US007371727B2
`I 1111111111111111 11111 1111111111 1111111111 111111111111111 IIIIII IIII IIII IIII
`
`c12) United States Patent
`Currie et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 7,371,727 B2
`May 13, 2008
`
`WO 02/079235
`10/2002
`WO 02/098912
`12/2002
`WO 03/072125
`9/2003
`WO 2004/071436
`8/2004
`
`OTHER PUBLICATIONS
`
`
`
`(73) Assignee: Microbia, Inc., Cambridge, MA (US)
`
`
`
`
`
`Arita et al., "Purification and characterization of a heat-stable
`
`Chan et al., "Amino Acid Sequence of Heat-stable Enterotoxin
`
`European Journal of Pharmacology,
`FEMS Microbiology Letters, vol.
`
`by Escherichia coli Pathogenic for Man" The Journal of
`Biological Chemistry, vol. 256, No. 15:
`Endocrinology,
`"Escherichia coli heat-stable
`What are they and what do they do?" The Journal
`of Laboratory and Clinical Medicine, vol. 125, No. 2: pp. 173-181
`
`
`
`enterotoxins, guanylins, and
`
`(54) METHODS AND COMPOSITIONS FOR THE
`
`
`WO
`TREATMENT OF GASTROINTESTINAL
`WO
`WO
`DISORDERS
`WO
`(75) Inventors: Mark G. Currie, Sterling, MA (US);
`
`
`
`
`
`Shalina Mahajan-Miklos, Stanford, CA
`
`
`
`(US); Angelika Fretzen, Somerville,
`Amarante et al., "The K-opioid agonist(±)-bremazocine elicits
`
`
`
`
`
`MA (US); Li Jing Sun, New York, NY
`
`
`
`peripheral antinociception by activation of the L-arginine/nitric
`(US); Thea Norman, San Diego, CA
`
`oxide/cyclic GMP pathway"
`
`(US); G. Todd Milne, Brookline, MA
`vol. 454: pp. 19-23 (2002).
`(US)
`
`
`
`
`enterotoxin of Vibrio mimicus"
`79/1: p. 105-110 (1991).
`
`
`( *) Notice: Subject to any disclaimer, the term of this
`
`
`
`Produced
`
`
`
`patent is extended or adjusted under 35
`pp. 7744-7746 (1981).
`
`U.S.C. 154(b) by 411 days.
`
`
`
`Forte et al., "Lymphoguanylin: Cloning and Characterization of a
`
`
`Unique Member of the Guanylin Peptide Family"
`
`vol. 140, No. 4: pp. 1800-1806 (1999).
`Giannela,
`
`their receptors:
`
`(21) Appl. No.: 10/899,806
`
`(22)
`Filed: Jul. 27, 2004
`
`(65)
`
`
`
`US 2006/0258593 Al Nov. 16, 2006
`
`FEES Letters, vol. 552: pp. 105-109
`
`Escherichia coli Heat-Stable (ST Ia)" Infection and
`Immunity, vol. 57,
`
`(1995).
`Prior Publication Data
`Gualillo et al., "Ghrelin, a widespread hormone: insights into
`
`
`
`
`
`
`
`
`
`molecular and cellular regulation of its expression and mechanism
`of action"
`(2003).
`Related U.S. Application Data
`
`
`
`
`Guarino et al., "Citrobacter freundii Produces an 18-Amino-Acid
`
`
`
`Heat-Stable Enterotoxin Identical to the 18-Amino-Acid
`(63)
`Continuation-in-part of application No. 10/845,895,
`
`
`Enterotoxin
`
`
`filed on May 14, 2004, which is a continuation-in-part
`
`
`No. 2: pp. 649-652 (1989).
`
`
`
`ofapplicationNo. 10/796,719, filed on Mar. 9, 2004,
`
`
`
`Huang et al., "Nucleotide sequence of a gene encoding the novel
`
`
`which is a continuation-in-part of application No.
`
`
`
`
`
`Yersinia enterocolitica heat-stable enterotoxin that includes a pro­
`
`10/766,735, filed on Jan. 28, 2004.
`
`
`region-like sequence in its mature toxin molecule"
`
`
`
`Microbial Patho­
`genesis, vol. 22: pp. 89-97 (1997).
`Brain Research, vol. 909: pp.
`NeuroReport, vol. 14, No. 10: pp.
`
`(60) Provisional application No. 60/443,098, filed on Jan.
`
`
`
`
`
`
`
`
`28, 2003, provisional application No. 60/471,288,
`
`
`the nitric oxide-cyclic GMP pathway"
`
`
`filed on May 15, 2003, provisional application No.
`
`170-178 (2001).
`
`
`60/519,460, filed on Nov. 12, 2003.
`
`
`
`
`according to feeding status"
`
`1317-1320 (2003).
`
`Jain et al., "Sildenfil-induced peripheral analgesia and activation of
`
`
`
`Kim et al., "Changes in ghrelin and ghrelin receptor expression
`
`
`(51) Int. Cl.
`A61K 38/10 (2006.01)
`
`
`
`
`
`(52) U.S. Cl. ...................... 514/14; 435/320.1; 435/325
`
`
`
`(58) Field of Classification Search ..................... None
`
`
`
`See application file for complete search history.
`
`(Continued)
`
`Primary Examiner----Christopher Tate
`Assistant Examiner-Roy Teller
`(74) Attorney, Agent, or Firm-Fish & Richardson
`
`(56)
`
`
`
`References Cited
`
`P.C.
`
`U.S. PATENT DOCUMENTS
`
`(57)
`
`ABSTRACT
`
`5,140,102 A 8/1992 Currie ........................ 350/326
`
`
`
`The present invention features compositions and related
`
`
`
`
`
`
`
`5,395,490 A 3/1995 Hoff et al. .................. 204/132
`
`
`methods for treating IBS and other gastrointestinal disorders
`
`5,489,670 A 2/1996 Currie
`
`
`et al. ............... 530/326
`
`
`
`and conditions ( e.g., gastrointestinal motility disorders,
`
`5,969,097 A 10/1999
`
`
`
`Wiegand et al. ............ 530/326
`
`
`functional gastrointestinal disorders, gastroesophageal
`
`
`
`6,060,037 A 5/2000 Waldman ................... 424/1.65
`
`
`
`
`
`reflux disease (GERD), duodenogastric reflux, Crohn's dis­
`
`
`
`
`2003/0073628 Al 4/2003 Shailubhai et al ............ 514/12
`
`
`
`
`ease, ulcerative colitis, Inflammatory bowel disease, func­
`
`
`
`2003/0232013 Al 12/2003 Siechman et al. ......... 424/1.69
`
`
`
`
`2004/0121961 Al 6/2004 Masferrer .................... 514/15
`
`
`
`
`
`tional heartburn, dyspepsia (including functional dyspepsia
`
`
`
`2004/0152868 Al 8/2004 Larsen et al. ............... 530/317
`
`
`
`
`or nonulcer dyspepsia), gastroparesis, chronic intestinal
`
`
`
`
`
`2004/0258687 Al 12/2004 Waldman et al. ........ 424/143.1
`
`
`
`pseudo-obstruction ( or colonic pseudo-obstruction), and dis­
`
`
`
`
`
`2004/0266989 Al 12/2004 Currie et al. ............... 530/326
`
`
`
`
`orders and conditions associated with constipation, e.g.,
`
`
`
`2005/0032684 Al 2/2005 Cetin et al. ................... 514/12
`
`
`constipation associated with use of opiate pain killers,
`
`
`
`
`post-surgical constipation (post-operative ileus), and consti­
`
`
`
`pation 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.
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`WO
`WO
`WO
`WO
`
`
`1012188 6/2000
`
`WO 99/14239 3/1999
`
`WO 01/25266 4/2001
`
`WO 02/062369 8/2002
`
`WO 02/078683 10/2002
`
`
`
`
`6 Claims, 69 Drawing Sheets
`
`Bausch Health Ireland Exhibit 2014, Page 1 of 106
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`OTHER PUBLICATIONS
`Lazaro-Ibanez et al., "Participation of the nitric oxide-cyclic GMP­
`ATP-sensitive 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 a Gene Encoding a Heat-Stable Enterotoxin of Escherichia coli"
`Infection and Immunity, vol. 39, No. 3: pp. 1167-1174 (1983).
`Nzegwu et al., "Luminal capsaicin inhibits fluid secretion induced
`by exterotoxin E. coli STa, but not by carbachol, in vivo in rat small
`and large intestines" Experimental Physiology, vol. 81, No. 2: pp.
`313-315 (1996).
`Rolfe et al., "Enterotoxin Escherichia coli STa activates a nitric
`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 ilea! Escherichia coli STa in the rat in vivo" GUT, vol.
`44: pp. 615-619 (1999).
`Shailubhai, "Therapeutic applications of guanylate cyclase-C recep­
`tor agonists" Drug Discover & 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 US.A., vol. 77, No. 7 [Part 2:
`Biological Sciences]: pp. 4011-4015 (1980).
`Soares, et al., "Dibutyryl-cyclic GMP
`induces peripheral
`antinociception via activation of ATP-sensitive K+ channels in the
`RAT PGE2-induced hyperalgesic paw" British Journal of Pharma­
`cology, vol. 134: pp. 127-131 (2001).
`Takao et al., "Amino acid sequence of heat-stable enterotoxin
`produced by Vibrio choleranon-01" FEES), vol. 193, No. 2: pp.
`250-254 (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).
`Vaandrager et al., "Structure and function of the heat-stable
`enterotoxin receptor/guanylyl cyclase C" Molecular and Cellular
`Biochemistry, vol. 230, Nos. 1&2: pp. 73-83 (2002).
`GenBank Accession No. QHECIB; GI:69638; Aimoto et al., Jun.
`18, 1999.
`GenBank Accession No. P01559; GI: 123711; So et al., Oct. 25,
`2004.
`GenBank Accession No. AAA24653:GI:147878; Sekizaki et al.,
`Apr. 26, 1993.
`
`US 7,371,727 B2
`Page 2
`GenBank Accession No. P01560; GI:123707; Chan et al., Jun. 15,
`2004.
`GenBankAccession No. AAA27561; GI:295439; Ogawa et al., Jun.
`12, 1993.
`GenBankAccession No. P04429; GI:123712; Ogawa et al., Jun. 15,
`2004.
`GenBank Accession No. S34671; GI:421286; Rossolini et al., Apr.
`12, 1995.
`GenBank Accession No. CAA52209; GI:395161; Guglielmetti et
`al., Jul. 27, 2995.
`GenBank Accession No. A54534; GI:628844; Arita et al., May 3,
`1996.
`GenBank Accession No. AAL02159; GI:15592919; Teixeira et al.,
`Sep. 13, 2001.
`GenBank Accession No. AAA18472; GI:487395; Mikulskis et al.,
`May 26, 1994.
`GenBank Accession No. S25659, GI:282047; Takao et al., Oct. 15,
`1999.
`GenBank Accession No. P74977: GI:3913874; Ramamurthy et al.,
`Jun. 15, 2004.
`GenBank Accession No. BAA23656; GI:2662339; Huang et al.,
`Feb. 13, 1999.
`GenBank Accession No. P31518; GI:399947; Ibrahim et al., Mar.
`15, 2004.
`GenBank Accession No. P07965; GI:3915589; Stieglitz et al., Jun.
`15, 2004.
`Camilleri, "Management of the Irritable Bowel Syndrome" Gastro­
`enterology 120:652-668, 2001.
`Drossman, D.A., "The functional gastrointesinal disorders and the
`Rome II process" Gut 45:Supp. II:111-113, 1999.
`Drossman, D.A., "Psychosocial aspects of
`the functional
`gastrointestinal disorders" Gut 45:Supp. II: 1125-1130, 1999.
`Drossman et al., "U.S. Householder Survey of Functional
`Gastrointestinal Disorders" Digestive Diseases and Sciences
`38(9):1569-1580, 1993.
`Ringel, et al., "Irritable Bowel Syndrom" Annu. Rev. Med. 52:319-
`38, 2001.
`Santos-Neto, et al., "Guanylin and its Lysine-Containing Analogue
`in the Isolated Perfused Rat Kidney" Pharmacol. & Toxicol. 92: 114-
`120, 2003.
`Talley, et al., "Irritable Bowel Syndrome in a Community: Sympton
`Subgroups, Risk .. " Am. J. of Epidemiology 142(1):76-83, 1995.
`Talley, et al., "Medical Costs in Community Subjects with Irritable
`Bowel Syndrome" Gastroenterology 109(6): 1736-1741, 1995.
`
`Bausch Health Ireland Exhibit 2014, Page 2 of 106
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`N
`=
`-....l
`N
`"""'
`w -....l
`-....l
`d r,r;_
`
`1
`
`I
`/
`
`41.61
`
`1
`
`t:,
`39.99
`
`I
`
`1
`
`/
`
`I
`1 38.95
`
`I
`/
`1
`
`36.14 37.26
`
`FIG. 1A
`
`I
`
`I
`
`I
`
`2
`
`3
`
`27.82 � /� 33.82 3531
`
`j
`I
`3
`
`I
`
`o
`
`1,0
`.... O'I
`.... 0
`rJJ =­('D
`.... � � N 0 0 QO
`� �
`
`.....
`
`('D
`
`�
`• � � � �
`e • 00
`
`Area
`
`1.78e3
`
`2093+1047
`1: TOF ES+
`
`i ==y= f
`
`I
`l� I ::,---A L
`
`2
`39.17
`
`143
`28.50
`
`SEQ ID NO: 5
`
`%
`
`MD_GCCA03JuI1_R118 Sm (SG, 2x3)
`
`100
`
`I
`
`I
`=-,:::: L 0 y '-1,1 I
`
`I
`
`I
`
`I
`
`I
`
`I
`
`0 I
`
`Area
`1.98e3
`2305+1153
`1: TOF MS ES+
`
`249
`36.40
`
`347
`33.67 373
`35.17
`
`LCMS ANALYSIS OF RECOMBINANT PEPTIDE VARIANTS
`
`%
`
`SEQ ID NO: 4
`
`MD_GCCA03Jul1�R119 Sm {SG, 2x3)
`
`100
`
`Bausch Health Ireland Exhibit 2014, Page 3 of 106
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`N
`=
`--...l
`--...l N
`--...l "'""' "'
`d r.,;_ "'--...l w
`
`('D ..... N 0 ....
`rJJ =­('D
`� � .... "'(H N 0 0 QO
`= �
`� � � �
`•
`e • 00
`
`1,0
`O'I
`
`FIG. 18
`
`60.00
`
`11TIME
`
`55.00
`I
`
`50.00
`�
`�
`
`45.00
`I. I
`
`40.00
`I 11 ·, I
`
`35.00
`
`· 30.00
`�·�··
`
`25.00
`
`20.00
`
`15.00
`
`I ; I ,,,,,,, ,,,,,,, 1111 11 �
`
`10.00
`
`5.00
`
`I
`0 � ,.
`
`LCMS ANALYSIS OF SYNTHETIC SEQ ID NO: 3
`
`(TOTAL ION CHROMATOGRAPH (TIC))
`
`30.79
`
`31.44
`
`31.10
`
`31.13"31.3A
`
`'
`
`31.21
`
`%
`
`100
`
`Bausch Health Ireland Exhibit 2014, Page 4 of 106
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`May 13, 2008
`
`Sheet 3 of 69
`
`US 7,371,727 B2
`
`LL
`
`:c a..-<( C/'J 0::: ci5 (!) >-
`0 ...J I- <( <(Z �<(
`O "'
`0::: .. ::r:O
`(.)z
`zQ
`Qo ...J w <( Cl.)
`1-Z
`o-I- Cl
`-w Cl) Cl) ci5 ::J ��
`<Cz
`z:5 <( al
`(/) �
`
`{.)
`...J
`
`0 0 .....
`
`0 "<t r-..: v
`
`(0
`
`w
`�
`�
`.
`i= 8
`ci (9
`LL
`0 0. I.O IO
`0 0 ci IO
`
`0 0 iri "<t
`0 0 ci
`
`0 0 iri ("')
`0 0. 0 ("')
`
`0 0 iri
`
`N
`
`0 0 ci
`
`N
`
`0 0 iri .....
`
`0
`
`·o ci .....
`
`0 0
`I.O
`
`0
`
`Bausch Health Ireland Exhibit 2014, Page 5 of 106
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`May 13, 2008
`
`Sheet 4 of 69
`
`US 7,371,727 B2
`
`.D
`-- --('Q
`'V LO
`C"')
`- -
`C"')
`0 0 0 0
`z z z z
`Cl
`Cl Cl
`Cl
`0 0 0 0
`Cl) Cl)
`Cl) Cl)
`w w w w
`-�□�
`
`-
`
`E
`C
`
`-
`
`C
`0
`CG
`·-
`I..
`.
`.... N
`C
`G)
`(.) (9
`0 u...
`C
`0
`G)
`·-
`a.
`....
`G)
`0.
`
`N
`
`T""
`
`v
`
`('t')
`T""
`
`0
`0
`0
`co
`
`0
`0
`0
`LO
`
`0
`0
`0
`v
`
`0
`0
`0
`C"')
`
`0
`0
`0
`N
`
`0
`0
`0
`
`T""
`
`0
`0
`0
`
`(1 WJIOWd} dWD=>
`
`(.)
`(.)
`<(
`z
`
`W>
`
`en z w I-
`z>-
`I Cl) I- Cl)
`w<C
`z <(
`-�
`en_
`o--I-
`I- (.)
`a.<(
`w 0:::
`Cl I-
`0.0
`Wa_
`Cl) (.)
`I 0:::
`WW
`
`>-
`CJ)
`>-
`....I
`
`Nw
`
`I-z
`
`I 0
`
`Bausch Health Ireland Exhibit 2014, Page 6 of 106
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`May 13, 2008
`
`Sheet 5 of 69
`
`US 7,371,727 B2
`
`0 I-
`
`UJ Cl) :J --
`�CJ LI.J­
`I- ....J
`:::> LU (.) 0
`<Co z � <(1-
`z Cl) - z
`® <( � c:::: c:::: l­
`....J
`z <( ....J z UJ­N 1-tn CIJ
`o
`
`> LU
`vl­.. z
`o-z�
`Cl 1-- 00
`o<C wCJ Cl)
`
`I
`
`I
`I
`
`I l
`
`I
`I
`
`I
`I
`
`@ C)
`E �
`.... ..._
`C)
`c: E -"""'"
`•
`Q)
`N O
`
`0
`
`C)
`<(
`•
`9��
`en z �
`a .. m
`wOE
`(9
`0
`-LL
`
`Q)
`-(.)
`·-.c Q)
`
`>
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`
`0 0 0
`00 0 0 0
`0 0 0
`0 O> CO I"- CO LO ,q-
`N �
`
`�
`
`('t")
`
`Bausch Health Ireland Exhibit 2014, Page 7 of 106
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`May 13, 2008
`
`Sheet 6 of 69
`
`US 7,371,727 B2
`
`C"')
`. .
`0
`E C It)
` - <:)
`C a <:)
`(/) Q,.
`- w V
`■ m
`
`®
`
`'-0
`
`z
`
`i(
`
`@
`
`<( Cf)
`_<(
`
`LU
`Cf) ::::, ...J
`Ow 20
`wO J-� ::::, J-t)-
`z z
`0::: 21-0:: ...J
`Q<( z z ...J -
`LU I-N f{3
`c/'J I-> z M-
`. . 0
`0 0::: zi-
`0 Cf) - <( 0 (.9
`w
`Cf)
`
`0 . ('t)
`
`LO
`,-.... . 0
`
`-C) �
`-LO C)
`N
`E
`-0
`z 0 al ct)
`.
`�
`(") 0:: (9
`� t-0 z LL
`w (.)
`z (") 0 (.)
`0
`0
`
`0
`
`0 0 0 0 0 0 0 0 0 0
`
`m ro ,-.... w � � ('t) N �
`(7\1101 %) 0373/\ Vtll 38NV lSI0
`
`Bausch Health Ireland Exhibit 2014, Page 8 of 106
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`Sheet 7 of 69
`
`US 7,371,727 B2
`
`U.S. Patent
`
`May 13, 2008
`� ("')
`
`0 0
`z z
`0 0
`
`0 0
`Cl) Cl)
`w w
`
`0 co
`
`Q) en
`
`0
`N
`
`0
`
`...J w Cl
`0 :ii:
` z
`0 z Cl
`a w (J) Cl z <3:'. �
`0 z Cl
`a w (J) Cl w
`LL 0:: :::, a..
`
`I­C!)
`
`('I")
`
`0
`0 "'r'"""
`
`0 co
`0 co
`(IBl0J_ %) P818/\BJJ_ 8:JUBJS�O
`
`0
`N
`
`0
`
`Bausch Health Ireland Exhibit 2014, Page 9 of 106
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`May 13, 2008
`
`Sheet 8 of 69
`
`US 7,371,727 B2
`
`....J UJ C)
`0 � I­(!)
`
`z
`Cf)
`w
`0
`
`t UJ a..
`0 w
`N Cf)
`w
`I
`>­z Cf)
`� ....J
`c3
`2 w
`I (.)
`
`co
`
`(.9
`-
`u.
`
`-q-.
`
`�
`�
`
`-�
`
`0 0
`0 0) �
`
`co """' (0 Lt)
`0 0 0 0
`
`0 0 0 0 0
`V CV) N "t"'""
`
`Bausch Health Ireland Exhibit 2014, Page 10 of 106
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`2 100 ...----�=-=-=====��-----
`
`---7
`
`� � .... � �
`= �
`� � � �
`� Chronic
`D Acute
`•
`e • 00
`
`QO
`0
`0
`N
`
`** ***
`
`* ***
`
`CHRONIC vs ACUTE DOSING IN GIT ASSAY
`
`40
`50
`
`ca '-
`
`
` >
`-Cl)
`
`60
`"C Cl)
`c 10
`0
`t-80
`o 90
`c,:s
`
` u
`I- <l)
`
`= N
`N -....l
`w -....l ""'"'
`-....l
`d r.,;_
`Zelnorm ®
`
`FIG. 4C
`
`SEQ ID NO: 3
`
`*** p < 0.0005
`** p < 0.005
`* p < 0.01
`
`1,0
`
`1,0
`
`I
`
`I
`
`h > > I
`
`I
`
`I
`
`I> > l
`
`I
`
`t
`
`h, ), ':> I
`
`I
`
`20
`30
`
`·- c
`0 j
`.. ti)
`10
`ca
` C
`
`Vehicle 0.06mg/kg 0.25mg/kg 1mg/kg
`Dr > > I t
`0 .... O'I
`('D .....
`rJJ =­('D
`
`Bausch Health Ireland Exhibit 2014, Page 11 of 106
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`May 13, 2008
`
`Sheet 10 of 69
`
`US 7,371,727 B2
`
`®
`E
`
`0 c:: -
`
`..--.. C) �
`C)
`E N .
`
`<(
`LO
`C)
`
`-�
`
` ><
`C)
`C)
`
`,q" . . 0
`
`z
`C
`-
`
`"q"
`
`LO
`('f)
`
`('f)
`
`LO
`
`N
`
`N
`
`LO
`
`T"""
`
`T"""
`
`LO
`0
`
`0
`
`�
`
`t-
`
`t- �
`
`
`
`�
`
`- - �
`
`
`
`i 0
`
`• • • • • • • • • • •
`
`•
`
`� �H
`
`��
`
`• • • • • • • • • • • • • • • •
`
`' ...
`_J.
`..
`'i.H
`�
`I N 0
`I
`I
`I
`I "q" C'\I T""" CO CO v
`I
`II
`0
`T""" T"""
`0 0 0
`0 0 ° 0 0 0
`O!lB� SSBOJB8/SlnE)
`
`...J
`
`w 0 0 � z 0 1-w 0:::
`
`u
`
`w Cl) ...J <(
`z I­C/)
`w 1-
`z
`w
`Cl)
`::::, 0 � <(
`� 0::: 0
`z ...J w N en > -.;;f"
`
`z
`
`0
`z
`0
`a w Cl)
`I
`I
`co co
`� T"""
`0 0
`
`Bausch Health Ireland Exhibit 2014, Page 12 of 106
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`US 7,371,727 B2
`
`0 LO N �
`
`0 'q" N
`
`LO 'q"'
`
`N
`
`Q)
`13 .c Q)
`
`-
`
`-=-=
`
`-en co
`en :::s
`LO
`.
`- (.9
`Cl) tn
`u. 0
`C
`
`>
`
`U.S. Patent
`
`May 13, 2008
`
`Sheet 11 of 69
`.. 0
`®
`E �
`z
`C
`0 C:
`-a,
`N �
`
`- a
`
`w tn
`rs.,
`
`
`
`_J <( z
`
`ti; UJ 1-z UJ (/)
`
`:::> _J
`Ow �Cl
`®�z 0:: 0
`zO -�
`0 G:i
`3 a:: UJ (.) NW Cf) Cl)
`0 z
`a LU Cf)
`
`0
`
`V � . 0
`
`N
`
`T""' . 0
`
`I 0
`T""' . 0
`
`I
`
`I
`
`'
`
`0 0 . 0
`
`'q" N
`I co 0
`(0 0
`.
`.
`0 0
`0 0
`0
`0
`uo11aJ:>as
`
`Bausch Health Ireland Exhibit 2014, Page 13 of 106
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`May 13, 2008
`
`Sheet 12 of 69
`
`US 7,371,727 B2
`
`0 N
`
`LO
`T"""
`
`-0
`
` �
`>< <(
`0 .e>co
`....._
`T""" en
`.
`E (.9
`- -
`U-
`i
`0
`C
`
`LO
`
`LO 'V
`0 0
`z z
`0 0
`- -
`a a
`w en en
`
`+ +
`
`0
`
`0
`
`CO■ CO v
`0 0 0
`0 0 0
`
`N 0
`0
`
`UJ en :J
`0
`�
`
`z ,q-.. 0
`z Cl
`0 ..J
`UJW eno Clo
`��
`I.Oz
`.. 0
`o­ztu
`Cl�
`ow w Cl)
`en ..J
`Q<( UJZ
`<( ti
`1---
`� w UJ 1-­z z
`
`-o
`
`w ­(9
`� 1-­
`z <(
`z CD
`� 0 (.)
`UJ er
`
`Bausch Health Ireland Exhibit 2014, Page 14 of 106
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`= N
`--...l
`--...l N
`--...l """" "'
`"'--...l w
`d rJl.
`
`FIG. 6B
`
`Dose (ug/kg)
`
`50 60
`
`0 10 20 30 40
`
`0
`
`I
`
`I
`
`I
`
`1,0
`O'I
`0 ....
`O 0.06
`.... �
`� 0.08
`0 °���-' I P I
`('D .....
`·-..,
`rJJ =­('D
`
`0.02-1-- ------------------j
`.04-1-- --------------------1
`
` 0
`-C>
`
`QO
`0
`0
`N
`"'�
`....
`
`� �
`= �
`� � � �
`•
`e • 00
`
`4-·r---------------,
`
`0.1
`
`.....,SEQ ID NO: 4
`
`11-SEQ ID NO: 3
`1\--SEQ ID NO: 5
`
`-soug/kg Sigma ST(+ control)
`
`(-control)
`
`-o-vehicle
`
`INTESTINAL SECRETION MODEL
`
`CHEMICALLY SYNTHESIZED PEPTIDES IN MOUSE
`
`Bausch Health Ireland Exhibit 2014, Page 15 of 106
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`May 13, 2008
`
`Sheet 14 of 69
`
`US 7,371,727 B2
`
`C) o.:i.::
`
`MC)
`
`*
`
`*
`
`Cl)
`��
`I- Cl)
`I- Cl)
`�:
`zo
`--
`('1')1-
`. . z
`0 Lll
`zt-
`0�
`0 ...J
`-0
`LU <( (/) I-
`u.. (.)
`0�
`1-Q
`(...) _,J
`LL (.)
`UJQ
`LL
`UJ
`
`-
`
`.
`"-
`0 (9
`z
`0 LL
`-
`a
`en
`w
`C) en
`M .:i,:
`.
`0 C)
`::L I-
`
`C)
`.
`0 .:i,:
`M C>
`
`-
`
`-
`
`M
`
`+
`
`m
`z
`
`Q)
`+
`Q) (,/J
`:::,
`co
`ca
`■-
`-
`-
`z
`■; I-
`o
`> ·a,
`-u
`■-
`.c
`G)
`u
`Q)
`■-.c
`-
`>
`-
`0
`G)
`... "C
`>
`cu 0.
`E 0
`CJ
`Cl)
`ca
`U)
`0
`. 0
`(U!W S)
`SUO!l:lBJlUO:> IBU!WOpqe JO JaqwnN V Q,.
`
`C
`N
`
`Lt)
`�
`
`0
`�
`
`It)
`
`C
`
`*
`
`Bausch Health Ireland Exhibit 2014, Page 16 of 106
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`May 13, 2008
`
`Sheet 15 of 69
`
`US 7,371,727 B2
`
`C') .¥:: M --C')
`
`E
`
`Wt-
`
`� en en en I- <( (.) (9
`Wz u. -u. :c
`w-> 0:::
`1-w 8:i en (.) ::>
`-$
`<( I-
`-o g�
`z
`z-<( LO _Jo <(
`z
`z 0:::
`WO (.) -en a
`-w > en u.
`
`C
`·-(.)
`C')
`ca
`.¥:: .J:.
`...,
`� --
`C')
`C1)
`E E 0 "C �
`- co
`C')
`.
`. --
`M .¥::
`0 C')
`C)
`E LL
`Lt)
`.. 0
`C') .¥:: z
`--C') C
`:::1. -
`w (/J
`
`C
`
`a
`
`�
`
`C1)
`-(.)
`·-.J:. C1)
`>
`
`It)
`M
`
`0 It)
`M N 0 N Lt) �
`
`Lt) 0
`
`Bausch Health Ireland Exhibit 2014, Page 17 of 106
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`May 13, 2008
`
`Sheet 16 of 69
`
`US 7,371,727 B2
`
`W
`
`C,) <9
`
`� Cf) CJ) (/) I- <(
`z LJ.. -LJ.. ::r: UJ t-
`w-> a:::
`-$ 1-w a.. (/) 1.1.1 :::,
`(.) 0
`g� z <(
`i= z
`z-<( ('I')
`.....J 0
`<C z ffi Cl
`u-(1)0
`-w
`>w u..
`0
`
`en Jae: M .._ en
`E
`C)
`·-
`C:
`�
`T- ..._
`(J
`C)
`C\1
`E .c:
`... Cl)
`0) E
`M::S:.
`0
`■ ...._ 0 C) "'C
`C:
`E
`-
`0)
`.._ T- C)
`::::::L
`C')
`It) ::.:. CW')
`■ ...._ C)
`■ • 0
`::i.
`z
`C) C
`.:.:: -
`T- ..._
`a C') :l. w ti)
`
`co
`co
`.
`(9
`u..
`
`-
`
`o::.:.
`
`<I)
`-(J
`■-.i::.
`
`It) 0 It) 0 U) 0 It) 0
`M M N N � �
`
`Bausch Health Ireland Exhibit 2014, Page 18 of 106
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`May 13, 2008
`
`Sheet 17 of 69
`
`US 7,371,727 B2
`
`-----=-----,---,---r---,- It)
`
`I
`
`�
`LO .
`'q"
`I I "'O ::x::
`
`•
`
`• U)
`
`I
`
`t,-.
`
`I
`
`C0
`
`I
`
`en
`
`0 �
`
`I
`
`� �
`
`I
`
`.--..
`:IE ..__..
`C)
`0 ..J
`.. M O')
`• • 0 (.9
`
`z
`C
`
`LL
`
`-
`
`a
`UJ
`
`z
`C)
`z co
`C)
`
`Z M <( . . t') 0
`- z
`o o - -
`D o <( LJ.J 0::: C/)
`
`W u.
`
`I-I-LU
`
`� o
`
` CL �
`
`0
`(.)
`
`,___--4-----+----t----;------t- N �
`Lt)
`Lt) t,-.
`Lt) N �
`N
`
`I
`
`0
`
`0
`It)
`
`Bausch Health Ireland Exhibit 2014, Page 19 of 106
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`based on LCMS
`
`< 0.11 °/o Bioavailable
`
`.... � �
`� � �
`I :::::) I
`= �
`� � � �
`•
`e • 00
`
`I
`
`MINIMUM SYSTEMIC ABSORPTION OF
`
`SEQ ID NO: 3 (BASED ON LCMS)
`
`200
`•
`
`o• ■ ■ ■=a .
`
`0
`
`5
`
`10
`
`(.)
`C 0
`... ..., C (1) 0
`·-..., cu
` 0
` -... C') ::l
`
`15
`
`20
`
`--E
`
`-C
`
`L
`
`251
`
`= N
`
`w -....l ""'"' � N -....l
`
`-....l
`d r.,;_
`
`1,0
`O'I
`0 ....
`.... QO
`rJJ =-('D
`
`('D
`
`QO
`0
`0
`N
`
`FIG. 10A
`
`on 0.00063 µg/ml (0.6 nM)
`
`• Dosing at 10 mg/kg
`• Limit of detecti
`
`240
`
`40 80 120 160
`
`Time (min)
`, • 1
`
`Bausch Health Ireland Exhibit 2014, Page 20 of 106
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`May 13, 2008
`
`Sheet 19 of 69
`
`US 7,371,727 B2
`
`·-
`
`Cl)
`f f
`-.c <( ..! en
`-C'O ..J
`� C
`> W
`·- 0 cc "C
`� Cl)
`0 u,
`C"! C'O N .C
`V
`
`z 0
`0 UJ
`CJ') LL
`0
`z �
`ocn I- ...J a. W
`oo CJ') 0
`O:: z
`cow
`<!. en
`(.) <!.
`- c:o � ­UJ
`
`0
`
`� >­CJ') � :::::, �
`
`.
`(!)
`LL
`
`-0 C
`■-0
`�
`E
`Q)
`E ·-t-
`
`0 It)
`
`C: ::!!:
`
`E
`-C) ::t
`� U) 0 . 0 C)
`0 C) ;; E 0 Q) 0 .... �
`Q) ... "C ca '+- C)
`0 ... C:
`·e ·en
`■- 0
`J O
`,fC
`
`z �
`
`It) N
`
`0 N
`
`It) �
`
`0
`
`0
`
`It)
`
`Bausch Health Ireland Exhibit 2014, Page 21 of 106
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`May 13, 2008
`
`Sheet 20 of 69
`
`US 7,371,727 B2
`
`G l u T y r Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr
`Tyr
`Tyr cys Cys Asn Pro Ala Cys Thr Gly Cys
`
`--- Cys Cys Asn Pro Ala Cys Thr G l y Cys
`
`Tyr
`
`--- Cys Cys --- Pro Ala Cys
`
`Thr G l y Cys
`
`Tyr
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`--- Cys Cys --- --- Ala Cys
`- - - Cys Cys --- Pro --- Cys
`--- Cys Cys --- Pro Ala Cys
`--- Cys Cys --- Pro Ala Cys
`--- Cys Cys - - - Pro Ala Cys
`
`--- Cys
`
`Cys Asn --- Ala Cys
`
`Thr G l y Cys
`
`Tyr
`
`Thr G l y Cys
`
`Tyr
`
`--- Gly Cys
`
`Tyr
`
`Thr - - - Cys
`
`Tyr
`
`Thr Gly Cys
`
`Thr Gly Cys
`
`Tyr
`
`--- ---
`
`- - - Cys
`
`Cys Asn
`
`Cys
`
`Thr Gly Cys
`
`Tyr
`
`- - - Cys
`
`Cys Asn --- Ala Cys
`
`--- Gly Cys
`
`Tyr
`
`--- Cys
`
`Cys Asn - - - Ala
`
`Cys
`
`Thr _; __ Cys
`
`Tyr
`
`- - - Cys
`
`Cys Asn --- Ala
`
`Thr Gly Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`Cys Cys
`
`Cys Cys
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Asn Pro - --
`
`Cys
`
`Thr Gly Cys
`
`Tyr
`
`Cys
`
`__ _; Cys
`- -- Cys
`
`Cys Asn Pro ---
`
`Cys
`
`Cys
`
`Cys Asn Pro ---
`
`Cys
`
`--- Gl y Cys
`Thr --- Cys
`
`Tyr
`
`Tyr
`
`- - - Cys
`
`Cys Asn Pro ---
`
`Cys
`
`Thr Gly Cys
`
`--- Cys
`
`Cys Asn Pro Ala
`
`Cys
`
`-- - Gly Cys
`
`Tyr
`
`Cys
`
`Cys Asn Pro Ala
`
`Cys
`
`--- --- Cys
`
`Tyr
`
`--- Cys
`
`Cys Asn Pro Ala
`
`Cys
`
`--- Gly Cys
`
`--- Cys
`
`Cys Asn Pro Ala
`
`Cys
`
`Thr --- Cys
`
`Tyr
`
`--- Cys
`
`Cys Asn Pro Ala
`
`Cys
`
`Thr --- Cys
`
`--- Cys
`
`Cys Asn
`
`Pro Ala
`
`Cys
`
`Thr Gly Cys
`
`(SEQ ID N0:3)
`( SEQ ID NO: 1 30 )
`( SEQ ID NO: 1 31 )
`( SEQ ID NO: 1 32 )
`( SEQ ID NO: 1 33 )
`( SEQ I D NO: 1 34 )
`( SEQ ID NO: 1 35 )
`( SEQ ID NO: 1 36 )
`( SEQ ID NO: 1 37 )
`( SEQ ID NO: 1 38 )
`( SEQ ID NO: 1 39 )
`( SEQ ID NO: 1 40 )
`( SEQ ID NO: 141 )
`( SEQ ID NO: 1 42 )
`( SEQ ID NO: 1 43 )
`( SEQ ID NO: 144 )
`( SEQ ID NO: 145)
`( SEQ ID NO: 1 46 )
`( SEQ ID NO: 1 47 )
`( SEQ ID NO: 148)
`( SEQ ID NO: 1 49 )
`( SEQ I D NO: 1 50 )
`( SEQ ID NO: 1 51 )
`( SEQ ID NO: 1 52 )
`( SEQ ID NO: 1 53 )
`( SEQ I D NO: 1 54 )
`( SEQ I D NO: 1 55 )
`( SEQ I D NO: 1 56 )
`( SEQ I D NO: 1 57 )
`( SEQ ID NO: 1 58 )
`( SEQ ID NO: 1 59 )
`( SEQ ID NO: 1 60 )
`( SEQ ID NO: 1 6 1 )
`( SEQ ID NO: 1 62 )
`( SEQ ID NO: 1 63 )
`( SEQ ID NO: 1 64 )
`( SEQ ID NO: 1 65 )
`( SEQ ID NO: 1 66 )
`( SEQ ID NO: 1 67 )
`( SEQ ID NO: 1 68 )
`( SEQ ID NO: 1 69 )
`( SEQ ID NO: 1 70 )
`( SEQ ID NO: 1 71 )
`( SEQ ID NO: 1 72 )
`
`Cys
`
`Thr G l y Cys
`
`Cys
`
`Cys
`
`Cys
`
`G l y Cys
`
`Tyr
`
`Cys
`
`Tyr
`
`G l y Cys
`
`Cys
`
`Thr - - - Cys
`
`Tyr
`
`Cys
`
`Thr - - - Cys
`
`Cys
`
`Thr G l y Cys
`
`Ala Cys - Th r G l y Cys
`
`Tyr
`
`Cys Thr G l y Cys
`
`Tyr
`
`Cys
`
`G l y Cys
`
`T y r
`
`Cys T h r - - - C y s T y r
`
`F I G . 1 1 - 1
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys
`
`Cys
`
`Cys
`
`Cys
`
`Cys
`
`Cys
`
`Cys
`
`Cys Cys
`
`Cys
`
`Cys
`
`Pro
`
`Pro Ala
`
`Pro Ala
`
`Pro Ala
`
`Pro Ala
`
`Pro Ala
`
`Pro Al a
`
`--- Tyr Cys
`--- Tyr Cys
`--- Tyr Cys
`--- Tyr Cys
`--- Tyr Cys
`--- Tyr Cys
`--- Tyr Cys
`--- Tyr Cys Cys Asn
`--- Tyr Cys Cys Asn
`- -- Tyr Cys Cys Asn
`Cys Cys
`Cys C y s --- Tyr C y s C y s A s n - - -
`
`Cys Cys
`Cys Cys
`
`Cys Cys
`Cys Cys
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Tyr Cys
`
`Cys
`
`Tyr Cys
`
`Cys
`
`Tyr Cys
`
`Cys
`
`P ro Ala
`
`--- Ala
`
`--- ---
`
`Cys
`
`Thr Gly Cys
`
`Tyr
`
`Cys
`
`Thr Gly Cys
`
`Tyr
`
`Cys
`
`Thr G l y Cys
`
`Tyr
`
`Tyr Cys
`
`Cys
`
`- - - Ala
`
`Cys
`
`--- G ly Cys
`
`Tyr
`
`Tyr Cys
`
`Cys
`
`--- Ala
`
`Cys
`
`Thr - - - Cys
`
`Tyr
`
`Tyr Cys
`
`Cys
`
`--- Ala
`
`Cys
`
`Thr G l y Cys
`
`--- Tyr Cys
`--- Tyr Cys
`
`Cys
`
`Cys
`
`Tyr Cys
`
`Pro
`
`Pro
`
`Pro
`
`Cys
`
`Thr G l y Cys
`
`Tyr
`
`Cys
`
`--- G l y Cys
`
`Tyr
`
`Thr - - - Cys
`
`Tyr
`
`Bausch Health Ireland Exhibit 2014, Page 22 of 106
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`May 13, 2008
`
`Sheet 21 of 69
`
`US 7,371,727 B2
`
`Tyr Cys
`
`Cys Asn
`
`Tyr Cys
`
`Cys Asn
`
`--- ---
`
`Cys
`
`Thr Gly Cys
`
`Ala
`
`Cys
`
`--- Gly Cys
`
`Tyr
`
`Tyr Cys
`
`Cys Asn
`
`--- Ala
`
`Cys
`
`--- --- Cys
`
`Tyr
`
`Tyr Cys
`
`Cys Asn
`
`--- Ala
`
`Cys
`
`--- Gly Cys
`
`Tyr Cys
`
`Cys Asn
`
`--- Ala
`
`Cys
`
`Thr --- Cys
`
`Tyr
`
`Tyr Cys
`
`Cys Asn --- Ala
`
`Cys
`
`Thr --- Cys
`
`Tyr Cys Cys Asn --- Ala
`Tyr Cys Cys Asn Pro ---
`Tyr Cys Cys Asn Pro ---
`
`Cys
`Tyr Cys Cys Asn Pro --- Cys
`
`--- Gly Cys
`
`Tyr
`
`--- Cys
`
`Tyr
`
`Cys
`
`Thr Gly Cys
`
`Cys
`
`Thr Gly Cys
`
`Tyr
`
`Tyr Cys Cys Asn Pro --- Cys
`--- Gly Cys
`Tyr Cys Cys Asn Pro --- Cys Thr --- Cys
`Tyr Cys Cys Asn Pro ---
`Cys
`.Thr - - - Cys
`Tyr Cys Cys Asn Pro ---
`Tyr Cys Cys Asn Pro Ala
`Tyr Cys Cys Asn Pro Ala
`Tyr Cys Cys Asn Pro Ala
`Tyr Cys Cys Asn Pro Ala
`Tyr Cys Cys Asn Pro Ala
`Tyr Cys Cys Asn Pro Ala
`Tyr cys Cys Asn Pro Ala
`Glu --- Cys Cys Asn Pro Ala
`Glu --- Cys Cys - - - Pro Ala
`Glu - - - Cys Cys
`- - - Ala
`Cys Cys
`Glu
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`Cys Cys
`
`Cys Cys
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`Cys Cys
`Cys Cys
`Cys Cys
`Cys Cys
`Cys Cys
`Cys Cys
`
`Cys Cys
`cys Cys
`
`Cys
`
`Thr Gly Cys
`
`Cys
`
`Cys
`
`Cys
`
`Cys
`
`Gly Cys
`
`Cys
`
`--- Cys
`Gly Cys
`
`Cys
`Cys
`
`Thr --- Cys
`Thr --- Cys
`
`Cys
`
`Cys
`
`Thr Gly Cys
`Thr Gly Cys
`
`Cys
`Cys
`
`Thr Gly Cys
`Thr Gly Cys
`
`Cys
`
`Thr Gly Cys
`
`--- ---
`
`Tyr
`
`Tyr
`
`Tyr
`
`Tyr
`
`Tyr
`
`Tyr
`Tyr
`
`( SEQ ID NO:1 73 )
`( SEQ ID NO:1 74 )
`( SEQ ID NO: 1 75 )
`( SEQ ID NO: 176 )
`( SEQ ID NO: 1 77 )
`( SEQ ID NO: 1 78 )
`{ SEQ ID NO: 1 79 )
`{ SEQ ID NO: 180 )
`{ SEQ ID NO: 1 81 )
`{ SEQ ID NO: 1 82 )
`( SEQ ID NO: 1 83 )
`{ SEQ ID NO: 1 84 )
`( SEQ ID NO: 185 )
`{ SEQ ID NO: 1 86 )
`( SEQ ID NO: 1 87 )
`{ SEQ ID NO: 1 88 )
`( SEQ ID NO: 1 89 )
`( SEQ ID NO: 1 90 )
`( SEQ ID NO: 1 91 )
`( SEQ ID NO: 1 92 )
`{ SEQ ID NO: 193 )
`( SEQ ID NO: 1 94 )
`( SEQ ID NO: 1 95 )
`( SEQ ID NO: 1 96 )
`( SEQ ID NO:1 97 )
`( SEQ ID NO: 1 98 )
`( SEQ ID NO: 1 99 )
`{ SEQ ID NO:200 )
`( SEQ ID NO:201 )
`( SEQ ID NO:202 )
`( SEQ ID NO:203 )
`( SEQ ID NO:204 )
`{ SEQ ID NO:205 )
`( SEQ ID NO:206 )
`( SEQ ID NO:207 )
`( SEQ ID NO:208 )
`( SEQ ID NO:209 )
`( SEQ ID NO:2 1 0 )
`( SEQ ID NO:21 1 )
`( SEQ ID NO:212 )
`( SEQ ID NO:213 )
`( SEQ ID NO:21 4 )
`( SEQ I D NO:215 )
`( SEQ ID NO:21 6 )
`( SEQ ID NO: 21 7 )
`( SEQ ID NO:218 )
`
`Gly Cys
`
`Tyr
`
`Cys
`Gly Cys
`Cys
`
`Tyr
`
`Tyr
`
`Cys
`
`Thr
`
`Thr
`
`Thr Gly Cys
`
`Thr Gly Cys
`
`Tyr
`
`Thr Gly Cys
`
`Tyr
`
`Gly Cys
`
`Tyr
`
`Thr
`
`Cys
`
`Tyr
`
`Thr Gly Cys
`
`Gly Cys
`
`Tyr
`
`Cys
`
`Tyr
`
`Gly Cys
`
`FIG.
`
`1 1-2
`
`Cys Cys
`
`Cys Cys
`Cys Cys
`
`Glu
`
`Glu
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`Glu
`Glu --- Cys Cys
`Glu --- Cys Cys
`Glu --- Cys Cys
`Cys Cys
`
`Glu
`
`Tyr
`
`- - - Ala
`
`Cys
`
`Gly Cys
`
`Tyr
`
`Ala
`
`Cys
`
`Ala
`
`Cys
`
`Cys
`Cys
`
`Cys
`
`Thr - - - Cys
`Thr Gly Cys
`Thr Gly Cys
`Gly Cys
`Cys
`
`Thr
`
`Tyr
`
`Tyr
`Tyr
`
`Tyr
`
`Cys
`
`Thr Gly Cys
`
`Pro
`
`Pro
`
`Pro
`
`Pro
`
`Glu
`
`Cys Cys
`Cys Cys
`Cys Cys
`Cys Cys
`
`Cys Cys
`Cys Cys
`
`Cys Cys
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`
`Cys Cys
`Cys Cys
`Glu
`Glu --- Cys Cys
`Glu --- Cys Cys
`Glu --- Cys Cys
`Glu --- Cys Cys
`Glu --- Cys Cys Asn
`Glu --- Cys Cys Asn
`Glu - -- Cys Cys Asn
`Glu --- Cys Cys Asn
`Glu --- Cys Cys Asn
`Cys Cys
`Cys Cys Glu --- Cys Cys Asn --- Ala
`Cys Cys Glu --- Cys Cys Asn - - - Ala
`Cys
`Cys Cys Glu --- Cys Cys Asn - - - Ala Cys
`
`Pro Ala
`
`Cys
`
`Pro Ala
`
`Cys
`
`Pro Ala
`
`Cys
`
`Pro Ala
`
`Cys
`
`Pro Ala
`
`Cys
`
`Pro Ala
`
`Cys
`
`Ala
`
`Cys
`
`Cys
`
`Cys
`
`Cys
`
`Cys
`
`Cys
`
`Bausch Health Ireland Exhibit 2014, Page 23 of 106
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`U.S. Patent
`
`May 13, 2008
`
`Sheet 22 of 69
`
`US 7,371,727 B2
`
`--- ---
`--- ---
`
`( SEQ ID NO:21 9 )
`cys Cys Glu ---Cys Cys Asn ---Ala Cys Thr - --Cys Tyr
`( SEQ I D NO:220 )
`cys cys Glu Cys Cys Asn ---Ala Cys Thr --- Cys
`( SEQ ID NO:221 )
`Cys Cys Glu Cys Cys Asn ---Ala Cys Thr Gly Cys
`( SEQ ID NO:222 )
`Cys Cys Glu Cys cys Asn Pro Cys Thr Gly
`Cys Tyr
`( SEQ ID NO:223 )
`cys Cys Glu Cys Cys Asn Pro Cys ---Gly Cys Tyr
`( SEQ ID NO:224 )
`cys Cys Glu ---Cys Cys Asn Pro Cys --- --- Cys Tyr
`( SEQ ID NO:225 )
`Cys Cys Glu ---Cys Cys Asn Pro Cys ---Gly Cys ---
`( SEQ ID NO:226 )
`Cys Cys Glu ---Cys Cys Asn
`Pro --- Cys Thr ---Cys
`Tyr
`( SEQ 1D N0: 227 )
`Cys Cys Glu --- Cys Cys A.s n Pro ---Cys
`
`Thr ---Cys
`( SEQ ID NO: 228 )
`cys Cys Glu --- Cys Cys Asn Pro - -- Cys
`
`
`Thr Gly Cys
`( SEQ ID NO:229 )
`
`a Cys Cys Cys Glu ---Cys Cys Asn Pro Al
`
`Tyr
`---Gly Cys
`( SEQ ID NO:230 )
`Cys Cys Glu --- Cys Cys Asn Pro Ala Cys
`
`Tyr
`Cys
`( SEQ ID NO:231 }
`Cys Cys Glu Cys Cys Asn Pro Ala Cys
`Cys
`( SEQ ID NO:232 )
`Cys Cys Glu ---Cys Cys Asn Pro Ala Cys
`Cys
`---Gly
`( SEQ ID NO :233 )
`Cys Cys Glu --- Cys
`Cys Asn Pro Ala Cys
`Tyi:
`Thr - - -
`Cys
`( SEQ ID NO:234 )
`cys· cys Glu ---Cys Cys Asn Pro Ala Cys
`
`Thr --- Cys
`( SEQ ID NO:235 )
`Cys Cys Glu --- Cys Cys Asn Pro Ala
`Thr Gly Cys
`Cys
`( SEQ ID NO:236 )
`Cys Cys Glu Tyr Cys Cys Pro Ala
`Tyr
`Thr Gly Cys
`Cys
`( SEQ ID NO:237 )
`Cys Cys Glu Tyr Cys Cys - -- ---Ala Cys
`Thr Gly Cys
`Tyr
`( SEQ ID NO:238 )
`Cys Cys Glu Tyr Cys Cys ------ Cys
`
`Thr Gly Cys
`Tyr
`( SEQ ID NO:239 )
`Cys Cys .Glu T":,•r Cys Cys
`---Gly Cys
`Tyr
`Cys
`( SEQ ID NO:240 )
`
`Glu Tyr Cys Cys --- --- Cys
`Tyr
`Thr ---Cys
`Cys Cys
`( SEQ ID NO:241 )
`Cys cys Glu Tyr Cys Cys --- ---Cys
`Thr Gly Cys
`( SEQ ID NO:242 )
`Cys Cys Glu Tyr Cys Cys -�- ---Ala Cys
`---Gly Cys
`Tyr
`( SEQ ID NO:243 )
`Cys Cys Glu Tyr Cys Cys ------Ala Cys
`--- ---Cys
`Tyr
`( SEQ ID NO:244 )
`Cys Cys Glu Tyr Cys
`Cys ---Ala Cys
`---Gly Cys
`( SEQ ID NO:245 )
`Cys Cys Glu Tyr Cys Cys ---Ala Cys
`Thr ---Cys
`Tyr
`( SEQ ID NO:246 )
`cys Cys Glu Tyr Cys Cys ---Ala Cys
`Thr ---Cys
`( SEQ ID NO:247 )
`Cys Cys Glu Tyr Cys Cys ---Ala Cys
`Thr Gly Cys
`( SEQ ID NO:248 )
`Cys Cys Glu Tyr Cys Cys Pro Cys
`Thr Gly Cys
`Tyr
`( SEQ 1D NO:249 )
`Cys Cys Glu Tyr Cys Cys Pro Cys
`Tyr
`Gly Cys
`( SEQ ID NO:250 )
`Cys Pro Cys
`Cys Cys Glu Tyr Cys
`---Cys
`Tyr
`( SEQ 10 NO:251 }
`Cys Cys Glu 'lyr Cy:s Cys Pro Cys
`Gly Cy:s
`( SEQ ID NO:252 }
`Cys Cys Pro Cys
`cys Cys Glu Tyr
`Thr --- Cys
`Tyr
`( SEQ ID NO: 253 )
`Cys Cys Glu Tyr Cys Cys Pro ---Cys
`Thr ---Cys
`( SEQ ID NO: 254 )
`cys Cys Glu Tyr Cys Cys ---Pro ---Cys
`Thr Gly Cys
`( SEQ ID N0:255)
`Cys Cys Glu Tyr Cys Cys Pro Ala Cys
`Gly Cy:s
`Tyr
`( SEQ ID N0: 256 )
`Cys Cys Glu Tyr Cys
`Cys Pro Ala Cys
`Tyr
`Cys
`( SEQ ID NO:257 )
`Cys Cys Glu Tyr Cys Cys Pro Ala Cys
`Cys
`( SEQ ID NO: 258 )
`cys Cys Glu Tyr Cys Cys Pro Ala Cys
`Gly Cys
`( SEQ ID NO: 259 )
`Cys Cys Glu Tyr Cys
`Cy:s ---Pro Ala
`Thr Cys
`Cys
`Tyr
`( SEQ ID NO:260 )
`
`Cys Cys Glu Tyr Cys Cys ---Pro Ala
`