I 1111111111111111 11111 111111111111111 11111 111111111111111 IIIIII IIII IIII IIII
`US00S 110553B2
`
`c12) United States Patent
`Currie et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 8,110,553 B2
`*Feb. 7, 2012
`
`(54) METHODS AND COMPOSITIONS FOR THE
`TREATMENT OF GASTROINTESTINAL
`DISORDERS
`
`(75)
`
`Inventors: Mark G. Currie, Sterling, MA (US);
`Shalina Mahajan-Miklos, Stanford, CA
`(US); G. Todd Milne, Brookline, MA
`(US); Thea Norman, Cambridge, 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.: 12/788,979
`
`(22) Filed:
`
`May 27, 2010
`
`(65)
`
`Prior Publication Data
`
`US 2011/0118195 Al
`
`May 19, 2011
`
`Related U.S. Application Data
`
`(60) Division of application No. 11/949,340, filed on Dec.
`3, 2007, now Pat. No. 7,745,409, which is a division of
`applicationNo.10/796,719, filed on Mar. 9, 2004, now
`Pat. No. 7,304,036, which is a continuation-in-part 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.
`A61K 38/10
`(2006.01)
`(52) U.S. Cl. ....................................... 514/21.5; 530/327
`(58) Field of Classification Search ........................ None
`See application file for complete search history.
`
`Primary Examiner - Christopher R. Tate
`Assistant Examiner - Roy Teller
`(7 4) Attorney, Agent, or Firm - Honigman Miller Schwartz
`and Cohn LLP; Kelly T. Murphy; Jonathan P. O'Brien
`
`ABSTRACT
`(57)
`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 (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.
`
`11 Claims, 19 Drawing Sheets
`
`Bausch Health Ireland Exhibit 2018, Page 1 of 74
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`FIG. 1A
`
`1
`
`1
`
`41.61
`
`39.99
`
`Area
`1.7Be3
`2093+1047
`1·. TOF ES+
`
`143
`28.50
`
`%
`
`100
`
`SEQ ID NO: 5
`
`o .b=-;;-;;;;;;;;;;~=--i"'--..,..;;;;;;;:;~-=~~....,...--!!;;;;;=.=:;:::::::::::r~~""""r---,(cid:173)
`
`Mo_GccAo3Ju11_R11a Sm (SG, 2x3)
`
`39.17
`
`2
`
`Area
`1.98e3
`2305+1153
`1: TOf MS ES+
`
`%
`
`SEQ ID NO: 4
`
`347
`33.67 373
`35.17
`
`MD_GCCA03Jul1_R119 Sm (SG, 2x3)
`
`100
`
`LCMS ANALYSIS OF RECOMBINANT PEPTIDE VARIANTS
`
`Bausch Health Ireland Exhibit 2018, Page 2 of 74
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`FIG. 1 B
`
`60.00
`
`55.00
`
`50.00
`
`45.00
`
`o L...e:.\..,..,..,.~~-,.,......,.....,..,..,..,.....,_,....,..,...,.,...,.,.,,..,....,,..,..,~~~~~:;:::~~...,..,.,.....,..,...,......,..,.,.~~"'T'""~..,.....,.,.....,..,..,.,nME
`
`40.00
`
`35.00
`
`30.00
`
`25.00
`
`20.00
`
`15.00
`
`1000
`
`5.00
`
`....
`Q .....
`N
`.....
`ti>
`~ =- ti>
`
`l,C;
`
`Q ,...
`N
`... -J
`?'
`ti>
`~
`
`N
`
`l"'I'-
`~
`~
`•
`r:.,/1
`~ •
`
`tC> =
`
`l"'I'-
`
`45.45 47.37
`
`30.79
`
`31.44
`
`31.10
`31.13 31.34
`
`(TOTAL ION CHROMATOGRAPH (TIC))
`
`LCMS ANALYSIS OF SYNTHETIC SEQ ID NO: 3
`
`31.21
`
`%
`
`100
`
`Bausch Health Ireland Exhibit 2018, Page 3 of 74
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`Feb.7,2012
`
`Sheet 3 of 19
`
`US 8,110,553 B2
`
`LL
`0
`:r: a.,,-.
`~~
`(.')~
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`
`Bausch Health Ireland Exhibit 2018, Page 4 of 74
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`\0
`
`....
`Q ....
`.... ...
`00 =- ('t
`
`('t
`
`N = ....
`
`N
`
`~.....:i
`?'
`('t
`"'!'.'1
`
`~ MO-1100(b)
`□ MD-1100(a)
`~ MO-915
`■ MM--416776
`
`FIG. 2
`
`Peptide Concentration (nm)
`
`37
`
`12
`
`4
`
`1.3
`
`0.00 ·
`
`10.00
`
`20.00
`
`30.00
`
`40.00
`
`50.00·
`
`60.oo·..------------------------------.
`
`RECEPTOR ACTIVITY ASSAY
`
`CHEMICAL Y SYNTHESIZED PEPTIDES IN THE INTENSTINAL GC-C
`
`(J
`C)
`~
`
`C. -Q.
`E
`.._ -0
`
`
`
`--E
`
`Bausch Health Ireland Exhibit 2018, Page 5 of 74
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`Feb.7,2012
`
`Sheet 5 of 19
`
`US 8,110,553 B2
`
`w
`Cf)
`:::),_
`01-
`~(9 w-
`1- ...J
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`z (/) -z
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`
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`
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`
`r
`0 0 0 0 0 0 0 0 0 0 0
`O 0) ro
`ID LO ~ M N
`'\"""'
`t---
`
`l
`
`Bausch Health Ireland Exhibit 2018, Page 6 of 74
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`~ --
`
`c
`
`r:J').
`
`N
`t:,::,
`th w
`= tr.
`
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`
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`=-
`
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`
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`=
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`rJJ. •
`~ •
`
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`
`FIG. 3B
`
`CONCENTRATION (mg/kg)
`
`3.0
`
`0.75
`
`0.25
`
`0.13
`
`0.03
`
`0
`
`* P<0.05
`
`f2J MD-1100
`■Zelnorm®
`
`*
`-~·
`
`t
`
`GASTROINTESTINAL TRANSIT MODEL
`MD-1100 vs ZELNORM® IN ACUTE MOUSE
`
`80 -
`
`0 -
`0
`I-10
`CJ)
`<(
`z 20
`0
`w
`30
`I-
`
`~ 40
`w
`50 -
`w
`0 60 -
`--
`~ 70
`I-
`0
`~
`-90
`
`_J
`
`0
`
`_J
`
`Bausch Health Ireland Exhibit 2018, Page 7 of 74
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`Feb.7,2012
`
`Sheet 7 of 19
`
`US 8,110,553 B2
`
`....I w
`Cl
`0
`:E
`!:::
`(!)
`
`z -<D r--
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`en
`8
`
`Bausch Health Ireland Exhibit 2018, Page 8 of 74
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`Feb.7,2012
`
`Sheet 8 of 19
`
`US 8,110,553 B2
`
`....J
`UJ
`Cl
`0
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`
`(j -LL
`
`Bausch Health Ireland Exhibit 2018, Page 9 of 74
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`Feb.7,2012
`
`Sheet 9 of 19
`
`US 8,110,553 B2
`
`·-
`
`(1' C:
`.., 0
`:::J
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`
`Bausch Health Ireland Exhibit 2018, Page 10 of 74
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`(0.2mg/kg)
`4·5 Zelnorm®
`
`FIG. 5A
`
`MM-416776 (mg/kg x10-3)
`
`4
`
`3.5
`
`3
`
`2.5
`
`2
`
`1.5
`
`1
`
`0.5
`
`0
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`
`r
`
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`
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`
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`
`I
`
`~
`
`0
`0.02
`Cl 0.04
`J
`00 0.06
`~
`...
`-,f'.L
`t) ro 0.08
`~~~~ ........................................... •••• •••••••••••
`~ 0.1
`00
`:;::; rl. 0.12
`0 0.14
`0.16
`
`;~·
`
`i
`-r
`
`-:
`
`'
`
`- "
`
`MM-416776 vs ZELNORM® IN A MOUSE INTESTINAL SECRETION MODEL
`
`0.18
`
`Bausch Health Ireland Exhibit 2018, Page 11 of 74
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`UI w = N
`""'"' = tit
`
`""'"'
`"'Of:)
`
`d r.,;_
`
`0 -. .... -c
`....
`....
`.....
`rJJ =(cid:173)
`
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`('D
`
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`?'
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`"f'j
`
`0 ....
`
`N
`
`1250
`
`240
`
`FIG. 5B
`
`Dose(ug/kg)
`
`45
`
`15
`
`2
`
`Vehicle
`
`l?.I MD-1100
`
`1§'.jZelnorm®
`
`~ = ~
`
`~
`~
`~
`•
`00
`~
`
`MD-1100 VS ZELNORM® IN MOUSE INTESTINAL
`
`SECRETION MODEL
`
`0.00
`
`0.02
`
`0.04
`
`C/'J
`~ 0.06
`'-
`Q)
`~
`.2 0.08
`C:
`
`0.10
`
`0.12
`
`0.14
`
`Bausch Health Ireland Exhibit 2018, Page 12 of 74
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`UI w = N
`"""" = tit
`""""
`
`"'Of:)
`
`d r.,;_
`
`FIG. 6A
`
`Dose (mg/kg x10-3)
`
`20
`
`15
`
`10
`
`5
`
`■ MM-416776
`
`• MD-915
`
`■■■■■W■■■■■■■■■■■■■■■■■■■■■■■■■■■■-■■■■■-■■■■■■■■■■
`
`0
`
`0
`
`0.02
`
`0.04
`
`0.06 ·
`o.oe ..
`0.1
`
`0.12
`
`0.14
`
`0.16
`
`0.18
`
`0 -(!)
`
`0:::
`co
`0 ·- ....,
`
`RECOMBINANTLY GENERATED MD-915 AND MM-416776 IN MOUSE
`
`INTESTINAL SECRETION MODEL
`
`Bausch Health Ireland Exhibit 2018, Page 13 of 74
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`60
`0 -t---~r------r-----.----.----.---------1
`0.021-!-----------------~
`CJ 0.04-1-------------------,
`.._
`o 0.06
`·-..., fi 0.08
`0.1---1'",<I"
`0.12:t;1~~~~~~~~~~~~~~~~-~
`0.14---.----------------------,
`
`FIG. 68
`
`Dose (ug/kg)
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`0
`
`-O-MM-416776
`
`■ MD-1100
`• MD-915
`
`• 50ug/kg Sigma ST ( + control)
`
`-o-vehicle (-control)
`
`CHEMICALLY SYNTHESIZED PEPTIDES IN MOUSE
`
`INTESTINAL SECRETION MODEL
`
`Bausch Health Ireland Exhibit 2018, Page 14 of 74
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`Feb.7,2012
`
`Sheet 14 of 19
`
`US 8,110,553 B2
`
`0)
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`
`Bausch Health Ireland Exhibit 2018, Page 15 of 74
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`Feb. 7,2012
`
`Sheet 15 of 19
`
`US 8,110,553 B2
`
`0,
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`
`Bausch Health Ireland Exhibit 2018, Page 16 of 74
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`FIG. 8B
`
`lndomethacin
`
`MD-1100
`
`mg/kg
`
`mg/kg
`
`mg/kg
`
`3
`
`1
`
`0.3
`
`µg/kg
`
`10
`
`µg/kg
`2.5
`
`µg/kg
`
`1
`
`Vehicle
`
`OF MD-1100 IN A MOUSE WRITHING ASSAY
`
`VISCERAL ANTINOCICEPTIVE EFFECTS
`
`0
`
`5
`
`10
`
`15
`
`20 -
`
`25 -
`
`30 -
`
`35
`
`:::s z
`E
`.c
`Cl)
`~
`
`,._, ·-~
`C: ·-..c
`
`0
`'I-
`~
`
`C)
`CJ)
`
`Bausch Health Ireland Exhibit 2018, Page 17 of 74
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`Feb.7,2012
`
`Sheet 17 of 19
`
`US 8,110,553 B2
`
`(9 z -Cl z -co
`
`0 z
`c::( 0
`C9o
`-..-_I..(cid:173)o,
`-Cl O:z
`~LL
`wO
`>
`I-
`i==
`LU
`0..
`'.2
`0
`(..)
`
`•
`
`(0
`I
`
`C)
`0
`_J
`.,_
`M O')
`• ■ 0
`.
`z
`(!)
`C LL
`
`-0 w en
`
`O')
`I
`
`0
`'oir-
`1
`
`•
`
`Lt)
`N
`
`0
`0
`
`Lt) r--
`
`0
`It)
`
`Lt')
`N
`
`0
`
`Bausch Health Ireland Exhibit 2018, Page 18 of 74
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`FIG. 10A
`
`• Dosing at 10 mg/kg
`• Limit of detection 0.00063 µg/ml (0.6 nM)
`
`Time (min)
`
`0 ~~~~~~~~~~~~
`
`240
`
`200
`
`160
`
`120
`
`80
`
`40
`
`0
`
`0 -. .... -c
`QO
`....
`.....
`=-
`
`rJJ
`
`('D
`('D
`
`N
`0
`N
`~-....J
`?'
`('D
`"f'j
`
`....
`
`~ =
`
`~
`
`~
`~
`~
`•
`00
`~
`
`based on LCMS
`
`< 0.11 % Bioavailable
`
`• Oral*
`• IV*
`
`MD-1100 (BASED ON LCMS)
`
`MINIMUM SYSTEMIC ABSORPTION OF
`
`5
`
`10
`
`(.)
`0
`s:::
`0
`(1)
`s:::
`'- ,._
`ca
`·-
`,._
`0
`-15
`s:::
`:i.
`Cl
`-20
`
`
`
`-
`-E
`
`25
`
`Bausch Health Ireland Exhibit 2018, Page 19 of 74
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`\0
`
`"""
`,...
`
`0
`\0
`
`,...
`ti> ....
`\,('.I =- ti>
`
`N
`._.-.l
`?'
`ti>
`~
`
`Q ,...
`
`N
`
`!"'I'-
`~
`~
`•
`r:.,/1
`~ •
`
`tC> = !"'I'-
`
`I
`le
`
`based on ELISA
`
`< 2.2% Bioavailable
`
`• Oral*
`• IV*
`
`MINIMUM SYSTEMIC ABSORPTION OF MD-1100
`
`(BASED ON ELISA)
`
`FIG. 10B
`
`Time (min)
`
`Dosing at 10 mg/kg
`
`* Limit of detection 0.061 µg/ml
`
`150
`
`100
`
`50
`
`0
`
`5
`
`(J
`0
`C
`(.)
`Q) 10
`C
`+'
`
`0 ·-1u I.
`::t -C 15
`-20
`
`
`
`25
`
`S)
`
`-E
`-C
`
`Bausch Health Ireland Exhibit 2018, Page 20 of 74
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`US 8,110,553 B2
`
`1
`METHODS AND COMPOSITIONS FOR THE
`TREATMENT OF GASTROINTESTINAL
`DISORDERS
`
`CLAIM OF PRIORITY
`
`This application is a divisional ofU.S. Utility patent appli(cid:173)
`cation Ser. No. 11/949,340, filed Dec. 3, 2007, which claims
`priority to U.S. Utility patent application Ser. No. 10/796,
`719, filed Mar. 9, 2004, which claims priority to U.S. Utility
`patent application Ser. No. 10/766,735, filed Jan. 28, 2004,
`which claims priority under 35 USC §119(e) to U.S. Provi(cid:173)
`sional Patent Application Ser. No. 60/443,098, filed on Jan.
`28, 2003; U.S. Provisional Patent Application Ser. 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 all of these priority applications
`are hereby incorporated by reference.
`
`TECHNICAL FIELD
`
`2
`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
`5 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
`10 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
`2001, Gastroenterology 120:652-668). Recently, there has
`15 been increasing evidence for a role of inflanimation in etiol(cid:173)
`ogy ofIBS. Reports indicate that subsets ofIBS patients have
`small but significant increases in colonic inflanimatory and
`mast cells, increased inducible nitric oxide (NO) and synthase
`(iNOS) and altered expression of inflammatory cytokines
`20 (reviewed by Talley 2000, Medscape Coverage of DDW
`week).
`
`SUMMARY
`
`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-
`30 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
`35 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
`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
`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-
`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-
`ing a peptide of the invention and a second therapeutic agent,
`e.g., an agent for treating constipation ( e.g., a chloride chan(cid:173)
`nel activator such as SPI-0211; Sucampo Pharmaceuticals,
`60 Inc.; Bethesda, Md., a laxative such as MiraLax; Braintree
`Laboratories, Braintree Mass.) or some other gastrointestinal
`disorder. Examples of a second therapeutic agent include:
`acid reducing agents such as proton pump inhibitors ( e.g.
`omeprazole, esomeprazole, lansoprazole, pantorazole and
`65 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),
`
`This invention relates to methods and compositions for
`treating various disorders, including gastrointestinal disor(cid:173)
`ders, obesity, congestive heart failure and benign prostatic 25
`hyperplasia.
`
`SEQUENCE LISTING
`
`This application incorporates by reference in its entirety
`the Sequence Listing entitled 14184-43001.txt, containing
`124 kilobytes of data, created Jan. 9, 2007, and filed with the
`parent application U.S. application Ser. No. 10/796,719 on
`Jan. 12, 2007 and incorporated in U.S. application Ser. No.
`11/949,340 in computer readable-format (CRF) and paper
`copy format.
`
`BACKGROUND
`
`Irritable bowel syndrome (IBS) is a common chronic dis- 40
`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 45
`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
`ofhealth care use and indirect costs of absenteeism from work
`(Talley 1995, Gastroenterology 109:1736-1741). Patients 50
`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 55
`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-
`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).
`
`Bausch Health Ireland Exhibit 2018, Page 21 of 74
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`US 8,110,553 B2
`
`3
`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-inflammatory agents, antispasmodics, antide(cid:173)
`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
`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
`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
`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 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
`
`4
`small molecule. The peptides and methods of 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
`5 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
`peptides, a functional chymotrypsin site is altered, increasing
`10 the stability of the peptide in vivo.
`The invention includes methods for treating other disorders
`such as congestive heart failure and benign prostatic hyper(cid:173)
`plasia by administering a peptide or small molecule
`(parenterally or orally) that acts as an agonist of the GC-C
`15 receptor. Such agents can be used in combination with natri(cid:173)
`uretic peptides (e.g., atrial natriuretic peptide, brain natri(cid:173)
`uretic peptide or C-type natriuretic peptide), a diuretic, or an
`inhibitor of angiotensin converting enzyme.
`The invention features methods and compositions for
`20 increasing intestinal motility. Intestinal motility involves
`spontaneous coordinated dissentions and contractions of the
`stomach, intestines, colon and rectum to move food through
`the gastrointestinal tract during the digestive process.
`In certain embodiments the peptides include either one or
`25 two or more contiguous negatively charged amino acids (e.g.,
`Asp or Glu) or one or two or more contiguous positively
`charged 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 flank-
`30 ing amino acids at the carboxy terminus 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
`35 Lys Lys Lys Lys (SEQ ID NO:123);Asp Lys Lys Lys Lys Lys
`Lys (SEQ ID NO: 124 ); 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 peptide compris(cid:173)
`ing, consisting of, or consisting essentially of the amino acid
`40 sequence (I): Xaa1 Xaa2 Xaa3 Xaa4Xaa5Cys6 Cys7 Xaa 8 Xaa9
`Cys 10 Cys 11 Xaa12 Xaa13 Xaa14 Cys15 Xaa16 Xaa17 Cys 18
`Xaa19 Xaa20 Xaa21 (SEQ ID NO:119) wherein: Xaa1 Xaa2
`Xaa3 Xaa4 Xaa5 is Asn Ser Ser Asn Tyr (SEQ ID NO: 121) or
`is missing or Xaa1 Xaa2 Xaa3 Xaa4 is missing. In certain
`45 embodiments Xaa8 , Xaa9, Xaa12, Xaa13 , Xaa14, Xaa1 7, and
`Xaa19 can be any amino acid. In certain embodiments Xaa5 is
`Asn, Trp, Tyr, Asp, or Phe. In other embodiments, Xaa5 can
`also be Thr or Ile. In other embodiments Xaa5 is Tyr, Asp or
`Trp. In some embodiments Xaa8 is Glu, Asp, Gin, Gly or Pro.
`50 In other embodiments Xaa 8 is Glu; in some embodiments
`Xaa9 is Leu, Ile, Val, Ala, Lys, Arg, Trp, Tyr or Phe in some
`embodiments Xaa9 is Leu, Ile, Val, Lys, Arg, Trp, Tyr or Phe.
`In certain embodiments, the peptide includes disulfide
`bonds between Cys6 and Cys1 i, between Cys7 and Cys15 and
`55 between Cys 10 and Cys16. In other embodiments, the peptide
`is a reduced peptide having no disulfide bonds. In still other
`embodiments the peptide has one or two disulfide bonds
`selected from the group consisting of: a disulfide bond
`between Cys6 and Cys 11 , a disulfide bond between Cys7 and
`60 Cys15 and a disulfide bond between Cys 10 and Cys16.
`In certain embodiments, an amino acid can be replaced by
`a non-naturally occurring amino acid or a naturally or non(cid:173)
`naturally occurring amino acid analog. For example, an aro(cid:173)
`matic amino acid can be replaced by 3,4-dihydroxy-L-phe-
`65 nylalanine, 3-iodo-L-tyrosine, triiodothyronine, L-thyroxine,
`phenylglycine (Phg) or nor-tyrosine (norTyr). Phg andnorTyr
`and other amino acids including Phe and Tyr can be substi-
`
`Bausch Health Ireland Exhibit 2018, Page 22 of 74
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`US 8,110,553 B2
`
`5
`tuted by, e.g., a halogen, -CH3, -OH, ----CH2NH3 , ----C(O)
`H, ----CH2 CH3 , -CN, -CH2CH2 CH3 , -SH, or another
`group. Further examples of unnatural amino acids include: an
`unnatural analogue of tyrosine; an unnatural analogue of
`glutamine; an unnatural analogue of phenylalanine; an
`unnatural analogue of serine; an unnatural analogue of threo(cid:173)
`nine; an alkyl, aryl, acyl, azido, cyano, halo, hydrazine,
`hydrazide, hydroxyl, alkenyl, alkynl, ether, thiol, sulfonyl,
`seleno,
`ester,
`thioacid, borate, boronate, phospho,
`phosphono, phosphine, heterocyclic, enone, imine, aldehyde,
`hydroxylamine, keto, or amino substituted amino acid, or any
`combination thereof; an amino acid with a photoactivatable
`cross-linker; a spin-labeled amino acid; a fluorescent amino
`acid; an amino acid with a novel functional group; an amino
`acid that covalently or noncovalently interacts with another
`molecule; a metal binding amino acid; a metal-containing
`amino acid; a radioactive amino acid; a photocaged and/or
`photoisomerizable amino acid; a biotin or biotin-analogue
`containing amino acid; a glycosylated or carbohydrate modi(cid:173)
`fied amino acid; a keto containing amino acid; amino acids
`comprising polyethylene glycol or polyether; a heavy atom
`substituted amino acid ( e.g., an amino acid containing deute(cid:173)
`rium, tritium, 13C, 15N, or 180); a chemically cleavable or
`photocleavable amino acid; an amino acid with an elongated
`side chain; an amino acid containing a toxic group; a sugar
`substituted amino acid, e.g., a sugar substituted serine or the
`like; a carbon-linked sugar-containing amino acid; a redox(cid:173)
`active amino acid; an a.-hydroxy containing acid; an amino
`thio acid containing amino acid; an a,a disubstituted amino
`acid; a ~-amino acid; a cyclic amino acid other than pro line;
`an O-methyl-L-tyrosine; an L-3-(2-naphthyl)alanine; a
`3-methyl-phenylalanine; a p-acetyl-L-phenylalanine; an 0-4-
`allyl-L-tyrosine; a 4-propyl-L-tyrosine; a
`tri-O-acetyl(cid:173)
`GlcNAc~-serine; an L-Dopa; a fluorinated phenylalanine; an
`isopropyl-L-phenylalanine; a p-azido-L-phenylalanine; a
`p-acyl-L-phenylalanine; a p-benzoyl-L-phenylalanine; an
`L-phosphoserine; a phosphonoserine; a phosphonotyrosine;
`a p-iodo-phenylalanine; a 4-fluorophenylglycine; a p-bro(cid:173)
`mophenylalanine; a p-amino-L-phenylalanine; a isopropyl(cid:173)
`L-phenylalanine; L-3-(2-naphthyl)alanine; an amino-, iso(cid:173)
`propyl-, or O-allyl-containing phenylalanine analogue; a
`dopa, O-methyl-L-tyrosine; a glycosylated amino acid; a
`p-(propargy loxy )pheny !alanine, dimethy 1-Lysine, hydroxy(cid:173)
`proline, mercaptopropionic acid, methyl-lysine, 3-nitro-ty(cid:173)
`rosine, norleucine, pyro-glutamic acid, Z (Carbobenzoxyl),
`E-Acetyl-Lysine, ~-alanine, aminobenzoyl derivative, ami(cid:173)
`nobutyric acid (Abu), citrulline, aminohexanoic acid, ami(cid:173)
`noisobutyric acid, cyclohexylalanine, d-cyclohexylalanine,
`hydroxyproline, nitro-arginine, nitro-phenylalanine, nitro-ty(cid:173)
`rosine, norvaline, octahydroindole carboxylate, omithine,
`penicillamine, tetrahydroisoquinoline, acetamidomethyl pro(cid:173)
`tected amino acids and a pegylated amino acid. Further
`examples of unnatural amino acids can be found in U.S.
`20030108885, U.S. 20030082575, and the references cited
`therein.
`Methods to manufacture peptides containing unnatural
`amino acids can be found in, for example, U.S. 20030108885,
`U.S. 20030082575, Deiters et al., J Am Chem Soc. (2003)
`125: 11782-3, Chin et al., Science (2003) 301 :964-7, and the
`references cited therein.
`The peptides of the invention can be modified using stan(cid:173)
`dard modifications. Modifications may occur at the amino
`(N-), carboxy (C-) terminus, internally or a combination of
`any of the preceeding. In one aspect of the invention, there
`may be more than one type of modification on the peptide.
`Modifications include but are not limited to: acetylation, ami(cid:173)
`dation, biotinylation, cinnamoylation, farnesylation, fanny-
`
`6
`lation, myristoylation, palmitoylation, phosphorylation (Ser,
`Tyr or Thr), stearoylation, succinylation, sulfurylation and
`cyclisation (via disulfide bri