC ACC TAT GGC AAG TTT GTC TCT GCC GTA
`Tyr Ala Ser Thr Tyr Gly Lys Phe Val Ser Ala Val
`825
`830
`835
`
`GAG GTG ATT GCC ATC CTG GCA GCC AGC TTT GGC TTG
`Glu Val Ile Ala Ile Leu Ala Ala Ser Phe Gly Leu
`840
`845
`
`CTG GCG TGC ATC TTC TTC AAC AAG ATC TAC ATC ATT
`Leu Ala Cys Ile Phe Phe Asn Lys Ile Tyr Ile Ile
`860
`850
`855
`
`CTC TTC AAG CCA TCC CGC AAC ACC ATC GAG GAG GTG
`Leu Phe Lys Pro Ser Arg Asn Thr Ile Glu Glu Val
`865
`870
`
`CGT TGC AGC ACC GCA GCT CAC GCT TTC. AAG GTG GCT
`Arg Cys Ser Thr Ala Ala His Ala Phe Lys Val Ala
`875
`880
`
`GCC CGG GCC ACG CTG CGC CGC AGC AAC GTC TCC CGC
`Ala Arg Ala Thr Leu Arg Arg Ser Asn Val Ser Arg
`885
`890
`895
`
`AAG CGG TCC AGC AGC CTT GGA GGC TCC ACG GGA TCC
`Lys Arg Ser Ser Ser Leu Gly Gly Ser Thr Gly Ser
`900
`905
`
`ACC CCC TCC TCC TCC ATC AGC AGC AAG AGC AAC AGC
`Thr Pro Ser Ser Ser Ile Ser Ser Lys Ser Asn Ser
`910
`915
`920
`
`GAA GAC CCA TTC CCA CAG CCC GAG AGG CAG AAG CAG
`Glu Asp Pro Phe Pro
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