PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`(51) International Patent Classification 6;
`C07K 14/605, A61K 38/26, A61P 3/04,
`3/10, 5/50
`
`(11) International Publication Number:
`
`WO 99/43705
`
`(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, Cl, CM, GA, GN, GW, ML, MR,NE,
`SN, TD, TG).
`
`amino acid residue.
`
`(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).
`
`(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~1 DERIVATIVES
`
`(57) Abstract
`The presentinvention relates to N-terminally truncated derivatives of human glucagon-like peptide-1 (GLP-1) and analoguesthereof
`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-1 derivatives have a lipophilic substituent attached to at least one
`
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`

`

`Zimbabwe
`
`Codes used to identify States party to the PCT onthe 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
`Turkmenistan
`GN
`The former Yugoslav
`Belgium
`GR
`Burkina Faso
`Turkey
`Republic of Macedonia
`Mali
`HU
`Trinidad and Tobago
`Bulgaria
`Ukraine
`IE
`Benin
`Mongolia
`Mauritania
`IL
`Brazil
`Uganda
`United States of America
`Malawi
`IS
`Belarus
`Uzbekistan
`Mexica
`IT
`Canada
`Viet Nam
`JP
`Niger
`Centrat African Republic
`Netherlands
`KE
`Yugoslavia
`Congo
`KG
`Switzerland
`Norway
`New Zealand
`KP
`Cate d'Ivoire
`Poland
`Cameroon
`China
`Portugal
`Romania
`Cuba
`Russian Federation
`Czech Republic
`Sudan
`Germany
`Sweden
`Denmark
`Estonia
`Singapore
`
`™T
`
`R
`TT
`UA
`UG
`US
`UZ
`VN
`YU
`ZW
`
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`Mx
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`sD
`SE
`SG
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Ttaly
`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
`
`5
`
`10
`
`45
`
`FIELD OF THE INVENTION
`
`The presentinvention relates to novelderivatives of human glucagon-like peptide-1
` (GLP-1) and fragments analoguesthereof having a protracted profile of action and to the use of
`such derivatives in pharmaceutical compositions.
`
`BACKGROUNDOF THE INVENTION
`
`GLP-1 (Glucacon-Like-Peptide-1) is an important gut hormonewith regulatory function in
`glucose metabolism and gastrointestinal secretion and metabolism. Human GLP-1 is a 37 amino
`acid residue peptide originating from preproglucagon whichis synthesised /.a. in the L-cells in the
`distal ileum, in the pancreas andin 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
`
`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
`exceedsthe 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:
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`#18
`#19
`20
`
`7
`
`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
`
`30
`
`31
`
`32
`
`#33
`
`34
`
`#35
`
`36
`
`{I}
`
`Ala-Ala-Lys~-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-X
`
`wherein X is NH, for GLP-1(7-36)amide and X is Gly-OH for GLP-1(7-37).
`WO 91/11457 (Buckleyef al.) discloses analogues of the active GLP-1 peptides 7-34,7-
`
`35, 7-36, and 7-37.
`
`30
`
`WO98/08871 discloses GLP-1 derivatives in whicha lipophilic substituent is attached to
`
`at least one amino acid residue. Thelipophilic 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 26)
`
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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.
`
`SUMMARYOF THE INVENTION
`In its broadest aspect, the presentinvention relates to derivatives of GLP-1 and
`analogues thereof. The derivatives according to the invention haveinteresting pharmacological
`properties, including a protractedprofile of action. The derivatives also are more metabolically
`and physically stable, and more soluble.
`The GLP-1 derivatives and analoguesof the present invention are truncated at the N-
`terminal end and comprise a lipophilic substituent (optionally via a spacer) attachedto atleast
`one amino acid residue. The lipophilic substituentis in particular a long-chain group ofthe 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 formulaII
`
`A — GLP-1(19-B) - X
`
`(Il)
`
`wherein
`
`A is a peptide comprising the amino acid residues of GLP-1(8-18) or a fragment thereof,
`
`B is an integerin the range of 35-45; and
`
`X is —OH, —NH,, or a C,., alkyl amide or C,., dialkyl amide group;
`
`or an analoguethereof;
`and whereina 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, Gly*-GLP-1(7-37) designates a fragment whichrelates 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, Lys*(N*-tetradecanoyl)-GLP-1(7-37)
`designates GLP-1(7-37) wherein the s-amino groupof the Lys residuein 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 otherwiseindicated, the amino acid residuein
`position 39 is also Arg unless otherwise indicated and the aminoacid residuein position 40is
`Asp unless otherwiseindicated. Also, if a C-terminally extended analogue extendsto position 41,
`
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`

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`WO 99/43705
`
`:
`
`PCT/DK99/00081
`
`-3-
`
`42, 43, 44 or 45, the amino acid sequenceofthis extensionis as in the corresponding sequence
`
`in human preproglucagon unless otherwiseindicated.
`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
`fragmentthereof. 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(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,
`
`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.
`
`20
`
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`
`GLP-1 Analogs
`
`The presentinvention 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 exchangedwith any a-amino acid residue, in particular with any a-amino acid
`
`residue which can be codedfor by the genetic code. Preferred analogues are those in which up
`
`to six amino acid residues have been exchanged with any a-amino acid residue which can be
`
`codedfor by the genetic code.
`
`Preferred GLP-1 derivatives or analoguesare thosein which:
`
`Ais 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 aminoacid substitutions selected
`from the group consisting of Arg’, Arg and Lys*®:
`
`B is 37, and the parent peptide comprises one or more amino acid substitutions selected
`
`from the group consisting of Arg”, Arg™, Lys® and Lys®’; or
`
`B is 38, and the parent peptide comprises one or more amino acid substitutions selected
`from the group consisting of Arg”, Arg™, Lys® and Lys™.
`
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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
`Arg”-GLP-1 (8-37); Arg™-GLP-1(8-37); Lys*-GLP-1(8-37);
`Arg?®“Lys*-GLP-1(8-37); Arg**Lys*®GLP-1 (8-38):
`Arg>™Lys®°-GLP-1 (8-39); Arg?*™Lys*-GLP-1 (8-40);
`Arg”*Lys*°-GLP-1 (8-37); Arg™Lys*-GLP-1 (8-37):
`Arg*Lys**-GLP-1(8-39); Arg™Lys*-GLP-1 (8-40);
`Arg?®*Lys***°-GLP-1(8-39); Arg”*‘Lys®*“°-GLP-1(8-40);
`Gly*’Arg”-GLP-1 (8-37); Gly’Arg*-GLP-1 (8-37);
`Gly*Lys®-GLP-1 (8-37); Gly’Arg”“Lys®°-GLP-1(8-37);
`Gly*Arg*“Lys®-GLP-1 (8-39); Gly*Arg”*“Lys®°-GLP-1 (8-40);
`Gly®Arg*Lys**-GLP-1 (8-37); Gly’Arg™Lys*-GLP-1 (8-37);
`Gly®’Arg*Lys®**-GLP-1(8-39); Gly®*Arg™*Lys*°-GLP-1 (8-40);
`Gly*Arg”*™“Lys****-GLP-1 (8-39); or
`Gly*Arg’®™“Lys**°-GLP-1 (8-40).
`
`In a further preferred embodiment, a parent peptide for a derivative of the inventionis:
`Arg?>™Lys®GLP-1 (8-38);
`
`Arg”*™Lys*°GLP-1 (8-39);
`Arg?**Lys“GLP-1(8-40);
`
`Arg*®**Lys"'GLP-1(8-41);
`Arg*“Lys“GLP-1(8-42);
`Arg?*“Lys“GLP-1(8-43):
`Arg”**Lys“GLP-1 (8-44);
`Arg”**Lys**GLP-1 (8-45);
`Arg*Lys®GLP-1(8-38);
`Arg™Lys*®GLP-1 (8-38);
`Arg”™“Lys**=8GLP-1 (8-38);
`
`Arg**Lys*®GLP-1(8-38);
`Arg”*Lys*°GLP-1(8-39);
`Arg™Lys*°GLP-1 (8-39); or
`Arg”**Lys®*°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 Arg*°-GLP-1 (8-37), Arg*-GLP-
`1(8-37), Lys®°-GLP-1(8-37), Arg“Lys**-GLP-1(8-37), Arg*Lys®-GLP-1(8-37), Arg™Lys®*-GLP-
`1(8-37), Gly®Arg”°-GLP-1 (8-37), Gly’Arg™-GLP-1(8-37), Gly’Lys®*-GLP-1(8-37), Gly’Arg*™Lys*-
`GLP-1(8-37), Gly*ArgLys**-GLP-1 (8-37), and Gly*Arg™Lys**-GLP-1 (8-37).
`
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`WO 99/43705
`
`PCT/DK99/00081
`
`-5-
`
`In a further preferred embodiment, the presentinvention relates to a GLP-1 derivative
`wherein the parent peptide is selected from the group comprising Arg“Lys*-GLP-1 (8-38),
`Arg”**Lys*°-GLP-1 (8-38), Arg”*“Lys***°-GLP-1(8-38), Gly*Arg”*Lys*-GLP-1 (8-38) and
`Gly®Arg’>™“Lys****-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 Arg*Lys**-GLP-1(8-39),
`Arg”**Lys®*°-GLP-1 (8-39), Gly*Arg”Lys**-GLP-1 (8-39) and Gly*Arg*™Lys*°-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 Arg™“Lys*°-GLP-1 (8-40),
`Arg?*“Lys*“°_GLP-1 (8-40), Gly’Arg“Lys*°-GLP-1(8-40) and Gly*Arg”*“Lys*“°-GLP-1(8-40).
`In a further preferred embodiment, the present invention relates to a GLP-1 derivative
`
`wherein the parent peptide is:
`Arg”°-GLP-1 (8-36); Arg**-GLP-1 (8-36); Arg”*™“Lys**-GLP-1 (8-36); Arg”’-GLP-1(8-36)amide;
`Arg™-GLP-1(8-36)amide; Arg”*“Lys®*-GLP-1 (8-36)amide; Arg’*-GLP-1(8-37); Arg*-GLP-1 (8-37);
`Arg”®*4Lys°*-GLP-1 (8-37); Arg’*-GLP-1 (8-38); Arg™-GLP-1 (8-38);
`Arg®*“Lys*GLP-1(8-38); Arg’®-GLP-1(8-39); Arg*-GLP-1 (8-39);
`Arg?>*4Lys®°-GLP-1 (8-39); Gly’Arg”-GLP-1 (8-36);
`Gly®Arg*-GLP-1(8-36); Gly’Arg”*™Lys®*-GLP-1(8-36);
`Gly*Arg”®-GLP-1(8-36)amide; Gly*Arg*-GLP-1(8-36)amide;
`Gly®Arg”*™Lys®*-GLP-1(8-36)amide; Gly*Arg”*-GLP-1 (8-37);
`Gly*Arg™-GLP-1(8-37); Gly’Arg“Lys®*-GLP-1 (8-37);
`Gly*’Arg”*-GLP-1 (8-38); Gly*Arg™-GLP-1 (8-38);
`Gly*Arg?®™Lys**GLP-1 (8-38); Gly*Arg?°-GLP-1(8-39);
`Gly*Arg*-GLP-1(8-39); Gly’Arg”**Lys®°-GLP-1(8-39);
`Val’Arg®-GLP-1 (8-36); Val’Arg™-~GLP-1 (8-36);
`Val’Arg”*™Lys**-GLP-1 (8-36); Val’Arg*®-GLP-1(8-36)amide;
`
`Val’Arg™-GLP-1(8-36)amide; Val’Arg*™Lys*®*-GLP-1 (8-36)amide;
`Val’Arg”-GLP-1(8-37); Val’Arg*-GLP-1 (8-37);
`Val’Arg”*™Lys**-GLP-1 (8-37); Val®Arg”*-GLP-1 (8-38);
`Val’Arg™-GLP-1 (8-38); Val@Arg“Lys*GLP-1 (8-38);
`ValArg*-GLP-1 (8-39); Val°Arg™-GLP-1 (8-39);
`Val*Arg’*“Lys**-GLP-1(8-39); Ser’Arg”*-GLP-1(8-36);
`Ser’Arg™*-GLP-1(8-36); Ser’Arg**“Lys*-GLP-1 (8-36);
`Ser’Arg”-GLP-1(8-36)amide; Ser’Arg™-GLP-1(8-36)amide;
`SerArg*™Lys*®-GLP-1(8-36)amide; Ser?Arg”*-GLP-1 (8-37);
`
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`WO 99/43705
`
`PCT/DK99/00081
`
`-6-
`
`SerArg*-GLP-1(8-37); Ser’Arg”™Lys*-GLP-1(8-37);
`Ser’Arg”*-GLP-1(8-38); Ser’Arg*-GLP-1 (8-38);
`Ser’Arg”*™“Lys*GLP-1 (8-38); Ser*Arg”-GLP-1(8-39);
`SerArg*-GLP-1(8-39); SerArg”™Lys**-GLP-1 (8-39);
`ThrArg”®-GLP-1 (8-36); Thr’Arg™-GLP-1 (8-36);
`ThrArg*™Lys*®*-GLP-1 (8-36); ThreArg’*-GLP-1(8-36)amide;
`ThrArg*-GLP-1(8-36)amide; Thr’Arg”™“Lys*-GLP-1(8-36)amide;
`ThPArg?-GLP-1(8-37); ThrArg*-GLP-1(8-37):
`ThrArg***Lys**-GLP-1 (8-37); Thr®Arg”*-GLP-1 (8-38);
`ThrArg™-GLP-1 (8-38); ThrArg™™Lys*GLP-1 (8-38);
`ThreArg”*-GLP-1(8-39); ThrArg™-GLP-1 (8-39);
`ThreArg**Lys**-GLP-1 (8-39); Val’Glu*Arg”*“Lys**-GLP-1 (8-36);
`Val’Glu*Arg?*4Lys**-GLP-1 (8-36)amide; Val’Glu*®Arg”*“Lys*GLP-1 (8-37);
`Val’Giu*”Arg”“Lys**GLP-1(8-38); Val’Glu*Arg”Lys°-GLP-1 (8-39); Val?Glu*Arg*“Lys*°-GLP-
`
`4(8-36);
`Val’Glu*Arg**Lys*°-GLP-1(8-36)amide; Val®Giu*Arg”*“Lys*’GLP-1 (8-37);
`Val’Giu?"Arg*®4LysGLP-1(8-38):
`Val’Glu*Arg”**4Lys**-GLP-1(8-39); Val’Asp**Arg”4Lys°*-GLP-1 (8-36); Val®Asp*Arg”Lys*-
`
`GLP-1(8-36)amide;
`Val’Asp*Arg™Lys*”GLP-1(8-37); ValfAsp*”Arg”“Lys**GLP-1 (8-38); ValfAsp*Arg”™“Lys**-
`GLP-1(8-39); Val@Asp**Arg?°“Lys®-GLP-1 (8-36); Val’Asp*Arg”™Lys®*-GLP-1(8-36)amide;
`Val’Asp*Arg™Lys*’GLP-1(8-37); Val’Asp*’Arg”™“Lys™GLP-1(8-38), ValPAsp*Arg”™Lys*-
`
`GLP-1(8-39);
`SerGlu“Arg*™Lys®-GLP-1 (8-36); Ser’Glu*Arg**™Lys*-GLP-1 (8-36)amide;
`Ser’Glu*Arg*™Lys*GLP-1 (8-37);
`SerGlu’Arg*™“Lys*GLP-1 (8-38), SerGlu*Arg”“Lys*-GLP-1 (8-39), Ser’Glu*Arg”*™Lys*-
`GLP-1(8-36); Ser’Glu*Arg*“Lys**-GLP-1(8-36)amide; Ser’Glu*Arg*™“Lys*”’GLP-1 (8-37);
`Ser’Glu*’Arg™“Lys*GLP-1 (8-38); SeFrGlu*Arg”*Lys-GLP-1(8-39); Ser’Asp*Arg”™Lys**-
`GLP-1(8-36); Ser-Asp*Arg”“Lys*®-GLP-1(8-36)amide; Ser’Asp*Arg”™“Lys*”GLP-1 (8-37);
`SerAsp*"Arg2™Lys**GLP-1(8-38); SerPAsp*Arg”™Lys*-GLP-1 (8-39); Ser?Asp*Arg*™“Lys*-
`GLP-1(8-36); Ser’Asp*Arg”*Lys**-GLP-1(8-36)amide; Ser*Asp*Arg”“Lys*”GLP-1(8-37);
`SerAsp*’Arg2™“Lys*GLP-1 (8-38); Ser’Asp*Arg”*“Lys**-GLP-1(8-39); Thr’Glu*Arg*“Lys**-
`GLP-1(8-36); Thr’Glu*Arg”*“Lys**-GLP-1(8-36)amide; Thr’Glu*Arg”™“Lys*’GLP-1 (8-37);
`ThrGiu*Arg**Lys“GLP-1 (8-38); Thr°Glu*Arg**“Lys*-GLP-1 (8-39); ThrGluArg”*“Lys*-
`GLP-1(8-36); Thr°Giu=Arg”*™Lys**-GLP-1 (8-36)amide; Thr°Glu*Arg”*™“Lys*’GLP-1 (8-37);
`
`20
`
`25
`
`30
`
`33
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1032, p. 8 of 50
`
`

`

`WO 99/43705
`
`PCT/DK99/00081
`
`-7-
`
`ThrGiu"Arg*“Lys*GLP-1 (8-38); Thr’Glu®Arg“Lys®-GLP-1 (8-39);
`TheAsp*Arg??™Lys®-GLP-1 (8-36); ThrAsp*Arg**Lys**-GLP-1(8-36)amide;
`ThrAsp*Arg”™Lys?GLP-1(8-37);
`ThAsp*Arg*“Lys*GLP-1 (8-38); TheAsp“Arg*Lys**-GLP-1 (8-39); Thr’Asp*Arg*“Lys*°-
`GLP-1(8-36); Thr°Asp*Arg?™“Lys®-GLP-1(8-36)amide; ThrAsp*Arg”*Lys*’GLP-1(8-37);
`ThrAsp*’Arg*“Lys*®GLP-1 (8-38); ThréAsp*Arg”™Lys**-GLP-1 (8-39);
`Gly’Glu*Arg*™Lys**-GLP-1 (8-36); Gly°Glu*Arg”™Lys®-GLP-1(8-36)amide;
`Gly’Glu*Arg”™Lys*’GLP-1 (8-37);
`Gly®Glu>Arg“Lys*GLP-1 (8-38); Gly’Glu*Arg”“Lys®®-GLP-1 (8-39); Gly®’Glu*Arg”™“Lys*-
`GLP-1(8-36); Gly®’Glu*Arg**™Lys®*-GLP-1 (8-36)amide; Gly’Glu*Arg”*™“Lys*’GLP-1 (8-37);
`Gly’Glu*’Arg*Lys*®GLP-1(8-38); Gly®Glu*Arg”*™Lys**-GLP-1(8-39); Gly*Asp*Arg*Lys*-
`GLP-1(8-36); Gly’Asp**Arg*“Lys°**-GLP-1(8-36)amide; Gly°Asp**Arg”*“Lys*’GLP-1(8-37);
`Gly*Asp*’Arg”*“Lys*®GLP-1 (8-38); Gly°’Asp**Arg”Lys®*-GLP-1(8-39); Gly*Asp*Arg”’™“Lys**-
`GLP-1(8-36); Gly*Asp*Arg’*Lys®*-GLP-1(8-36)amide; Gly*Asp“*Arg®*Lys*”GLP-1(8-37),;
`Gly®Asp*’Arg”*™Lys*GLP-1(8-38); Gly*Asp*Arg**“Lys*°-GLP-1 (8-39); Arg*™“Lys®-GLP-1 (8-36);
`Arg”™Lys'®-GLP-1(8-36)amide; Arg“Lys'®GLP-1(8-37); Arg®“Lys"*GLP-1 (8-38);
`Gly*Asp'*Arg*“Lys"*-GLP-1 (8-36); Gly’Asp'7Arg”“Lys'®-GLP-1(8-36); Gly’Asp'*Arg”*™“Lys"*-
`GLP-1(8-36)amide; Gly*Asp'’Arg*“Lys'*-GLP-1(8-36)amide; Gly*Asp*Arg”*“Lys°GLP-1 (8-37);
`Gly*Asp"*Arg**™Lys®GLP-1(8-38); Gly’Asp'’Arg*™“LysGLP-1 (8-38);
`Arg“Lys*-GLP-1(8-36); Arg”°“Lys**-GLP-1(8-36)amide; Arg”*“Lys*GLP-1(8-37);
`Arg*“Lys*GLP-1(8-38); Gly’Asp**Arg?*“Lys**-GLP-1(8-36); Gly’Asp”Arg”*™“Lys”*-GLP-1 (8-36);
`Gly®Asp“Arg*“Lys*-GLP-1(8-36)amide; Gly*Asp*Arg”**Lys”-GLP-1 (8-36)amide;
`Gly®Asp*Arg**“Lys*GLP-1 (8-37); Gly’AspArg”*“Lys*GLP-1 (8-38); Gly’Asp”Arg*™Lys*GLP-
`
`4(8-38):
`Arg*™Lys?’-GLP-1 (8-36); Arg”™Lys?’-GLP-1 (8-36)amide; Arg”™Lys?’GLP-1 (8-37);
`Arg’**Lys?’GLP-1(8-38); Gly’Asp*Arg**Lys?”-GLP-1(8-36); Gly’Asp”Arg”*“Lys”’-GLP-1 (8-36);
`Gly*Asp”Arg”™Lys?’-GLP-1(8-36)amide; Gly*Asp*Arg”™Lys”’-GLP-1 (8-36)amide;
`Gly’Asp*Arg”™Lys”’"GLP-1(8-37); Gly*AspArg”*Lys”’GLP-1(8-38); Gly’Asp*Arg”“Lys”’GLP-
`
`4(8-38);
`Arg”*™Lys'®-GLP-1 (8-36); Arg”*“Lys"*-GLP-1(8-36)amide; Arg”*“*Lys"®GLP-1 (8-37);
`Arg”*“Lys®GLP-1 (8-38); Val’Asp'*Arg**™“Lys'*-GLP-1 (8-36); Val’Asp'’Arg”“Lys°-GLP-1 (8-36);
`ValAsp"Arg*™Lys'®-GLP-1 (8-36)amide; Val®Asp"’Arg”*“Lys'®-GLP-1(8-36)amide;
`Val*Asp"*Arg”™“Lys"*GLP-1 (8-37); Val’Asp'°Arg”*™“Lys°GLP-1(8-38); Val’Asp"’Arg”’™“Lys'®GLP-
`
`4(8-38);
`
`20
`
`25
`
`30
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1032, p. 9 of 50
`
`

`

`WO 99/43705
`
`PCT/DK99/00081
`
`-8-
`
`Arg**™Lys?°-GLP-1(8-36); Arg”“Lys”*-GLP-1 (8-36)amide; Arg*“Lys*GLP-1 (8-37);
`Arg?*Lys*GLP-1(8-38); Val?Asp“Arg”™Lys*-GLP-1(8-36); ValSAsp”Arg”"™Lys*-GLP-1 (8-36);
`Val’Asp“Arg”*Lys?°-GLP-1(8-36)amide; Val’Asp”Arg*™Lys”*-GLP-1 (8-36)amide;
`Val’Asp“Arg”*™“Lys2°GLP-1 (8-37); ValPAsp*“Arg”“Lys*GLP-1 (8-38); Val’Asp”Arg”’Lys*GLP-
`
`4(8-38);
`Arg?**4Lys?’-GLP-1 (8-36); Arg”**4Lys””-GLP-1(8-36)amide; Arg*™“Lys”’GLP-1 (8-37);
`Arg®™Lys?"GLP-1(8-38); Val’Asp*Arg*“Lys””-GLP-1(8-36); Val®Asp”*Arg”*“Lys”’-GLP-1 (8-36);
`Val’Asp”Arg”“Lys?’-GLP-1(8-36)amide; Val’Asp”*Arg”**Lys”’-GLP-1 (8-36)amide;
`ValAsp2Arg”™Lys?”GLP-1(8-37); Val?Asp“Arg*™Lys””GLP-1 (8-38); Val’Asp”*Arg*“Lys*’GLP-
`
`1 (8-38);
`Arg*“Lys'®-GLP-1 (8-36); Arg”*“Lys'®-GLP-1(8-36)amide; Arg**“Lys"*GLP-1(8-37);
`Arg”**Lys"*GLP-1(8-38); Ser’Asp"*Arg”™Lys"-GLP-1(8-36); Ser’Asp"’Arg®™Lys"*-GLP-1(8-
`36); Ser’AspArg?Lys®-GLP-1(8-36)amide; Ser’Asp*“Arg”"“Lys*-GLP-1(8-36)amide;
`SerAsp"Arg**Lys'®GLP-1 (8-37); Ser’Asp'°Arg”™“Lys°GLP-1 (8-38);
`SerAsp”Arg?™Lys"®GLP-1 (8-38):
`Arg”***Lys*-GLP-1 (8-36); Arg”*™“Lys*-GLP-1(8-36)amide; Arg>™“Lys*GLP-1 (8-37);
`Arg?**“Lys*GLP-1 (8-38); Ser’Asp“Arg”*“Lys*-GLP-1 (8-36); Ser*Asp”Arg”"™“Lys”-GLP-1(8-
`36); Ser’Asp**Arg”*™Lys?°-GLP-1(8-36)amide; Ser’Asp”Arg*™Lys*-GLP-1 (8-36)amide;
`SerAsp“Arg*“Lys*GLP-1 (8-37); Ser’Asp“Arg”™Lys*GLP-1 (8-38);
`SerAsp”Arg*™“Lys*GLP-1 (8-38);
`Arg**™Lys?’-GLP-1 (8-36); Arg”*“Lys”’-GLP-1(8-36)amide; Arg”™“Lys””GLP-1(8-37);
`Arg?**Lys?”GLP-1(8-38); SerAsp#Arg”*“Lys?”-GLP-1 (8-36), Ser’Asp*Arg”™Lys”’-GLP-1(8-
`36); Ser-Asp”Arg”*™Lys”’-GLP-1(8-36)amide; Ser’Asp*Arg”™Lys*”~-GLP-1(8-36)amide;
`Ser’Asp*Arg*Lys”GLP-1 (8-37), Ser’Asp*Arg”™Lys”’GLP-1 (8-38);
`SerAsp*Arg”™“Lys*’GLP-1 (8-38);
`Arg*“Lys"®-GLP-1 (8-36); Arg?*“Lys'®-GLP-1(8-36)amide; Arg”™“Lys"*GLP-1 (8-37);
`Arg?™“Lys"GLP-1(8-38); Thr’Asp*Arg”™“Lys®-GLP-1 (8-36); ThreAsp'“Arg”’™“Lys'*-GLP-1 (8-36);
`Thr’Asp"’Arg*™Lys'*-GLP-1(8-36)amide; Thr’Asp’’Arg*™Lys*-GLP-1 (8-36)amide;
`ThrAsp*Arg*™Lys®GLP-1(8-37); ThrAsp*Arg®“Lys'®GLP-1(8-38); Thr’Asp'’Arg”™“LysGLP-
`
`4(8-38);
`Arg®™Lys?-GLP-1(8-36); Arg?*“Lys”-GLP-1(8-36)amide; Arg?“Lys”°GLP-1(8-37);
`Arg®LysGLP-1(8-38); ThAsp“Arg”™“Lys®-GLP-1(8-36); ThrAspArg**Lys*-GLP-1 (8-36);
`Thr’Asp“Arg®™Lys®-GLP-1(8-36)amide; Thr’AspArg”Lys””-GLP-1(8-36)amide;
`ThrAsp“Arg®™Lys”GLP-1 (8-37); ThrAsp“Arg“Lys“GLP-1 (8-38); ThrAsp”Arg”™Lys*GLP-
`
`15
`
`20
`
`25
`
`30
`
`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
`
`-Q9-
`
`Arg”®“Lys?’~-GLP-1(8-36); Arg”*™Lys?’-GLP-1 (8-36)amide; Arg”*“Lys”/GLP-1 (8-37);
`Arg”*™“Lys?’GLP-1(8-38); TheAsp”Arg”Lys”’-GLP-1 (8-36); Thr’Asp*Arg”“Lys*’-GLP-1(8-36),
`ThrAsp*Arg”*Lys*’-GLP-1(8-36)amide; ThrAsp*Arg*™Lys”’-GLP-1 (8-36)amide;
`ThrAsp*Arg*Lys?’GLP-1(8-37); TheAsp*Arg”™Lys”’GLP-1 (8-38); or
`ThrAsp“Arg*™Lys”"GLP-1(8-38).
`In a further preferred embodiment, the present invention relates to a GLP-1 derivative
`
`wherein the parent peptide is:
`Arg*Lys**-GLP-1 (8-36); Arg“Lys®*-GLP-1(8-36); Arg”*Lys**-GLP-1 (8-37); Arg“Lys*°-GLP-1(8-
`37); Arg”*Lys*’~-GLP-1(8-37); Arg™“Lys*’-GLP-1 (8-37); Arg”Lys*°-GLP-1(8-39); Arg™Lys*”-GLP-
`4(8-39); Arg®™“Lys*°°9-GLP-1 (8-39):
`Arg*Lys"*-GLP-1(8-36); Arg*Lys'®-GLP-1(8-36); ArgLys'®GLP-1 (8-37); Arg*Lys"*GLP-1 (8-37);
`Arg“Lys"*GLP-1(8-38); Arg™Lys*GLP-1(8-38); ArgLys"®GLP-1 (8-39); Arg™Lys"*GLP-1 (8-39);
`Arg”*Lys”-GLP-1 (8-36); Arg“Lys”*-GLP-1 (8-36); Arg”*Lys*GLP-1(8-37); Arg“Lys*GLP-1(8-37);
`Arg”LysGLP-1(8-38); Arg“Lys*GLP-1 (8-38); Arg”*Lys*GLP-1(8-39); Arg“Lys“GLP-1(8-39);
`Arg*Lys*’-GLP-1(8-36); Arg“Lys?’-GLP-1 (8-36); Arg”®Lys?’GLP-1 (8-37); Arg™Lys*’GLP-1(8-37);
`Arg”*Lys””GLP-1(8-38); Arg™“Lys””GLP-1 (8-38); Arg”Lys?”GLP-1 (8-39); Arg™Lys’’GLP-1(8-39);
`Arg’*“Lys'®°-GLP-1 (8-36); Arg”*“Lys"®GLP-1 (8-37); Arg”*“Lys'**"GLP-1 (8-37);
`Arg’***Lys'®°GLP-1 (8-38); Arg”°“Lys'®*°GLP-1 (8-39); Arg”“Lys”***-GLP-1 (8-36);
`Arg***LysGLP-1 (8-37); Arg*™Lys”**’GLP-1(8-37); Arg”“Lys°GLP-1 (8-38);
`Arg?®*Lys®9GLP-1(8-39); Arg®*Lys?”°*-GLP-1(8-36); Arg®*Lys?”GLP-1 (8-37):
`Arg*™“Lys?”*"GLP-1(8-37); Arg?™“Lys”’*GLP-1 (8-38); Arg”’“Lys””*°GLP-1(8-39);
`Gly*GLP-1 (8-36); Gly®GLP-1(8-37); Gly°GLP-1(8-38); Gly®GLP-1 (8-39);
`Gly®Arg*Lys**-GLP-1(8-36); Gly*Arg™Lys®*-GLP-1 (8-36); Gly’Arg*Lys*°-GLP-1 (8-37);
`Gly®Arg™Lys*°-GLP-1 (8-37); Gly°Arg”*Lys*”-GLP-1(8-37); Gly’Arg™Lys*’-GLP-1 (8-37);
`Gly*Arg*Lys*°-GLP-1 (8-39); Gly’Arg™Lys*®-GLP-1 (8-39); Gly*Arg”*“Lys*°°°-GLP-1 (8-39);
`Gly®Arg*Lys"®-GLP-1 (8-36); Gly*Arg™Lys"®-GLP-1 (8-36); Gly’Arg*Lys*GLP-1 (8-37);
`Gly’Arg™Lys"*GLP-1 (8-37); Gly’Arg”Lys"GLP-1(8-38); Gly’Arg™“Lys"®GLP-1 (8-38);
`Gly*Arg”Lys"*GLP-1 (8-39); Gly*Arg™“Lys"GLP-1(8-39);
`Gly*Arg**Lys®’-GLP-1 (8-36); Gly*Arg*Lys*-GLP-1(8-36); Gly*Arg”Lys*GLP-1 (8-37):
`Gly’Arg™Lys*GLP-1(8-37); Gly*Arg”Lys@GLP-1 (8-38); Gly*Arg™Lys*GLP-1 (8-38);
`Gly*Arg“Lys*GLP-1 (8-39), Gly’Arg™Lys*GLP-1 (8-39);
`Gly®Arg**Lys*’-GLP-1 (8-36); Gly®Arg*Lys?’-GLP-1(8-36); Gly®Arg”*Lys*”GLP-1(8-37);
`Gly’Arg™Lys”’GLP-1(8-37); Gly*Arg”Lys”’GLP-1 (8-38); Gly*Arg™Lys”’GLP-1(8-38);
`Gly*Arg”Lys”’GLP-1(8-39); Gly*Arg*Lys””GLP-1(8-39):
`
`20
`
`25
`
`30
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1032, p. 11 of 50
`
`

`

`WO 99/43705
`
`PCT/DK99/00081
`
`-10-
`
`Gly*Arg”*™“Lys®°*-GLP-1 (8-36); Gly*Arg”“Lys"*GLP-1(8-37); Gly’Arg”*™Lys'**’GLP-1 (8-37);
`Gly’Arg?**“Lys"®**°GLP-1(8-38); Gly*Arg?™Lys"®*°GLP-1 (8-39); Gly*Arg”Lys”*°*-GLP-1 (8-36);
`Gly®Arg®*LysGLP-1 (8-37); Gly’Arg*“Lys**’"GLP-1 (8-37); Gly’Arg™“Lys**°°GLP-1(8-38);
`Gly*Arg?*Lys®"°GLP-1(8-39); Gly*Arg”Lys?”°*-GLP-1 (8-36); Gly’Arg”***Lys*”GLP-1 (8-37);
`Gly*Arg’*“Lys?”*’GLP-1(8-37); Gly®Arg*™Lys””*8GLP-1 (8-38); Gly*’Arg?™Lys?”°GLP-1 (8-39);
`Val®GLP-1 (8-36); Val®GLP-1(8-37); Val’GLP-1 (8-38); Val®@GLP-1 (8-39)
`Val®Arg*Lys*°-GLP-1 (8-36); Val’Arg™Lys*°-GLP-1 (7-36); Val’Arg*Lys*°-GLP-1(8-37);
`ValArg™Lys**-GLP-1 (8-37); Val’Arg”*Lys®”-GLP-1 (8-37); Val’Arg™Lys*’-GLP-1 (8-37);
`Val’Arg**Lys°*°-GLP-1(8-39); Val’Arg™Lys**-GLP-1 (8-39); Val®Arg”*™“Lys**°*-GLP-1 (8-39);
`Val’Arg*Lys"®-GLP-1 (8-36); Val’Arg™“Lys'®-GLP-1 (8-36); Val’Arg*Lys"*GLP-1(8-37);
`Val*Arg™Lys®GLP-1 (8-37); Val®Arg*Lys"*GLP-1(8-38); Val’Arg™Lys'°GLP-1 (8-38);
`Val’Arg*Lys*GLP-1 (8-39); ValArg™Lys"®GLP-1(8-39);
`Val*Arg”*Lys*-GLP-1 (8-36); Val’Arg™Lys”°-GLP-1(8-36); Val’Arg”*Lys”GLP-1 (8-37);
`Val’Arg™Lys°GLP-1 (8-37); Val’Arg”Lys”*GLP-1 (8-38); Val’Arg™Lys“GLP-1 (8-38);
`Val’Arg>Lys*°GLP-1 (8-39); Val’Arg™Lys*GLP-1(8-39);
`Val®Arg”*Lys”’-GLP-1 (8-36); Val’Arg™Lys””-GLP-1(8-36); Val’Arg”*Lys”’GLP-1 (8-37);
`Val’Arg™Lys?”GLP-1 (8-37); Val’Arg”Lys”GLP-1(8-38); Val’?Arg™Lys””GLP-1 (8-38);
`ValPArg”Lys”’GLP-1 (8-39); Val®@Arg™Lys”’GLP-1(8-39);
`Val®Arg***Lys"°*_GLP-1 (8-36); Val’Arg?Lys'®GLP-1 (8-37); Val’Arg®™Lys"**’GLP-1 (8-37);
`Val®Arg’**Lys'®°°GLP-1(8-38); Val’Arg“Lys"®*GLP-1(8-39); Val®Arg*“Lys®**-GLP-1 (8-36);
`Val’Arg?**Lys*°GLP-1 (8-37); ValArg”*“Lys**’GLP-1(8-37); Val’Arg*“Lys**GLP-1(8-38);
`Val®Arg?*Lys?2°GLP-1 (8-39); Val?Arg?**Lys?”*°-GLP-1 (8-36); Val’Arg”“Lys*”GLP-1 (8-37):
`Val’Arg**™“Lys?”*"GLP-1(8-37); Val’Arg?*“Lys?”=GLP-1 (8-38); or ValPArg”*“Lys?”*°GLP-1 (8-39).
`
`in a most preferred embodiment, the present invention relates to derivatives of GLP-1
`
`analoguesof formulaIII:
`8
`9
`10
`
`11
`
`12
`
`#13
`
`24
`
`#15
`
`16
`
`#17
`
`Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-KXaa-Xaa-Kaa-
`
`18
`
`#19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`26
`
`27
`
`28
`
`Xaa~Xaa-Xaa-Xaa-Xaa-KXaa-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
`
`39
`
`40
`
`41
`
`42
`
`43
`
`44
`
`45
`
`20
`
`25
`
`30
`
`35
`
` 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-
`
`a)
`
`wherein
`
`Xaaat position 8 is Ala, Gly, Ser, Thr, Leu,lle, Val, Glu, Asp, or Lys, oris deleted,
`
`Xaa at position 9 is Glu, Asp, or Lys, or is deleted,
`
`Xaa at position 10 is Gly oris deleted,
`Xaa atposition 11 is Thr, Ala, Gly, Ser, Leu, lle, Val, Glu, Asp, or Lys, oris deleted,
`
`Xaa at position 12 is Phe or is deleted,
`
`Xaa at position 13 is Throris deleted,
`Xaaat position 14 is Ser, Ala, Gly, Thr, Leu, lle, Val, Glu, Asp, or Lys, or is deleted,
`
`Xaaat position 15 is Asporis 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, tle, Val, Glu, Asp, or Lys, oris deleted,
`
`Xaaat position 18 is Ser, Ala, Gly, Thr, Leu, lle, Val, Glu, Asp, or Lys,
`
`Xaaat position 19 is Tyr, Phe, Trp, Giu, Asp, or Lys,
`
`Xaaat 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, lle, Vai, Glu, Asp, or Lys,
`
`Xaaat position 23 is Gin, Asn, Arg, Glu, Asp, or Lys,
`
`Xaaat position 24 is Ala, Gly, Ser, Thr, Leu, lle, Val, Arg, Glu, Asp, orLys,
`
`Xaaat position 25 is Ala, Gly, Ser, Thr, Leu, lle, 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,
`
`Xaaat position 30is Ala, Gly, Ser, Thr, Leu, lle, Val, Glu, Asp, or Lys,
`
`Xaaat position 31 is Trp, Phe, Tyr, Glu, Asp, or Lys,
`
`Xaaatposition 32 is Leu, Gly, Ala, Ser, Thr, ile, Val, Glu, Asp, or Lys,
`
`Xaaatposition 33 is Val, Gly, Ala, Ser, Thr, Met, Leu, lle, Glu, Asp, or Lys,
`
`Xaaat 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 atposition 37 is Gly, Ala, Ser, Thr, Leu, lle, Val, Glu, Asp, or Lys, or is deleted,
`
`Xaaat 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,
`
`Xaaat position 41 is Phe, Trp, Tyr, Glu, Asp, or Lys, or is deleted,
`
`20
`
`25
`
`30
`
`35
`
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`

`

`WO 99/43705
`
`PCT/DK99/00081
`
`-12-
`
`Xaaat 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 aminoacidis also deleted,
`
`(i) when the aminoacid at position 37, 38, 39, 40, 41, 42, 43 or 44 is deleted, then each
`
`amino acid downstream of the aminoacid 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 e-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 numberof 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 orsix.
`
`The total numberof 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 numberof
`
`different amino acidsis five. More preferably, the numberof different amino acids is four. Even
`
`more preferably, the numberof different amino acids is three. Even more preferably, the number
`
`of different amino acids is two. Most preferably, the numberof different amino acidsis one.In
`
`orderto determine the numberofdifferent amino acids, one should compare the amino acid
`
`sequence of the derivative of the GLP-1 analog of the present invention with the corresponding
`
`native GLP-1. For example, there are two different amino acids (at positions 8 and 26) between
`the derivative Gly*Arg”*Lys™(N*-(7-deoxycholoyl))-GLP-1(7-40) and the correspondiing native
`
`GLP-1 (i.e., GLP-1(7-40)). Similarly, there is only one different amino acid (at position 34)
`betweenthe derivative Lys”(N*-(7-deoxycholoyl))Arg™-GLP-1(7-40) and the corresponding
`
`native GLP-1.
`
`The derivatives of the GLP-1 analogs of the present invention preferably have only one
`
`or two Lys. The e-amino group of one or both Lys is substituted with a lipophilic substituent,
`
`Preferably, the derivatives of the GLP-1 analogs of the present invention have only one Lys. Ina
`
`more preferred embodiment, there is only one Lys whichis located at the carboxy terminus of
`
`the derivative of the GLP-1 analogs.
`
`In an even more preferred embodiment, the derivatives of
`
`the GLP-1 analogs of the present invention have only one Lys and Glu or Aspis adjacentto Lys.
`
`20
`
`25
`
`30
`
`35
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1032, p. 14 of 50
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`

`

`WO 99/43705
`
`PCT/DK99/00081
`
`-13-
`
`In a preferred embodiment, the amino acids at positions 37-45 are absent.
`
`In another preferred embodiment, the aminoacidsat positions 38-45 are absent.
`
`In another preferred embodiment, the amino acids at positions 39-45 are absent.
`
`in another preferred embodiment, Xaa at position 8 is Ala, Gly, Ser, Thr, or Val.
`
`In another preferred embodiment, Xaa at position 9 is Glu.
`
`In another pref