`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 6 :
`
`(11) International Publication Number:
`
`W0 99/43705
`
`C07K 14/605, A61K 38/26, A61P 3/04,
`3/10, 5/50
`
`(43) International Publication Date:
`
`2 September 1999 (02.09.99)
`
`(21) International Application Number:
`
`PCT/DK99/00081
`
`(22) International Filing Date:
`
`25 February 1999 (25.02.99)
`
`(30) Priority Data:
`0264/98
`0509/98
`
`27 February 1998 (27.02.98)
`8 April 1998 (08.04.98)
`
`DK
`DK
`
`(71) Applicant: NOVO NORDISK A/S [DK/DK]; Novo A116,
`DK—2880 Bagsvaerd (DK).
`
`(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
`BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD,
`GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP,
`KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK,
`MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG,
`SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZW,
`ARIPO patent (GH, GM, KE, LS, MW, SD, SL, SZ, UG,
`ZW), Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`TM), European patent (AT, BE, CH, CY, DE, DK, ES, FI,
`FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OAPI patent
`(BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE,
`SN, TD, TG).
`
`amino acid residue.
`
`(72) Inventors: KNUDSEN, Liselotte, Bjerre; Valby Langgade
`49A, 1.
`tv., DK—2500 Valby (DK). HUUSFELDT, Per,
`Olaf; Applebys Plads 27,5. mf., DK—1411 Copenhagen K
`(DK).
`
`Published
`With international search report.
`
`(54) Title: N—TERMINALLY TRUNCATED GLP—l DERIVATIVES
`
`(57) Abstract
`
`The present invention relates to N—terminally truncated derivatives of human glucagon—like peptide—l (GLP—1) and analogues thereof
`having a protracted profile of action, as well as the use of such derivatives in pharmaceutical compositions for the treatment of obesity,
`insulin dependent or non—insulin dependent diabetes mellitus. The GLP—l derivatives have a lipophilic substituent attached to at least one
`
`MYLAN INST. EXHIBIT 1032 PAGE 1
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`MYLAN INST. EXHIBIT 1032 PAGE 1
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`MYLAN INST. EXHIBIT 1032 PAGE 1
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`
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`cote d’lvoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungao'
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People’s
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Zimbabwe
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`Slovenia
`SI
`LS
`Lesotho
`ES
`SK
`Slovakia
`LT
`Lithuania
`FI
`SN
`LU
`FR
`Senegal
`Luxembourg
`SZ
`Swaziland
`LV
`Latvia
`GA
`Chad
`TD
`Monaco
`MC
`GB
`TG
`MD
`GE
`Togo
`Republic of Moldova
`MG
`TJ
`GH
`Madagascar
`Tajikistan
`TM
`Turkmenistan
`MK
`GN
`The former Yugoslav
`TR
`GR
`Turkey
`Republic of Macedonia
`TT
`Mali
`HU
`Trinidad and Tobago
`Ukraine
`UA
`IE
`Mongolia
`UG
`Mauritania
`IL
`Uganda
`US
`United States of America
`Malawi
`IS
`UZ
`Uzbekistan
`Mexico
`IT
`VN
`Viet Nam
`JP
`Niger
`YU
`Netherlands
`KE
`Yugoslavia
`ZW
`KG
`Norway
`New Zealand
`KP
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`MYLAN INST. EXHIBIT 1032 PAGE 2
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`MYLAN INST. EXHIBIT 1032 PAGE 2
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`MYLAN INST. EXHIBIT 1032 PAGE 2
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`
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`WO 99/43705
`
`PCT/DK99/00081
`
`_ 1 _
`
`N-TERMINALLY TRUNCATED GLP-1 DERIVATIVES
`
`FIELD OF THE INVENTION
`
`The present invention relates to novel derivatives of human glucagon-like peptide-1
`
`(GLP-1) and fragments analogues thereof having a protracted profile of action and to the use of
`
`such derivatives in pharmaceutical compositions.
`
`BACKGROUND OF THE INVENTION
`
`GLP-1 (Glucacon-Like-Peptide—1) is an important gut hormone with regulatory function in
`
`glucose metabolism and gastrointestinal secretion and metabolism. Human GLP-1 is a 37 amino
`
`acid residue peptide originating from preproglucagon which is synthesised i. a. in the L-cells in the
`
`distal ileum, in the pancreas and in the brain. Processing of preproglucagon to give GLP-1(7-
`
`36)amide, GLP-1(7-37) and GLP-2 occurs mainly in the L-cells.
`
`WO 87/06941 (The General Hospital Corporation) disclose peptide fragments which
`
`comprises GLP-1(7-37) and functional derivatives thereof and to its use as an insulinotropic
`
`10
`
`15
`
`agent
`
`WO 90/11296 (The General Hospital Corporation) disclose peptide fragments which
`
`comprise GLP-1(7-36) and functional derivatives thereof and have an insulinotropic activity which
`
`exceeds the insulinotropic activity of GLP-1 (1 -36) or GLP-1(1-37) and to their use as
`
`20
`
`insulinotropic agents.
`
`The amino acid sequence of GLP-1(7-36)amide and GLP-1(7-37) is:
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`His—Ala—Glu—Gly—Thr—Phe—Thr—Ser—Asp—Val—Ser-Ser—Tyr—Leu—Glu—Gly—Gln—
`
`25
`
`24
`
`25
`
`26
`
`27
`
`28
`
`29
`
`3O
`
`31
`
`32
`
`33
`
`34
`
`35
`
`36
`
`(I)
`
`Ala—Ala—Lys—Glu—Phe—I1e-Ala—Trp—Leu—Val—Lys—Gly—Arg—X
`
`wherein X is NH2 for GLP-1(7—36)amide and X is Gly—OH for GLP-1(7-37).
`
`WO 91/11457 (Buckley et al.) discloses analogues of the active GLP-1 peptides 7-34, 7-
`
`35, 7-36, and 7-37.
`
`30
`
`WO 98/08871 discloses GLP-1 derivatives in which a lipophilic substituent is attached to
`
`at least one amino acid residue. The lipophilic substituents are in particular long-chain groups
`
`containing e.g. 12-24 carbon atoms.
`
`EP 0699686-A2 (Eli Lilly & Co.) discloses certain N-terminal truncated fragments of GLP—
`
`1 that are reported to be biologically active.
`
`SUBSTITUTE SHEET (RULE 23)
`
`MYLAN INST. EXHIBIT 1032 PAGE 3
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`MYLAN INST. EXHIBIT 1032 PAGE 3
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`MYLAN INST. EXHIBIT 1032 PAGE 3
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`
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`WO 99/43705
`
`'
`
`PCT/DK99/00081
`
`- 2 -
`
`>
`
`It is an object of the present invention to provide improved N-terminal truncated
`
`fragments of GLP-1.
`
`SUMMARY OF THE INVENTION
`
`In its broadest aspect, the present invention relates to derivatives of GLP-1 and
`
`analogues thereof. The derivatives according to the invention have interesting pharmacological
`
`properties, including a protracted profile of action. The derivatives also are more metabolically
`
`and physically stable, and more soluble.
`
`The GLP-1 derivatives and analogues of the present invention are truncated at the N-
`
`terminal end and comprise a lipophilic substituent (optionally via a spacer) attached to at least
`
`one amino acid residue. The lipophilic substituent is in particular a long-chain group of the type
`
`described in WO 98/08871 (Novo Nordisk A/S).
`
`In particular, the invention relates to an N-terminal truncated GLP-1 derivative comprising
`
`a parent peptide of formula II
`
`A — GLP-1(19—B) — X
`
`(ll)
`
`wherein
`
`A is a peptide comprising the amino acid residues of GLP-1(8-18) or a fragment thereof;
`
`B is an integer in the range of 35-45; and
`
`X is —OH, —NH2, or a CH; alkyl amide or CH, dialkyl amide group;
`
`or an analogue thereof;
`
`and wherein a lipophilic substituent is attached to at least one amino acid residue.
`
`10
`
`15
`
`20
`
`25
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`A simple system is used to describe the GLP-1 derivatives of the present invention. For
`
`example, GlyB-GLP-1(7-37) designates a fragment which relates to GLP-1(1-37) by the deletion
`
`of the amino acid residues at poSitions 1 to 6 and the substitution of the naturally occurring
`
`amino acid residue in position 8 (Ala) with Gly. Similarly, Lys34(N‘-tetradecanoyl)—GLP—1(7-37)
`
`30
`
`designates GLP-1(7-37) wherein the a—amino group of the Lys residue in position 34 has been
`
`tetradecanoylated. Where a reference is made to C—terminally extended GLP-1 analogues, the
`
`amino acid residue in position 38 is Arg unless othenivise indicated, the amino acid residue in
`
`position 39 is also Arg unless otherwise indicated and the amino acid residue in position 40 is
`
`Asp unless otherwise indicated. Also, if a C—terminally extended analogue extends to position 41,
`
`MYLAN INST. EXHIBIT 1032 PAGE 4
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`MYLAN INST. EXHIBIT 1032 PAGE 4
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`MYLAN INST. EXHIBIT 1032 PAGE 4
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`
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`WO 99/43705
`
`'
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`PCT/DK99/00081
`
`_ 3 _
`
`42, 43, 44 or 45, the amino acid sequence of this extension is as in the corresponding sequence
`
`in human preproglucagon unless othenNise indicated.
`
`The present invention relates to derivatives of native GLP-1 and derivatives of GLP-1
`
`analogs.
`
`In a preferred embodiment, the derivatives are derivatives of native GLP-1(8-45) or a
`
`fragment thereof. In a more preferred embodiment, the derivatives are derivatives of native GLP-
`
`1(8-36). In another more preferred embodiment, the derivatives are derivatives of native GLP-
`
`1(8-37). In another more preferred embodiment, the derivatives are derivatives of native GLP-
`
`1(8-38).
`
`In a preferred embodiment of GLP-1 derivatives of the present invention, A is a peptide
`
`selected from the group consisting of GLP-1(8—18), GLP-1(9-18), GLP-1(10-18), GLP-1(11-18),
`
`GLP-1(12-18), GLP-1(13-18), GLP-1(‘i4-18), GLP-1(15-18), GLP-1(16-18), GLP-1(17-18) and
`
`GLP-1(18). Preferably, A is GLP-1(8-18), GLP—1(9-18), GLP-1(10-18), GLP-1(11-18) or GLP-
`
`1(12—18), and B is 36, 37 or 38. Most preferably, A is GLP-1(8-18).
`
`In a preferred embodiment of GLP-1 derivatives of the present invention, B is 35, 36, 37,
`
`38, 39, 40, 41,42, 43 or 44. In a more preferred embodiment, B is 36.
`
`In another more preferred
`
`embodiment. B is 37.
`
`In another more preferred embodiment, B is 38.
`
`GLP-1 Analogs
`
`The present invention also relates to derivatives of analogs of GLP-1. The term
`
`“analogue” is defined herein as a peptide which relates to a parent peptide by the substitution of
`
`one or more amino acid residues of the parent peptide with other amino acid residue(s).
`
`In the GLP-1 derivatives of formula II, up to fifteen, preferably up to ten amino acid
`
`residues may be exchanged with any or-amino acid residue, in particular with any a—amino acid
`
`residue which can be coded for by the genetic code. Preferred analogues are those in which up
`
`to six amino acid residues have been exchanged with any oc-amino acid residue which can be
`
`coded for by the genetic code.
`
`Preferred GLP-1 derivatives or analogues are those in which:
`
`A is selected from the group consisting of GLP-1(8-18), GLP-1 (9-18) and GLP-1(10-18);
`
`i)
`
`and
`
`ii)
`
`B is 36, and the parent peptide comprises one or more amino acid substitutions selected
`
`from the group consisting of Arg”, Arg34 and Lys36;
`
`B is 37, and the parent peptide comprises one or more amino acid substitutions selected
`
`from the group consisting of Argzs, Arga“, Lysa‘5 and Lys37; or
`
`B is 38, and the parent peptide comprises one or more amino acid substitutions selected
`
`from the group consisting of Arg”, Arg3“, Lys36 and Lys”.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`MYLAN INST. EXHIBIT 1032 PAGE 5
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`MYLAN INST. EXHIBIT 1032 PAGE 5
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`MYLAN INST. EXHIBIT 1032 PAGE 5
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`
`
`WO 99/43705
`
`PCT/DK99/00081
`
`_ 4 _
`
`In a further preferred embodiment, a parent peptide for a derivative of the invention is
`
`Argzs-GLP-1(8-37); Arg‘“—GLP-1 (8—37); Lys36-GLP-1(8-37);
`
`Argzs'MLysas-GLP-1 (8-37); Argzs'MLysmGLP-1 (8-38);
`
`Arg2wLys39-GLP-1 (8-39); Argze-“Lysm-GLP-t (8—40);
`
`ArgzsLysas-GLP—1 (8~37); ArguLysss—GLP-1(8-37);
`
`ArgzsLysa9-GLP-1 (8—39); Arg3‘Lys“°-GLP-1(8-40);
`
`Arg’e-“Lysas'ag-GLPJ (8-39); Argze'MLysmm-GLP-1 (8-40);
`
`GlyBArgze-GLP-1 (8-37); GlyaArgu-GLP-1 (8-37);
`
`GlyBLysae-GLP-1(8-37); GIyBArgze'“Lys"6-GLP-1(8—37);
`
`GlyBArgzs'MLysag-GLP—i (8—39); GinArgzs'MLysm-GLP-1 (8-40);
`
`GlyaArgzsLysas-GLP-1(8-37); GlyBArguLysas-GLPJ (8-37);
`
`GlyaArgzsLys39-GLP—1 (8-39); GlyaArg34Lys40-GLP-1 (8-40);
`
`GlysArgze'MLysw'sg-GLP-1(8-39); or
`
`GlyaArgzs'“Lys"6-4°-GLP-1 (8-40).
`
`In a further preferred embodiment, a parent peptide for a derivative of the invention is:
`
`10
`
`15
`
`Argzs'MLys”GLP-1 (8—38);
`
`Argzs'MLys39GLP-1 (8-39);
`
`Argze'MLys‘wGLP-1 (8-40);
`
`Argzs'uLys4‘GLP—1 (8-41 );
`
`20
`
`Argzs'MLys42GLP-1 (8-42);
`
`Argzs'MLys43GLP-1 (8-43);
`
`Argze'MLys‘“GLP-1 (8—44);
`
`Argzs'MLys45GLP-1 (8-45);
`
`ArgzsLysaaGLP—1 (8-38);
`
`25
`
`Arg34Lys38GLP-1 (8-38);
`
`ArgmLys36~38GLP-1 (8-38);
`
`Argzs'MLysssG LP-1 (8-38);
`
`ArgzeLysssGLP-1 (8—39);
`
`Arg3‘Lys39GLP-1(8-39); or
`
`30
`
`ArgZG'MLysse'SSGLP—1 (8-39).
`
`In a further preferred embodiment, the present invention relates to a GLP-1 derivative
`
`wherein the parent peptide is selected from the group comprising ArgZG-GLP-1(8-37), Argy-GLP-
`
`1(8-37), Lys“-GLP—1(8-37), Argzs'a‘Lysa’S-GLP-1(8-37), ArgZGLys36-GLP-1(8-37), ArgMLysas-GLP-
`
`1(8-37), GlyaArgzs-GLP-1(8-37). G|y8Arg“-GLP-1(8-37), GIyBLys36-GLP—1(8-37), GlyBArgzs'MLysw-
`
`35
`
`GLP-1(8-37), GIyBArgzeLysae-GLP-1(8-37), and GlyaArguLysae-GLPJ (8-37).
`
`MYLAN INST. EXHIBIT 1032 PAGE 6
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`MYLAN INST. EXHIBIT 1032 PAGE 6
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`MYLAN INST. EXHIBIT 1032 PAGE 6
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`
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`WO 99/43705
`
`'
`
`PCT/DK99/00081
`
`_ 5 -
`
`In a further preferred embodiment, the present invention relates to a GLP-1 derivative
`
`wherein the parent peptide is selected from the group comprising ArgzeLysas-GLP-1(8-38),
`
`Argzs'MLys38-GLP-1(8-38), Argze'MLysas'as-GLP-i (8-38), GlyaArgzeLysas-GLPJ (8—38) and
`
`GlyaArgza'uLysz's'”-GLP-1 (8-38).
`
`In a further preferred embodiment, the present invention relates to a GLP-1 derivative
`
`wherein the parent peptide is selected from the group comprising ArgzeLysag-GLP-1(8—39),
`
`Argze'MLysas-sg-GLP-1(8—39), GlyeArgzeLysag-GLP-l (8-39) and Gly3Argze'34Lys36'39-GLP-1(8-39).
`
`In a further preferred embodiment, the present invention relates to a GLP-1 derivative
`
`wherein the parent peptide is selected from the group comprising Arg34Lys4°-GLP-1(8-40),
`
`Argzs'MLysae'40-GLP-1(8—40), GlyaArg34Lys4°-GLP-1(8-40) and GlyeArgzs'MLys36'4°-GLP-1(8—40).
`
`In a further preferred embodiment, the present invention relates to a GLP-1 derivative
`
`wherein the parent peptide is:
`
`Argze-GLP-t (8-36); Arga“-GLP-1 (8—36); ArgZG'MLysae-GLP-1 (8-36); Argze-GLP-1 (8-36)amide;
`
`Arg“-GLP-1(8-36)amide; Argzs'a‘Lysaa-GLPJ (8-36)amide; Argzs-GLP—l (8-37); Arg“-GLP-1(8—37);
`
`Argzs'MLysae-GLPJ (8—37); Argzs-GLP-1(8-38); ArgM-GLP—1 (8-38);
`
`Argze'MLysaaGLP-1 (8—38); ArgZS-GLP—1(8—39); Arg“—GLP-1(8—39);
`
`Argzs'MLys39-GLP-1 (8-39); GlyaArgzs-GLP-1 (8—36);
`
`GlyBArgu-GLP-1(8-36); GIySArgzs'y'Lysae-GLPJ (8-36);
`
`GlyaArgzs-GLP-1(8-36)amide; GlyaArgm-GLP-1(8-36)amide;
`
`GlyBArgza'MLysae-GLPJ (8-36)amide; GlyaArgze-GLP-1 (8-37);
`
`GlysArgu-GLP-1(8-37); GlyBArgzs'MLysas—GLPJ (8-37);
`
`GlyaArgzs-GLP-1 (8-38); Gly"Arg“-GLP-1 (8-38);
`
`GIyBArgzs'MLysm’GLP-1 (8—38); GlyaArgzs-GLP-1(8-39);
`
`GlyBArgu—G LP-1 (8-39); GlyaArgzs'MLys39-GLP-1 (8-39);
`
`ValaArgzs-GLP-1 (8-36); ValaArQM-GLP-1(8-36);
`
`ValBArgzs'“Lys°6-GLP-1 (8-36); ValaArgze—GLP-l (8-36)amide;
`
`ValBArgu-GLP-1(8—36)amide; ValaArgza'S‘LySSS-GLP-t (8-36)amide;
`
`ValeArgze-GLP-1(8-37); ValBArgu-GLP-1 (8-37);
`
`ValsArgzs'MLysa’s-GLP-t (8-37); VaIBArgze-GLP-1 (8-38);
`
`ValBArgu-GLP-1(8-38); ValBArgze'“Lys38GLP-1(8-38);
`
`ValaArgzs-GLP-1 (8-39); ValBArg34-GLP-1(8-39);
`
`ValaArgzs'MLyssg-GLP-l (8-39); SerBArgzs—GLP—1 (8-36);
`
`SerBArgm-GLP-t (8—36); SersArgze'a‘Lysas—GLP-1 (8-36);
`
`SeraArgze-GLP-1 (8-36)amide; SeraArgm-GLP-t (8-36)amide;
`
`SerBArgzs'MLysaa-GLPJ (8-36)amide; SerBArgze-GLP-1(8-37);
`
`1O
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`15
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`20
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`25
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`30
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`35
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`MYLAN INST. EXHIBIT 1032 PAGE 7
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`MYLAN INST. EXHIBIT 1032 PAGE 7
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`MYLAN INST. EXHIBIT 1032 PAGE 7
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`
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`WO 99/43705
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`‘
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`PCT/DK99/0008l
`
`_ 5 _
`
`SerBArgu-GLP—1 (8-37); SeraArgze'MLysss-GLPJ (8-37);
`
`SeIflArgze-GLP-‘l (8-38); SeI‘BArg“-GLP-1 (8-38);
`
`SereArgzs'uLysaaGLP-1(8-38); SePArgze-GLP-1 (8-39);
`
`SerBArg34-GLP-1 (8-39); SersArgzs'MLySSQ-GLPJ (8-39);
`
`Thr8Argze-GLP-1 (8-36); ThraArQM-GLP-1 (8—36);
`
`Th [BArgze'MLysss-GLPJ (8-36); ThraArgze-GLP-1 (8-36)amide;
`
`ThrBArgu-GLP-1 (8-36)amide; ThraArgzs'MLysas-GLPJ (8-36)amide;
`
`ThrBArgze—GLP-1 (8-37); ThrBArQM-GLP-1 (8-37);
`
`ThraArgzs'MLysa5-GLP-1(8-37); ThPArgZS-GLP-1 (8-38);
`
`10
`
`ThrBArgu-GLP-1 (8-38); ThtaArgzsleys38GLP-1 (8-38);
`
`ThraArgze-GLP-1 (8-39); Th raArgu-GLP-1 (8-39);
`
`ThrBArgze'MLysag—GLP-1 (8-39); Val8G|u35Argzs'34Lysse-GLP-1(8-36);
`
`ValaGlu35Argz‘5-34Lys36-GLP-1(8-36)amide; ValBGlu36Argzs'34Lysa7GLP-1 (8-37);
`
`Val8G|u37Argze'3‘Lys”GLP-1(8-38); ValBGluaeArgZG'MLyss9-GLP-1(8-39); VaIBGlu35Argzs'“Lys36-GLP-
`
`15
`
`1(8-36);
`
`VaIBGluasArgzs'MLysae-GLPJ (8-36)amide; VaIBGIuaeArgze'MLysflGLP-1(8-37);
`
`ValaGlu37Argza'34Lys35GLP-1 (8-38);
`
`VaIBGlu38Argze'34Lys39—GLP-1(8-39); ValsAsp35Argze'34Lys36-GLP-1(8-36); ValBAsp35Argzev34Lysas-
`
`GLP—1(8-36)amide;
`
`VaIBAspmArgzs-“LystLP-1(8—37); VaIBAsp37Argze'34LysasGLP-1(8-38); ValaAsp38Argzs'34Lysag-
`
`GLP-1 (8-39); ValsAsp35Argzs'3‘Lys36-GLP-1(8-36); ValsAsp35Argz‘5'3‘Lys36—GLP—1 (8-36)amide;
`
`VaIBAspseArgzs'uLySWGLP-1(8-37); VaIBAsp37Argzs'3“LysaaGLP-1(8-38); ValaAspaaArgze'MLy539-
`
`GLP-1(8-39);
`
`SeraGlu35Argze'34Lysa‘5-GLP-1(8-36); SerBGluasArgze'uLysw—GLP-1 (8—36)amide;
`
`SerSGluasArgze-“LystLP-1 (8-37);
`
`SerBGlu37Argze'34LyssaGLP-1(8-38); SersG|u33Argzs'34Lys39-GLP-1(8-39); SerBGlu35Argzs'34Lys35-
`
`GLP-1(8-36); SeraGluasArgzs'MLysae-GLP-1(8-36)amide; SereGluaeArgze'MLysNGLP-1(8—37);
`
`SePGlu37Argze'34LysaeGLP-1(8-38); SersGIUSSArgZB'MLysag-GLP-1(8-39); SerBAsp35Argze'34Lys36-
`
`GLP-1 (8-36); SeraAsp35Argzs'34Lysas-GLP-1 (8-36)amide; SerBAspaeArgzs'MLysa7GLP-1 (8—37);
`
`SerBAsp37Argze'34LystLP-1(8-38); SeraAspaaArgzs'MLy539-GLP-1(8-39); SerBAsp35Argze'34Lys36-
`
`GLP—1 (8-36); Ser‘BAspasArgzs'MLyse’s-GLP-1 (8-36)amide; SerBAsp3aArgze'34Lysa7GLP-1 (8—37);
`
`SersAsp37Argzs'34Ly533GLP-1(8-38); SerBAspaaAr925'3‘Ly539-GLP-1(8—39); Thr8G|u35Argzs'3“Ly536-
`
`GLP-1 (8-36); ThraGluasArgzs'MLysae-G LP-1 (8—36)amide; ThraGlufiArgzs'MLysa7GLP-1 (8-37);
`
`ThraGlu37Argze'34Lys33GLP-1(8—38); ThraGluaaArgza'MLySSQ-GLP-1(8-39); ThraGlu35Arg25'34Ly536—
`
`GLP-1 (8—36); ThPGIu35Argze'34Lysae-GLP-1 (8-36)amide; ThraGluaeArgze'MLysaG LP-1 (8-37);
`
`20
`
`25
`
`30
`
`35
`
`MYLAN INST. EXHIBIT 1032 PAGE 8
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`MYLAN INST. EXHIBIT 1032 PAGE 8
`
`MYLAN INST. EXHIBIT 1032 PAGE 8
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`
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`WO 99/43705
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`'
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`PCT/DK99/0008l
`
`_ 7 _
`
`ThraGlu37Argzs'34Lys3BGLP-1 (8-38); ThrBGlumArgzs'MLysw—GLP-1 (8-39);
`
`ThraAsp35Argz‘5'34Lys35-GLP-1 (8-36); Thr8Asp35Ar926'3‘Ly336—GLP~1 (8-36)amide;
`
`ThraAspssArgze'MLysa7GLP-1 (8-37);
`
`ThraAsp37Argzs'34Ly338GLP-1(8-38); ThreAspmArgze'uLysse-GLP-1(8-39); ThrsAsp35Argz‘5’34Ly336-
`
`GLP-1 (8-36); ThFAsprrgze-“Lysae-GLP-1 (8-36)amide; ThraAspasArgzs'MLyss7GLP—1(8-37);
`
`ThrBAsp37Argza'34LysasGLP-1 (8-38); ThrBAspSBArgzs'MLysss-GLP-1 (8-39);
`
`GlyaGlussArgze'MLysae-GLP-1 (8-36); GlyBGlU35Argzs'34Lysss-GLP-1(8-36)amide;
`
`GlyaGluwArgzs'MLysyGLP-1 (8-37);
`
`Gly3G|u37Argzs'34Lys38GLP-1(8—38); GlyBGIusaArgzs'MLys39-GLP-1(8-39); GlyBGlu35Argzs'34Lysas-
`
`GLP-1 (8-36); GlyBG|u35Argzs'“Lysss-GLP-1 (8-36)amide; GIyBGIusBArgWLySNGLP-1 (8-37);
`
`Gly°G|u37Argze'34Lys3aGLP-1(8—38); GIyaGlu38Argze'34Ly539-GLP-1(8—39); GlyaAsp35Argzs'34Lysae-
`
`GLP-1(8-36); GlyaAspasArgzs-“Lysas—GLP-1 (8-36)amide; GlyaAspaeArgzs'MLystLP-1 (8-37);
`
`G|y8ASp37ArgzwLysmGLP~1(8-38); GIyBAsp38Argze'34Lysa9-GLP-1(8—39); GlyaAsp35Argzev34Lysae-
`
`GLP-1(8—36); GlyaAsp35Argzs-“Ly836-GLP-1 (8-36)amide; GlyaAspaaArgze'flysflGLP-1 (8-37);
`
`GIyBAsp37Argze'34LysaaGLP-1 (8-38); GIyBAsprrgzs'MLyssg-GLP-1(8-39); Argze'MLys‘B-GLPJ (8—36);
`
`Argzs'MLys‘B-GLPJ (8-36)amide; Argze'MLys‘aGLP-1(8-37); Argzs'MLys‘aGLP-1 (8-38);
`
`GlyBAsp‘9Ar926'3‘Lys‘B-GLP-1(8-36); GIyBAsp‘7Ar926'34Lys18-GLP-1(8-36); GlyBAsp‘QArgzs'“Lys‘8-
`
`GLP-1(8-36)amide; GIyBAsp17Ar926-34Lys‘8-GLP-1(8—36)amide; GlyBAsp19Argze-34Lys18GLP-1 (8-37);
`
`GlyeAsp‘9Argzs'3‘Lys‘BGLP—1 (8—38); GIyBAsp‘7Argzs'34Lys‘8GLP-1 (8-38);
`
`Argzs'“Ly523-GLP-1(8-36); Argze'34Ly323-GLP-1 (8-36)amide; Argze'MLyszaGLP-1 (8-37);
`
`Argze'MLyszaGLP-1 (8—38); GlysAspz‘Argze'MLysn-GLP—1 (8—36); GlyBAspzzArgzs'uLysza—GLP-1(8-36);
`
`GlyaAsp24Ar926'3‘LySZ3-GLP-1(8-36)amide; GlyBAspzzArgzs'MLysza-GLP-1 (8-36)amide;
`
`GIyBAsp24Argzs'34LyszaGLP-1(8-37); GIyBAsp24Argzs'34LySZ3GLP-1(8-38); GIy8Asp22Argze'34Ly523GLP-
`
`1(8-38);
`
`Argzs-“LySZ7-GLP-1(8-36); Argzs-“Ly527-GLP-1 (8-36)amide; Argzs'MLySZ7GLP-1(8-37);
`
`Argzs'MLysz7GLP-1 (8-38); GlysAspzaArgze'MLysfl-GLP-1 (8-36); GlyBAspzeArgze'MLysy-GLP-1 (8-36);
`
`G|y8Asp28Argzs'34Ly527-GLP-1 (8—36)amide; GlysAspzsArgzs'MLysm-GLP-1 (8-36)amide;
`
`GlyaAspZBArgzs'MLysfiGLP-1(8—37); GlyaAspZBArgzs'MLysflGLP-1(8-38); GIyBAspzeArgze'MLysflGLP-
`
`1(8-38);
`
`Argzs'MLys‘B-GLP-1(8-36); Argza'MLys‘B-GLPJ (8—36)amide; Argza'MLys‘BGLP-1(8-37);
`
`Argzs'MLys18GLP-1 (8-38); VaIBAsp19Argzs'34Lys‘8-GLP-1 (8-36); VaIBAsp‘7Ar926'34Lys18-GLP-1(8-36);
`
`ValaAsp‘gArgzs'“Lys‘8-GLP-1 (8—36)amide; ValeAsp17Argzs'34Lys1B-GLP-1 (8—36)amide;
`
`VaIaAsp‘gArgzs'“Lys‘BGLP-1(8-37); VaIBAsp‘gArgzs'MLys1BGLP-1(8-38); VaIBAsp‘7Argze'34Lys18GLP-
`
`1 (8—38);
`
`10
`
`15
`
`20
`
`25
`
`30
`
`MYLAN INST. EXHIBIT 1032 PAGE 9
`
`MYLAN INST. EXHIBIT 1032 PAGE 9
`
`MYLAN INST. EXHIBIT 1032 PAGE 9
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`
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`WO 99/43705
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`7
`
`PCT/DK99/00081
`
`- 3 _
`
`Argza'MLysza-GLPJ (8—36); ArgZG-“Lysza-GLPJ (8-36)amide; Argze'MLysszLP-1 (8-37);
`
`Argze'MLyszaGLP—1(8-38); VaIBAspz‘Argze'MLysza-GLP-1(8-36); ValsAspzzArgzs‘MLysza-GLP-1 (8-36);
`
`ValaAspz‘Argzs'MLysm-GLP-1(8-36)amide; ValeAspzzArgze'MLysza-GLP-1 (8—36)amide;
`
`VaIBAspz‘Argze'MLyszaGLP-1(8-37); VaIBAsp24Argze'34Lys23GLP-1(8-38); VaIBAsp22Argzs'34Lysz3GLP-
`
`1(8-38);
`
`ArgZG'MLySZ7-GLP-1(8-36); Argzs'MLy527-GLP-1 (8-36)amide; Argzs'MLy327GLP-1(8-37);
`
`Argze'uLy527GLP-1 (8-38); VaIBAsp28Argzs'34Ly527-GLP-1(8-36); ValaAspzeArgzs'MLysfl-GLP-1 (8-36);
`
`VaIBAspzaArgzs'uLysm-GLP-1(8-36)amide; VaIBAspZSArgzs-“Lysm-GLP-1 (8-36)amide;
`
`VaIBAspzaArgze'“Lysz7GLP-1(8-37); VaIBAspzaArgze'a‘LysflGLP-1(8—38); VaIBAspzeArgzs'MLysflGLP-
`
`10
`
`1(8-38);
`
`Argze'mLys‘B-GLP-1 (8—36); Argzs'MLys‘B-GLP-1 (8-36)amide; Argze'“Lys‘8GLP-1(8-37);
`
`Argzs'MLys‘sGLP-1 (8—38); SePAsp‘gArgm'MLys‘B—GLP-1 (8-36); SerBAsp‘7Argzs'34Lys‘8-GLP-1 (8—
`
`36); SersAsp‘gArgza-“Lysw-GLP—1(8—36)amide; SerBAsp‘7Argzs’34Lys‘8-GLP-1(8-36)amide;
`
`SerBAsp‘sArgze'MLys‘BGLP-1 (8—37); SeraAsp‘SArgzs'MLys‘BGLP-1(8-38);
`
`SereAsp‘7Argzs'34Lys‘BGLP-1 (8-38);
`
`Argze'uLys23-GLP-1 (8-36); Argzs'uLysza-GLPJ (8-36)amide; Argz‘5’34Ly523GLP-1 (8-37);
`
`Argza'MLy523GLP-1 (8-38); SeraAsp24Argze'34Lysza-GLP-1 (8-36); SerBAspZZArgze'“Lysza-GLP-1 (8-
`
`36); SerSAsp24Ar926'34Lys23-GLP-1(8-36)amide; SerBAspZZArgzs'MLysza-GLPJ (8-36)amide;
`
`SeraAspz‘Argzs'MLyszaGLP-1 (8—37); SerBAsp24Argzs'34LyszaG LP-1 (8-38);
`
`SeraAspzzArgzs-“LysszLP-1 (8-38);
`
`Argzs'MLysfl-GLPJ (8-36); Argzs'MLy527—GLP-1(8-36)amide; Argzs'MLy527GLP-1(8-37);
`
`Argze'“Ly527GLP-1(8-38); SerBAspzaArgzs'MLysfl-GLP-1 (8-36); SeraAspzsArgza'MLySN-GLP-1(8-
`
`36); SerBAspZBArgzs'“LysZ7-GLP-1(8-36)amide; SerBAspZGArgze'“Ly527-GLP-1(8-36)amide;
`
`15
`
`20
`
`SeraAspZBArgzs'uLysfiGLP—1(8—37); SerEAspzaArgzwLysflGLP-1 (8-38);
`
`25
`
`SeraAspzaArgzs'MLysyGLP-1 (8-38);
`
`Argzs'MLys‘B-GLPA (8-36); Arng-“Lys‘B-G LP-1 (8-36)amide; Argzs'MLys‘BGLP—1 (8-37);
`
`Argze'“Lys‘“GLP-1(8-38); ThraAsp‘gArgzs'MLys‘a-GLP-1 (8-36); ThreAsp‘7Argze'3“Lys‘8-GLP-1 (8-36);
`
`ThraAsp‘QArgzs'“Lys‘8-GLP-1 (8-36)amide; ThraAsp‘7Argze'34Lys‘8-G LP-1 (8—36)amide;
`
`ThrBAsp‘gArgze'MLys‘BGLP-1(8-37); ThrBAsp‘9Argzs'34Lys‘3GLP-1(8-38); ThraAsp‘7Argza'3‘Lys18GLP-
`
`30
`
`1(8-38);
`
`ArgZS'MLysza-GLPJ (8-36); Argzs'MLysza-GLPJ (8-36)amide; Argzs'MLy523GLP-1 (8-37);
`
`Argzs'uLysz3GLP-1(8-38); Thr8A5p24Argz‘5'3‘Lysza-GLP-1(8—36); ThraAspzzArgm'MLysza-GLP—1(8-36);
`
`ThrBAspMArgZG-“Lysm-GLP-1(8-36)amide; ThrBAspzzArgze'a‘LySZ3-GLP-1 (8-36)amide;
`
`ThrBAsp24Argzs'34Ly523GLP-1(8-37); ThrBAsp24Argze'34LyszaGLP-1(8-38); ThreAspzzArgzs'MLysnGLP-
`
`35
`
`1(8-38);
`
`MYLAN INST. EXHIBIT 1032 PAGE 10
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`MYLAN INST. EXHIBIT 1032 PAGE 10
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`MYLAN INST. EXHIBIT 1032 PAGE 10
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`
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`WO 99/43705
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`'
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`PCT/DK99/00081
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`_ 9 _
`
`Argzs'MLySZ7-GLP-1 (8-36); Argze'MLy527-GLP-1 (8-36)amide; Argze-“Ly527GLP-1 (8-37);
`
`Argza'34Ly527GLP-1(8-38); ThraAspzaArgzs'MLysm-GLPJ (8-36); ThraAspzsArgze'“LySZ7-GLP-1 (8-36);
`
`ThPAspzaArgzs'“Lys”-GLP-1(8-36)amide; ThraAspzeArgzs'MLysfl-GLP-1 (8-36)amide;
`
`ThraAspZBArgze'MLy327GLP-1(8—37); ThraAspzaArgze'MLysflGLP-1(8-38); or
`
`ThrBAspzeArgze'MLysmGLP-1 (8—38).
`
`In a further preferred embodiment, the present invention relates to a GLP-1 derivative
`
`wherein the parent peptide is:
`
`ArgzeLysaa-GLP-1 (8—36); Arg“Lys36-GLP-1(8-36); ArgzeLys36-GLP-1 (8-37); Arg34Lys36-GLP-1 (8-
`
`37); ArgzsLys37—GLP—1(8-37); Ar934Lys37-GLP-1(8-37); ArgzsLys39-GLP-1(8-39); ArgS4Ly539-GLP—
`
`1 (8-39); Argzs'MLys36'39-GLP-1 (8-39);
`
`ArgzeLys‘B-GLP-1(8-36); ArguLys‘B-GLP-i (8-36); ArgzsLys‘sGLP-1(8-37); ArgfiLys‘BGLP—1(8—37);
`
`Ar926Lys‘8GLP-1(8-38); ArguLys‘BGLP—1(8—38); ArgzsLys‘aGLP-1(8-39); ArguLys‘aGLP-1(8-39);
`
`ArgzeLySZ3—GLP—1(8~36); Arg3“LySZ3-GLP-1(8-36); ArgzsLy323GLP-1(8-37); ArQMLyszaGLP-1(8-37);
`
`ArgzeLyszaGLP-1 (8-38); Arg‘“LysZ3GLP-1 (8—38); ArgzsLySZSGLP-1 (8-39); ArgmLyszaGLP-1 (8—39);
`
`ArgzsLy527—GLP-1(8—36); ArgS4Ly327-GLP—1 (8-36); ArgzsLy527GLP—1 (8-37); Arg“Lys”GLP-1(8-37);
`
`ArgZSLysz7GLP-1 (8-38); Arg34LySZ7GLP-1 (8-38); ArgzeLysZ’7GLP—1 (8-39); Arga4Ly327GLP-1 (8-39);
`
`Argze'MLys‘B'ae-GLPJ (8-36); Argze'uLys‘BGLP-1 (8-37); Argzs-“Lys‘8'37GLP-1 (8-37);
`
`Argze'MLys‘B'”GLP-1 (8-38); Argze'MLys‘3'39GLP-1(8-39); Argzs'MLy323'36-GLP-1(8-36);
`
`Argzs'MLysz3GLP-1 (8-37); Argzs'uLy523'37GLP-1(8-37); Argzs'MLysza'aeGLP—1 (8-38);
`
`ArgZG'MLyszs'SQGLP-1(8—39); Argze'MLy527'36-GLP-1(8-36); Argzs'MLySZ7GLP-1(8-37);
`
`Argze'MLy527'37GLP-1 (8—37); Argzs-“Ly527'3BGLP-1(8-38); Argzs'34Ly527'39GLP-1 (8—39);
`
`GIy"GLP-1(8-36); GlyaGLP-1(8-37); GlyBGLP-1(8-38); GIyBGLP-1(8-39);
`
`GiyaArgzeLysw-GLP-1 (8-36); GlyBArg3‘Ly335-GLP-1(8—36); GIyBArgzeLysas-GLPJ (8—37);
`
`GlyaArQMLysas-GLPJ (8-37); GIyBArgzsLysa7-GLP-1 (8—37); GinArguLysa7-GLP-1(8-37);
`
`GlyaArgzeLys39-GLP-1 (8—39); GlyeArguLysae-GLPJ (8-39); GlyBArgze'MLysas'as-GLP-1 (8-39);
`
`GinArgzsLys‘e-GLPJ (8-36); GiyaArguLys‘B-GLPJ (8-36); GIyBArgzsLys‘aGLP-1(8-37);
`
`GIyBArg34Lys‘°GLP-1(8-37); GlysArgzeLys‘BGLP-1(8-38); GIyBArg34Lys18caLP-1 (8-38);
`
`GIyBArgzeLys‘BGLP-1 (8-39); GlyBArQMLys‘aGLP-1(8-39);
`
`GlyBArgzeLy323—GLP-1(8-36); GIyBArgMLysza-GLP-1 (8—36); GlyBArgzsLysz3GLP-1(8-37);
`
`GlyBArgmLyszaGLP-1 (8-37); GlyBArgzeLy323GLP-1(8-38); GiysArQMLyszaGLP-1 (8-38);
`
`GlyaArgzeLysszLP-1 (8-39); GinArguLyszaGLP-1(8—39);
`
`GlyaArgzeLy527-GLP-1(8-36); GIyBArga‘Ly527-GLP-1(8-36); GlyBArgzsLysflGLP-i (8-37);
`
`G|y°Arga4Ly527GLP-1 (8-37); GinArgzeLySZ7GLP-1(8-38); GlysArQMLysfiGLP-i (8-38);
`
`GlySArgzsLy527GLP-1 (8-39); Giy‘Arg34Ly527GLP-1(8-39);
`
`10
`
`15
`
`20
`
`25
`
`30
`
`MYLAN INST. EXHIBIT 1032 PAGE 11
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`MYLAN INST. EXHIBIT 1032 PAGE 11
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`MYLAN INST. EXHIBIT 1032 PAGE 11
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`
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`WO 99/43705
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`'
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`PCT/DK99/00081
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`_ 10 _
`
`GlysArgzs'MLys‘B'SG-GLP-l (8-36); GlyBArgze'MLys‘aGLP-1(8-37); GlyBArgzs-“Lys‘8'37GLP-1(8-37);
`
`GlyBArgze'uLys‘B'”GLP-1 (8-38); GlyaArgzs'MLys‘8'39GLP-1 (8-39); GlyaArgze'MLyszm-GLPJ (8-36);
`
`GlyaArgze'S‘LyszaGLP-1 (8-37); GlyBArgze's‘Lysza'37GLP-1 (8-37); GlyBArgzs'MLy523'38GLP-1 (8-38);
`
`GlySArgze'MLysza'39GLP-1(8-39); GlyBArgze'uLysmG—GLP-1 (8-36); GlyaArgzs'“Ly527GLP-1(8-37);
`
`GlyaArgzs'MLy327'37GLP-1 (8-37); GlyBArgze'MLys27-38GLP-1 (8-38); GlyaArgze'MLy327'SgGLP-1 (8-39);
`
`Val“GLP-1(8—36); ValeGLP-1(8-37); ValBGLP-1(8-38); ValaGLP-1(8-39)
`
`ValBArgzeLysas-GLP-1 (8-36); VaIBArQMLysae-GLP-1 (7-36); ValBArgzeLysas-GLP-1 (8-37);
`
`ValaArguLysse-GLP-1 (8-37); ValBArgzeLys37-GLP-1 (8-37); ValsArgs“Lysa7-GLP-1 (8-37);
`
`VaIBArgzsLysa9-GLP-1 (8-39); ValaArgmLysa9-GLP-1(8-39); ValaArgzs'uLysae'e'g-GLP—1 (8-39);
`
`ValBArgzeLys‘B-GLP-1 (8-36); VaIBArguLys‘B-GLPA (8-36); ValBArgzsLys13GLP-1 (8-37);
`
`ValaArgfiLys18GLP—1 (8-37); ValeArgzeLys1aGLP-1(8-38); ValaArgmLys‘eGLP-1(8—38);
`
`ValeArgzsLys‘aGLP—1 (8-39); VaIBArg34Lys‘BGLP-1(8-39);
`
`ValBArgzsLysz’3-GLP-1(8-36); ValaArg34Ly323—GLP—1(8—36); ValBArgzeLyszaGLP-1 (8—37);
`
`VaIBArQMLyszaGLP-1 (8-37); ValBArgzsLyszaGLP-1 (8-38); Val°Arg34Ly323GLP-1 (8-38);
`
`ValBArgzeLyszaGLP—1 (8-39); ValaArgmLySZ3GLP-1 (8-39);
`
`ValaArgzeLysfl-G LP-1 (8-36); ValBArg3‘Ly327—GLP-1 (8-36); VaIBArgzsLy527GLP-1 (8-37);
`
`ValBArg34LySZ7GLP-1 (8-37); Val8ArgzeLy327GLP-1(8-38); Val“Arg“Lys27GLP-1 (8-38);
`
`ValaArgzeLy327GLP-1 (8-39); VaiaArgMLys27GLP-1 (8-39);
`
`ValsArgzs-“Lys‘8'36-GLP-1 (8-36); VaIBArgzs'uLys‘sGLP-i (8—37); ValBArgzs'MLys‘B'WGLP-l (8-37);
`
`ValaArgzs'MLys‘s'mGLP-1(8-38); VaIBArgzs'MLys1a'3gGLP-1(8-39); ValaArgzs'MLyszs'ae-GLP-1 (8-36);
`
`ValaArgzs'MLysszLP-1(8-37); ValaArgzs'MLy523'37GLP-1 (8-37); Val8Ar925'34Ly323'38GLP-1 (8-38);
`
`ValBArgzev“Lysza'39GLP-1(8-39); ValBArgzs'MLySZ7'35-GLP—1(8-36); ValaArgze'MLysflGLP-l(8-37);
`
`ValBArgze'uLy327'37GLP-1(8—37); ValaArgzs-“Ly327'38GLP-1(8-38); or ValaArgzs-“LysmgGLP-l (8-39).
`
`In a most preferred embodiment, the present invention relates to derivatives of GLP-1
`
`analogues of formula III:
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`Xaa—Xaa—Xaa—Xaa—Xaa—Xaa-Xaa-Xaa-Xaa—Xaa—
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`26
`
`27
`
`28
`
`Xaa—Xaa—Xaa-Xaa—Xaa-Xaa—Xaa—Xaa—Xaa—Xaa—Phe—
`
`29
`
`3O
`
`31
`
`32
`
`33
`
`34
`
`35
`
`36
`
`37
`
`38
`
`I1e—Xaa—Xaa—Xaa—Xaa-Xaa~Xaa-Xaa—Xaa—Xaa
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`39
`
`4O
`
`41
`
`42
`
`43
`
`44
`
`45
`
`MYLAN INST. EXHIBIT 1032 PAGE 12
`
`MYLAN INST. EXHIBIT 1032 PAGE 12
`
`MYLAN INST. EXHIBIT 1032 PAGE 12
`
`
`
`WO 99/43705
`
`PCT/DK99/00081
`
`Xaa—Xaa—Xaa—Xaa-Xaa—Xaa—Xaa
`
`-11-
`
`(Ill)
`
`wherein
`
`Xaa at position 8 is Ala, Gly, Ser, Thr, Leu, lle, Val, Glu, Asp, or Lys, or is deleted,
`
`Xaa at position 9 is Glu, Asp, or Lys, or is deleted,
`
`Xaa at position 10 is Gly or is deleted,
`
`Xaa at position 11 is Thr, Ala, Gly, Ser, Leu, lle, Val, Glu, Asp, or Lys, or is deleted,
`
`Xaa at position 12 is Phe or is deleted,
`
`Xaa at position 13 is Thr or is deleted,
`
`Xaa at position 14 is Ser, Ala, Gly, Thr, Leu, lle, Val, Glu, Asp, or Lys, or is deleted,
`
`Xaa at position 15 is Asp or is deleted,
`
`Xaa at position 16 is Val, Ala, Gly, Ser, Thr, Leu, lle, Tyr, Glu, Asp, or Lys, or is deleted,
`
`Xaa at position 17 is Ser, Ala, Gly, Thr, Leu, lle, Val, Glu, Asp, or Lys, or is deleted,
`
`Xaa at position 18 is Ser, Ala, Gly, Thr, Leu, lle, Val, Glu, Asp, or Lys,
`
`Xaa at position 19 is Tyr, Phe, Trp, Glu, Asp, or Lys,
`
`Xaa at position 20 is Leu, Ala, Gly, Ser, Thr, Leu, lle, Val, Glu, Asp, or Lys,
`
`Xaa at position 21 is Glu, Asp, or Lys,
`
`Xaa at position 22 is Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys,
`
`Xaa at position 23 is Gln, Asn, Arg, Glu, Asp, or Lys,
`
`Xaa at position 24 is Ala, Gly, Ser, Thr, Leu, lle, Val, Arg, Glu, Asp, or Lys,
`
`Xaa at position 25 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys,
`
`Xaa at position 26 is Lys, Arg, Gln, Glu, Asp, or His,
`
`Xaa at position 27 is Glu, Asp, or Lys,
`
`Xaa at position 30 is Ala, Gly, Ser, Thr, Leu, lle, Val, Glu, Asp, or Lys,
`
`Xaa at position 31 is Trp, Phe, Tyr, Glu, Asp, or Lys,
`
`Xaa at position 32 is Leu, Gly, Ala, Ser, Thr, lle, Val, Glu, Asp, or Lys,
`
`Xaa at position 33 is Val, Gly, Ala, Ser, Thr, Met, Leu, Ile, Glu, Asp, or Lys,
`
`Xaa at position 34 is Lys, Arg, Glu, Asp, or His,
`
`Xaa at position 35 is Gly, Ala, Ser, Thr, Leu, lle, Val, Glu, Asp, or Lys,
`
`Xaa at position 36 is Arg, Lys, Glu, Asp, or His,
`
`Xaa at position 37 is Gly, Ala, Ser, Thr, Leu, lle, Val, Glu, Asp, or Lys, or is deleted,
`
`Xaa at position 38 is Arg, Lys, Glu, Asp, or His, or is deleted,
`
`Xaa at position 39 is Arg, Lys, Glu, Asp, or His, or is deleted,
`
`Xaa at position 40 is Asp, Glu, or Lys, or is deleted,
`
`Xaa at position 41 is Phe, Trp, Tyr, Glu, Asp, or Lys, or is deleted,
`
`MYLAN INST. EXHIBIT 1032 PAGE 13
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`MYLAN INST. EXHIBIT 1032 PAGE 13
`
`MYLAN INST. EXHIBIT 1032 PAGE 13
`
`
`
`WO 99/43705
`
`PCT/DK99/0008]
`
`-12-
`
`Xaa at position 42 is Pro, Lys, Glu, or Asp, or is deleted,
`
`Xaa at position 43 is Glu, Asp, or Lys, or is deleted,
`
`Xaa at position 44 is Glu, Asp, or Lys, or is deleted, and
`
`Xaa at position 45 is Val, Glu, Asp, or Lys, or is deleted, or
`
`(a) a C-1-6-ester thereof, (b) an amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or
`
`(c) a pharmaceutically acceptable salt thereof,
`
`wherein
`
`(i) when the amino acid at position 9, 10, 11, 12, 13, 14, 15, 16 or 17 is deleted, then
`
`each amino acid upstream of the amino acid is also deleted,
`
`10
`
`(ii) when the amino acid at position 37, 38, 39, 40, 41, 42, 43 or 44 is deleted, then each
`
`amino acid downstream of the amino acid is also deleted,
`
`(iii) a lipophilic substituent is attached optionally via a spacer to one or more of (a) the
`
`amino group of the N—terminal amino acid, (b) the carboxy group of the C—terminal amino acid,
`
`(c) the s-amino group of Lys, and/or (d) the carboxy group which is part of the R group of Asp or
`
`15
`
`Glu, and
`
`(iv) the total number of different amino acids between the derivative of the GLP-1 analog
`
`and the corresponding native form of GLP-1 is one, two, three, four, five or six.
`
`The total number of different amino acids between the derivative of the GLP-1 analog
`
`and the corresponding native form of GLP-1 does not exceed six. Preferably, the number of
`
`different amino acids is five. More preferably, the number of different amino acids is four. Even
`
`more preferably, the number of different amino acids is three. Even more preferably, the number
`
`of different amino acids is two. Most preferably, the number of d