`
`WO 2007/101158
`
`PCT/US2007/062815
`
`Asp ar Glu; 2) any amine acidother than Cys; e) Glu f) missing: e@) Prep, Tyr or Phes
`or h)} Lys or Arg;
`
`Naas isca) Thr, Asp, Ser Ghia,Pro, Val or Len: Asp ar Ghiy; b) any amino actd
`other than Cys:-cy Glen d) Thr e} Thr, Asp, Ser, Gila, Pro, Valor Lew or is missing: 2
`‘Typ, Tyr or Phe; or g} Lyecr ArgBa
`Naayisc ay Cys, Mpt cnereaptopraline),Por (penicillamine), Dpr
`{diaminopreqonic acid), Asp,or Chay
`Nass iS: a) Gryamino acid b) Gu, Asp, Glo, Gly or Proz o} Gha a} Glu or
`Asp; ey Asp, Te or Gly § any ABING acid; Gr g} any amino acidotherthan ¢ya;
`Ray ist a) Leu, Le, Val, Ala, Lys, Arg, Trp, Tyr or Phe: b) Leu, fe, Val, Lye,
`Arg, Trp, Tyr or Phe; Leu, HeLL“ys, Arg, Trp, Tyr or Phe; c) Leu, Me, Val. Trp.Tyr OF
`Phe: d} Tre, Tyr, Phe or Let: , Leu; Tle or VaO leyTrpor Leu; 9) Trp, Tyr or Phe:
`b} Beor Leus 3) Tyr) any amine acid: k} any amine acid exceptLew, 2) any natural
`or non-tatral aromatic aming acid: or m) anyamino acidother than Cys:
`Naayz W7 a} Cys,Ser, onTyr; Cys; b) Cys, Mpt Gnercaptoproline), Pen
`fpenicilansine),DprGhsnispronioneacid),AsporGho}Ser;or.djanamineacid
`Nasa isa} Ala, Val, arye:by Ala, Val, Thr, Te, Metor is neesing; c) any
`amino acid; d) Vals ¢) any amino acid other than Cys; or f) missing:
`Naas ig a} any amind seid; b) any aming acid other than-Phe and Tyay o} any
`ep}
`agsino seid other than Phe, Tyr, and Trp; d) any amine acid otherthan Phe, Tyr, Trp,
`
`
`Ge, Lou and Val ¢} any:amine acid other than Phe, Tyr,Trp, He, Leu, Val, and His; 2)
`any amine scid-other than. or a) any aminoacid other than Lys, Arg, Phe, Tyr, and
`‘Crp; h) anyaminoacid other
`than Lys,Arg, Phe, Tye, Trp, He, Leu and Val; i) any
`
`armino avid otterthan Lys, Are
`Phe, Tyr, Trp, le, Leu, Val, and His; J) any none
`aromatic arming acid:k) missing: 1) Phe, Tyr,Asn, orTrp, m) Asn, ye Aspor Alaon)
`
`Asn, Gh, or Tyr, 0) Phe or Tyr p} Asny org) any amino acid other than Cys}
`rotyy b) Pro or Gly; ¢) Proyd) Ala, Val, Met,The or He;
`Nagiist a} Ala, Pro or
`
`i
`e)any aming ved £ Vals g)Val orPro; h)Ala orVal; i) anyating acid otherthan
`
`other than Oya
`
`Cyst j) Peo, or ky Gly:
`
`TK
`
`20
`
`reeaye
`
`MYLAN - EXHIBIT 1022 Part 4 of 16
`1092
`
`1092
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`MYLAN - EXHIBIT 1022 Part 4 of 16
`
`

`

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`PCT/US2007/062815
`
`ayy TR A any ain‘acid: b) Ala, Leu, Ser, Gly, Val, Cdn, Gin, fe, Leu, Lys,
`Arg, orAsm o} Ala or Gly; a)Alay e} Ala or Vali D anyamino acid; g} Ala or Alb
`(alinhe-arninobobutyrie acid): h) any antine acid other than Cys Akvar Thr, or).
`“Thr.fad
`
`ant
`
`w
`
`en
`
`Nays ia} Cys, Mpt (mereaptoprotine), Pert (penicillamine), Dpr
`(aminopropionie acid), Asp.or Gla; or b) any aminoacid otherthan Cys;
`ayy ia a} The, Ala,Asn, loys, Arg, or Trp:b) The, Ala, Lys, Arg, orPik o}
`any amine acid;d) any non-arinatie amino acid; e) Thr, Ala, or Tepe8 ‘Pep, Pyr or
`Phe: g) Thr er Ala; hb} aayamino ncid, 2) Thisj) any amino aid other than Cys: ke)
`The.ValorOty;Pheor Val, m) Thror Gly, a) Val or Thr, 3)
`p)Thr: or q} Gls:
`Naaig ih a) Gly,Pro or Ala; b) Gly; c) anyamino avid; HG y, Ala or Ser;
`Oty or Ala: § anyamine aed
`other than Cys: or ¢) Ala:
`
`Naays is: a) Cys, Tyr or is missing; b) Cys; c) Cys, Mpt (mersaptoproline}, Pen
`ipeniclamine}, Opr (laminepropionie acid), Asp, Glu; ar d) any amine acid other
`
`than Cysor is missing; and
`Nawyg isv a} Trp, Tyr, Phe, Asn, Ile, Val, His-or Lew: bh) Trp, Tyr, Phe, Asn or
`Leay ec) Trp, Py, Pheer Leu; i Tryp,Tyr, or Phe; ¢) Leu, He or Valy 8 Ris, Len or
`
`
`
`Ser: g) Tyr or Leuy Lys or Arg;
`h} His; i) any aminoacid, 7) Len, or missing; k) Tip,
`
`‘Tyr, Phe, Lys, Arg oris missing; 1) missing: m) any aminoacid other than Cys; or)
`
`
`
`2000
`
`Tyr.
`
`
`
`26
`
`36
`
`Alsofeatured is parified polypeptide comprising, consiting of or consistingessentially
`
`ay; NaarNatty Xaay Naas Aadg Kady Rady Nadg AQAjy
`ofthe amino acid saguence: s
`
`Nadi (SEQ ID NOL) wherein:
`Maayy Naar Xadiy RaaXa
`Naay ig any aminoacid or is missing:
`Nad ia any amine acidor is missing,
`Xaay is any amino acidor-is missing:
`
`Xaay ig Cys, Mpt Gueteaptoproline), Pen (penicillamine), Der
`(diaminoprosionic acid), Asp or Gh
`
`Massa Ghis
`aXaayis Tyr, Trp, Phe orLeu;
`
`Ad
`
`1093
`
`1093
`
`

`

`WO 2007/101158
`
`,
`
`PCT/US2007/062815 -
`
`Rady 1g Cys, Mot (jnercaptoprotine), Pen (penicillamine), Der
`(diesninopropionic acid),Aspor Gh;
`Nagyis any amino acid otherthan Cys oris missing:
`Naasis any amino acid;
`Awaig is Proor Gly,
`|
`aay 6 any amine eld;
`Aaais Cys, Mpt (mereaptoprotine), Pen (penicillamine), Dpr
`semengionio acid},AsporOh
`ais is Thr, Val ar oly;
`Aaajgis Gly or Alar
`|
`Naas is Cys, Mpt (mereaptoproline), Pen (penicillamine), Dpr
`idiaminopropionic seid}, Aspor Chay and
`Nadia iSanyammo uch OY 1S MUSSINE..
`
`‘The diselosure algo features peptides whichmay include one or more ofthe peptide
`modifications, ane or more non-natural arnino acid or amino acidanalogs, ene or
`more ofthe disulfide band alternatives orone more ofthe altemaiive peptidebonds
`
`deseribod heres,
`
`GIONagonists ofthe disclosureeanalso coinprise, consist esseritial]y of ar consist af
`
`poplides derived from.the C-terminal domainofanyofthe peptides described herein.
`Thas, they can-centain,for cxample,anywhere from 13-73 amino acids inclading13,
`14, 15, 16, U7, 18, 198, 20, 21,22,223,24, 25, 26,27, 28, 29, 30, 31,32, 33, 34, 35,36,
`37, 38, 39, 40, 41, 42, 43, 44,AS, 46,AT, 48, 4, 30, 31,pe 53, 34, 33, 36, 37, 38, 39,
`6D, 61, 62, 63, 64, 65,66,67,88, 69, 70, 71, 72, 73,74, and/or 75 anuing acids ofthe.
`C-terminal domain ofanyofthepeptides teseibed heherein,
`
`The various peptides can bepresent witha counterion. Useful counterions include
`saltsof acetate, benzenesulfonate,benzoate, calaininedetate, vamsvlate, carbonate,
`titrate, edetate (EDTA), odisylate, embonate, esylate, fumarate, gluceplate, glaconate,
`glutamate, 2)yeollylarsanilate, hexylresorcinate, iodide, bromide, chloride,
`
`~ a5 -
`
`§
`
`40
`
`18
`
`200
`
`28
`
`30.
`
`
`
`1094
`
`1094
`
`

`

`WO 2007/101158
`
`PCT/US2007/062815
`
`the
`
`hydroxynaphthoate, isethionate, lactate, lactoblonate, ostolate, maleate, malate,
`mandelate, mesylate, mucite, napsylate, niirate, pantothenate, phosphate, salicylate,
`iemrate, suecinate, sulfate, tarlarate, theoclate, acclaridobenzoate, adipste, ulginale,
`arninosalicviate, anhydtromethy!enecitrate, ascorbate, aspartate,cammphorate, caprate,
` vaproate, caprylate, chmamate eyclamate, dichloroacctate, lormaic, gentisate,
`ghucuronate, glycorophosphate,&ycolate, hipporate, Huoride, malonate, napadisylate
`picatitain, oleate, orotate, Ox late,oxoglutarate, palinitate,pectinate, pectiiate
`
`polymer, phenylethvibarbiturale,. plorate, promonate, pidolate, sebacate,rhodanide,
`tosylate, and tanmate.
`
`8
`
`4
`
`20.
`
`
`arealso features atherapeutic or prophylactic method
`Ina seeand aspect, the dise
`comprising administering a compositioncomprising a purified peptide comprisiag,
`consisting essentially ofof consisting ofthe amino acid senence ofSEQ. TD NOcL or
` disclosure, Forthe treatment of gastrointestinal
`ay
`another peptide or agoniat oft
`18—disorders, thepeptidecanbeadministeredorally,byrectal suppositoryor parenterally.
`
`jnvarious embodiments, the pationis aiffering from. a gastrointestinal disorder,the
`patient is sulfering from adisorder selected from the group consisting of
`
`gastrointestinal siotihity disorders, chronic intestinal pseado-obstraction, colonic
`paoudc-obstraction, Crohn’s disease, duodenogastricreflax, dyspepsia, functional
`dyspepsia, nonalcerdyspepsia,afunctional gastrointestinal disarder, functional
`heartburn,gastroesophagealretlaxdisease (GERD), gastroparesis, iritable bowof
`syndrome, post-operative §ileus, ulcerative colitis, chronic constipation,« iddigerders
`and conditions associated withconstipation (e.g. constipation associated with use of
`opiatepainkillers; post-surgival constipation, and constipation associatedwith
`neuropathie disorders aswell as other conditions and disarders are describedherein);
`thé patientis seffering fom agastrointestinal motility disorder, chronicintestinal
`pseuda-obstraetion, colonic pscudo-obstruction, Crohn's disease, duodenogastric
`reflux, dyspepsia, functional dyspepsia, fonulserdyspepsia, 8 fanctianal
`gastiointestinal disorder, functional heartburn, gastroesophageal refluxdisease
`(GERD), gastroparesia, inflammatory bowel disease, irritablebowel syndrome, poat-
`
`25
`
`36
`
`1095
`
`1095
`
`

`

`WO 2007/101158
`
`PCT/US2007/062815
`
`oF4
`
`
`speritive Hens, ulcerative colitis, chronie constipation, and disorders and conslitions
`associated with constipation,(ogg. constipation associated with useofopiate pain
`killers, post-surgical constipation, and conatipation associated with neuropathic
`disdrders ae well aa other conditions and disorders are described herein); the.
`composition ig administered orally; the peptide comprises: 30or fewer amine acids,
`the peptide sasprises 20or fewer amino acids, and the peptide comprises no more
`than § amino acids prior to ade; the peptide comprises 150, 140,150, 220, T£0, 100,
`80, 80, 70, 60, 50,40, or 30 of fewer amino acids. In other embodiments, the peptide
`ccanprises 20 of fewer-amino-acids.
`in other embodiments the peptideconyriges. uc
`19 mare than 20, 15, 10, ord peptides subsequentto Aaajs.
`fo certain embodiments
`Mads isa chymatrypsia or trypsin cleavagesitednd an analgesic peptideis present
`iminecdiately followingRaaye.
`
`Amongihe nsefkal peptides are+ thése comprising consisting ofor consisting
`essentiallyof any ofthe folowiing amino acid sequence
`
`$
`
`SHTCEICAPAACAGC lopogsun guanylin) (SEQ ID NO: };
`
`POTCEICAYAACTOCcominguanylin)(SEQIDNO: };
`PSTCHICAYAACAGC (ig:uegoanylin) (SEQID NO:);
`PNTCEICAVYAACTGC(rat goanylin) (SEQ ID NO: ),
`FOPCEICANAACTGCLoo eel guanylin,inferred) (SEQ ID NCk )s
`DDCELCVNVACTOCT:Crvropuanylin) (SEQ ID NOL };
`ORECELCINMACTOY (opossum lymphoguanytin) (SEQID NO:
`ODDCELCYNVACTOCS{neeroguanylin)(SEQIDNO: 3;
`NDECELOVNIACTOC(4guineaa pig uroguanylin) (SEQ ID NCK
`
`20
`
`whe
`
`1096
`
`1096
`
`

`

`wo 2007/101158
`
`:
`
`PCT/US2007/062815
`
`TDECELCINVACTOC(rat utoguanylin) (SEQID NO: );
`
`QEDCELCINVACTGC(opossum uroguanylin) (SEQ ID NO:
`
`MPSTQVIRRPASSYASCIWCTTACASCHGRITKPSLAT(EAST 1 (SEQ ID NO:
`
`3 M
`
`PSTQYIRRPASSYASCIWGATACASCHORTTKPSLAT (SEQ ID.NO:
`MBESTOYIRRETSSYASCICATACASCHGRITEPSLAt(SEQIDNO: }:
`MPSTOVIRRPTSSYASCIWCATYCASCHGRTTKPSLAT (SEQIDNO:
`MPSTOYIRRPASSYASCIW [ATACASCHORTTEPSLAt(SEQ IDNO: }:
`QRECELSINMACTGOYCoposgu lymphoguanylin analog) (SEQ IDNO: 5;
`YDOSCRICMPAACTGC (apanoseeel guanylin) (SEQ ID NQ:
`x
`VORICARAACTOC Cobras granylin, inferred) SEQ ID NO:
`ADLCRICAPAACTGOCL Oieelrenoguanylin, inferred) (SEQ ID NO;
`POTCEICAYAACTGCL(SEQ INO:
`}
` }
`POTCEICAYAACTGCLER ce IDNO:
`pNTCHICAYAACTGCKKKKKK (SEQUIONO:
`PNTCEICAYAACTGCD &Bo 1D. Ne:
`);
`PNTCEICAYAACTOCDK(8Q IDNO:
`YFENTCEICAYAACTGOC (sn9 IDNOQ:
`
`i
`
`1097
`
` }.
`
` }
`
`);
`
`RNICEICAYAACTGC (SEQ IDNO:
`
`1097
`
`

`

`
`
`1098
`
`WO 2007/101158
`
`:
`
`PCT/US2007/062815
`
`KPNTCEICAYAACTGC(SEQ ID NO:
`
`);
`
`EDPOTCRICAYAACTGC (SEQ ID NO:
`
`—);
`
`VEVODG NESESLESVE KLKDLOQEPQE PRVGRLRNPA PIPGEPVVPI
`LOSNPNPPEE LEPLCKEPNA QEILORLERIAEDPGTCEICAYAACTGC(SEQ ID
`NO:
`):
`|
`
`*a
`
`n
`
`are
`
`an
`
`tari
`
`DRGTCEICAYAACTGC(SEQIDNO:
`
`—);
`
`MNAELLSALC LLGAWAALAG GVTIVODGNES FSLESVKRLE DLOEPORPRV
`CGRLRNEAPIP GEPVVPLLes NPNFPEELKP LCKEPNAQE! LORLERBIAED
`POTCRICAYAACTOC (SEQ IDNO:
` }
`
`MNAPLLFALC LLGAWAALAG GVIVODGNES FSLEPRVORL RNEAPIPGEP
`VVPILCSNPN EPEELKPLCOK EPNAQBEILOR LEEIAEDPGTCEICAYAACTGC
`(SEQ IDNO:
`|
`
`TOSMNARLLE ALCLLGAWAA LAGGVYVODGNESESLEPRY GELRNEAPIP
`CEPVVPILCS NPNFPEELKP LUKEPNAQREI
`LORLEBIARDPGTCBICAYAACTOCLEG (SEQ ID NO:
`NDRCELCYNVACTGOCL (sxINO.
`ECELCVNVACTOCL (SEQc NO:
`);
`EDCRLOINVACTGOC (SEQ
`NQ:
`)
`
`);
`
`);
`NDDCRELCVACTOCL (SEQ©NO:
`FRTLRTIANDDCELCVNY,ACTGCL (SEOIDNO:
`PRPLRTYTANDDCLOVNVACTOCL GEQIDNQ:
`DDCELCVNVACTGCL (SHQ IDNO:
`NCELCVNVACTOCL (SEQ IDNO.
`);
`
`49.
`
` ¥
` ):.
`
`1098
`
`

`

`WO 2007/101158
`
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`
`CELCVNVACTGCL (SEQ ID NO:
`
`);
`
`KDDCELCVNVACTGCL(SEQ ID NO:
`
`);
`
`PNTCEICANPACTOC(SEQID NO.
`
`);
`
`oR
`
`7900
`
`18
`
`NDDCELCVNVACTGCS (vowuroguanylin) (SEQ ID NO...)
`
`POYCDYVCARAACSGC (Xenopus guanylin) (SEQ ID NO. op
`LDOLOBRICAPAACTGCae guanylin) (SEQID NO. ks
`VDVCEICAPAACTSC obatish gnanylin) (SEQ ID NO...):
`LDICEICAFAACTOC (Pasett guanylin} (SEQIDNO.)
`ADLOSICANAACSGCF (chickenuropuanylin)(SEO ID NO...);
`LDPCRICANPSCFOCLNTuga wroguanylin) (SEO ID NG...);
`{OPCHICANVACTGE(cel areguanylin) (SEQ ID NO...
`SDPCERICANPRCRGCLD(uti uroguanylin) (SEQID NO);
`BOTCRICAYAACTAO SEQID NO. 3s
`POTCBICAVYAACAGCG 09 TD NO. is
`POTCEICAAAACTGCISBQ 1} NO.);
`POTCEACAVAACTGC (axe TDNOL}
`
`POTCAICAYAACTOC(SEQ ID NO. )
`
`+30.
`
`
`
`1099
`
`1099
`
`

`

`WO 2007/101158
`
`PCT/US2007/062815
`
`POACEICAYAACTOC(SEQ ID NO. );
`
`BATOBICAYAACTGC(SEQ ID NO. ):
`
`AGTCEICAYAACTOC (SEQ ID NO. );
`
`PTCRICAYAACTGC(SEQ ID NO.5;
`
`POTCRICVNVACTGC(SEQ INO. ):
`
`POPTCRICANPACTGC(SEQ 1D NO. };
`
`PUTCEICAYAACTCC(SEQ ID NO. };
`
`POTCEICAYAACTDC(SEQ ID NOL):
`
`POTCERCAYAACTEC(SEQID NO. );
`
`10
`
`POTORICAYAACTERC(SEQ TD NO.)
`
`POTCRICAVAACTHC(SEQ ID NO, );
`
`POTCRICAYAACTIC(SEQ ID NO);
`
`POTCHICAYAACTE.C (SEQ 1D NO. );
`
`POTCEICAYAACTLEC(SEQID NO.
`
`18
`
`POTCHICAYAACTMC(SEQ.ID NO. );
`
`POPORICAVAACTNG(SEQ ID NOh }:
`
`POTCEIOAVAACTPC (SEQ ID NOL):
`
`~ 5h +
`
`
`
`1100
`
`1100
`
`

`

`WO 2007/101158
`
`PCT/US2007/062815
`
`POTCEICAYAACTOC(SEQ ID NG. );
`
`OTCEICAYAACTRE (SEQ ID NO,
`
`POTCHICAYAACTSE (SEQ TD NO. );
`
`POTCRICAYAACTYC(SROID NO, );
`
`xR
`
`FOTCERCAY,AACTYE(SEQ|D NO, );
`
`TORICAYAAOCTWE(SEQ ID NO.)
`
`BOTCHICAYAACTY(SEQ ID NO.);
`
`NDDCELCVNVACTGCA(SRO ID NOL):
`Maree
`
`NDDCELCVNVACTACL(SEQ ID NO);
`
`400
`
`NDDCELCVNVACAGCL(SEQID NO.):
`
`NDDCELCVNAACTOCL (SEQ ID.NO.J;
`
`NDDCELCVAVACTGCL(SEQID NO.)s
`
`NDBCELCANVACTOOLSEQID NOL);
`
`NDDCEACYNVACTOCL(SEQ ID NQ,)},
`
`18
`
`NDDCALOVNVACTSOCL(SEQ.ID NO..):
`
`NOACELCVNVACTGCL(SED 1D NO..;
`
`NADCELOVNVACTGOL(SEG ID NOL);
`
`1101
`
`1101
`
`

`

`WO 2007/101158
`
`PCT/US2007/062815
`
`ADDCELCVNVACTGCL(SEQ ID NO,
`
`NODCELCAYAACTOCL (SEQ [D NOL);
`
`NDDCELCVNPACTOCL (SEQID NO);
`
`LRITATDECELCINVACTOC(SEQ ID NO.
`
`).
`
`Additional guonylin‘arguanylnelike sequences include:
`
`TATBECELOINYACTOC,
`
`MNAWLISVECLLOALAVLVEGVTVODGDLSFPLESVEOLEHLREVGEPTLM
`
`
`SHREFALRLPRPVAPELCSOSAPPEALRPLCERPNAREILORLEALAODPNICEL
`DAYARCTOCS
`
`EDPGTCHICAYAACTGC:
`
`PSTOBICAYAACAGC:
`
`PRICEICAYAACTOC
`
`NDRCELCVNBACTGCL:
`
`28
`
`PRTLRTIANDDCELCVNVACTOCL;
`
`PRTLRTIANDDCLCYNVACTOCL:
`
`LOALRTMDNDECELCVNIACTOC, and
`
`PRTLRTIANDOCELCYVNVACTOCL
`x
`Further usefid guanylin/uroguanylin-Hke sequenceswhich mayeither exhibit slower
`
`or quicker introvcenversion between the A and B isoforms, deseribedin greater detail
`below, when.comparedto wild-type sequences include:
`NDOCELCYNVACTOCL
`
`NDDCELCYNVACTACL
`
`NDOCELOVNVACAGCL
`
`NDDCELCVNAACTCCL
`
`1102
`
`1102
`
`

`

`
`
`WO 2007/101158
`
`PCT/US2007/062815
`
`NDBCELOVAVACTGCL
`
`NDDCELCANVACTOCL
`
`NEDCEACVNVACTGCL
`NODCALCVYNVACTOCL
`
`i
`
`NDACELOVNVACTGCL
`
`NADCELEVNVACTOCL
`
`ADDCRLOVNVACTOCL.
`
`NDDCRLCAVYAACTOCL
`
`NDDCELCYNPACTGOCL
`
`40
`
`NDODCELOVNVACTOOLKER
`NDDCELCVNVACTACLER
`
`NDDCELOVNVACTOCI
`
`NDECELOVNVACTOCL
`
`NDECELOVNVACTACL
`
`1S
`
`NDECELCVNVACAGCL
`
`NDECELCOVNAACTOCL
`
`NOECELOY AVACTGCL
`NRECELCANVACTGCL
`
`NBECEACVAVACTOCL
`
`200
`
`NDECALCVNVACTGCL
`
`ADACELCVNVACTGCL
`
`NADCELOYNVACTOCL
`
`ADECELOVNVACTGCL.
`
`NDECELCAYAACTCCL
`2§@ NDECELCVNPACTGCL
`
`NDECELCVNYVACTOCLER
`
`
`NDECELOVN VACTACLRK
`
`NBECELCVYNVACTOCI
`
`NEDCELCYNVACTSC
`
`30.
`
`NDDCELCVNVACTAC
`
`NDDCELOVNVACAGC
`
`- 3d -
`
`1103
`
`1103
`
`

`

`WO 2007/101158
`
`PCT/US2007/062815
`
`NDDCELOVNAACTOC
`
`BPCELOVAVACTOC:
`z
`
`NDDCELCARVACTOC
`
`NDDCBACVNVACTOC
`
`iy:
`
`NDDCALCVYNVACTOC
`
`NDACELOVNVACTOC
`
`NABCELCVYNVACTGC
`
`ADDCELOVNVACTGC
`
`NDODCELCAYAACTO®
`
`40
`
`NDDCELOVNPACTOC
`
`NORCELCVRNVACTGC
`
`NDECELCYNVACTAC
`
`NDECELCVNVACAGC
`
`NDECELCVNAACTOC®
`
`18
`
`NDECELCVAVACTOC
`
`NDECELCANVACTGC
`
`NDECEACVNVACTGC
`
`NDECALCVNVACTGC
`
`NDACELCVNVACTOC
`
`90
`
`NADCELCVNVACTOC
`
`ADECELCVNVACTGC:
`
`NDECELCAYAACTGC
`
`NDECRLEVNPACTGOC
`
`NDDCELOVNVACTOCA
`
`88
`
`NDECELCVNVACTOCA
`
`
`POTCEICAYAACTAC
`
`POPOERAYAACTOCL
`
`PCCRIC AYAACTOCLER.
`
`and
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`3300
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`POTCEICAYAACTGCI
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`
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`s
`‘The peptides can inchide the aminoacid sequenee ofa peptide thal ocours naturally iu
`
`4 vertebrate (e.g., manunalian) speciesor in a bacterial species, Ia addition,ihe
`
`peptides ean be pariially or completely non-naturallyovcurring peptides.
`
`In a third aspect, the disclosure features a method fortreatinga pationt suffering from
`constipation, the racthad comprising administering a composition comprising a
`
`poptide comprising, consisting essentially ofor consisting oftheamino acid sequence
`ofSEO 1D NO: or another peptide or agonist ofthe disclosure. CHnivally acoepted
`oritoria that define constipationrange fromthefrequency ofbewel movements, the
`
`consistenoy offeces and the case of bowel movement, One common definition of
`
`constipationis less than three bowél movements per week, Other definitions include
`
`abnormally herd stools or defecation that requires excessivestraining (Schiller 2001
`Allmeat Pharmucel Ther 15:749-763). Constipation maybe idlepathic (functional
`constipation. or slow {rinsit constipation) or'secondary tcother causes including
`neurologic, metabolic or endocrine disorders. These disorders include diabetes
`
`meflitus, ‘opetigraidisan|hyperthvrata,hypocalcacania MulapiesScleyoxts,
`Chagasdisease, Hirseachsprangdiseaseandeysticfibrosis, Constipation mayalsobe
`the result ofgurgery or due id the use ofdrugs such as analgesios (ike opiokds},
`antiinygertensives, anticonvulsants, antidepressants, artispasmodies and
`
`GUPSYCRONGS.
`
`in various embodiments, the constipation is associated withuse of a therapeuticagent:
`
`the constipation is associated with a neuropathic distrdérthe:constipation: is post-
`
`surgical constipation; the constipation isdssociated with a gastrointestinal disorder:
`the constipation isddiopathic (functional constipation or slow transit-constippation}, the
`constipation is aasociatedwith nenropathic, metabolic or endocrine disdrder (e.g,
`diabetes melldas, lypothyreidism, hyperthyroidism, hypocalcaemia, Multiple
`&Sclerosis, Parkinson's disease, spmal cord lesions, nearofibromatosis, autonomic
`
`nerropathy, Chagasdisease, Hitschapringdiseaseor tysticfibrosis). Constipation
`
`mayalso be the result of surgery or due to the use of drags such as analvesios (e.g...
`
`- BR
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`al
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`fecoz
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`apivids), autihypertensives, anticonvulsants, antidepressants, antispasmodics and
`
`antipsychotics,
`
`{n.a fourth aspect, the disclosarefeatures a method for treatinga pationt suffering
`frama gastrointestinal disorder, the method comprising administering to the patient a
`ccanpositisny conyprising apurified peptide comprising, consistingessentiallyof or
`
`consisting of the amino acid sequence oF82Q ID NO: | or avether peptide or agonist.
`
`ofthe disclosure
`
`in varigas embodiments, the patieut is suffering froma gastrointestinal Maorder: the
`patient is safiving from a disorderselected from. the groap consisting of
`gastreintestinal motility disorders, chronic intestinal pssudo-obstraction, colanie
`pseudo-obstruction, Croho’s disease, daodenogastrie reflux, dyspepsia, fimetional
`dyspepsia, nonuloer dyspepsia, a fmetional gastrointestinal diserder, fanctional
`
`heartburn, gastroesaphageal refluxdisease (GERD),gastroparesis, irritable bowel
`
`syndrome, post-operative tlous, ulcerative colitis, chronic constipation, and disorders
`
`and conditions associated with canatipation (e.g. constipation associated with useof
`uplate pam. killers, postsargical constipation, andconstipation associatedwith
`neuropathic disorders as well as other conditions and disorders are deseribed herein},
`
`obesity, congestive heart failure, or bemen prostatic hyperplasia
`
`In a 4}Nb aspect, the disclosure features a method for inoreasing gastrointestinal
`motility in a patient, the method comprising administering to the patient 4
`composition comprising’a purified peptide comprising, consisting essentially ofor
`eongisting of the amine acid sequence of SEQ IDNOs] or another peptide ar agonist
`
`atthe disclosure,
`
`In asixth aspect, she'disclasure features a.method for decreasing gastrointestinal pain
`or visceral pain in a patient, the method camprising administering to the patienta
`gompesition comprising 8 purified peptide comprising, consisting essentially af or
`
`wy
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`20
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`consisting of ihe amino scid sequence of SEQ ID NO oranother peptide or aganist
`
`ofthe disclosure,
`
`in aseventh aspect, the disclosure featares a method for norcasing the activity of an
`intestinal guanylate cyclase (CAC-C)receptorin a patient, the method comprising
`administeriig to the patient a composition comprising 4 purified peptide comprising,
`conmaling casentiallyof ar-consisting ofthe amino avid sequenceofSEG ID NQ:1 or
`
`omaa
`
`another peptide or agonist of the disclosure.
`
`in an eighth aspect, the disclosure features ah isolaied nucleicacid molecule
`
`comprising a nacleatide sequence encoding a peptide comprising, consisting
`essentiallyof or consisting of the amino acid sequence of SEO ID NO:1 or anather
`
`vont ae
`
`peptide or agonist of the disclosure,
`
`in atinth aspect, the disclosure deatares a composition comprising a purified
`nolypepiide seinprising, consisting essentially of or consisting ofthe aminoavid,
`
`sequence oP SEQ ID NOvor another peptide or agonist of the disclosure. In an
`embodiment, the composition is 4 pharmaceutical composition,
`
`woe Rr
`
`in a tenthaspect, the disclosure features a method fortreating obesity, the method.
`comprising admuniatering a composition comprising4 poritied peptide comprising,
`consisting essentiallyofor vonsisting ofthe aminoacidsequence ofSEQ.ID NOL or
`another poptide or agonist. ofthe disclosure. The peptidecan beadminiafarad in
`combination with one or more agents for treatment of cbesity, including, without
`imilgtion, the anti-obesity agents describedherein. A peptide usefal fortreating
`obesity can be adrhinisiereda3 a co-therapy with a peptide of the disclosure cilferas @
`
`tl
`
`distinct molecule or as part ofa fasionprotein with a peptideofthe disclosure, Thus,
`for example, PYV¥i.a9 dan be fused to the carboxyor amino terminus ofa peptideof
`
`the diaclosure. Such a fusion pratemn can imclude.a chymostrypsin or trypsin cleavage
`
`Bo.
`
`25.
`
`site that can permit cleavage to separatethe fvo peptides,
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`in aueleventh aspect, the disclosure features a method for treating congestive heart
`
`failure, themethod comprising: adeninistering te the patient a composition comprising
`a purified peptide comprising, consisting essentiallyofor consistingefthe aminacid
`orgy
`sequence of SEQ LD NOL or another peptide-or agonist ofthedisclosure, The
`peptide can be administered in combination with one ar more agente for treatmentof
`congestive heart fallure, forexample, a natriuretic peptide suchag atrial natriuretic
`peptide, hyainnatriuretic peptide or C-type natriuretic peptide}, a diuretic, or an
`
`jnhilitor of angiotensin converting enzyme.
`
`In atwellth aspect, the disclosure features amethodfor treating benign prostatic
`
`hyperplasia, the method comprising: administering to the patient a compasition
`comprising a purified peptide comprising, consisting essentially of or consisting of the
`4
`sinino seid.gequence of SEQ ID NO:1 or another peptideor agonist of the disclosure.
`ry
`Yhepeptide can be administered in combination with one or more agents for
`Fw
`treatment of BPH, for example, a S-alpha reductase tohibitor(e.g., Hnaateride) ar ani
`alpha adrenergic inhibitor @.g., doxazosine).
`
`BF:
`
`10
`
`16
`
`20s
`
`ina thirteenth aspect,the disclosurefeatures a method fortreating a patient suffering
`fYonl apastreintestiagl disorder, the methodcomprisingadministeringto the pationt a
`compasition comprising a complete. or partial agenist of the GC-C receptar, including
`but not Hmited to the peptides and agonists deseribed-herein, Ip variousembodiments,
`the disorder is & gastrointestinal motilitydisorder, chronic intestinal pseude-
`obstraction, colonic psoado-obstruction, Crohn’s disease, duodenogastric refhix,
`dyspepsia, functional dyspepsia, nonulcer dyspepsia, a fanctional gastrointestinal
`disorder, fanctional heartburn, gastroesophageal reflirxdisease (GERD),
`gastroparesis, imitable.bowel syndrome, post-operativeileus, alcerative colitis,
`28—chronis: constipation,and disorders and conditions associated with constipation (e.g.
`constipation associated with ase of opiate pain killers, post-surgical constipation, and
`vonatipation associated with neuropathic disorders ag. well as other conditions and
`disorders are deseribed herem), obesity, congestive heartfailare, or benign prostatic
`
`hyperplasia.
`
`In varivas embodiments the composition comprising an agonist-af the
`
`
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`intestinal guanylate vyelase (GC-C) receptoris administered orally, by rectal
`suppositery, oF parenterally, Jnvarious embodiments: the agonistisapeptide, the
`peptide inchides two Cysthat formonedisulfide band,the peptide includestwo Cys,
`the peptide inchides four Cys that formtwodisalfide bands, the peptide includes four
`mys, two of which form a disulfide bond.
`
`Ina dourtaenthaspect, thedisclosure features a methodfor treating 8 patient suffering
`irom oonstipation, the method comprising administering a composition comprisinga
`
`completo ar partial agonist of theGC-C receptor.
`
`In various embodiments: the
`
`10
`
`agonLIS a peptide, thenide inctadestwo Cys that formone disulfide bond, the
`peptide meladestwo Cys,
`the peptide includes’four Cys that form two disulfide
`bonds, the peptide includes four Cys, pwo of which firma disulfide bond, 1s various
`
`embadiments, the constipation is.assnciated with the use ofa therapeutic agent (e.g,
`
`antihypertaisives, anlconvulvanis, antispasmoiics, analgesics, anticholinergics,
`
`antidepressants, antipsychotics, cation-containing agents, anticonvulsants, ganglion
`
`445EAS
`
`blockers, vines alkaloids); associatedwith a musenlar, neuropathic, metabolic or
`endocrine disorder (including bat notlimited to myotonic dystrophy, dermamyositis,
`systemicsclerasis, sclerodoma, amylvidasis (neurologic or muscular), ischemia,
`tumor of the ventral nervous gyatem, agionomic neuropathy, Chagas disease, oystic
`fibrosis, iabetes mellitus, Hirachsprungdisease, hyperthyroidism, bypocaleaenda,
`Aypathyrdidiam, Maluple Sclerasis, nearofibromatosis, Parkinsen’s disease, and
`spinal cord lesions (lor example, related to sacral nerve damagerelated to traumaor a
`
`tumorortheentericnervonssystem));pest-surgicalconstipation(resoneus);
`Neoplism, stricture,volvalus,anorectal, inflarimation,prolapse,vate
`
`associated with a structeral colonalteration (for example that associated wit
`
`$2oh
`
`fissure), associated withthe a gastrointestinal disorder; associated with a systerme
`
`Hlness-ar disarder (for example, electrolyte abnormalities, thyron! disease, diabetes
`mallitus, psnhypopitultarism, Addison's disease, phedchtomacytoma, ured,
`
`porphyria}: chronig constipation; associated with the use of analgesia drugs (e.g.
`aptaid indueed constipation), associated with megacolon idiopathic constipation,
`functicnsl constipation: fanetional constipation. asseieiated with nonnal transit, slow
`
`30
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`transi (e.g. Gos or fewer bowel movements per week} or pelvie Toor dyssynergiay
`
`associated with bloating and abdominal pain,
`
`ina fileenth aspeot, thedisclosurefeatures a method for increasing gastrointestinal
`
`motility in a patient, the method comprising administeringtothe patient-a
` <anposition comprising a completeorpartial agonist of the GC-Creceptor, including.
`
`§
`
`bat not Tinted to the peptides and agonists described herein.
`
`dna sixteesth aspect, the disclosure features.a method for decreasing gastrointestingl
`nain or visceral pain in a patient, the method comprising administering to the patient a
`womposition comprisiig a complete or partial agonist ofthe GC-C receptor, inchiding
`
`
`+0
`
`but not Hmited to the peptides and agonists described herein.
`
`in a seventoanth aspect, the diselusare features a rnethad for treating congestive heart
`
`fathure, the mothod coniprising administering a completeorpartial agowlst of the GC-
`
`© receptor, including bat not limited to the peptides and agonists deseribed herein.
`
`15
`
`GCC avendets can act in the kidney and adrenal gland to control natnuresis,
`Kalluresi and diuresis thereby reducingthe build-upoffluid associated with
`oigestive heartfallure (Lorenget al.7 Cia doves? 1121138, 2003; Carrithers et al.
`Avalney.hu68:40,2004). The agonist can be adrninisteredin combination withaneor
`
`more agents fir treatment of congestive heart failure, includingbut not limited to the
`agentsaselal for combitherapy described herewn, For example, the agonist can be
`2 administered in combination with a nateiaretic peptide suchas atrial natsieretic
`
`peptide, brain natriureticpeptideor C-type natriuretic peptides,a diaretic, or an
`
`In various embodiments the congestive
`inhibitor of angiotensin converting enzyme,
`heart failureis categorized as Class [tl congestive heart faihee; the congestive heart
`failute ip-categorized as Class [LH] congestive heart failure; and the congestiveheart
`failure jscutegorized as Class IVcongestive heart failure. The New York Heart,
`Association (NYHA) functional classification systemrélates congestiveheart fatlure
`symptoms to everydayactivities and the patient's quality of hfe. The NYHA defines
`4,
`ihe classes ofpationt, symptoms relatingto congestive heartfailure as: Class U-slight
`
`26
`
`~ GT
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`
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`limitation of physical activity, comfortable at rest, but ordinary physical activity
`reguits in fatigue, palpitation, or dyspnea; Claas [- markedlimiistion of physical
`activity, comiortable at rest, but less than ordinary activilycauses Latigne, palpitation,
`or dyspneagnd Class TV unable to carry out anyphysical activity without disconifort,
`symptoms of cardiac insufficiencyat rest, if any physical activity is undertaken,
`discomfortis Increased, Heart failure treatment using the polypeptides and methods
` dese
`ribed herein can also be classified agcording to theACC/VAHA guidelines Stage
`AcAtriskfor developing heart failore without evidence of cardiac dysfanetion; Stage
`Ks Evidence ofcardiac.dysfinction without symptoms; Stage C: Evidence of cardiac
`dyafinetion with symptoms; and Stage D: Symptoms ofheart fhilure despite maximal
`therapy}
`
`In an eighteenth aspect, the disclosure features. methadfortreating BPH, the method
`comprising administering a complete or partial agonist of the GC-C receptor,
`includiag but notfimited te the peptides described herein, GC-C agonisisacting in
`theprostate can reduce cellular hypertrophy and complications associated with
`velludar hypertrophy. The agonist can be administered in combinationwith one ar
`mare agents for treatment ofBEA, forexample, a S-alpha redactase inhibitor (e2.,
`nasteride) or an alpha adrenergicinhibitor(e.g-doxazosine).
`
`‘Q
`
`in a nineteenth aspeot,thi: disclosure features a methodlor treating obesity, the
`sethed comprisingadminisieting a coniplete or partial agonist of the GO-C receptor,
`includingtut not Hmiled to thepeptides and agonists describedherein. “The agonist
`can beadnitnistered alone or in. combination with one or more agents for treatment of
`obesity, ikGloding butnot Hrmited to the anti-ohesity agents described herein. Thus,
`for example, PYYs.ag can be fused fo the carboxyor antino terminusofa puptide of
`the disclosure. Sucha fasion protein can include.a chymosirypsin or trypsin cleavage
`site that can perndt cleavage to separate the.twe peptides.
`
`In various embodiments: the agonist is a peptide, the peptide includes two Cys-that
`form one disulfide bond, the peptide includes two Cys, the peptide includes four Cys
`
`§
`
`30
`
`15
`
`2)
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`25.
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`shat formfwo disulfide bonds, the peptide includes four¢Cys, two of which form 4
`
`disidfide bond,
`
`ne peptides and agonists ofthe GC-Creceptor, including bot notlimited te the.
`
`a
`
`peptides and agonists deseribed herein can be used fotreat, for example, constipation,
`decreased intestinal motility, slowdigestion, slowstomach amptying, The peptides
`can be used to raliove ons or more symptoms of IBS (bloating, pain, conatipation),
`GERD (acid reflux into the csophagus), duodenogastric reflux, fimetional dyspepsia,
`or gaslropardsis (nansea, vomiting, bloating, delayed gastricemptying) and ather
`arders desecibed herein.
`
`
`Clinically acogpted criteria thal define constipation range framthe frequency ofbowel
`novemens, the consistency offeces andthe case of bowel movement. Qne common
`
`nifion of constipation is less.thanthree bowel movements per week, Other
`
`definitions iachide abnormally hard stools or defecation that requires excessive
`
`straining (Schler 2001, Aliment Pharmacol Ther 15:749-763}. Constipation maybe
`
`idiopatiie Ghiictional constipation or slowtransit constipation} or secondaryto ather
`ranges fnoluding