(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`1111111111111111 IIIIII IIIII 11111111111111111111111111111111111 IIIII IIIII IIII IIIIIII IIII IIII IIII
`
`(43) International Publication Date
`24 February 2005 (24.02.2005)
`
`PCT
`
`(10) International Publication Number
`WO 2005/016244 A2
`
`(51) International Patent Classification7:
`
`A61K
`
`(21) International Application Number:
`PCT/US2004/018751
`
`[US/US]; 18 Hall Avenue, Sterling, MA 01564 (US). MA(cid:173)
`HAJAN-MIKLOS, Shalina [IN/US]; 14 Holland Street,
`Needham, MA 02492 (US). LI, Jing, Sun [US/US]; 41
`Fenno Street, Cambridge, MA 02138 (US).
`
`(22) International Filing Date:
`
`14 June 2004 (14.06.2004)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30)
`
`Priority Data:
`60/478,492
`60/532,361
`60/571,386
`
`13 June 2003 (13.06.2003) US
`23 December 2003 (23.12.2003) US
`14 May 2004 (14.05.2004) US
`
`(71)
`
`Applicant (for all designated States except US): MICRO(cid:173)
`BIA, INC. [US/US]; 320 Bent Street. Cambridge. MA
`02141 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): CURRIE, Mark, G.
`
`(74) Agent: MEIKLEJOHN, Anita, L.; Fish & Richardson
`P.C., 225 Franklin Street, Boston, MA 02110-2804 (US).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, Fl,
`GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
`KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD,
`MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG,
`PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM,
`TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM,
`zw.
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`
`[Continued on next page]
`
`(54) Title: METHODS AND COMPOSITIONS FOR THE TREATMENT OF GASTROINTESTINAL DISORDERS
`
`(57) Abstract: Compositions and related methods for treating
`IBS and other gastrointestinal disorders and conditions (e.g.,
`gastrointestinal motility disorders, functional gastrointestinal dis (cid:173)
`orders, gastroesophageal reflux disease (GERD), duodenogastric
`reflux, Crohn's disease, ulcerative colitis, inflammatory bowel
`disease, functional heartburn, dyspepsia (including functional
`chronic
`dyspepsia or nonulcer dyspepsia), gastroparesis,
`intestinal pseudo-obstruction (or colonic pseudoobstruction),
`and disorders and conditions associated with constipation,
`e.g., constipation associated with use of opiate pain killers,
`post-surgical constipation, and constipation associated with
`neuropathic disorders as well as other conditions and disorders
`are described. The compositions feature peptides that activate
`the guanylate cyclase C (GC-C) receptor.
`
`Fi::o Gl.y 'I'hr Cys Gly GJ.u Ilo Cyo Alo. Tyr Al.a Ala Cys Thr Gly Cys
`
`Human Guanylin (SEQ ID NO:
`
`)
`
`--- Gly Tllr cy.s Gly GJ.u Ile, cys Ala Tyr Ala Al a cys Thi: Gly cys
`--- --- Thr Cys Gly Glu Ile Cys Ala Tyr Ala Ala Cys The Gly Cys
`--- --- --- Cys Gly Glu Ile Cys Ala Tyr Ala. Ala Cys Thr Gly Cys
`--- --- --- Cys - -- Glu Ile Cys Ala Ty.i:: Ala Ala Cys Thi:- Gly Cys
`--- --- --- Cys Gly --- Ile Cys Ala Ty.i:; Ala Ala Cys '!'hr Gly Cys
`--- --- --- Cys Gly Glu --- Cys Ala Tyr Ala Ala Cys Th r Gly Cys
`--- ---
`- -- Cys Gly Glu Ile Cys --- Tyr Ale Ala Cy."5
`'Ihr Gly Cy."5
`--- --- --- Cys Gly Glu Ile cys Ala --- Ala Ala Cys Thr Gl:Y cys
`--- --- --- Cys Gly Glu Ile Cys Ala T',ir --- Ala Cys Thr Gly C~•s
`--- --- --- Cys Gly Glu Ile Cys Ala Tyr Ala --- Cys Thr Gly C~•s
`--- --- --- Cys Gly Glu Ile Cys Ala Tyr Ala Ala Cys --- Gly Cys
`--- --- --- Cys Gly Glu Ile Cys Ala Tyr Ala Ala Cys Thr --- Cys
`--- --- Thr Cys --- Gl u Ile Cys Al a Tyr Ala AJa Cys Thr Gl y Cys
`- -- --- Thr Cys --- --- Ile Cys Ala Tyr Alo Ala Cy.!! Thr Gly Cyo
`--- --- 'l'hr cys --- Glu --- Cys Ala Tyr Ala Ala cys Thr Gly C~•s
`--- --- Thr Cys --- Glu Ile cys --- Tyr Ala Ala Cys Thr Gly Cys
`--- --- Thr Cys --- Glu Ile Cys Ala --- Ala Ala Cys Thr Gl y Cys
`--- --- Thr Cys --- Gl u Ile Cys Ala Tyr --- Ala CyS Thr Gly Cys
`--- --- Thr Cys --- Glu Il G Cy:;; Ala Ty.i- Al.i --- Cys Thr Gly Cys
`--- --- Thr Cys --- Glu Ile Cys Ala Tyr Ala Ala Cys --- Gly cys
`--- --- Th r Cys --- Glu Ile Cys Ala Tyr Ala Ala Cys Thr --- Cys
`--- --- Thr Cys Gly --- Ile Cys Ala Tyr Al a Al a Cys Thr Gl y Cys
`-- -
`- -- Thr Cyo Gly --- --- Cyo Al a Tyr Al a Ala Cy,:i Thr Gly Cy::;
`--- --- 'l'hr Cys Gly --- Ile Cys --- .Tyr Ala Ala Cys Thr Gly Cys
`--- --- Thr Cys Gly --- Ile Cys Ala --- Al a Ala Cys Thr Gly Cys
`--- --- Thr Cys Gly --- Ile Cys Ala Tyr --- Ala Cys Thr Gly Cys
`--- --- Thr cys Gly --- Ile Cys Ala Tyr Ala --- cys 'l'hr Gly cys
`--- --- Thr Cys Gly --- Ile Cys Ala Tyr Ala Ala Cys --- Gly Cys
`--- --- Thr Cys Gly --- Ile Cys Ala Tyr Al a Ala Cys Tht --- Cys
`--- -- - Thr Cy."5 Gly Glu --- Cy::; Alo. Tyr Ala Ala Cy5 Thi:; Gl y Cys
`--- --- Thr Cys Gly Glu --·- Cys --- Tyr Ala Ala Cys Thr Gly Cys
`--- --- Th:r Cys Gly Glu --- Cys Ala --- Ala Ala Cys Thr Gly Cys
`--- --- Thr Cy~ Gly Glu --- Cy~ F.la Tyr --- Ala Cy5 Thr Gly Cys
`--- --- Thr Cys Gly Glu --- cys Ala Tyr Ala --- Cys Thr Gly Cys
`--- --- Thr Cys Gly Glu --- Cys. Ala Tyr A.l a Ala Cys --- Gl y Cys
`--- --- Thr Cys Gly Glu --- Cyn AL:i. Tyr Alu Alo Cy.:; Thr --- -Cy:'1
`--- --- Thr Cys Gly Glu Il e Cys, --- Tyr Ala Ala Cys Thr Gly Cys
`--- --- Thr Cys Gly Glu Ile Cys --- --- Ala Ala Cys Thr Gly Cys
`--- --- Thr Cys Gly Glu _Ile Cys --- Tyr --- Ala Cys Thr Gl y Cys
`- -- - -- Thr Cy:'1 Gly Glu Ile Cyo --- Tyr Ala --- Cy:i Thr Gl y Cy:i
`--- --- Thr Cys Gly Glu Ile cys --- 'fyr Ala Ala Cys --- Gly Cys
`--- --- Thr Cys Gly Glu Ile Cys --- Tyr A.la Ala Cys Thr --- Cys
`--- --- Thr Cys Gly Glu Ile Cys Ala --- Ala l,h. Cyn Thr Gly Cy,:;
`--- --- Thi:; Cys Gly Glu Ile cys Ala --- --- hla Cys Thr Gly Cys
`--- --- Thr Cys Gly Glu Ile Cys Ala --- Ala --- Cys Thr Gly Cys
`--- --- Thr Cys Gly Gl u Il1a, Cys Ala --- Ala Ala Cys --- Gly Cys
`--- --- Thr Cy:"l Gl}' Glu Ile Cyr-; Ala --- Al a Ala Cys 'rhr --- Cy:,
`--- --- 'C!'. r Cys Gly Glu Ile Cys Ala Tyr --- Ala Cys Thr Gl y Cys
`--- --- Th r Cys Gly Gl u Ile Cys Ala Tyr --- --- Cys Thr G: l y Cys
`- - - Thr Cya Gly Glu IlG Cys Al a Tyr --- Ala Cy:, --- Gly Cyo
`-- -
`--- --- Thr Cys Gly Glu Ile cys Ala Tyr -.-- Ala Cys Thr --- cys
`--- --- Thr Cys Gly Glu Ile Cys Ala Ty:i: Al a --- Cys Thr Gly Cys
`--- --- Thr - Cys Gly Glu Ile Cys Ala Tyr All). --- cya - - - Gly Cys
`--- --- .Thi:; Cy1:l ·Gly Glu Ile Cys Al a Tyr .A.la --- Cys Thr --- cys
`--- --- Thr Cys Gly Gl u Ile Cys Ala Tyr Ala Ala Cys --- Gly Cys
`--- --- Thr Cys Gly Gl u Ile Cys Ala Tyr Ala Ala Cys --- --- Cys
`- - -
`- -- Thr Cy-5 Gly Glu Ile Cy5 Ald Tyr .A.la Al::1 Cy:; Thi:: --- Cys
`--- Gly --- Cys Gly Glu Ile Cys Ala Tyr Ala Ala Cys Th:i: Gly Cys
`--- Gly --- Cys --- Glu Ile Cys Al a Tyr A.l a Ala Cys Thr Gly Cys
`
`(SEQ ID NO:
`(SEQ ID NO:
`(SEQ ID NO:
`(SEQ ID NO:
`(SEQ IO NO:
`(SEQ I D NO:
`(SEQ ID NO;
`{SEQ ID NO:
`{SEQ ID NO:
`{SEQ ID NO:
`(SEQ ID NO:
`(SEQ_ ID NO:
`(SEQ ID NO:
`(SEQ ID NO;
`(SEQ ID NO:
`(SEQ ID NO:
`(SEQ ID NO:
`(SEQ ID NO:
`(SEQ ID »o:
`(SEQ ID NO:
`(SEQ ID NO:
`(SEQ ID NO:
`(SEQ ID NO:
`(SEQ ID NO:
`(SEQ ID NO:
`(SEQ ID NO:
`( SEQ ID NO:
`(SEQ ID NO:
`(SEQ ID NO:
`(SEQ ID NO:
`{SEQ ID NO:
`(SEQ ID 110:
`(SEQ ID NO:
`(SEQ ID NO:
`(SEQ ID NO:
`(SEQ ID HO:
`(SEQ ID NO:
`(SEQ ID NO:
`(SEQ ID NO:
`(SEQ ID NO;
`(SEQ ID NO:
`(SEQ ID NO:
`(SEQ ID UO:
`(SEQ ID NO:
`(SEQ ID NO:
`(SEQ ID NO:
`(SEQ ID NO:
`(SEQ ID NO:
`(SEQ ID NO:
`(SEQ ID NO:
`{SEQ ID NO:
`(SEO ID NO:
`(SEQ ID UO:
`(SEQ ID NO:
`(SEQ ID NO:
`(SEQ ID NO:
`(SEQ ID NO:
`(SEQ ID NO:
`(SEQ ID NO:
`
`---iiiiiiiiiiiiii
`iiiiiiiiiiiiii -iiiiiiiiiiiiii
`iiiiiiiiiiiiii -iiiiiiiiiiiiii -
`
`iiiiiiiiiiiiii
`
`iiiiiiiiiiiiii -
`
`!!!!!!!!
`iiiiiiiiiiiiii
`iiiiiiiiiiiiii
`
`
`Bausch Health Ireland Exhibit 2002, Page 1 of 247
`Mylan v. Bausch Health Ireland - IPR2022-01104
`
`

`

`WO 2005/016244 A2
`
`1111111111111111 IIIIII IIIII 11111111111111111111111111111111111 IIIII IIIII IIII IIIIIII IIII IIII IIII
`
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HU, IE, IT, LU, MC, NL, PL, PT, RO, SE, SI,
`SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, ON, GQ,
`OW, ML, MR, NE, SN, '11), TO).
`
`Declarations under Rule 4.17:
`as to applicant's entitlement to apply for and be granted
`a patent (Rule 4.17( ii)) for the following designations AE,
`AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ,
`CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE,
`EC, ES, Fl, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS,
`JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA,
`MD, MG, MK, MN, MW, MX, MZ, NA, NJ, NO, NZ, OM,
`PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ,
`TM, TN, TR, TT, TZ, UA, UG, UZ, VC, VN, YU, ZA, ZM,
`ZW, AR/PO patent (BW, CH, GM, KE, LS, MW, MZ, NA,
`SD, SL, SZ, TZ, UC, ZM, ZW), Eurasian patent (AM, AZ,
`BY, KG, KZ, MD, RU, Tl, TM), European patent (AT, BE,
`BG, CH, CY, CZ, DE, DK, EE, ES, Fl, FR, GB, GR, HU, IE,
`IT, LU, MC, NL, PL, PT, RO, SE, SI, SK, TR), OAP/ patent
`(BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE,
`SN, TD, TG)
`as to applicant's entitlement to apply for and be granted
`a patent (Rule 4.17(ii)) for the following designations AE,
`AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ,
`CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE,
`EG, ES, Fl, GB, GD, GE, GH, GM, HR, HU, JD, JL, IN, JS,
`JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA,
`MD, MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM,
`PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ,
`TM, TN, TR, TT, TZ, UA, UG, UZ, VC, VN, YU, ZA, ZM,
`ZW, AR/PO patent (BW, GH, GM, KE, LS, MW, MZ, NA,
`SD, SL, SZ, TZ, VG, ZM, ZW), Eurasian patent (AM, AZ,
`BY, KG, KZ, MD, RU, Tl, TM), European patent (AT, BE,
`BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE,
`IT, LU, MC, NL, PL, PT, RO, SE, SI, SK, TR), OAP/ patent
`(BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE,
`SN, TD, TG)
`
`as to the applicant's entitlement to claim the priority of the
`earlier application ( Rule 4.17( iii)) for the following desig(cid:173)
`nations AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW,
`BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ,
`EC, EE, EG, ES, FI, GB, GD, GE, CH, GM, HR, HU, ID,
`IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU,
`LV, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ,
`OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY,
`Tl, TM, TN, TR, TT, TZ, UA, UG, UZ, VC, VN, YU, ZA, ZM,
`ZW, AR/PO patent (BW, CH, GM, KE, LS, MW. MZ, NA,
`SD, SL, SZ, 1Z, UC, ZM, ZW), Eurasian patent (AM, AZ,
`BY, KG, KZ, MD, RU, Tl, TM), European patent (AT, BE,
`BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE,
`IT, LU, MC, NL, PL, PT, RO, SE, SI, SK, TR), OAP/ patent
`(BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE,
`SN, TD, TG)
`as to the applicant's entitlement to claim the priority of the
`earlier application (Rule 4.17( iii)) for the following desig(cid:173)
`nations AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW,
`BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ,
`EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID,
`IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU,
`LV, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ,
`OM, PG, PH, PL, PT, RO, RU, SC. SD, SE, SG, SK, SL, SY,
`Tl, TM, TN, TR, TT, TZ, UA, UG, UZ, VC, VN, YU, ZA, ZM,
`ZW, AR/PO patent (BW, GH, GM, KE, LS, MW, MZ, NA,
`SD, SL, SZ, 1Z, UG, ZM, ZW), Eurasian patent (AM, AZ,
`BY, KG, KZ, MD, RU, Tl, TM), European patent (AT, BE,
`BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE,
`IT, LU, MC, NL, PL, PT, RO, SE, SI, SK, TR), OAP/ patent
`(BF, BJ, CF, CG, CI, CM, GA, GN, GQ, G\-V, ML, MR, NE,
`SN, TD, TG)
`
`Published:
`without international search report and to be republished
`upon receipt of that report
`
`For two-letter codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`
`Bausch Health Ireland Exhibit 2002, Page 2 of 247
`Mylan v. Bausch Health Ireland - IPR2022-01104
`
`

`

`WO 2005/016244
`
`PCT/US2004/018751
`
`METHODS AND COMPOSITIONS FOR THE TREATMENT OF
`GASTROINTESTINAL DISORDERS
`
`TECHNICAL FIELD
`
`This invention relates to methods and compositions for treating gastrointestinal disorders,
`
`5
`
`obesity, congestive heart failure, benign prostatic hyperplasia and other disorders.
`
`BACKGROUND
`
`Irritable bowel syndrome (IBS) is a common chronic disorder of the intestine that affects 20 to
`
`60 million individuals in the US alone (Lehman Brothers, Global Healthcare-Irritable Bowel
`
`10
`
`Syndrome Industry Update, September 1999). IBS is the most common disorder diagnosed by
`
`gastroenterologists (28% of patients examined) and accounts for 12% of visits to primary care
`
`physicians (Camilleri 2001 Gastroenterology 120:652-668). In the US, the economic impact of
`
`IBS is estimated at $25 billion annually, through direct costs of health care use and indirect costs
`
`of absenteeism from work (Talley 1995 Gastroenterology 109:1736-1741). Patients with IBS
`
`15
`
`have three times more absenteeism from work and report a reduced quality oflife. Sufferers may
`
`be unable or unwilling to attend social events, maintain employment, or travel even short
`
`distances (Drossman 1993 Dig Dis Sci 38:1569-1580). There is a tremendous unmet medical
`
`need in this population since few prescription options exist to treat IBS.
`
`Patients with IBS suffer from abdominal pain and a disturbed bowel pattern. Three subgroups of
`
`20
`
`IBS patients have been defined based on the predominant bowel habit: constipation-predominant
`
`( c-IBS), diarrhea-predominant ( d-IBS) or alternating between the two ( a-IBS). Estimates of
`
`individuals who suffer from c-IBS range from 20-50% of the IBS patients with 30% :frequently
`
`cited. In contrast to the other two subgroups that have a similar gender ratio, c-IBS is more
`
`common in women (ratio of 3:1) (Talley et al. 1995 Am J Epidemiol 142:76-83).
`
`25
`
`The definition and diagnostic criteria for IBS have been formalized in the "Rome Criteria"
`
`(Drossman et al. 1999 Gut 45:Suppl II:1-81), which are .well accepted in clinical practice.
`
`However, the complexity of symptoms has not been explained by anatomical abnormalities or
`
`
`Bausch Health Ireland Exhibit 2002, Page 3 of 247
`Mylan v. Bausch Health Ireland - IPR2022-01104
`
`

`

`WO 2005/016244
`
`PCT/US2004/018751
`
`metabolic changes. This has led to the classification ofIBS as a functional GI disorder, which is
`
`diagnosed on the basis of the Rome criteria and limited evaluation to exclude organic
`
`disease(Ringel et al. 2001 Annu Rev Med 52: 319-338). JBS is considered to be a
`
`"biopsychosocial" disorder resulting from a combination of three interacting mechanisms:
`
`5
`
`altered bowel motility, an increased sensitivity of the intestine or colon to pain stimuli (visceral
`
`sensitivity) and psychosocial factors (Camilleri 2001 Gastroenterology 120:652-668). Recently,
`
`there has been increasing evidence for a role of inflammation in the etiology of IBS. Reports
`
`indicate that subsets ofIBS patients have small but significant increases in colonic inflammatory
`
`and mast cells, increased inducible nitric oxide (NO) and synthase (iNOS) and altered expression
`
`10
`
`of inflammatory cytokines (reviewed by Talley 2000, Medscape Coverage ofDDW Week).
`
`SUMMARY OF THE INVENTION
`
`The present invention features compositions and related methods for treating IBS and other
`
`gastrointestinal disorders and conditions ( e.g., gastrointestinal motility disorders, functional
`
`gastrointestinal disorders, gastroesophageal reflux disease (GERD), duodenogastric reflux,
`
`15
`
`Crohn's disease, ulcerative colitis, inflammatory bowel disease, functional heartburn, dyspepsia
`
`(including functional dyspepsia or nonulcer dyspepsia), gastroparesis, chronic intestinal pseudo(cid:173)
`
`obstruction ( or colonic pseudoobstruction), and disorders and co~ditions associated with
`
`constipation, e.g., constipation associated with use of opiate pain killers, post-surgical
`
`constipation, and constipation associated with neuropathic disorders as well as other conditions
`
`20
`
`and disorders. The compositions feature peptides that activate the guanylate cyclase C (GC-C)
`
`receptor.
`
`The present invention also features compositions and related methods for treating obesity,
`
`congestive heart failure and benign prostatic hyperplasia (BPH).
`
`Without being bound by any particular theory, in the case ofIBS and other gastrointestinal
`
`25
`
`disorders the peptides are useful because they can increase gastrointestinal motility.
`
`-2-
`
`
`Bausch Health Ireland Exhibit 2002, Page 4 of 247
`Mylan v. Bausch Health Ireland - IPR2022-01104
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`

`

`WO 2005/016244
`
`PCT/US2004/018751
`
`Without being bound by any particular theory, in the case of IBS and other gastrointestinal
`
`disorders the peptides are useful, in part, because they can decrease inflammation.
`
`Without being bound by any particular theory, in the case of IBS and other gastrointestinal
`
`5
`
`disorders the peptides are also useful because they can decrease gastrointestinal pain or visceral
`
`pam.
`
`The invention features pharmaceutical compositions comprising certain peptides that are capable
`
`of activating the guanylate-cyclase C (GC-C) receptor. Also within the invention are
`
`pharmaceutical compositions comprising a peptide of the invention as well as combination
`
`10
`
`compositions comprising a peptide of the invention and one or more additional therapeutic
`
`agents, e.g., an agent for treating constipation (e.g., a chloride channel activator such as SPI-
`
`0211; Sucampo Pharmaceuticals, Inc.; Bethesda, MD, a laxative such as MiraLax; Braintree
`
`Laboratories, Braintree MA) or some other gastrointestinal disorder. Examples of additional
`
`therapeutic agents include: acid reducing agents such as proton pump inhibitors ( e.g.
`
`15
`
`omeprazole, esomeprazole, lansoprazole, pantorazole and rabeprazole), H2 receptor blockers
`
`(e.g., cimetidine, ranitidine, famotidine and nizatidine), pro-motility agents such as motilin
`
`agonists ( e.g., GM-611 or mitemcinal fumarate ), 5HT receptor agonists ( e.g. 5HT4 receptor
`
`agonists such as Zelnorm®; 5HT3 receptor agonists such as MKC-733), 5HT receptor
`
`antagonists (e.g., 5HT1, 5HT2, 5HT3 (e.g., alosetron), 5HT4 receptor antagonists, muscarinic
`
`20
`
`receptor agonists, anti-inflammatory agents, antispasmodics, antidepressants, centrally-acting
`
`analgesic agents such as opioid receptor agonists, opioid receptor antagonists (e.g., naltrexone),
`
`agents for the treatment of Inflammatory bowel disease, Crohn's disease and ulcerative colitis
`
`(e.g., Traficet-EN™ (ChemoCentryx, Inc.; San Carlos, CA)), agents that treat gastrointestinal or
`
`visceral pain, and cGMP phosphodiesterase inhibitors (e.g., motapizone, zaprinast, and suldinac
`
`25
`
`sulfone). The peptides of the invention can also be used in combination with agents such as
`
`tianeptine (Stablon®) and other agents described in U.S. 6,683,072, (E)-4
`
`(1,3bis( cyclohexylmethyl)- l ,2,34,-tetrahydro-2,6-diono-9H-purin-8-yl)cinnamic acid
`
`nonaethylene glycol methyl ether ester and related compounds described in WO 02/067942. The
`
`peptides can also be used in combination with treatments entailing the administration of
`
`30 microorganisms useful in the treatment of gastrointestinal disorders such as IBS. Probactrix®
`
`-3-
`
`
`Bausch Health Ireland Exhibit 2002, Page 5 of 247
`Mylan v. Bausch Health Ireland - IPR2022-01104
`
`

`

`WO 2005/016244
`
`PCT/US2004/018751
`
`(The BioBalance Corporation; New York, NY) is one example of a formulation that contains
`
`microorganisms useful in the treatment of gastrointestinal disorders. The peptides can also be
`
`used in combination with purgatives that draw fluids to the intestine (e.g., Visicol®, a
`
`combination of sodium phosphate monobasic monohydrate and sodium phosphate dibasic
`
`5
`
`anhydrate.
`
`In addition, the pharmaceutical compositions can include one or more agents selected from the
`
`group consisting of: Ca channel blockers ( e.g., ziconotide ), complete or partial 5HT receptor
`
`antagonists (for example 5HT3 (e.g., alosetron, ATI-7000; Aryx Thearpeutics, Santa Clara CA),
`
`10
`
`5HT4, SHT2, and SHTl receptor antagonists), complete or partial SHT receptor agonists
`
`including 5HT3, 5HT2, 5HT4 (e.g., tegaserod, mosapride and renzapride), 5HT1 receptor
`
`agonists, CRF receptor agonists (NBI-34041), P-3 adrenoreceptor agonists, opioid receptor
`
`agonists ( e.g., loperamide, fedotozine, and fentanyl, naloxone, naltrexone, methyl nalozone,
`
`nalmefene, cypridime, beta funaltrexamine, naloxonazine, naltrindole, and nor-binaltorphimine,
`
`15 morphine, diphenyloxylate, enkephalin pentapeptide, asimadoline, and trimebutine), NK.1
`
`receptor antagonists (e.g., ezlopitant and SR-14033), CCK receptor agonists (e.g., loxiglumide),
`
`NK.1 receptor antagonists, NK3 receptor antagonists (e.g., talnetant, osanetant (SR-142801),
`
`SSR-241586), norepinephrine-serotonin reuptake inhibitors (NSRI; e.g., milnacipran), vanilloid
`
`and cannabanoid receptor agonists ( e.g., arvanil), sialorphin, sialorphin-related peptides
`
`20
`
`.comprising the amino acid sequence QHNPR (SEQ ID NO: ) for example, VQHNPR (SEQ ID
`
`NO: ); VRQHNPR (SEQ ID NO: ); VRGQHNPR (SEQ ID NO: ); VRGPQHNPR (SEQ ID
`
`NO: ); VRGPRQHNPR (SEQ ID NO: ); VRGPRRQHNPR (SEQ ID NO: ); and RQHNPR
`
`(SEQ ID NO: ), compounds or peptides that are inhibitors ofneprilysin, frakefamide (H-Tyr-D(cid:173)
`
`Ala-Phe(F)-Phe-NH2; WO 01/019849 Al), loperamide, Tyr-Arg (kyotorphin), CCK receptor
`
`25
`
`agonists ( caerulein), conotoxin peptides, peptide aµalogs of thymulin, loxiglumide,
`
`dexloxiglumide (the R-isomer ofloxiglumide) (WO 88/05774). These peptides and compounds
`
`can be administered with the peptides of the invention (simultaneously or sequentially). They
`
`can also be covalently linked to a peptide of the invention to create therapeutic conjugates.
`
`- 4 -
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`WO 2005/016244
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`PCT/US2004/018751
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`The invention includes methods for treating various gastrointestinal disorders by administering a
`
`peptide that acts as a partial or complete agonist of the GC-C receptor. The peptide contains up
`
`to four cysteines that form one or zy.,o disulfide bonds. In certain embodiments the disulfide
`
`bonds are replaced by other covalent cross-links and in some cases the cysteines are substituted
`
`5
`
`by other residues to provide for alternative covalent cross-links. The peptides may also include
`
`at least one trypsin or chymotrypsin cleavage site and/or a carboxy-terminal analgesic peptide or
`
`small molecule, e.g., AspPhe or some other analgesic peptide. When present within the peptide,
`
`the analgesic peptide or small molecule may be preceded by a chymotrypsin or trypsin cleavage
`
`site that allows release of the analgesic peptide or small molecule. The peptides and methods of
`
`1 o
`
`the invention are also useful for treating pain and inflammation associated with various
`
`disorders, including gastrointestinal disorders. Certain peptides include a functional
`
`chymotrypsin or trypsin cleavage site located so as to allow inactivation of the peptide upon
`
`cleavage. Certain peptides having a functional cleavage site undergo cleavage and gradual
`
`inactivation in the digestive tract, and this is desirable in some circumstances. In certain
`
`15
`
`peptides, a functional chymotrypsin site is altered, increasing the stability of the peptide in
`
`vivo(e.g., guanylin).
`
`The invention includes methods for treating other disorders such as congestive heart failure and
`
`benign prostatic hyperplasia by administering a peptide or small molecule (parenterally or orally)
`
`20
`
`that acts as an agonist of the GC-C receptor. Such agents can be used in combination with
`
`natriuretic peptides (e.g., atrial natriuretic peptide, brain natriuretic peptide or C-type natriuretic
`
`peptide), a diuretic, or an inhibitor of angiotensin converting enzyme.
`
`The invention features methods and compositions for increasing intestinal motility. Intestinal
`
`motility involves spontaneous coordinated distentions and contractions of the stomach,
`
`25
`
`intestines, colon and rectum to move food through the gastrointestinal tract during the digestive
`
`process.
`
`The peptide can contain additional carboxy terminal or an1ino terminal amino acids or both. For
`example, the peptide can include an amino terminal sequence that facilitates recombinant
`
`production of the peptide and is cleaved prior to administration of the peptide to a patient. The
`
`-5-
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`WO 2005/016244
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`PCT/US2004/018751
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`peptide can also include other amino terminal or carboxy terminal amino acids. In some cases
`
`the additional amino acids protect the peptide, stabilize the peptide or alter the activity of the
`
`peptide. In some cases some or all of these additional amino acids are removed prior to
`
`administration of the peptide to a patient. The peptide can include 1, 2, 3, 4, 5, 10, 15, 20, 25,
`
`5
`
`30, 40, 50, 60, 70 80, 90, 100 or more amino acids at its amino terminus or carboxy terminus or
`
`. both. The number of flanking amino acids need not be the same. For example, there can be 10
`
`additional amino acids at the amino terminus of the peptide and none at the carboxy terminus.
`
`In certain embodiments the peptides include either one or two or more contiguous negatively
`
`charged amino acids ( e.g., Asp or Glu) or one or two or more contiguous positively charged
`
`10
`
`residues (e.g., Lys or Arg) or one or two or more contiguous positively ,or negatively charged
`
`amino acids at the carboxy terminus. In these embodiments all of the flanking amino acids at the
`
`carboxy tem1inus are either positively or negatively charged. In other embodiments the carboxy
`
`terminal charged amino acids are preceded by a Leu. For example, the following amino acid
`
`sequences can be added to the carboxy terminus of the peptide: Asp; Asp Lys; Lys Lys Lys Lys
`
`15
`
`Lys Lys; Asp Lys Lys Lys Lys Lys Lys; Leu Lys Lys; and Leu Asp. It is also possible to simply
`
`add Leu at the carboxy terminus.
`
`In a first aspect, the invention features a polypeptide comprising, consisting of, or consisting
`
`essentially of the amino acid sequence: Xaa1 Xaa2Xaa3 Cys4 Xaa5 Xa8<5 Xaa7 Xaa8 Xaa9 Xaa10
`Xaa11 Cys12 Xaa13 Xaa14 Xaa15 Xaa,6 (SEQ ID N0:1) wherein:
`Xaa1 is Ser, Asn, Tyr, Ala, Gin, Pro, Lys, Gly, or Thr, or is J.nissing;
`
`Xaa2 is His, Asp, Glu, Ala, Ser, Asn, Gly, or is missing;
`
`Xaa3 is Thr, Asp, Ser, Glu, Pro, Val or Leu;
`
`Xaa5 is Asp, Ile or Glu;
`
`Xaa6 is Ile, Trp or Leu;
`Xaa7 is Cys, Ser, or Tyr;
`Xaa8 is Ala, Val, Thr, Ile, Met or is missing;
`
`20
`
`25
`
`Xaa9 is a) any amino acid, b) Phe, Tyr, Asn, Trp, c) an amino acid other than Phe, Trp, or
`
`Tyr, d) n~n-aromatic amino acid ore) is missing;
`
`Xaa10 is Ala, Val, Met, Thr or Ile;
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`- 6 -
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`Xaa11 is Ala or Val;
`Xaa13 is Ala or Thr;
`Xaa14 is Gly, Ala or Ser;
`Xaa15 is Cys, Tyr or is missing; and
`X:aa16 is: a) Trp, Tyr or Phe to create a chymotrypsin cleavage site; b) Lys or Arg to create
`a trypsin cleavage site; c) is missing or d) His or Leu or Ser.
`
`5
`
`In some embodiments, Xaa1 is preceded by Lys or Tyr.
`
`In certain embodiments, a Cys is replaces by any amino acid other than Cys. Ce1iain such
`
`polypeptides will have fewer disulfide bonds.
`
`1 o
`
`In a related aspect the invention features a composition comprising a polypeptide comprising,
`
`consisting of, or consisting essentially of the amino acid sequence: Xaa1 Xaa2 Xaa3 Cys4 Xaa5
`Xaa6 Xaa7 Xaa8 Xaa9 Xaa10 Xaa11 Cys12 Xaa13 Xaa14 Xaa1s Xaa16 (SEQ ID N0:1) wherein: Xaa1
`is Ser, Asn, Tyr, Ala, Gln, Pro, Lys, Gly, or Thr, or is missing; Xaa2 is His, Asp, Glu, Ala, Ser,
`Asn, Gly, Pro or is missing; Xaa3 is Thr, Asp, Ser, Glu, Pro, Val or Leu; Xaa5 is Asp, Ile or Glu;
`15 Xaa6 is Ile, Trp or Leu; Xaa7 is Cys, Ser, or Tyr; Xaa8 is Ala, Val, Thr, Ile, Met or is missing; Xaa9
`is Phe, Tyr, Asn, Trp, an amino acid other than Phe, Trp, or Tyr, is a non-aromatic amino acid or
`
`I
`
`is missing; Xaa10 is Ala, Val, Met, Thr or Ile; Xaa11 is Ala or Val; Xaa13 is Ala or Thr; Xaa14 is
`Gly, Ala or Ser; Xaa15 is Cys, Tyr or is missing; and Xaa16 is: a) Trp, Tyr or Phe to create a
`chymotrypsin cleavage site; b) Lys or Arg to create a trypsin cleavage site; c) is missing or d) His
`
`20
`
`or Leu or Ser and a pharmaceutically acceptable carrier. In related aspects, the invention features
`
`a phannaceutically acceptable tablet, pill, capsule comprising the peptide.
`
`In a related aspect, the invention features a polypeptide comprising, consisting of, or consisting
`
`essentially of the amino acid sequence: Xaa1 Xaa2 Xaa3 Cys4 Xaa5 Xaa6 Xaa7 Xaas Xaa9 Xaa10
`25 Xaau Cys12 Xaa13 Xaa14 Xaa15 Xaa16 (SEQ ID N0:1) wherein:
`
`Xaa1 is Asn, any amino acid or is missing;
`Xaa2 is Asp, Glu, any amino acid or is missing;
`
`Xaa3 is Asp or Glu;
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`-7-
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`WO 2005/016244
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`PCT/US2004/018751
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`Xaa5 is any amino acid or Glu;
`Xaa6 is any amino acid or Leu;
`Xaa7is Cys;
`Xaa8 is any amino acid or Val;
`Xaa9isAsn, Gln, Tyr;
`Xaa10 is is any amino acid or Val;
`Xaa11 is any amino acid or Ala;
`Xaa13 is is any amino acid or Thr;
`
`Xaa14 is is any amino acid or Gly;
`
`Xaa15 is Cys;
`Xaa16 is any amino acid, Leu or missing
`
`In a related aspect, the invention features a polypeptide comprising, consisting of, or consisting
`
`essentially of the amino acid sequence: Asn1 Xaa2 Xaa3 Xaa4 Glu5 Leu6 Xaa7 Valg Asn9 Xaa10
`
`Xaa11 Xaa12 Thr13 Xaa14 Xaa1s Leu16 (SEQ ID NO:_J
`
`Xaa2 is Asp or Glu;
`
`Xaa3 is Asp or Glu;
`
`Xaa4 is Cys or Mpt (mercaptoproline) or Pen (penicillamine) or Dpr ( diaminopropionic
`acid) or Asp or Glu;
`
`Xaa7 is Cys or Mpt (mercaptoproline) or Pen (penicillamine) or Dpr ( dian1inopropionic
`acid) or Asp or Glu;
`
`Xaa10 is Val or Pro;
`
`Xaa11 is Ala or Aib (alpha-aminoisobutyric acid);
`Xaa12 is Cys or Mpt (mercaptoproline) or Pen (penicillamine) or Dpr (diaminopropionic
`
`5
`
`10
`
`15
`
`20
`
`acid) or Asp or Glu;
`
`25
`
`Xaa14 is Gly or Ala;
`
`Xaa15 is Cys or Mpt (mercaptoproline) or Pen (penicillamine) or Dpr (diaminopropionic
`acid) or Asp or Glu; and
`
`In certain embodiments, where Xaa15 is other than Cys or is missing, Xaa7 is Ser or an amino
`acid other than Cys.
`
`30
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`- 8 -
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`Bausch Health Ireland Exhibit 2002, Page 10 of 247
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`WO 2005/016244
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`PCT/US2004/018751
`
`In certain embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ofXaa1,Xaa2,Xaa3, Xaa5, X3¾, Xaa7,
`Xaa8, Xaa9, Xaa10, Xaa11 , Xaa13 , Xaa14, and Xaa16 are any amino acid other than Cys.
`
`In certain embodiments, Xaa9 is any amino acid other than Gln. In other embodiments where
`Xaa2 and Xaa3 are Glu, Xaa9 is any amino acid other than Gln.
`
`5
`
`In certain embodiments Xaa1 and Xaa2 are missing; Xaa3 is Thr; Xaas is Glu; X3¾ is Ile or Leu;
`Xaasis Ala, Val, or Ile; Xaa9is Phe or Tyr; Xaa1o is Ala or Val; Xaa11 is Ala; Xaa1 3 is Ala or Thr;
`Xaa14 is Gly; and Xaa16 is Trp, Tyr, Phe, Lys, Arg or is missing.
`
`In certain embodiments the polypeptide comprising, consisting of, or consisting essentially of the
`
`amino acid sequence: Xaa1 Xaa2 Xaa3 Cys4 Xaa5 Xaa6 Xaa7 Xaas Xaa9 Xaa10 Xaa11 Cys1 2 Xaa13
`10 Xaa14 Xaa15 Xaa16 (SEQ ID N0:1) is not cleaved after Xaa9 by chymotrypsin. In these
`embodiments wherein:
`
`Xaa1 is Ser, Asn, Tyr, Ala, Gin, Pro, Lys, Gly, or Thr, or is missing;
`Xaa2 is His, Asp, Glu, Ala, Ser, Asn, or Gly, or is missing;
`Xaa3 is Thr, Asp, Ser, Glu, Pro, Val or Leu or is missing;
`Xaa5 is Asp, Ile or Glu;
`
`15
`
`Xaa6 is Ile, Trp or Leu;
`
`Xaa7 is Cys, Ser, or Tyr;
`
`Xaa8 is Ala, Val, Thr, Ile, Met or is missing;
`
`Xaa9 is either: a) any amino acid other than Phe and Tyr, b) any amino acid other than
`
`20
`
`Phe, Tyr, and Trp, c) any amino acid other than Phe, Tyr, Trp, Ile, Leu and Val; d) any amino acid
`
`other than Phe, Tyr, Trp, Ile, Leu, Val, and His; d) any non-aromatic amino acid or e) is missing;
`
`25
`
`Xaa10 is Ala, Val, Met, Thr or Ile;
`Xaa 11