I 1111111111111111 11111 111111111111111 111111111111111 111111111111111 IIII IIII
`US00770494 7B2
`
`c12) United States Patent
`Currie et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 7,704,947 B2
`* Apr. 27, 2010
`
`(54) METHODS AND COMPOSITIONS FOR THE
`TREATMENT OF GASTROINTESTINAL
`DISORDERS
`
`(75)
`
`Inventors: Mark G. Currie, Sterling, MA (US);
`Shalina Mahajan-Miklos, Stanford, CA
`(US); Thea Norman, San Diego, CA
`(US); G. Todd Milne, Brookline, MA
`(US)
`
`(73) Assignee: Ironwood Pharmaceuticals, Inc.,
`Cambridge, MA (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 51 days.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`(21) Appl. No.: 11/930,696
`
`(22) Filed:
`
`Oct. 31, 2007
`
`(65)
`
`Prior Publication Data
`
`US 2009/0005534 Al
`
`Jan. 1, 2009
`
`Related U.S. Application Data
`
`(62) Division of application No. 10/766,735, filed on Jan.
`28, 2004, now abandoned.
`
`(60) Provisional application No. 60/443,098, filed on Jan.
`28, 2003, provisional application No. 60/471,288,
`filed on May 15, 2003, provisional application No.
`60/519,460, filed on Nov. 12, 2003.
`
`(51)
`
`Int. Cl.
`C07K 7108
`(2006.01)
`(52) U.S. Cl. ........................................... 514/2; 530/327
`(58) Field of Classification Search ....................... None
`See application file for complete search history.
`
`(56)
`
`References Cited
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`(Continued)
`
`Primary Examiner-Christopher R. Tate
`Assistant Examiner-Roy Teller
`(74) Attorney, Agent, or Firm-Honigman Miller Schwartz
`and Cohn LLP; Kelly T. Murphy; Johnathan P. O'Brien
`
`(57)
`
`ABSTRACT
`
`The present invention features compositions and related
`methods for treating IBS and other gastrointestinal disorders
`and conditions ( e.g., gastrointestinal motility disorders, func(cid:173)
`tional gastrointestinal disorders, gastroesophageal reflux dis(cid:173)
`ease (GERD), Crohn's disease, ulcerative colitis, Inflamma(cid:173)
`tory bowel disease,
`functional heartburn, dyspepsia
`(including functional dyspepsia or nonulcer dyspepsia), gas(cid:173)
`troparesis, chronic intestinal pseudo-obstruction ( or colonic
`pseudo-obstruction), and disorders and conditions associated
`with constipation, e.g., constipation associated with use of
`opiate pain killers, post-surgical constipation, and constipa(cid:173)
`tion associated with neuropathic disorders as well as other
`conditions and disorders using peptides and other agents that
`activate the guanylate cyclase C (GC-C) receptor.
`
`16 Claims, 19 Drawing Sheets
`
`Bausch Health Ireland Exhibit 2015, Page 1 of 66
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`US 7,704,947 B2
`Page 2
`
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`
`* cited by examiner
`
`Bausch Health Ireland Exhibit 2015, Page 2 of 66
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

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`Bausch Health Ireland Exhibit 2015, Page 3 of 66
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

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`Bausch Health Ireland Exhibit 2015, Page 4 of 66
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

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`
`Bausch Health Ireland Exhibit 2015, Page 5 of 66
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`-....l = N
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`
`PEPTIDE CC)NCENTRATION (nrn)
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`Bausch Health Ireland Exhibit 2015, Page 6 of 66
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`-....l = N
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`Bausch Health Ireland Exhibit 2015, Page 7 of 66
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`-....l = N
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`Bausch Health Ireland Exhibit 2015, Page 8 of 66
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`Apr. 27, 2010
`
`Sheet 7 of 19
`
`US 7,704,947 B2
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`Bausch Health Ireland Exhibit 2015, Page 9 of 66
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`Apr. 27, 2010
`
`Sheet 8 of 19
`
`US 7,704,947 B2
`
`f
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`Bausch Health Ireland Exhibit 2015, Page 10 of 66
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`-....l = N
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`Bausch Health Ireland Exhibit 2015, Page 11 of 66
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`Apr. 27, 2010
`
`Sheet 10 of 19
`
`US 7,704,947 B2
`
`-.... J•-•r..>».
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`Bausch Health Ireland Exhibit 2015, Page 12 of 66
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`Apr. 27, 2010
`
`Sheet 11 of 19
`
`US 7,704,947 B2
`
`-,m
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`Bausch Health Ireland Exhibit 2015, Page 13 of 66
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

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`
`Bausch Health Ireland Exhibit 2015, Page 14 of 66
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`Apr. 27, 2010
`
`Sheet 13 of 19
`
`US 7,704,947 B2
`
`........ ··r-
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`
`Bausch Health Ireland Exhibit 2015, Page 15 of 66
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`-....l = N
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`FIG. 7
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`'.~, p<O. 05 as eornpared to '*vehicle't va!ue
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`COLOREC.TAL DiS'T.ENS!ON l~.SSAY
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`IN RAT TNBS
`
`EFFECT OF SEQ ID NO: 31
`
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`Bausch Health Ireland Exhibit 2015, Page 16 of 66
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

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`FIG. 8A
`
`indornethacin
`
`SEQ !D NO: 28
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`
`Bausch Health Ireland Exhibit 2015, Page 17 of 66
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

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`
`Bausch Health Ireland Exhibit 2015, Page 18 of 66
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`-....l = N
`~
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`
`FIG" 9
`
`SEQ iD NO: 31, Log (M)
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`
`Bausch Health Ireland Exhibit 2015, Page 19 of 66
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`....
`0 ....
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`rJJ =(cid:173)
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`FIG. 10A
`Tirne (min)
`
`100
`
`0
`
`* Urnit of detection 0.061 p.fJ/ml
`
`Dosing at ·10 mg/kg
`
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`Q Irr , ~.·.. . . .. '11' .·. .
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`
`(based on EUSA)
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`
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`
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`
`Bausch Health Ireland Exhibit 2015, Page 20 of 66
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`Apr. 27, 2010
`
`Sheet 19 of 19
`
`US 7,704,947 B2
`
`200
`
`240
`
`FIG 108
`
`Bausch Health Ireland Exhibit 2015, Page 21 of 66
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`US 7,704,947 B2
`
`1
`METHODS AND COMPOSITIONS FOR THE
`TREATMENT OF