PCT
`
`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 Allé,
`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—ZSOO 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-1 (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—i derivatives have a lipophilic substituent attached to at least one
`
`PFIZER, INC. v. NOVO NORDISK AIS - IPR2020-01252, Ex. 1032, p. 1 of 50
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`
`

`

`FOR THE PURPOSES OF INFORMATION ONLY
`
`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
`Albania
`SK
`Slovakia
`Lithuania
`FI
`Armenia
`SN
`FR
`Senegal
`Austria
`Luxembourg
`SZ
`Swaziland
`Latvia
`GA
`Australia
`Chad
`TD
`Monaco
`GB
`Azerbaijan
`TG
`GE
`Togo
`Republic of Moldova
`Bosnia and Herzegovina
`TJ
`GH
`Barbados
`Tajikistan
`Madagascar
`TM
`Turkmenistan
`GN
`The former Yugoslav
`Belgium
`TR
`GR
`Burkina Faso
`Turkey
`Republic of Macedonia
`TT
`Mali
`HU
`Trinidad and Tobago
`Bulgaria
`UA
`Ukraine
`IE
`Benin
`Mongolia
`UG
`Mauritania
`IL
`Brazil
`Uganda
`US
`United States of America
`Malawi
`IS
`Belarus
`Uzbekistan
`UZ
`Mexico
`IT
`Canada
`Viet Nam
`VN
`JP
`Niger
`Central African Republic
`YU
`Netherlands
`KE
`Yugoslavia
`Congo
`ZW
`KG
`Switzerland
`Norway
`New Zealand
`KP
`cote d’lvoire
`Poland
`Cameroon
`China
`Portugal
`Romania
`Cuba
`Russian Federation
`Czech Republic
`Sudan
`Germany
`Sweden
`Denmark
`Estonia
`Singapore
`
`Zimbabwe
`
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`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
`
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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
`
`5
`
`(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
`
`10
`
`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
`
`15
`
`comprises GLP-1(7—37) and functional derivatives thereof and to its use as an insulinotropic
`
`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
`
`Hi s—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—Ile-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 91I11457 (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)
`
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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 AIS).
`
`In particular, the invention relates to an N-tenninal truncated GLP-1 derivative comprising
`
`a parent peptide of formula II
`
`A— GLP—1(19—B) —x
`
`(H)
`
`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 Cm alkyl amide or 01.6 dialkyl amide group;
`
`or an analogue thereof;
`
`and wherein a lipophilic substituent is attached to at least one amino acid residue.
`
`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—‘l (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, Lys“(N‘-tetradecanoyl)—GLP-1(7-37)
`
`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—‘l 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,
`
`10
`
`15
`
`20
`
`25
`
`30
`
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`

`

`WO 99/43705
`
`'
`
`PCT/DK99/00081
`
`_ 3 _
`
`42, 43, 44 or 45, the amino acid sequence of this extension is as in the corresponding sequence
`
`in human preprogiucagon unless othewvise 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
`
`5
`
`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
`
`10
`
`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(14—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,
`
`15
`
`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
`
`20
`
`“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 oc-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
`
`25
`
`to six amino acid residues have been exchanged with any a—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
`
`30
`
`ii)
`
`B is 36, and the parent peptide comprises one or more amino acid substitutions selected
`
`from the group consisting of Argze, Arg34 and Lys36;
`
`B is 37, and the parent peptide comprises one or more amino acid substitutions selected
`
`from the group consisting of Argzs, Arg34, Lys36 and Lys“; or
`
`B is 38, and the parent peptide comprises one or more amino acid substitutions selected
`
`35
`
`from the group consisting of Argze, Arg3“, Lysa6 and Lys38.
`
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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); Lysas-GLP-1(8-37);
`
`Argzs'MLysas-GLP-1 (8-37); ArgzevMLysPBGLP-1 (8—38);
`
`ArgZG-“Lysa9-GLP-1 (8-39); Argze-“Lysw-GLPJ (8-40);
`
`ArgzsLysas-GLP—1 (8—37); ArguLysae-GLP-1(8-37);
`
`ArgzeLys39-GLP-1 (8—39); Arg34Lys“°-GLP-1 (8-40);
`
`Argze-“Lys36'39-GLP-1 (8-39); Argzs'34Lys36'4°-GLP—1 (8-40);
`
`GlyBArgzs-GLP-1 (8-37); GlysArga-G LP-1 (8-37);
`
`GlyBLysafi-GLP-1(8-37); GIyBArgZWLysas-GLP-1(8-37);
`
`GlyBArgze'MLysas-GLP-1 (8—39); GlyBArgze'MLysm-GLP-1 (8-40);
`
`Gly8ArgzsLys36-GLP-1(8—37); GlyBArguLysae-GLPJ (8-37);
`
`GlyaArgzsLysa9-GLP-1 (8-39); GlyBArguLys‘w-GLP-‘I (8-40);
`
`GlySArgze'“Lys36'39-GLP-1(8-39); or
`
`GlyaArgzs'MLysm'm-GLPJ (8—40).
`
`In a further preferred embodiment, a parent peptide for a derivative of the invention is:
`
`Argzs'MLysaaGLP-1 (8—38);
`
`Argzs'a‘Lys39GLP-1 (8-39);
`
`Argze'a‘Lys‘wG LP—1 (8-40);
`
`Argzs'MLys4‘GLP—1(8-41);
`
`Argzs'“Lys‘zGLP-1 (8-42);
`
`Argza'MLys‘aGLP-1(8-43);
`
`Argze'MLys“GLP—1 (8—44);
`
`Argzs'34Ly345GLP-1 (8-45);
`
`ArgzsLysssGLP-1(8-38);
`
`Arga‘LysaaGLP-1 (8-38);
`
`Argzs'MLysw'”GLP-1 (8-38);
`
`ArgZG'MLysasGLP-i (8-38);
`
`ArgzeLysssGLP-1 (8—39);
`
`Arg“Lys39GLP-1(8—39); or
`
`Argzs'a‘Lysas'SQGLP-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), Argu-GLP-
`
`1(8-37), Lys”-GLP-1(8-37), Argzs'“Lys35-GLP-1(8-37), ArgZSLys36-GLP-1(8-37), Arg“Lys36-GLP-
`
`1(8—37), GlyeArgzs-GLP-1(8-37), GlyaArgM-GLP-1(8-37), GlyBLysse-GLP-1(8-37), GIyBArgzs’MLysw-
`
`GLP-1(8—37), GlysArgzsLys36—GLP-1(8-37), and GlyaArguLys3e-GLP—1(8-37).
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
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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 ArgZGLys38-GLP-1(8-38),
`
`ArgZG'MLysaa-GLPJ (8-38), ArgZS'MLy536'35-GLP-1(8-38), GlyBArgzeLyssa-GLPJ (8—38) and
`
`GlyaArgze'MLysmw-GLPJ (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 ArgZGLys39-GLP-1(8-39),
`
`Argze'MLysas'39-GLP-1(8—39), GlyBArgZGLysa9-GLP-1(8-39) and GlyaArgzevuLysae'ag-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 Arg34Lys‘°—GLP-1(8-40),
`
`Arng'MLysm'W-GLP-1(8-40), GlysArg34Lys‘°-GLP-1(8-4O) and GlyBArgzs-“Lysae'm-GLP-1(8—40).
`
`in a further preferred embodiment, the present invention relates to a GLP-1 derivative
`
`wherein the parent peptide is:
`
`ArgZS-GLP-t (8-36); ArQM-G LP-1 (8—36); Argzs'MLysas-GLPJ (8-36); Argzs-GLP—1 (8—36)amide;
`
`Arg“-GLP-1(8-36)amide; Argzs'uLysae-GLP-l (8-36)amide; Argze-GLP-1(8-37); Arg“—GLP-1(8-37);
`
`ArgzwLysae-GLP-1 (8-37); Argzs-GLP-1 (8-38); ArgM-GLP-1 (8-38);
`
`Argzs'MLys35GLP—1(8-38); Argzs-GLP-1(8-39); Arg34-GLP-1(8-39);
`
`Argzs'MLysag-G LP-1 (8-39); GlysArgze-GLP-1 (8-36);
`
`GIyBArgM-GLPA (8-36); GlyaArgze'a‘Lysae-GLP-1 (8-36);
`
`GlysArgzs—GLP-1 (8-36)amide; GlysArgu-GLP-1 (8-36)amide;
`
`GlySArgze'MLysss-GLP-l (8—36)amide; GlyeArgze-GLP-1 (8-37);
`
`Gly“Arg“-GLP-1(8-37); GlyBArgzs'MLysm—GLP-i (8—37);
`
`GlyBArgza-G LP—1 (8—38); GlyaArgy-GLP-1 (8-38);
`
`GlyaArgzs'MLys”GLP-1 (8-38); GlyaArgze—GLP—1(8-39);
`
`GIyBArgM-GLP-i (8-39); GiyaArgWLys39-GLP-1(8-39);
`
`ValaArgze-GLP-1(8-36); ValeArQM-GLP-1(8-36);
`
`ValeArgzs'“Lys35-GLP-1 (8—36); ValaArgze—GLP-1(8-36)amide;
`
`VaIBArgu—GLP-1(8—36)amide; ValsArgze'MLysas-GLPJ (8-36)amide;
`
`VaIBArgzs-GLP-1(8-37); VaiBArgM-GLP-i (8-37);
`
`ValBArgzs'MLysas-GLP-i (8—37); ValBArgze-GLP-1 (8-38);
`
`VarArgM-GLP-i (8-38); ValBArgze'MLys38GLP—1(8-38);
`
`ValsArgzs-GLP-1 (8-39); ValBArgm-GLP-l (8-39);
`
`ValaArgzs'MLysss-GLP-‘l (8-39); SeraArgzs-GLP-1 (8-36);
`
`SerBArgu-GLP-i (8—36); SersArgzs'MLysse—GLP-1 (8-36);
`
`SerBArgzs-GLP-1(8-36)amide; SeraArgu-G LP-1 (8—36)amide;
`
`SeIEArgzs'MLysaa—G LP—1 (8-36)amide; SerBArgze—GLP-1(8-37);
`
`10
`
`15
`
`20
`
`25
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`30
`
`35
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`wo 99/437115
`
`‘
`
`PCT/DK99/00081
`
`_ 6 -
`
`SeraArgu-GLP—1 (8-37); SersArgzs'MLysas-GLP—‘l (8-37);
`
`SeraArgza-GLP-1 (8-38); SerBArgm-GLP-1 (8-38);
`
`SeraArgzs'MLysaaGLP-1 (8-38); SersArgzs-GLP-1 (8-39);
`
`SerBArQM-GLP-1(8-39); SerzArgzs'MLyssg-GLP—‘I (8-39);
`
`ThrBArgze-GLP-1 (8-36); ThrBArgM-GLP-1 (8—36);
`
`Th rBArgze'MLysas-GLP-1 (8—36); ThrsArgze-GLP-1 (8-36)amide;
`
`Th PArgu-GLP-1 (8-36)amide; ThrBArgzs-“Lysafi-GLPJ (8-36)amide;
`
`ThrsArgzs-GLP-1 (8-37); ThraArgu-GLP-1 (8-37);
`
`ThraArgzs-“Lys35-GLP-1(8-37); ThraArgzs-G LP-1 (8-38);
`
`10
`
`ThrBArgm-GLP-1 (8-38); ThI‘BArgzs'MLys3BGLP-1 (8-38);
`
`ThrsArgze—GLP-1 (8-39); Th rBArgu-GLP-1 (8-39);
`
`ThraArgze'MLysag—G LP-1 (8—39); ValBG|u35Argzs'34Lys36-GLP—1 (8—36);
`
`ValaGlu35Argze-34Lys35-GLP-1 (8-36)amide; ValBGlu35Argzs'34Lys37GLP-1 (8—37);
`
`VaIBGIu37Arg25'3‘Ly538GLP-1(8-38); ValBGluasArgzs'uLysw-GLP-1(8-39); ValeGluasArgzs'MLysse-GLP-
`
`15
`
`1(8-36);
`
`VaIBGlU35Argzs'34Ly336-GLP—1 (8-36)amide; ValBGluaeArgzs'MLystLP-1 (8—37);
`
`ValaGlu37Argzs'34Lys3aGLP-1 (8-38);
`
`VaIBGluasArgzs'a‘Lysas-GLP-1(8-39); VaIBAsp35Argze'34Lys36-GLP-1(8-36); Val5A5p35Argz‘5'34Lysas—
`
`GLP—1(8-36)amide;
`
`VaIBAsprrgzs-“LysmGLP-1(8-37); VaIBAsp°7Argze'34Lys35GLP-1(8-38); ValaAspaeArgzs*3‘Ly539-
`
`GLP-1 (8-39); VaIsAspasArgzs'“Lys"6-GLP-1 (8-36); VaISAsp35Argze'3‘Lysae-GLP—1 (8—36)amide;
`
`ValaAspasArgze’uLysyGLP-1(8-37); VaIBAsp37Argzs'3“LysaBGLP-1(8-38); ValBAspaaArgzs'MLysag-
`
`GLP-1(8—39);
`
`SerBGluasArgzs'MLyse'S-GLPJ (8—36); SerBGlu35Argzs'34Lysas-GLP-1 (8—36)amide;
`
`SePGluaeArgze'MLystLP-1 (8-37);
`
`SerBGiu37Argz‘5'3‘LyssaGLP-1(8-38); SereGluaaArgzs's‘Lysag-GLP-1(8-39); SerBGlu35Argze'34Ly336-
`
`GLP-1(8-36); SePGlu35Argzs'34Lys36-GLP-1(8-36)amide; SerBGluaeArgze'MLysyGLP-1(8-37);
`
`SeraGlu37Argze-“LysmGLP-1(8-38); SeraGluaaArgze'“Lysag-GLP-1(8-39); SersAsp35Argzs'34Lysae-
`
`GLP-1 (8-36); SeraAspssArgze-“Lysas-GLP—1 (8—36)amide; SerflAspssArgze'MLys‘57GLP-1 (8-37);
`
`SeraAsp37Argzs'34Lys3aGLP-1(8-38); SerBAspaaArgzs-“Lyssg-GLP-1(8—39); SersAsp35Argzs'34Lysae-
`
`GLP-1(8-36); SeI‘AspasArgze'MLysa’G-GLP-1(8-36)amide; SerBAspasArgze-“Lysa7GLP-1(8—37);
`
`SerBAsp37Argze'34LysuGLP-1(8-38); SersAspssArgze'S‘Lysag-GLP-1(8-39); Thr3G|u35Argzsla4Lys3fi
`
`GLP-1(8-36); ThrsG|u35Argze'3‘Ly336—GLP-1 (8—36)amide; ThraGluasArgzs'uLysa7GLP-1 (8—37);
`
`ThraGlu37ArgZS'34Lys35GLP-1(8-38); ThrBGluaaArgzs'MLysae-GLP-1(8-39); Thr8G|u35Arg26'34Ly536-
`
`GLP-1(8—36); ThraGIu35Argzs'34Lysas-GLP-1 (8-36)amide; ThrfiGluaeArgze'uLyst LP-1 (8—37);
`
`20
`
`25
`
`30
`
`35
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1032, p. 8 of 50
`
`

`

`WO 99/43705
`
`PCT/DK99/00081
`
`_ 7 _
`
`ThrBGIu37Argzfi'3‘LysuGLP-1 (8-38); ThrBGlumArgzs'a‘Lysag-GLP-1 (8-39);
`
`ThraAspssArQZWLysss-GLP—1 (8-36); Th PAspasArQZGvMLysw-GLP-1 (8—36)amide;
`
`ThrBAspasArgze'“Lysa7G LP-1 (8-37);
`
`ThraAsp37Argzs'34LysaeGLP-1(8-38); ThreAspMArgze-“Lyss9-GLP-1(8-39); ThraAsp35Argze’34Lysss—
`
`GLP-1(8-36); ThraAspasArgze'MLysas-GLP-1(8—36)amide; ThrBAspasArgzs'MLysmGLP-1(8-37);
`
`ThrBAsp37Argze'34LysaaGLP-1(8-38); ThrBASpSBArgzs'MLyss‘g—G LP-1 (8-39);
`
`GlyaGluasArgze'MLysae-G LP-1 (8-36); GIyBGlu35Argzs'34Ly336-G LP-1 (8—36)amide;
`
`GlysGluseArgzs-“Lysa7GLP-1 (8-37);
`
`GlysG|u37Argze'34Lys38GLP-1(8—38); GlyaGIu3°Argzs'34Lys39—GLP-1(8-39); GlyeGlu35Argze'34Lys36-
`
`GLP-1 (8-36); GlyBGluasArgzs'MLysss-GLPJ (8-36)amide; GlyaGlussArgze'MLysyGLP-1 (8-37);
`
`Gly°G|u37Argas'34Lys”GLP-1(8—38); GlyaGluaeArgze'MLysag-GLP-1(8-39); GlyaAsp35Argze'34Lysae-
`
`GLP-1 (8-36); GlyaAspssArgzs'uLysaa-GLP-1 (8-36)amide; GlyaAspaeArgze'MLystLP-1 (8-37);
`
`G|y8Asp37Argze'34Lys35GLP-1(8-38); GlySAsp33Argz‘5'3‘Ly539-GLP-1(8—39); GlyaAsp35Argze'34Ly536-
`
`GLP-1 (8—36); GlyaAspasArgzs'MLysas-GLP-1 (8-36)amide; GlyaAspSGArgmLysWG LP-1 (8-37);
`
`GIyBAsp37Argze‘34LysaaGLP-1 (8-38); GlyBAspssArgzs'a“Lysag-GLP-1 (8-39); Argzs'MLys‘B-GLPJ (8-36);
`
`Argze'MLys‘a-GLPJ (8-36)amide; Argze-“Lys‘aGLP-1 (8-37); Argzs'MLys‘aGLP-1 (8-38);
`
`GlyaAsp'sArgzs'MLys‘B-GLP-1(8-36); GIyBAsp‘7Ar925'34Lys1B-GLP—1(8-36); GlyBAsp‘QArgzs'MLys‘s-
`
`GLP-1(8-36)amide; GIyBAsp‘7Argzs'34Lys‘8-GLP-1(8—36)amide; GlysAsp1QArgze'uLysmGLP-1 (8—37);
`
`Gly8Asp‘9Argze'34Lys'aGLP—1 (8—38); GlyaAsp17Argzs'34Lys‘8GLP-1 (8—38);
`
`Argzs-“Lysza-G LP-1 (8-36); Argzs-“Lysza-GLPJ (8—36)amide; Argze'MLyszaGLP-1 (8-37);
`
`Argze'MLy523GLP-1(8-38); GlysAspz‘Argze'MLysn-GLP—1 (8-36); GlyBAspzzArg26'34Ly823—GLP-1 (8-36);
`
`GlyaAspz‘Argze'MLysm-GLP-1 (8-36)amide; GlyBAsp22Arg25'34Ly323-GLP-1 (8-36)amide;
`
`GlyBAspZ‘Argze'MLysmGLP-1(8-37); GlyBAsp24Argz‘5'34LyszaGLP-1(8-38); GlysAspzzArgze'MLysnGLP-
`
`1(8—38);
`
`Argze-“LySZ7-GLP-1(8-36); Argzs'MLysz7—GLP-1 (8—36)amide; Argzs'MLySZ7GLP-1 (8-37);
`
`Argze'“Ly627GLP-1(8-38); GIyBAspzaArgze'MLysfl-GLP-1(8-36); GlyBAsp25Argze'34LySZ7-GLP-1 (8—36);
`
`GIyBAspzaArgzs'a‘LySN-GLP-1 (8-36)amide; GIyBAspZGArgzs'MLysfl-GLP-1 (8-36)amide;
`
`GlyBAspZBArgZS'MLySZ7GLP-1(8-37); GlyaAspzaArgzs'MLysflGLP-1(8-38); GlyBAspzsArgze'S‘LysflGLP-
`
`1(8-38);
`
`Argze'MLys‘a-GLP-1 (8-36); Argzs'MLys‘a-GLPJ (8—36)amide; Argza'a‘Lys‘BG LP-1 (8-37);
`
`Argzs'uLys1aGLP-1 (8-38); VaIBAsp19Argz‘5'34Lys‘8-GLP—1 (8-36); VaIBAsp‘TArgzs'MLys‘a-GLP—1 (8-36);
`
`ValsAsp19Argzs'34Lys‘8-G LP-1 (8-36)amide; VaIBAspWArgzs'MLys‘B—GLP-1 (8-36)amide;
`
`ValaAsp‘gArgzs'“Lys‘“GLP-1 (8-37); VaIBAsp‘9Ar926'34Lys‘3GLP-1(8-38); VaIBAsp‘7Argzs'34Lys‘”GLP-
`
`1(8—38);
`
`10
`
`15
`
`20
`
`25
`
`30
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1032, p. 9 of 50
`
`

`

`WO 99/43705
`
`'
`
`PCT/DK99/00081
`
`- 3 _
`
`Argz‘s'MLysza-GLPJ (8—36); Argze-“Lyszs-GLPJ (8-36)amide; Argzs'MLyszaGLP-1 (8-37);
`
`Argze'“Ly323GLP-1(8—38); VaIBAspz‘Argzs'MLysza-GLP-1 (8-36); VaIBAspzzArgze'MLysza-GLPJ (8-36);
`
`ValaAspz‘Argze’MLysza-GLP-1 (8-36)amide; ValBAspzzArgzs'MLysza-GLP-1 (8—36)amide;
`
`VaIBAspz‘Argze'MLyszaGLP-1(8-37); Val°Asp24Argzs-°4LyszaGLP-1(8-38); Va|3Asp22Argzs'34LyszaGLP-
`
`1(8-38);
`
`ArgZS'MLySZ7-GLP-1 (8—36); ArgZG'MLy527-GLP-1 (8—36)amide; Argzs'“Ly327GLP-1 (8-37);
`
`Argzs'uLySZ7GLP-1 (8-38); ValaAspzsArgzs'“LySZ7-GLP-1(8-36); ValeAspzeArgzs'MLysfi—GLP-1 (8-36);
`
`ValBAspzaArgzs's‘Lysfi-GLP-1(8-36)amide; VaIBAspzsArgzs'MLysm-GLP-1 (8-36)amide;
`
`VaIBAspZBArgze-“Ly527GLP-1(8—37); VaIBAspzaArgze's‘LysflGLP-1(8-38); VaIBAspmArgze-MLysZ7GLP-
`
`1O
`
`1(8-38);
`
`Argze'MLys‘B-GLP-1 (8-36); Argzs'MLys‘B-GLPJ (8-36)amide; Argzs'MLys‘BGLP-1 (8—37);
`
`Argzs'MLys‘sGLP-1 (8-38); SersAsp'eArgze-S‘Lysm-G LP-1 (8-36); SerBAsp‘7Argzs'34Lys‘8-GLP-1 (8-
`
`36); SeraAsp19Argzs'34Lys18-GLP—1(8-36)amide; SeraAsp‘7Ar925'34Lys15-GLP-1 (8-36)amide;
`
`SeraAsp19Argzs'34Lys‘BGLP-1 (8-37); SereAsp‘gArgze'MLys‘BGLP-1 (8—38);
`
`SeraAsp‘7Argzs'34Lys‘BGLP-1(8-38);
`
`Argzs'MLyszs-GLPJ (8-36); Argzs'S‘LySZ3-GLP-1(8-36)amide; ArgZG'MLySZSGLP-1 (8-37);
`
`ArgZS'MLySZ3GLP-1 (8-38); SerBAsp24Argze'34Lys”~GLP-1 (8-36); SerBAspzzArgze'“Ly523-GLP-1 (8-
`
`36); SeraAspZ‘Argze'S‘Lyszs-GLP-1(8-36)amide; SersAspzzArgzs'MLysn-GLPJ (8-36)amide;
`
`SerBAspZ‘Argze'“Lysz°GLP-1 (8-37); SeraAsp24Argzs'3‘LyszaGLP-1 (8-38);
`
`SerBAspzzArgzs'a‘LysszLP-1 (8-38);
`
`Argzs'MLysfi-G LP—1 (8—36); Argzs'MLy527—GLP-1 (8-36)amide; Argze'MLysflGLP-‘l (8-37);
`
`Argze'“Ly527GLP-1(8-38); SeraAspzaArgzs'MLySN-GLPJ (8-36); SerBAspZSArgze'MLysfi-GLP—1 (8-
`
`36); SerBAspZBArgzs'a‘Ly527-GLP-1(8-36)amide; SerBAspZGArgze'MLySN-GLP-1(8-36)amide;
`
`SerBAspzaArgze'“Lys”GLP—1 (8—37); SerBAspzaArgzs'MLysflGLP-1 (8-38);
`
`SeraAspzsArgzs-“LysflGLP-1 (8-38);
`
`15
`
`20
`
`25
`
`Argzs'a‘Lys‘a-GLPJ (8-36); Argzs'MLys'B-GLPJ (8-36)amide; Argzs'MLys‘sGLP-1 (8-37);
`
`Argze'a‘Lys‘aGLP-1 (8-38); ThrBAsp‘gArgzs'MLys‘a-GLP-1 (8-36); ThraAsp‘7Argze'3‘Lys‘3-GLP-1 (8-36);
`
`ThraAsp‘QArgzs'uLys‘S-GLP-1(8-36)amide; ThraAsp‘7Argze'34Lys‘8-GLP-1 (8-36)amide;
`
`ThraAsp‘9Argzs'34Lys‘BGLP-1(8-37); ThrBAsp19Argzs'34Lys'3GLP-1 (8-38); ThraAsp‘7Argz‘5'3‘Lys‘8GLP—
`
`30
`
`1(8—38);
`
`Argzs’MLysza-GLP-1 (8—36); ArgzevMLysZS-GLP-1 (8—36)amide; Argze'MLy323GLP-1 (8—37);
`
`Argz°~34Lys23csLP-1 (8-38); ThrsAsp24Argze~34Lys23-GLP-1(8-36); ThrBAspzzArgza'MLysfl—GLP-1(8—36);
`
`ThrBAspz‘Argzs-“Lysfi-GLP-‘l (8-36)amide; ThrBAspzzArgze'“Lys”—GLP-1(8-36)amide;
`
`ThraAspz‘Argzs-“LysmGLP-1(8-37); Thr’SAsp24Argze'34LyszaGLP-1(8—38); ThrsAspzzArgze'uLyszaGLP—
`
`35
`
`1 (8-38);
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1032, p. 10 of 50
`
`

`

`wo 99/43705
`
`PCT/DK99/00081
`
`_ 9 _
`
`Argza'a‘Lysfi-GLPJ (8-36); Argzs'MLysm-G LP-1 (8—36)amide; Argzs'“Ly827GLP—1(8-37);
`
`Argzs'“Ly827GLP—1(8-38); ThrBAspzaArgzs'S‘Lysm-GLPJ (8-36); ThraAspzsArgze'MLysn-GLP-1 (8-36);
`
`ThrsAspzsArgzs'MLysm-GLP-1 (8-36)amide; ThrsAspzeArgzs'S‘Lysfi-GLP-1 (8-36)amide;
`
`ThraAspzsArgze'MLysflGLP-1(8-37); ThrBAspZBArgzs'MLysflGLP-1(8—38); or
`
`ThrBAspZGArgze'MLysflGLP-1 (8-38).
`
`In a further preferred embodiment, the present invention relates to a GLP-1 derivative
`
`wherein the parent peptide is:
`
`ArgzeLysse-G LP-1 (8-36); ArguLys35-GLP-1(8-36); ArgzsLysss-G LP-1 (8-37); Arg34Lys36-GLP-1(8-
`
`37); ArgzsLys37-GLP-1(8-37); Arg3‘Lysa7-GLP-1(8-37); ArgZGLysag-GLP-1(8-39); Ar934Ly839-GLP-
`
`1 (8-39); Argze'MLysas'sg-GLPJ (8-39);
`
`ArgzeLys‘B-GLP-1 (8—36); ArgaLys‘B-GLP-1 (8-36); ArgzeLys18GLP-1(8-37); Arg34Lys1°GLP-1(8-37);
`
`ArgzeLys‘eGLP-1(8-38); ArguLys‘aGLP-1(8-38); ArgzaLys‘BGLP-1(8-39); ArQMLys‘aGLP—‘I (8-39);
`
`ArgzsLysza-GLP-‘i (8-36); ArguLySZS-GLPJ (8-36); ArgZBLy523GLP-1 (8-37); Arg“Lys”GLP-1(8—37);
`
`ArgzsLy523G LP-1 (8-38); ArguLyszaGLP-1 (8—38); ArgzeLySZ3GLP—1(8—39); ArQMLyszaGLP-1 (8-39);
`
`ArgzsLy827-GLP-1 (8-36); ArgE'4Ly327-GLP-1 (8-36); ArgzsLy827GLP~1 (8-37); Arg3“Lys”GLP-1(8-37);
`
`ArgZGLySNGLP-‘i (8-38); Arg34Ly527GLP-1 (8-38); ArgzsLy827GLP—1 (8-39); Arg34Ly327GLP-1 (8—39);
`
`Argzs'MLys‘B'sa—GLPJ (8-36); Argza's‘Lys‘sG LP-1 (8—37); ArgZG-“Lys18'37GLP-1 (8-37);
`
`Argzs-“Lys‘B'z‘BGLP-1 (8-38); Argze'MLys‘B'3gGLP—1(8-39); Argzs'MLysza'SG-GLPJ (8-36);
`
`Argzs-“Ly323G LP-1 (8-37); Argzs'MLysza'37GLP-1 (8—37); Argzs'MLyszav3eGLP—1 (8-38);
`
`Argzs'a‘Lysza'asGLP-1 (8-39); Argze'34Ly827'36-G LP-1 (8—36); Argze-“Lys27GLP-1 (8-37);
`
`ArgZG'MLySZ7'37GLP-1 (8—37); Argzs-“Ly827'35GLP-1 (8-38); Argzs-“Ly527'39GLP-1 (8-39);
`
`GIySGLP-1(8-36); GlyaGLP—1 (8-37); GlyBGLP-1 (8-38); GlyBGLP-1(8-39);
`
`GinArgzsLysae-GLP-1 (8-36); GlysArgs‘Lysae-GLP-1(8-36); GlyBArgzaLysss-GLPJ (8—37);
`
`GlyaArgaLysas-GLPJ (8-37); GlyBArgzsLys37-GLP-1 (8—37); GlyaArgMLysW-GLP-‘i (8-37);
`
`GlysArgzeLysag-GLPJ (8—39); GIyBArguLysag-GLP-1 (8-39); GlyBArgze'MLysae'ag-GLPJ (8-39);
`
`GIyBArgzsLys‘a-GLPJ (8-36); GlyaArgMLys‘a-G LP-1 (8-36); GlyaArgz‘sLys‘sGLP-1(8-37);
`
`GIyBArgmLysmGLP-1 (8-37); GlyaArgzsLys‘aGLP-1(8-38); GlyaArgmLys'aGLP-1 (8-38);
`
`GinArgzsLys‘eGLP-1 (8-39); GlyBArQMLys18GLP—1 (8-39);
`
`GlyBArgzsLysza-G LP-1 (8-36); GIyBArgMLysza-GLP-1 (8-36); GlyBArgzeLy823GLP-1 (8-37);
`
`GIyBArgMLysZBGLP-1 (8-37); GIyBArgzeLysz°GLP-1 (8-38); GiyeArg“Ly823G LP-1 (8-38);
`
`GiyaArgzeLySZBGLP-1 (8—39); GiysArguLyszaGLP-‘I (8-39);
`
`GiyaArgzeLy327-GLP-1 (8-36); GlyaArg“Ly827-GLP-1 (8-36); GlyBArgzeLy827GLP-1 (8-37);
`
`Giy“Arg“Lys”GLP-1(8—37); GlyBArgzeLy827GLP-1 (8-38); Gly"Arg“Lysz7GLP-1(8-38);
`
`GIyBArgZBLysz7GLP—1 (8-39); GiyaArgMLys27GLP-1 (8-39);
`
`10
`
`15
`
`20
`
`25
`
`30
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1032, p. 11 of 50
`
`

`

`WO 99/43705
`
`PCT/DK99/00081
`
`_ 1o _
`
`GlysArgzs'uLys‘a'”-GLP-1 (8-36); GlyBArgm'a‘Lys‘BG LP-1 (8-37); GlyBArgZS-“Lys‘s'WGLP-l (8-37);
`
`GlyaArgzs'a“Lys‘8'“GLP-1 (8—38); GlyBArgzs'MLys‘3'39G LP—1 (8-39); GIySArgZGvMLysZBvafi-GLP-1 (8-36);
`
`GlysArgzs'MLyszaGLP-1 (8-37); GlyBArgzs'MLy823'37GLP-1 (8-37); GlyBArgze'MLy823'38GLP-1 (8-38);
`
`GlySArgWLysZS'BSGLP-1 (8-39); GlyeAr926'34Ly527'36—GLP-1 (8-36); GlyaArgzwLysz7GLP-1 (8-37);
`
`GlyaArgzs'“Lys”'37GLP—1 (8-37); GIyBArgza'MLysz7'38GLP-1 (8-38); GlysArgze'MLySZ7‘ngLP-1 (8-39);
`
`VaIBGLP-1(8-36); ValeGLP-1(8-37); VaIBGLP-1(8—38); ValaGLP-‘l (8-39)
`
`ValaArgzeLysae-G LP-1 (8—36); ValaArg“Lysaa-GLP-1 (7-36); ValaArgzeLySSB—G LP-1 (8-37);
`
`VaIBArQMLyssa-GLP-l (8-37); ValaArgzeLys37-GLP-1 (8-37); ValaArg“Lys37-GLP-1 (8-37);
`
`ValaArgzsLysag-GLPJ (8-39); ValsArguLysa9-GLP-1(8-39); ValBArgzs-“Lysae'Sg-GLP-1(8-39);
`
`ValBArgzeLys‘B-GLP-1 (8-36); ValBArguLys‘B-GLP-l (8-36); ValBArgzsLys‘BGLP-1 (8-37);
`
`ValaArQMLys‘BGLP—1 (8—37); ValaArgzeLys‘BGLP-1(8-38); ValBArg‘MLys‘sGLP-1(8—38);
`
`ValaArgzeLys‘sGLP—1(8-39); ValBArguLys‘eGLP-1(8-39);
`
`ValaArgzsLys23-GLP-1 (8-36); VaIBArQMLyszs-GLP—1 (8—36); ValBArgzeLyszaG LP-1 (8-37);
`
`ValBArga“Ly523GLP-1 (8-37); VaIBArgzeLyszaGLP-1 (8-38); ValBArgMLyszaGLP-i (8—38);
`
`ValBArgzeLyszaG LP—1 (8—39); ValeArQMLyszaGLP-1 (8-39);
`
`ValaArgzaLy827-GLP-1 (8-36); ValBArga‘Ly827-GLP-1(8-36); VaIBArgzsLySZ7GLP-1 (8-37);
`
`Val“Arg“Lys”GLP-1 (8-37); ValeArQZBLySZ7GLP-1 (8-38); ValBArguLysflG LP-1 (8-38);
`
`ValaArgzsLy827GLP-1 (8—39); ValeArg34Ly327GLP-1 (8-39);
`
`ValsArgzs'MLys18'36-GLP-1(8-36); VaIBArgze'MLys1eGLP-1(8-37); ValaArgzs'MLysm'mGLP-‘I (8-37);
`
`ValaArgZS-“Lys‘3~3°GLP-1 (8-38); ValBArgzs'MLys‘a'ngLP-1(8-39); VaIBArgzs-“LysZS-SG-GLP-1(8-36);
`
`ValaArgzs'uLysszLP-1 (8-37); ValaArgzs'uLysza'37G LP-1 (8-37); ValsArgze'MLysza-SBGLPJ (8-38);
`
`VaIBArgzs'MLysnagG LP-1 (8-39); VaIBArgzs'“LySZ7'36-GLP-1 (8—36); ValaArgze'MLySZTGLP—‘l (8-37);
`
`VaIBArgze-“Ly527'37GLP-1(8-37); ValaArgze-“Ly827'38GLP-1(8-38); or ValaArgze-“LySZ7-39GLP-1(8-39).
`
`In a most preferred embodiment, the present invention relates to derivatives of GLP—1
`
`analogues of formula III:
`8 91011121314151617
`
`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
`
`30
`
`31
`
`32
`
`33
`
`34
`
`35
`
`36
`
`37
`
`38
`
`Ile—Xaa—Xaa—Xaa—Xaa~Xaa—Xaa-Xaa—Xaa—Xaa
`
`1O
`
`15
`
`20
`
`25
`
`30
`
`35
`
`39
`
`4O
`
`41
`
`42
`
`43
`
`44
`
`45
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1032, p. 12 of 50
`
`

`

`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, Ile, 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, lle, 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,
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1032, p. 13 of 50
`
`

`

`WO 99/43705
`
`PCT/DK99/00081
`
`_ 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 different amino acids is one. In
`
`order to determine the number of different amino acids, one should compare the amino acid
`
`sequence of the derivative of the GLP-1 analog of the present invention with the correspon