I 1111111111111111 11111 111111111111111 IIIII IIIII IIIII 111111111111111 IIII IIII
`US007745409B2
`
`c12) United States Patent
`Currie et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 7,745,409 B2
`*Jun. 29, 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 O days.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`(21) Appl. No.: 11/949,340
`
`(22) Filed:
`
`Dec. 3, 2007
`
`(65)
`
`Prior Publication Data
`
`US 2008/0227685 Al
`
`Sep. 18, 2008
`
`Related U.S. Application Data
`
`(62) Division of application No. 10/796,719, filed on Mar.
`9, 2004, now Pat. No. 7,304,036.
`
`(51)
`
`Int. Cl.
`A61K 38/00
`(2006.01)
`(52) U.S. Cl. ......................................... 514/14; 530/300
`(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 Cohen &
`Schwartz LLP; Jonathan P. O'Brien; Kelly T. Murphy
`
`(57)
`
`ABSTRACT
`
`The present invention features compos1t10ns 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 (post-operative
`ileus ), and constipation 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.
`
`7 Claims, 19 Drawing Sheets
`
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`

`

`US 7,745,409 B2
`Page 2
`
`OTHER PUBLICATIONS
`
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`ketorolac" European Journal of Pharmacology, vol. 426: pp. 39-44
`(2001).
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`Rolfe et al., "Enterotoxin Escherichia coli STa activates a nitric
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`The Journal of Physiology, vol. 475, No. 3: pp. 531-537 (1994).
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`Shailubhai, "Therapeutic applications of guanylate cyclase-C recep(cid:173)
`tor agonists" Drug Discovery & Development, vol. 5 No. 2: pp.
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`So et al., "Nucleotide Sequence of the Bacterial Transposon Tnl681
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`* cited by examiner
`
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`
`

`

`Area
`1.78e3
`2093+1047
`1: TOF ES+
`
`f
`
`f
`
`39.17
`
`2
`
`/
`
`I
`
`':::;::9:
`
`24
`
`38.35
`
`I
`1 .J
`
`l
`
`I
`"'u.. I
`
`I
`
`<) V
`
`90
`37.31
`
`30.95
`
`I
`
`0
`
`MD_GCCA03Jul1_R118 Sm (SG, 2x3)
`
`=,:: (
`
`I
`
`I
`
`I
`
`O I
`
`~ = ~
`
`~
`~
`~
`•
`r:J).
`~
`
`Area
`1.98e3
`2305+1153
`1: TOF MS ES+
`
`%
`
`SEQ ID NO: 4
`
`347
`33.67 373
`3.5~17
`
`MD_GCCA03JuI1_R119 Sm (SG, 2x3)
`
`100
`
`LCMS ANALYSIS OF RECOMBINANT PEPTIDE VARIANTS
`
`~ = \0 = N
`
`UI
`~
`--...l
`"'--...l
`rJl.
`d
`
`....
`0 ....
`....
`.....
`rJ'1 =(cid:173)
`
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`('D
`
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`
`N
`"'\,Ci
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`?
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`
`0 ....
`
`0
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`
`41.61
`
`1
`
`39.99
`
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`
`1
`38.95
`
`I
`/
`"j · • 37.26
`
`/
`
`I
`
`2
`
`3
`
`FIG. 1A
`
`I
`
`'I
`
`27.82 ~.\.,, /\_ 33.82 35.31
`
`I
`3
`
`143
`28.50
`
`I
`
`j
`
`0
`
`%
`
`100
`
`SEQ ID NO: 5
`
`Bausch Health Ireland Exhibit 2016, Page 3 of 75
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`~ = \0 = N
`
`UI
`~
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`d r.,;_
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`....
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`0 ....
`
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`
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`FIG. 18
`
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`
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`
`55.00
`
`45.00
`1•1•1111 •• ij
`
`50.00
`~
`
`I
`
`I
`
`I
`
`45.45 47.37
`
`II
`
`31.44
`
`31.10
`31.1131.34
`
`LCMS ANALYSIS OF SYNTHETIC SEQ ID NO: 3 \
`
`(TOTAL ION CHROMATOGRAPH (TIC))
`
`31.21
`
`, .. 'I ••11••••1••111111111
`
`i
`~-,.__~-·
`
`40.00
`
`35.00
`
`30.00
`
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`
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`
`20.00
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`
`15.00
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`
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`
`Bausch Health Ireland Exhibit 2016, Page 4 of 75
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`Jun.29,2010
`
`Sheet 3 of 19
`
`US 7,745,409 B2
`
`u.
`0
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`r2 ~
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`Bausch Health Ireland Exhibit 2016, Page 5 of 75
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`~ = \0 = N
`
`UI
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`. I ~ MD-1100(b)
`□ MD-1100(a)
`~ MD-915
`■ MM-416776
`
`FIG. 2
`
`Peptide Concentration (nm)
`
`37
`
`12
`
`4
`
`1.3
`
`l"-"-'-"-'\J
`
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` -.. -0 40.00·
`
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`
`CHEMICAL Y SYNTHESIZED PEPTIDES IN THE INTENSTINAL GC-C
`
`RECEPTOR ACTIVITY ASSAY
`
`60.00·
`
`Bausch Health Ireland Exhibit 2016, Page 6 of 75
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`

`

`U.S. Patent
`
`Jun.29,2010
`
`Sheet 5 of 19
`
`US 7,745,409 B2
`
`I
`I
`
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`
`Bausch Health Ireland Exhibit 2016, Page 7 of 75
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`~ = \0 = N
`
`UI
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`--...l
`'-"--...l
`
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`
`FIG. 3B
`
`CONCENTRATION (mg/kg)
`
`3.0
`
`0.75
`
`0.25
`
`0.13
`
`0.03
`
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`
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`
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`
`Bausch Health Ireland Exhibit 2016, Page 8 of 75
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`
`

`

`U.S. Patent
`
`Jun.29,2010
`
`Sheet 7 of 19
`
`US 7,745,409 B2
`
`It)
`
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`Bausch Health Ireland Exhibit 2016, Page 9 of 75
`Mylan v. Bausch Health Ireland - IPR2022-00722
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`

`

`U.S. Patent
`
`Jun.29,2010
`
`Sheet 8 of 19
`
`US 7,745,409 B2
`
`_J
`
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`0.. w
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`Cl w
`N
`Cf)
`w
`I
`>-z
`>-_J
`_J
`<(
`(.)
`~
`w
`I
`(.)
`
`Cf)
`
`0
`0
`T"""
`
`0
`0
`O') CX)
`
`0
`r,.....
`
`0 00 0
`0
`(0 LO ~ C'? N
`
`0
`
`0
`"'"""'
`
`~
`~~
`%
`'b
`<'
`~,
`~
`
`~
`~~
`%
`~
`~
`~
`~
`~
`
`,6'
`~~
`~
`@~
`VO
`~
`~
`
`~ .~
`
`~
`
`co
`~ .
`(9 -
`
`LL
`
`Bausch Health Ireland Exhibit 2016, Page 10 of 75
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`~ = \0 = N
`
`UI
`~
`~
`-....l
`
`d r.,;_
`
`....
`0 ....
`.....
`rJJ =(cid:173)
`
`\,Ci
`
`('D
`('D
`
`\,Ci
`
`N
`~\,Ci
`N
`?
`2'
`
`0 ....
`
`0
`
`~ = ~
`
`~
`~
`~
`•
`00
`~
`
`....,
`ta
`C:
`(.)
`Q)
`30
`I-
`E
`40
`>
`50
`Q) -Q)
`60
`'"C
`~ 70
`80
`t-
`'E 90
`2 100 ---------------~--------7
`
`** ***
`
`* ***
`
`~ Chronic
`D Acute
`
`CHRONIC vs ACUTE DOSING IN GIT ASSAY
`
`0
`10
`
`(I) ·-c 20LLJ~J--1:::;:L_L~--,--L--A-~
`
`Zelnorm®
`1mg/kg
`
`0.25mg/kg
`
`0.06mg/kg
`
`Vehicle
`
`FIG. 4C
`
`MO-1100
`
`*** p < 0.0005
`** p < 0.005
`* p < 0.01
`
`Bausch Health Ireland Exhibit 2016, Page 11 of 75
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`~ = \0 = N
`
`UI
`~
`~
`-....l
`
`d r.,;_
`
`(0.2mg/kg)
`4·5 Zelnorm®
`
`FIG. 5A
`
`MM-416776 (mg/kg x10-3)
`
`4
`
`I
`
`3.5
`
`/·
`
`3
`
`I
`
`2.5
`
`I
`
`2
`
`I
`
`1.5
`
`I
`
`1
`
`I
`
`0.5
`
`I
`
`0
`
`0
`
`....
`0 ....
`('D a ....
`rJJ =(cid:173)
`
`0
`
`1,0
`
`0 ....
`
`N
`
`0
`
`~
`
`~ = ?
`
`1,0
`N
`
`~ = ~
`
`~
`~
`~
`•
`00
`~
`
`-~~ ........................................... ••••••••••••••••
`
`'T'
`
`I
`....
`
`1
`X
`
`,.~
`
`MM-416776 vs ZELNORM® IN A MOUSE INTESTINAL SECRETION MODEL
`
`~J_
`
`0.02
`<.9 0.04 ~
`:J
`(_) en 0.06
`(.) ro o.oa
`~ 0.1
`~ 0.12
`:.;::::;
`0 0.14
`0.16
`0.18
`
`~
`
`(./)
`
`Bausch Health Ireland Exhibit 2016, Page 12 of 75
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`Jun.29,2010
`
`Sheet 11 of 19
`
`US 7,745,409 B2
`
`@)
`E
`L.
`0
`C -Cl)
`
`N
`~
`
`-C') ca
`~ ---
`. - C)
`
`I.!)
`
`LL
`
`C')
`::::s
`Cl)
`en
`0
`C
`
`0
`LO
`N
`
`~
`
`0
`~
`N
`
`LO
`"'1°
`
`LO
`
`~
`
`N
`
`Q)
`0
`.c
`Q) >
`
`0
`~ .
`0
`
`co
`<.O
`0
`0
`0
`0
`UO!JaJ~as
`
`-q-
`0
`0
`
`N
`0 .
`0
`
`0
`0
`0
`
`...I
`
`<( z
`i='.
`Cl)
`LJ.J
`I-z
`UJ
`(I')
`:::, ....J Ow
`20
`zO
`-2
`®2z
`0:: 0
`01-zW
`...I 0::
`UJO
`NUJ
`(/')(/')
`>
`0
`0 ..--
`..--
`I
`0
`2
`
`~ ~
`
`"'1°
`.
`
`0
`
`N
`.
`
`0
`
`Bausch Health Ireland Exhibit 2016, Page 13 of 75
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`~ = \0 = N
`
`UI
`~
`~
`-....l
`
`d r.,;_
`
`FIG. 6A
`
`Dose (mg/kg x10-3)
`
`20
`
`15
`
`10
`
`5
`
`....
`0 ....
`N
`....
`.....
`rJJ =(cid:173)
`
`('D
`('D
`
`\,Ci
`
`N
`~\,Ci
`N
`?
`2'
`
`0 ....
`
`0
`
`~ = ~
`
`~
`~
`~
`•
`00
`~
`
`II-MM-416776
`t-MD-915
`
`•••••••••••••••••••••••••••••••••••••••••••••••••••
`
`RECOMBINANTLY GENERATED MD-915 AND MM-416776 IN MOUSE
`
`INTESTINAL SECRETION MODEL
`
`0
`
`0
`
`0.02
`
`0.04
`
`C> 0.06
`~ o.oe.
`~
`ca
`0.1
`0 ·- .....,
`
`0.12
`
`0.14
`
`0.16
`
`0.18
`
`Bausch Health Ireland Exhibit 2016, Page 14 of 75
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`~ = \0 = N
`
`UI
`~
`~
`--..l
`d r.,;_
`
`\,Ci
`
`~
`
`('D
`('D
`
`....
`0 ....
`....
`......
`rJJ =(cid:173)
`
`N
`~\,Ci
`N
`?
`2'
`
`0 ....
`
`0
`
`~ = ~
`
`~
`~
`~
`•
`00
`~
`
`FIG. 68
`Dose {ug/kg)
`
`60
`
`50
`,.
`
`40
`,
`
`30
`
`20
`
`1 0
`,
`
`0
`
`O
`
`o.02·--1--~-----------------J
`C> 0.04-i-------------------1
`.._
`O 0.06
`~ 0.08
`·-+■I
`o 0.1
`0.12
`0.14r--=--~:--------------
`
`.,...
`
`--<>-MM-416776
`
`a-MD-1100
`.,_ MD-915
`
`50ug/kg Sigma ST ( + control)
`
`-
`
`-o-vehicle (-control)
`
`CHEMICALLY SYNTHESIZED PEPTIDES IN MOUSE
`
`INTESTINAL SECRETION MODEL
`
`Bausch Health Ireland Exhibit 2016, Page 15 of 75
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`Jun.29,2010
`
`Sheet 14 of 19
`
`US 7,745,409 B2
`
`(./) >-
`co <(
`z (./)
`I- (./')
`I- <(
`<i::z
`er: 0
`z-
`-
`I-
`oZ
`oUJ
`~-
`~ Cf)
`,o
`O_i
`~<(
`LL. I-oO
`1-w
`(.)~
`wO
`LL _I
`u_O
`LUO
`
`0
`N
`
`U)
`
`""""
`
`*
`
`*
`
`C>
`.......
`0 ~
`M C>
`::t
`
`. -
`
`C)
`t')Jil:
`. 0 0)
`::i.
`
`+
`Cl) UJ
`um
`·- z
`~I-
`>
`-
`Q)
`·-
`(.)
`..c
`CL)
`>
`
`0
`~
`
`It)
`
`0
`
`I'-,
`•
`0 C)
`0 -
`~ LL
`T-
`I
`0
`~
`+
`UJ
`Dl
`z
`I-
`
`-
`Q)
`:::,
`co
`>
`-
`·a, -u ·-
`;.C
`Q)
`-
`-
`>
`.s
`"C
`~
`('CS
`C.
`E
`0
`(,)
`rn
`co
`It).
`0 .
`0
`V
`C.
`*
`
`(U!W S)
`suo1i::reJJuo:> 1eu1wopqe JO JaqwnN
`
`Bausch Health Ireland Exhibit 2016, Page 16 of 75
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`Jun.29,2010
`
`Sheet 15 of 19
`
`US 7,745,409 B2
`
`0,
`~ M ...__
`
`0,
`E
`
`Cl)~
`
`I- Cl)
`()Cl)
`UJ <(
`LL (!)
`tb~
`UJ :c >I-
`I- 0:::
`a.: s
`UJ UJ
`OU)
`::::, Oo 0
`
`z~
`~<(
`<CZ
`-' ;,;
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`UJ
`I oCl
`Cl)~
`LL >o
`-
`
`s::: ·-
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`0,
`"""'" --
`~ .s:
`.....
`0,
`Q)
`E E
`0
`"CS
`C -
`
`. --
`
`0,
`M~
`0 0,
`E
`
`<(
`co
`.
`-LL
`C)
`
`"""'" --
`
`Lt,
`C,
`""'"
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`0,
`C
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`:E
`
`I
`
`Q) -(.) ·-..c:
`Q) >
`
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`M
`
`0
`M
`
`Lt)
`N
`
`0
`N
`
`0
`
`Bausch Health Ireland Exhibit 2016, Page 17 of 75
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`~ = \0 = N
`
`UI
`~
`--...l
`'-"--...l
`
`d r.,;_
`
`....
`0 ....
`O'I
`....
`.....
`rJJ =(cid:173)
`
`('D
`('D
`
`\,Ci
`
`0 ....
`
`0
`
`N
`'-"\,Ci
`N
`
`
`
`a(cid:173)?
`
`~ = ~
`
`~
`~
`~
`•
`00
`~
`
`FIG. 8B
`
`lndomethacin
`
`MD-1100
`
`µg/kg mg/kg mg/kg mg/kg
`
`3
`
`1
`
`0.3
`
`10
`
`µg/kg
`
`2.5
`
`µg/kg
`
`1
`
`Vehicle
`
`0
`
`:::::s z
`E
`.c
`(l)
`s..
`0
`.....
`~ 20 -
`....... ·-s..
`C ·- ..c:
`C) 30 -
`u,
`
`5
`
`10
`
`15
`
`25
`
`OF MD-1100 IN A MOUSE WRITHING ASSAY
`
`VISCERAL ANTINOCICEPTIVE EFFECTS
`
`35
`
`Bausch Health Ireland Exhibit 2016, Page 18 of 75
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`Jun.29,2010
`
`Sheet 17 of 19
`
`US 7,745,409 B2
`
`-----=---~--.,------;r----,- Lt)
`I
`
`..-..
`~ .._..
`C)
`0
`..J
`"" M
`■ ■ 0
`
`ti)
`
`z -C LL
`-a w
`
`cr,
`.
`(.9
`
`• (0
`
`I
`
`I'-
`I
`
`t0
`I
`
`c,)
`I
`
`0
`~
`I
`
`~
`~
`I
`
`N
`~
`I
`
`0)
`
`C) z
`0 z
`0 z
`<Co
`(.!) 0 -~
`-'~ 01 -o
`0~
`c2 LL.
`wO
`>
`.==
`I-
`LU a..
`~
`0
`(_)
`
`2
`C
`LO .
`V
`II
`"'CJ
`~
`
`•
`
`0
`Lt)
`N
`0
`~ ~
`
`Lt)
`I'-
`
`0
`It)
`
`Lt)
`N
`
`0
`
`0 8/8 %) 9Ll·WW·lsz~
`
`(
`
`Bausch Health Ireland Exhibit 2016, Page 19 of 75
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`0 ....
`
`N
`~\,Ci
`N
`
`0
`
`~ = ?
`
`~ = ~
`
`~
`~
`~
`•
`00
`~
`
`based on LCMS
`
`< 0.11 % Bioavailable
`
`I :: :,.11
`
`I
`
`MINIMUM SYSTEMIC ABSORPTION OF
`
`MD-1100 (BASED ON LCMS)
`
`L..
`
`-E
`
`(.)
`0
`C:
`(.)
`Q)
`C:
`'- ..,
`(ti
`·- ....,
`0
`::i. -15
`C:
` --C')
`-20
`251
`
`5
`
`10
`
`~ = \0 = N
`
`UI
`~
`~
`-....l
`
`d r.,;_
`
`....
`0 ....
`..... ....
`rJJ =- ('D
`
`QO
`
`('D
`
`\,Ci
`
`FIG. 1 OA
`
`• Dosing at 10 mg/kg
`• Limit of detection 0.00063 µg/mL (0.6 nM)
`
`Time (min)
`
`240
`
`•
`
`, •.
`
`200
`
`160
`
`120
`
`80
`
`o••••=-1
`
`40
`
`0
`
`Bausch Health Ireland Exhibit 2016, Page 20 of 75
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`~ = \0 = N
`
`UI
`~
`~
`-....l
`
`d r.,;_
`
`FIG. 10B
`
`j
`
`150
`
`I
`
`....
`0 ....
`....
`.....
`rJJ =- ('D
`
`\,Ci
`
`('D
`
`\,Ci
`
`0 ....
`
`N
`~\,Ci
`N
`
`0
`
`~ = ?
`
`~ = ~
`
`~
`~
`~
`•
`00
`~
`
`based on ELISA
`
`< 2.2% Bioavailable
`
`II
`
`.... Oral* 1
`
`I ._ IV*~~n
`
`MINIMUM SYSTEMIC ABSORPTION OF MD-1100
`
`(BASED ON ELISA)
`
`Dosing at 10 mg/kg
`
`* Limit of detection 0.061 µg/ml
`
`Time (min)
`
`100
`Ii
`
`50
`
`t It
`
`t
`
`0
`olf
`
`5
`
`' -
`2s rr
`
`(J
`0
`s::
`0
`G) 10
`C:
`....,
`ns ...
`0 ·-
`....,
`:t -C: 15
`---en
`E
`-20
`
`-
`
`Bausch Health Ireland Exhibit 2016, Page 21 of 75
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`US 7,745,409 B2
`
`1
`METHODS AND COMPOSITIONS FOR THE
`TREATMENT OF GASTROINTESTINAL
`DISORDERS
`
`CLAIM OF PRIORITY
`
`2
`2001, Gastroenterology 120:652-668). Recently, there has
`been increasing evidence for a role of inflannnation in etiol(cid:173)
`ogy ofIBS. Reports indicate that subsets ofIBS patients have
`small but significant increases in colonic inflannnatory and
`5 mast cells, increased inducible nitric oxide (NO) and synthase
`(iNOS) and altered expression of inflammatory cytokines
`(reviewed by Talley 2000, Medscape Coverage of DDW
`week).
`
`SUMMARY
`
`This application is a divisional of U.S. patent application
`Ser. No. 10/796,719, filed Mar. 9, 2004 now U.S. Pat. No.
`7,304,036, which claims priority to U.S. patent application
`Ser. No. 10/766,735, filed Jan. 28, 2004, which claims prior- 10
`ity under 35 USC §119(e) to U.S. Provisional Patent Appli(cid:173)
`cation Ser. No. 60/443,098, filed on Jan. 28, 2003; U.S. Pro(cid:173)
`visional PatentApplicationSer. No. 60/471,288, filed on May
`15, 2003 and U.S. Provisional Patent Application Ser. No.
`60/519,460, filed on Nov. 12, 2003, the entire contents of 15
`which are hereby incorporated by reference.
`
`TECHNICAL FIELD
`
`This invention relates to methods and compositions for
`treating various disorders, including gastrointestinal disor(cid:173)
`ders, obesity, congestive heart failure and benign prostatic
`hyperplasia.
`
`BACKGROUND
`
`Irritable bowel syndrome (IBS) is a common chronic dis(cid:173)
`order of the intestine that affects 20 to 60 million individuals
`in the US alone (Lehman Brothers, Global Healthcare-Irri(cid:173)
`table bowel syndrome industry update, September 1999). IBS
`is the most common disorder diagnosed by gastroenterolo(cid:173)
`gists (28% of patients examined) and accounts for 12% of
`visits to primary care physicians (Camilleri 2001, Gastroen(cid:173)
`terology 120:652-668). In the US, the economic impact of
`IBS is estimated at $25 billion annually, through direct costs 35
`ofhealth care use and indirect costs of absenteeism from work
`(Talley 1995, Gastroenterology 109:1736-1741). Patients
`with IBS have three times more absenteeism from work and
`report a reduced quality of life. 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 dis(cid:173)
`turbed bowel pattern. Three subgroups of IBS patients have
`been defined based on the predominant bowel habit: consti(cid:173)
`pation-predominant (c-IBS), diarrhea-predominant (d-IBS)
`or alternating between the two (a-IBS). Estimates ofindividu(cid:173)
`als 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).
`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 prac(cid:173)
`tice. However, the complexity of symptoms has not been
`explained by anatomical abnormalities or metabolic changes.
`This has led to the classification of IBS 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,AnnuRevMed52: 319-338). IBS is considered to be
`a "biopsychosocial" disorder resulting from a combination of
`three interacting mechanisms: altered bowel motility, an
`increased sensitivity of the intestine or colon to pain stimuli
`(visceral sensitivity) and psychosocial factors (Camilleri
`
`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-
`tory bowel disease,
`functional heartburn, dyspepsia
`(including functional dyspepsia or nonulcer dyspepsia), gas(cid:173)
`troparesis, chronic intestinal pseudo-obstruction ( or colonic
`20 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. The compositions feature peptides
`25 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
`30 of IBS and other gastrointestinal disorders the peptides are
`useful because they can increase gastrointestinal motility.
`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 disorders the peptides are
`also useful because they can decrease gastrointestinal pain or
`visceral pain.
`The invention features pharmaceutical compositions com-
`40 prising certain peptides that are capable of activating the
`guanylate-cyclase C (GC-C) receptor. Also within the inven(cid:173)
`tion are pharmaceutical compositions comprising a peptide of
`the invention as well as combination compositions compris(cid:173)
`ing a peptide of the invention and a second therapeutic agent,
`45 e.g., an agent for treating constipation ( e.g., a chloride chan(cid:173)
`nel activator such as SPI-0211; Sucampo Pharmaceuticals,
`Inc.; Bethesda, Md., a laxative such as MiraLax; Braintree
`Laboratories, Braintree Mass.) or some other gastrointestinal
`disorder. Examples of a second therapeutic agent include:
`50 acid reducing agents such as proton pump inhibitors ( e.g.
`omeprazole, esomeprazole, lansoprazole, pantorazole and
`rabeprazole) and H2 receptor blockers ( e.g. cimetidine, ran(cid:173)
`itidine, famotidine and nizatidine ), pro-motility agents such
`as motilin agonists (e.g GM-611 or mitemcinal fumarate),
`55 and 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 alos(cid:173)
`etron), and 5HT4 receptor antagonists; muscarinic receptor
`agonists, anti-inflannnatory agents, antispasmodics, antide-
`60 pressants, centrally-acting analgesic agents such as opiod
`receptor agonists, opiod receptor antagonists (e.g. naltrex(cid:173)
`one ), agents for the treatment oflnflammatory bowel disease,
`Crohn's disease and ulcerative colitis (e.g., Traficet-EN™
`(ChemoCentryx, Inc.; San Carlos, Calif.) agents that treat
`65 gastrointestinal or visceral pain and cGMP phosphodi(cid:173)
`esterase inhibitors (motapizone, zaprinast, and suldinac sul(cid:173)
`fone). The peptides of the invention can also be used in
`
`Bausch Health Ireland Exhibit 2016, Page 22 of 75
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`US 7,745,409 B2
`
`5
`
`3
`combination with agents such a tianeptine (Stablon®) and
`other agents described in U.S. Pat. No. 6,683,072; (E)-4
`(1,3bis( cyclohexylmethyl)-1,2,34,-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 microorgan(cid:173)
`isms useful in the treatment of gastrointestinal disorders such
`as IBS. Probactrix® (The BioBalance Corporation; New
`York, N.Y.) is one example of a formulation that contains
`microorganisms useful in the treatment of gastrointestinal
`disorders. In addition, the pharmaceutical compositions can
`include an (OK) agent selected from the group consisting of:
`Ca channel blockers ( e.g., ziconotide ), 5HT receptor agonists
`(e.g 5HT1, 5HT2, 5HT3 and 5HT4 receptor agonists) 5HT
`receptor antagonists (e.g 5HT1, 5HT2, 5HT3 and 5HT4),
`opioid receptor agonists (e.g., loperamide, fedotozine, and
`fentanyl, naloxone, naltrexone, methyl nalozone, nalmefene,
`cypridime, beta funaltrexamine, naloxonazine, naltrindole,
`and nor-binaltorphimine, morphine,
`diphenyloxylate,
`enkephalin pentapeptide, and trimebutine ), NKl receptor
`antagonists (e.g., ezlopitant and SR-14033, SSR-241585),
`CCK receptor agonists (e.g., loxiglumide), NKl receptor
`antagonists, NK3 receptor antagonists (e.g., talnetant, osan(cid:173)
`etant SR-142801, SSR-241585), norepinephrine-serotonin 25
`reuptake inhibitors (NSRI ; e.g., milnacipran), vanilloid and
`cannabanoid receptor agonists ( e.g., arvanil), sialorphin, sia(cid:173)
`lorphin-related peptides comprising the amino acid sequence
`QHNPR (SEQ ID NO: 111) for example, VQHNPR (SEQ ID
`NO:112); VRQHNPR (SEQ ID NO:113); VRGQHNPR
`(SEQ ID NO:114); VRGPQHNPR (SEQ ID NO:115); VRG(cid:173)
`PRQHNPR (SEQ ID NO: 116); VRGPRRQHNPR (SEQ ID
`NO:117); and RQHNPR (SEQ ID NO:118), compounds or
`peptides that are inhibitors of neprilysin, frakefamide (H-Tyr(cid:173)
`D-Ala-Phe(F)-Phe-NH2; WO 01/019849 Al), loperamide,
`Tyr-Arg (kyotorphin), CCK receptor agonists (caerulein),
`conotoxin peptides, peptide analogs of thymulin, loxiglu(cid:173)
`mide, dexloxiglumide (the R-isomer of loxiglumide) (WO
`88/05774) and other analgesic peptides or compounds can be
`used with or linked to the peptides of the invention.
`The invention includes methods for treating various gas(cid:173)
`trointestinal disorders by administering a peptide that acts as
`a partial or complete agonist of the GC-C receptor. The pep(cid:173)
`tide includes at least six cysteines that form three disulfide
`bonds. In certain embodiments the disulfide bonds are
`replaced by other covalent cross-links and in some cases the
`cysteines are substituted 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 mol(cid:173)
`ecule, e.g., AspPhe or some other analgesic peptide. When
`present within the p