I 1111111111111111 11111 1111111111 1111111111 111111111111111 111111111111111111
`US008080526B2
`
`c12) United States Patent
`Currie et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 8,080,526 B2
`Dec. 20, 2011
`
`(54) METHODS AND COMPOSITIONS FOR THE
`TREATMENT OF GASTROINTESTINAL
`DISORDERS
`
`(75)
`
`Inventors: Mark 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.
`
`(21) Appl. No.: 12/754,138
`
`(22) Filed:
`
`Apr. 5, 2010
`
`(65)
`
`Prior Publication Data
`
`US 2011/0124583 Al
`
`May 26, 2011
`
`Related U.S. Application Data
`
`Division of application No. 11/930,696, filed on Oct.
`31, 2007, now Pat. No. 7,704,947, and a division of
`application No. 10/766,735, filed on Jan. 28, 2004,
`now abandoned.
`
`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.
`
`Int. Cl.
`A61K 38/10
`(2006.01)
`U.S. Cl. ....................................... 514/21.5; 530/327
`Field of Classification Search ........................ None
`See application file for complete search history.
`
`References Cited
`
`(62)
`
`(60)
`
`(51)
`
`(52)
`(58)
`
`(56)
`
`U.S. PATENT DOCUMENTS
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`5/2000 Waldman
`7,304,036 B2
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`8/2010 Currie et al.
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`2003/0073628 Al
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`6/2004 Masferrer
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`2005/0032684 Al
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`2006/0281682 Al
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`2009/0191611 Al
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`2011/0118195 Al
`5/2011 Currie et al.
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`12/2002
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`WO 03/072754
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`8/2004
`WO 2004/071436
`8/2004
`WO 2005/087797
`9/2005
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`
`(Continued)
`
`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, 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.
`
`2 Claims, 19 Drawing Sheets
`
`Bausch Health Ireland Exhibit 2017, Page 1 of 63
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`
`

`

`US 8,080,526 B2
`Page 2
`
`OTHER PUBLICATIONS
`
`Giannela, "Escherichia coli heat-stable enterotoxins, guanylins, and
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`Huang et al., "Nucleotide sequence of a gene encoding the novel
`Yersinia enterocolitica heat-stable enterotoxin that includes a pro(cid:173)
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`Jain et al., "Sildenafil-induced peripheral analgesia and activation of
`the nitric oxide-cyclic GMP pathway" Brain Research, vol. 909: pp.
`170-178 (2001).
`Kim et al., "Changes in ghrelin and ghrelin receptor expression
`according to feeding status"NeuroReport, vol. 14, No. 10: pp. 1317-
`1320 (2003).
`Lazaro-Ibanez et al., "Participation of the nitric oxide-cyclic GMP(cid:173)
`ATP-senstive K+ channel pathway in the antinociceptive action of
`ketorolac" European Journal of Pharmacology, vol. 426: pp. 39-44
`(2001).
`Moseley et al., "Isolation and Nucleotide Sequence Determination of
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`Infection and Immunity, vol. 39, No. 3: pp. 1167-1174 (1983).
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`oxide-dependent myenteric plexus secretory reflex in the rat ileum"
`The Journal of Physiology, vol. 475, No. 3: pp. 531-537 (1994).
`Rolfe et al., "Vagotomy inhibits the jejuna! fluid secretion activated
`by luminal ileal Escherichia coli STa in the rat in vivo" GUT, vol. 44:
`pp. 615-619 (1999).
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`the Isolated Perfused Rat Kidney" Pharmacology & Toxicology, vol.
`92: pp. 114-120 (2003).
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`tor agonists" Drug Discovery & Development, vol. 5, No. 2: pp.
`261-268 (2002).
`So et al., "Nucleotide Sequence of the Bacterial Transposon Tnl681
`Encoding a Heat-Stable (ST) Toxin and Its Identification in
`Enterotoxigenic Escherichia coli Strains" Proceedings of the
`
`National Academy of Sciences of the USA, vol. 77, No. 7 [Part 2:
`Biological Sciences]: pp. 4011-4015 (1980).
`Soares et al., "Dibutyryl-cyclic GMP induces peripheral antinocicep(cid:173)
`tion via activation of ATP-sensitive K+ channels in the RAT PGE2-
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`134: pp. 127-131 (2001).
`Takao et al., "Amino acid sequence of heat-stable enterotoxin pro(cid:173)
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`(1985).
`Takao et al., "Isolation, primary structure and synthesis of heat-stable
`enterotoxin produced by Yersinia enterocolitica" European Journal
`of Biochemistry, vol. 152, No. 1: pp. 199-206 (1985).
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`of heat-stable enterotoxin produced by enterotoxigenic Escherichia
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`GenBankAccession No. QHECIB; GI:69638; Aimoto et al., Jun. 18,
`1999.
`GenBankAccessionNo. P01559; GI:123711; So eta!., Oct. 25, 2004.
`GenBank Accession No. AAA24653; GI:147878; Sekizaki et al.,
`Apr. 26, 1993.
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`12, 1993.
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`GenBankAccession No. S34671; GI:421286; Rossolini et al., Apr.
`12, 1995.
`GenBankAccession No. CAA52209; GI:395161; Guglielmetti et al.,
`Jul. 27, 1995.
`GenBank Accession No. A54534; GI:628844; Arita et al., May 3,
`1996.
`GenBank Accession No. AAL02159; GI:15592919; Teixeira et al.,
`Sep. 13, 2001.
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`May 26, 1994.
`GenBank Accession No. S25659; GI:282047; Takao et al., Oct. 15,
`1999.
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`Jun. 15, 2004.
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`13, 1999.
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`2004.
`GenBank Accession No. P07965; GI:3915589; Steiglitz et al., Jun.
`15, 2004.
`
`Bausch Health Ireland Exhibit 2017, Page 2 of 63
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`0--, = N
`QO = QO = tit
`
`N
`
`d r.,;_
`
`0 -. .... -c
`....
`.....
`rJJ =(cid:173)
`
`('D
`('D
`
`....
`0 ....
`N
`~o
`N
`~
`
`c ('D
`
`~ = ~
`
`~
`~
`~
`•
`00
`~
`
`FIG~ 1A
`
`-39.99 41.61
`
`_ 1
`
`. 1
`
`J~_g5
`
`33.82 35,31 36-1•37,26
`
`• 1
`
`, 1
`
`.,
`
`3_
`
`Aroa
`1.70e3
`2093+1047
`1: TOF MS ES+
`
`27Jl2
`
`3.
`
`0-
`
`%
`
`SEQ ID NO: 8
`
`I ~""f' T • 'i ..... ., '
`
`.,,~Jr\ fl 3~ 353917
`
`ii)
`
`_)(
`
`ul1 __ R11B Sm(SG 2 3),, ·~r~·nr~~-~ ,(. 2
`
`30.9532 6() I
`
`100 ~
`MD_g~z;i;~-r~{·-"
`
`•
`
`Area
`1.98e3
`2305+1153
`1: TOF MS ES+
`
`!
`347
`33,67373 l
`J5 U
`
`MD GCCA03,Jul1 f~119 Sm (SG. 2x3)
`
`·~
`
`-
`
`0"'h
`·; --
`
`1
`
`LCMS ANAL YS\S OF RECOMBlNANT PEPTIDE VARIANTS
`
`%-
`
`SEQ ID NO: 26
`
`Bausch Health Ireland Exhibit 2017, Page 3 of 63
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`00 = 00
`
`rJ)_
`~
`
`N
`'th
`~
`
`C°'I cc N
`
`.• ),,.. ifU tfhhfW\IHf Time
`
`i
`
`FIG. 1 B
`
`5.00 10.00 15.00 20.00 25,00 30.00 35.00 40.00 45.00 50.00 55.00 60.00
`
`f •• ,. n< .~!~,:::::;::::::: •
`
`....... ~.,,,,.,,
`
`o~ .. , ... _,,,,.,,
`
`....
`0 ,-.,
`N
`.....
`rJJ =(cid:173)
`
`!'t)
`!'t)
`
`1,0
`
`....
`0 ....
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`F-
`N
`~
`!'t)
`~
`
`!"'I'(cid:173)
`~
`~
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`00
`~
`
`~ a
`
`l
`30.79~
`
`31.44
`
`.34
`
`31.10
`31.13
`
`(TOTAL ION CHROMATOGRAPH (TtC)
`
`3121
`
`LCMS ANALYSIS OF SYNTHETIC SEQ ID NO: 31
`
`%
`
`100
`
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`
`

`

`00 = 00
`
`rJ).
`~
`
`N
`'th
`~
`
`C°'I cc N
`
`FIG.1 C
`
`• ~ I l[lil! 4qn .,.,.,, 1lme
`
`0 t,hP,Vlijh0'1¥•ff-•t••· ....... t.; nq • pdifhii\Hlli44 e,-cL; .. '' :~· •i .• if"*
`
`5.00 10.00 15.00 20.00 25.00 30.00 35.00 40.00 45.00 50,00 55.00 60,00
`
`....
`0 ,-.,
`(.;:.I
`
`1,0
`
`.....
`rJJ =- !'t)
`
`!'t)
`
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`0 ....
`N
`F-
`N
`~
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`
`!"'I'(cid:173)
`~
`~
`•
`00
`~
`
`~ a
`
`I
`
`ANALYSIS)
`
`BU-\NK USED IN SEQ ID NO·
`
`LCMS ANALYSIS (TOTAL ION CHROMATOGRAPH OF
`
`% l
`
`100
`
`Bausch Health Ireland Exhibit 2017, Page 5 of 63
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`
`

`

`U.S. Patent
`
`Dec. 20, 2011
`
`Sheet 4 of 19
`
`US 8,080,526 B2
`
`ro
`<D
`N N
`b b b
`z z z
`9 Q
`Cl
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`
`Bausch Health Ireland Exhibit 2017, Page 6 of 63
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`Dec. 20, 2011
`
`Sheet 5 of 19
`
`US 8,080,526 B2
`
`l
`
`'
`
`I
`
`:
`
`l
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`.,-
`
`Bausch Health Ireland Exhibit 2017, Page 7 of 63
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`0--, = N
`QO = QO = tit
`
`N
`
`d r.,;_
`
`0 -. .... -c
`
`0'I
`.....
`rJJ =(cid:173)
`
`('D
`('D
`
`* P<O.05
`
`■ SEQ ID NO: 31
`
`IZI Zelnorm@
`
`FIG. 3B
`
`Concentration (mg/kg)
`
`3.0
`
`0.75
`
`0.25
`
`0.125
`
`.03
`
`0
`
`10
`
`20
`
`30
`
`(U -(/) ·-
`
`0
`
`....
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`N
`~
`
`c ('D
`
`~ = ~
`
`~
`~
`~
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`00
`~
`
`*
`
`GASTROINTESTINAL TRANSIT MODEL
`
`SEQ ID NO: 3i vs ZELNORM'JY IN ACUTE MOUSE
`
`C:
`0
`{!)
`f--
`40
`~
`>
`(I) m 50
`u
`
`"#. -60
`-80
`
`70
`
`90
`
`f--
`0
`... .,
`ro
`
`Bausch Health Ireland Exhibit 2017, Page 8 of 63
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`Dec. 20, 2011
`
`Sheet 7 of 19
`
`US 8,080,526 B2
`
`co
`N
`0
`0
`z
`z
`0
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`0
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`
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`
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`b z
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`co
`N
`(IBlOl %,) P918r\8JJ.. e:iue+S!O
`
`0
`
`0
`
`-0)
`X -0) LL
`
`,.x
`0)
`
`.._ <(
`E ~
`.
`("')
`l
`(9
`.....
`0
`
`ff}
`0
`Cl
`
`Bausch Health Ireland Exhibit 2017, Page 9 of 63
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`Dec. 20, 2011
`
`Sheet 8 of 19
`
`US 8,080,526 B2
`
`l
`I _L-,. _
`0
`0
`I'---
`o:J
`
`0
`0
`'<'"""
`
`0
`0)
`
`0
`<.O
`
`0
`0
`L() V"
`
`0
`(I')
`
`0
`0
`0-J ~
`
`0
`
`co
`~ .
`(9
`LL
`
`Bausch Health Ireland Exhibit 2017, Page 10 of 63
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`0--, = N
`QO = QO = tit
`
`N
`
`rJl.
`d
`
`0 -. .... -c
`
`-c
`.....
`rJJ =(cid:173)
`
`('D
`('D
`
`....
`0 ....
`N
`~o
`N
`~
`
`c ('D
`
`~ = ~
`
`~
`~
`~
`•
`00
`~
`
`Zelnorm®
`1mg/kg
`
`--i
`
`. ,/r;:_
`:?;?;
`
`/
`
`FIG. 4C
`
`SEQ ID NO: 31
`
`0.25mg/kg
`
`0.06mg/kg
`
`Vehicle
`
`;;?~ 7,-;; ·i t » //
`"%
`>/½,~..-,
`;,.-, ~;
`,,-;;
`·''.%✓~'
`,;~
`
`***
`
`*-.:
`
`**'fl.
`
`.....
`
`*Hp< 0.0005
`** P < 0.005
`* P < 0.01
`
`0"1---
`10
`20
`30
`40
`50 -
`60
`70
`80
`
`90 -
`100,------------------------1
`Chronic
`
`Chronic vs. Acute Dosing in GIT Assay
`
`1M
`■ Acute
`
`Bausch Health Ireland Exhibit 2017, Page 11 of 63
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`00 = 00
`
`rJl
`~
`
`N
`'th
`~
`
`C°'I cc N
`
`\0
`
`....
`0 ....
`0
`....
`.....
`rJJ =(cid:173)
`
`!'t)
`!'t)
`
`....
`0 ....
`N
`F-
`N
`~
`!'t)
`~
`
`!"'I'(cid:173)
`~
`~
`•
`00
`~
`
`~ a
`
`(0.2mg/kg)
`Zelnorm®
`
`4.5
`
`FIG. 5A
`
`SEQ ID NO: 26 (mg/kg x10· 3)
`
`4
`
`3.5
`
`3
`
`2.5
`
`2
`
`1.5
`
`1
`
`0.5
`
`0
`
`0-------------.---.....---..------------..--
`
`0.021-----
`
`---•-·-·----·---------,---·-----··-·-·--------
`
`----··---·-········
`
`0.04·---
`
`•••••••••••••••••••••••••••••••••••••••••••••••••
`
`-----·•--····--··-···· """""
`
`0,18 ---------~-------------,
`
`lN A MOUSE INTEST\NAL SECRETION MODEL
`
`SE(l 1D NO·. 26 vs
`
`0.16
`
`(')
`:5 0.06
`rn
`J 0.08
`'-
`(.)
`~ 0.1
`~ 0.12
`.Q 0.14
`
`rJ)
`
`Bausch Health Ireland Exhibit 2017, Page 12 of 63
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`Dec. 20, 2011
`
`Sheet 11 of 19
`
`US 8,080,526 B2
`
`......
`(I)
`
`0 z
`0
`0
`w
`U)
`0
`
`0
`ID
`N ..-
`
`0
`"-t"
`N
`
`Uj
`..;;!'
`
`.....
`ll'>
`
`,....... co
`-g,
`Ol
`~ L()
`- (9
`.
`
`0 LL
`a
`
`(D
`(J)
`
`l.l
`-0
`0
`2
`_§
`1i5
`0
`,;?]
`U)
`
`m
`C
`~,,.;::;
`w
`
`~ -©
`
`(/J
`::::;
`0
`2
`.. ~
`
`/J)
`>
`
`'
`
`a
`U.l
`OJ
`
`0
`
`Bausch Health Ireland Exhibit 2017, Page 13 of 63
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`00 = 00
`
`rJ).
`~
`
`N
`'th
`~
`
`C'I cc N
`
`\0
`
`....
`0 ....
`N
`....
`.....
`rJJ =(cid:173)
`
`!'t)
`!'t)
`
`....
`0 ....
`N
`F-
`N
`~
`!'t)
`~
`
`!"'I'(cid:173)
`~
`~
`•
`00
`~
`
`~ a
`
`FIG. 6A
`Dose (mg/kg x10-3)
`
`20
`
`15
`
`1 (J
`
`5
`
`0
`
`SEQ ID NO: 26
`
`SEQ ID NO: 28
`
`---.,....,u~------------------i "' •■ ···•
`+--
`
`-
`
`RECOMBINANTL Y GENERATED SEQ ID NO: 28 AND SEQ IN NO: 26 IN MOUSE
`
`INlESTINAL SECRETION MODEL
`
`0
`
`0,02
`
`0.04
`
`0.06
`""
`0.08
`
`0.1
`
`0.12
`
`0.14
`
`0.16
`
`0.18
`
`--0
`0
`«I a::
`
`:.:;
`0
`
`Bausch Health Ireland Exhibit 2017, Page 14 of 63
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`N
`t:c
`0-,.
`N
`t.h
`-..
`0
`QO
`"' 0
`QO
`00
`0
`
`\0
`~ .....
`0
`..... w
`~ ....
`[,/)_ =(cid:173)~
`
`.....
`Q .....
`N
`:?
`N
`!">
`~
`c
`
`!"'f(cid:173)
`~
`~
`•
`iJj
`~
`
`~ a
`
`FIG. 6B
`Dose ( ug /kg)
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`o+--·"•""-•~--------.-------
`
`'•-=·
`
`-------------
`
`-------....... --,---~---------.--½ .. ,,. _____ ,., .. ,..,~------
`
`-0-SEQ ID NO.
`
`._ 50ug/kg Sigma ST ( + control)
`
`0.02 -,-------~-------
`
`0.04 -!--··"----
`
`"" A:
`----□----vehicle ( -control)
`
`ID NO: 31
`ID NO: 28
`
`0.06 ....
`
`0.08
`
`0.1 -•--
`
`(3
`(.)
`O'.'.
`ro
`:;::;
`0
`
`0.14 .-----
`
`-
`
`CHEM\CALL Y SYNTHESIZED PEPTIDES IN MOUSE \NTEST\NAL SECRETION MODEL
`
`Bausch Health Ireland Exhibit 2017, Page 15 of 63
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`Dec. 20, 2011
`
`Sheet 14 of 19
`
`US 8,080,526 B2
`
`.. LU
`
`-
`
`1- <(
`I- {/)
`~ ~
`zz _Q
`(J) nZ
`0 1-z (/)
`oO
`__J a-< w !(cid:173)
`if) 0
`LL W
`0 cc
`I- g
`() 0 H: u
`LL
`w
`
`(f)
`
`co z >-
`
`*
`
`+
`(lJ CJ)
`u CD
`r=z
`Q) !-(cid:173)>
`
`(l)
`Q
`E
`Cl) >
`
`0 .--
`0
`N
`(UJW 9) suog::lSJ+LJOO JBUjL:.JOpqe JO JaqwnN
`
`L{)
`
`0
`
`('")
`
`...-
`0 z
`0
`a w
`
`(/)
`+
`(/)
`en z
`I-
`
`,-..... .
`(9
`LL
`
`(D
`:::!
`(U
`>
`-OJ
`
`(..) :c
`(1)
`_>
`.8
`Q) ... (0
`"'O
`Q.
`E
`0
`(.)
`en
`OJ
`I..()
`0
`0
`V
`0.
`*
`
`Bausch Health Ireland Exhibit 2017, Page 16 of 63
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`0--, = N
`QO = QO = tit
`
`N
`
`d r.,;_
`
`0 -. .... -c
`....
`.....
`rJJ =(cid:173)
`
`('D
`('D
`
`(JI
`
`....
`0 ....
`N
`~o
`N
`~
`
`c ('D
`
`~ = ~
`
`~
`~
`~
`•
`00
`~
`
`FIG. BA
`
`lndometl1acin
`
`SEQ ID NO: 28
`
`mg/kg
`
`3
`
`mg/kg
`
`1
`
`mg/kg
`0.3
`
`µg/kg
`
`1
`
`Vehlcle
`
`*
`
`* L
`
`* _i ____ ~--
`
`o-·-
`
`5
`
`10
`
`15
`
`writhings 20
`Nurnber of
`
`25
`
`30
`
`SEQ ID NO: 28 IN A MOUSE WRITHING ASSAY
`VISCERAL ANTINOCICEPTIVE EFFECTS OF
`
`35 , ........ ____ ... ____ .,
`
`T
`
`Bausch Health Ireland Exhibit 2017, Page 17 of 63
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`00 = 00
`
`rJ).
`~
`
`N
`'th
`~
`
`C°'I cc N
`
`\0
`
`....
`0 ....
`="
`....
`.....
`rJJ =(cid:173)
`
`!'t)
`!'t)
`
`....
`0 ....
`N
`F-
`N
`~
`!'t)
`~
`
`!"'I'(cid:173)
`~
`~
`•
`00
`~
`
`~ a
`
`FIG. 8B
`
`lndomethacin
`
`SEQ ID NO: 31
`
`rngfkg
`
`3
`
`mg/kg
`
`1
`
`mg/kg
`
`0.3
`
`µg/kg
`
`10
`
`µg/kg
`2.5
`
`µg/kg
`
`1
`
`Vehicle
`
`*
`
`Q-i----
`
`5
`
`10 -
`
`writhings 15
`Number of
`
`20 -
`
`25
`
`30
`
`35 i-------------------~--------------
`
`SEQ ID NO: 31 IN A MOUSE WRITHING ASSAY
`VISCERAL ANTINOCICEPTIVE EFFECTS OF
`
`Bausch Health Ireland Exhibit 2017, Page 18 of 63
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`Dec. 20, 2011
`
`Sheet 17 of 19
`
`US 8,080,526 B2
`
`-------------------1.0
`
`-~ -0)
`
`0
`_J 0)
`-..,.....
`.
`<'1
`(9
`0
`z LL
`a w
`
`0
`
`Cl)
`
`(.:) z
`0 z -OJ
`
`0.,,....
`ZM
`4:: ..
`00
`..JZ
`Oo o-
`<r:: a
`0:: UJ
`w (./) >cs
`
`I-
`~
`UJ
`0..
`::'.?
`0
`(.)
`
`~
`C:
`1.()
`'tj"
`ll
`"O
`~
`
`•
`
`co
`
`r-
`
`co
`
`I
`
`0)
`!
`
`0 ..-
`
`...-
`
`~
`
`1----+----r----+---+----+-~
`0
`LO
`0
`0
`N
`lO
`0 .,.....
`
`l
`
`Bausch Health Ireland Exhibit 2017, Page 19 of 63
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`....
`0 ,...,
`~ .... QO
`r:.J"1 =(cid:173)
`
`('t)
`
`l,Q
`
`....
`0 ....
`N
`!?
`N
`~
`('t)
`~
`
`~
`""d
`•
`00
`~
`
`""'" n> a.
`
`----------···•-······---·
`
`··--•><• ·-·--·-·-····-··-·-•-><••-------··--·--·-·-·--. --·-··· ···----
`
`(based on ELISA)
`< 2.2% Bioavailable
`
`• \V* I
`.....
`
`__ .oral* J
`
`(BASED ON ELISA)
`
`MINIMUM SYSTEMIC ABSORPTION OF SEQ ID NO: 31
`
`0
`
`0
`
`5
`
`10
`
`15
`
`20
`
`25
`
`Concentration
`
`(~ig/rnl)
`
`QO = u.
`b
`QO
`c r.n
`
`N
`C0
`0',
`N
`
`150
`
`FIG. 10A
`Time (min)
`
`100
`
`50
`
`* Limit of detection 0.061 iig/ml
`
`Dosing at 10 mg/kg
`
`Bausch Health Ireland Exhibit 2017, Page 20 of 63
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`Dec. 20, 2011
`
`Sheet 19 of 19
`
`US 8,080,526 B2
`
`!N!MUM SYSTEr-,MC ABSORPTION OF
`SEQ ID NO: 31 (BASED ON LC/MS)
`
`I
`
`IV*
`• Oral"
`
`11
`
`•
`
`•
`
`•
`
`,........
`
`.§ 15"·--------·-------------(cid:173)
`gJ
`-'-
`1::
`< 0.11 Bioavai!able
`0
`(based on LC/MS)
`~ 1-
`2s
`C
`0
`0
`
`-C 10 ,-•--·• - - - - - - - - - - - - - - - - - - - - - i
`
`0
`
`40
`
`120
`(min)
`
`160
`
`200
`
`240
`
`* limit of detection 0.0063 ~Lg/f.~!
`* Dosing at 10 mg/kg
`
`6 nM)
`
`FIG 10B
`
`Bausch Health Ireland Exhibit 2017, Page 21 of 63
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`US 8,080,526 B2
`
`1
`METHODS AND COMPOSITIONS FOR THE
`TREATMENT OF GASTROINTESTINAL
`DISORDERS
`
`CLAIM OF PRIORITY
`
`This application claims priority to U.S. Divisional patent
`application Ser. No. 11/930,696, filed Oct. 31, 2007 now U.S.
`Pat. No. 7,704,947 and to U.S. patent application Ser. No.
`10/766,735, filed Jan. 28, 2004 now abandoned and to U.S.
`Provisional 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 which are hereby incorporated by
`reference.
`
`SEQUENCE LISTING
`
`2
`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
`5 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
`10 2001, Gastroenterology 120:652-668). Recently, there has
`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
`15 (iNOS) and altered expression of inflammatory cytokines
`(reviewed by Talley 2000, Medscape Coverage of DDW
`week).
`
`SUMMARY
`
`This application incorporates by reference in its entirety 20
`the Sequence Listing
`entitled
`"Sequence Listing
`22003040.txt", containing 33 kilobytes of data, created Aug.
`13, 2008, and filed with the parent application U.S. applica(cid:173)
`tion Ser. No. 11/930,696 on Aug. 18, 2008 in computer read(cid:173)
`able-format (CRF) and electronic .txt format.
`
`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
`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
`
`35
`
`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-
`25 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
`30 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
`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
`40 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
`45 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(cid:173)
`prising certain peptides that are capable of activating the
`50 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,
`e.g., an agent for treating constipation (e.g., SPI-0211;
`55 Sucampo Pharmaceuticals, Inc.; Bethesda, Md.) or some
`other gastrointestinal disorder. Examples of a second thera(cid:173)
`peutic agent include: acid reducing agents such as proton
`pump inhibitors and H2 receptor blockers, pro-motility
`agents such as 5HT receptor agonists (e.g. Zelnorm®), anti-
`60 inflammatory agents, antispasmodics, antidepressants, cen(cid:173)
`trally-acting analgesic agents such as opiod receptor agonists,
`opiod receptor antagonists, agents for the treatment of
`Inflammatory bowel disease, Crohn's disease and ulcerative
`colitis ( e.g., Traficet-EWM (ChemoCentryx, Inc.; San Carlos,
`65 Calif.) agents that treat gastrointestinal or visceral pain and
`cGMP phosphodiesterase inhibitors (motapizone, zaprinast,
`and suldinac sulfone ). Thus, for example, the pharmaceutical
`
`Bausch Health Ireland Exhibit 2017, Page 22 of 63
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`US 8,080,526 B2
`
`3
`compositions can include an analgesic agent selected from
`the group consisting of: Ca channel blockers ( e.g.,
`ziconotide), 5HT receptor antagonists (for example 5HT3,
`5HT4 and 5HT1 receptor antagonists), opioid receptor ago(cid:173)
`nists (e.g., loperamide, fedotozine, and fentanyl, naloxone,
`naltrexone, methyl nalozone, nalmefene, cypridime, beta
`funaltrexamine, naloxonazine, naltrindole, and nor-binaltor(cid:173)
`phimine, morphine, diphenyloxylate, enkephalin pentapep(cid:173)
`tide, and trimebutine ), NKl receptor antagonists ( e.g., ezlo(cid:173)
`(e.g.,
`pitant and SR-14033), CCK receptor agonists
`loxiglumide ), NKl receptor antagonists, NK3 receptor
`antagonists (e.g., talnetant, osanetant (SR-142801)), norepi(cid:173)
`nephrine-serotonin reuptake inhibitors (NSRI; e.g., milnacip(cid:173)
`ran ), vanilloid and cannabanoid receptor agonists ( e.g., arva(cid:173)
`nil), sialorphin, sialorphin-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); VRGPRQHNPR (SEQ ID NO:116);
`VRGPRRQHNPR (SEQ ID NO:119); and RQHNPR (SEQ
`ID NO: 118), compounds or peptides that are inhibitors of
`neprilysin,
`frakefamide
`(H-Tyr-D-Ala-Phe(F)-Phe-NH2 ;
`WO 01/019849 Al), loperamide, Tyr-Arg (kyotorphin), CCK
`receptor agonists (caerulein), conotoxin peptides, peptide
`analogs of thymulin, loxiglumide, dexloxiglumide (the
`R-isomer ofloxiglumide) (WO 88/05774) and other analge(cid:173)
`sic 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
`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
`cleavage site located so as to allow inactivation of the