PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`(71) Applicant: NOVO NORDISK A/S [DK/DK]; Novo Allé,
`DK-2880 Bagsvaerd (DK).
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`
`(11) International Publication Number:
`(51) International Patent Classification 6;
`WO 99/43707
`
`C07K 14/605, AG1K 38/26
`
`
`2 September 1999 (02.09.99)
`(43) International Publication Date:
`
`
`
`
`(21) International Application Number: PCT/DK99/00085|(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,
`(22) International Filing Date:
`25 February 1999 (25.02.99)
`
`
`KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK,
`
`
`MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG,
`
` (30) Priority Data:
`SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZW,
`
`ARIPO patent (GH, GM, KE, LS, MW, SD, SL, SZ, UG,
`0268/98
`27 February 1998 (27.02.98)
`DK
`
`
`
`ZW), Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`0263/98
`27 February 1998 (27.02.98)
`DK
`
`
`TM), European patent (AT, BE, CH, CY, DE, DK,ES,FI,
`0508/98
`8 April 1998 (08.04.98)
`DK
`
`
`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).
`
`
`
` Published
`
`
`With international search report.
`
`
`
`
`
`
`
` (54) Title: N-TERMINALLY MODIFIED GLP-1 DERIVATIVES (57) Abstract
`
`(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). NIELSEN,Per, Franklin; Dals@ Park 59, DK-3500
`Verlgse (DK). MADSEN, Kjeld; Nyvestergdrdsvej 3,
`DK-3500 Verlgse (DK).
`
`Thepresent invention relates to N-terminally modified 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-1 derivatives have a lipophilic substituent attached to at least one
`amino acid residue and are substituted at the N-terminal end with a substituent comprising an optionally substituted S— or 6-membered
`ring system, e.g. an imidazole.
`
`
`
`PFIZER, INC. v. NOVO NORDISKA/S - IPR2020-01252, Ex. 1034, p. 1 of 63
`
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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.
`SI
`Slovenia
`Ls
`Lesotho
`ES
`Albania
`SK
`LT
`Lithuania
`Slovakia
`Armenia
`FI
`LU
`SN
`FR
`Austria
`Luxembourg
`Senegal
`Latvia
`LV
`SZ
`Swaziland
`GA
`Australia
`TD
`Monaco
`Chad.
`MC
`GB
`Azerbaijan
`TG
`MD
`GE
`Togo
`Republic of Moldova
`Bosnia and Herzegovina
`MG
`Barbados
`GH
`TJ
`Tajikistan
`Madagascar
`Turkmenistan
`MK
`GN
`The former Yugoslav
`Belgium
`GR
`Burkina Faso
`Republic of Macedonia
`Turkey
`Mali
`HU
`Trinidad and Tobago
`Bulgaria
`Ukraine
`IE
`Benin
`Mongolia
`IL
`Mauritania
`Brazil
`Uganda
`United States of America
`Malawi
`1S
`Belarus
`IT
`Uzbekistan
`Mexico
`Canada
`Viet Nam
`JP
`Central African Republic
`Niger
`Netherlands
`KE
`Yugoslavia
`Congo
`Zimbabwe
`Switzerland
`KG
`Norway
`New Zealand
`KP
`Céte d’Ivoire
`Poland
`Cameroon
`China
`Portugal
`Romania
`Cuba
`Russian Federation
`Czech Republic
`Sudan
`Germany
`Sweden
`Denmark
`Estonia
`Singapore
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Treland
`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
`
`™T
`
`R
`TT
`UA
`UG
`US
`UZ
`VN
`YU
`Zw
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`cI
`CM
`CN
`cu
`CZ
`
`DK
`EE
`
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`
`

`

`WO 99/43707
`
`PCT/DK99/00085
`
`-4-
`
`N-TERMINALLY MODIFIED 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 and analogues thereof having a protractedprofile of action andto the
`
`use of such derivatives in pharmaceutical compositions.
`
`BACKGROUNDOF THE INVENTION
`
`GLP-1 (Glucacon-Like-Peptide-1) is an important gut hormone with reguiatory function in
`
`10 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
`
`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 aninsulinotropic 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:
`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-
`
`2 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 (Buckley ef 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 whichalipophilic 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 0708179-A2(Eli Lilly & Co.) discloses GLP-1 analogues and derivatives that include
`
`an N-terminal imidazole group and optionally an unbranched C,-C,, acyl group in attached to the
`
`35
`
`lysine residue in position 34.
`
`SUBSTITUTE SHEET (RULE 26)
`
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`

`

`WO 99/43707
`
`-2-
`
`PCT/DK99/00085
`
`It is an object of the present invention to provide improved GLP-1 derivatives.
`
`SUMMARYOF THE INVENTION
`
`In its broadest aspect, the present invention relates to derivatives of GLP-1(7-B) and
`
`analoguesthereof. 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 comprisea lipophilic
`
`substituent (optionally via a spacer) attached to at least one amino acid residue and the N-
`
`terminal amino acid, i.e., the histidine residue at position 7 is modified. The lipophilic substituent
`
`is in particular a long-chain group of the type described in WO 98/08871 (Novo Nordisk A/S), and
`
`the N-terminal substituent comprises an optionally substituted 5- or 6-membered ring system,
`
`e.g. an imidazole.
`
`Accordingly, the invention relates to a GLP-1 derivative comprising a parent peptide of
`formula II
`
`A-HN-GLP-1(8-B)-X
`
`(Il)
`
`wherein
`
`R3. R2°
`
`0
`
`Ais: XA or WK or
`
`R1
`
`R3-R2
`
`Y
`
`CH,x
`
`R3 Ro
`
`20
`
`25
`
`wherein R', R’ and R®are independently H, lower alkyl having 1 to 6 carbon atoms, optionally
`substituted phenyl, NH,, NH-CO-(loweralkyl), -OH, lower alkoxy having 1 to 6 carbon atoms,
`halogen, SO,-(loweralkyl) or CF3, said phenyl is optionally substituted with at least one group
`selected from NH2, -OH, loweralkyl or lower alkoxy having 1-6 carbon atoms, halogen, SO,-
`(loweralkyl), NH-CO-(loweralkyl) or CF, or R' and R? may together form a bond:
`Y is a five or six membered ring system selected from the group consisting of:
`
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`
`

`

`WO 99/43707
`
`PCT/DK99/00085
`
`N
`
`_
`
`Tre Oe a
`
`H
`N
`
`XN
`|
`
`Zz
`
`raaN-~
`
`a.aanYe—,
`
`of
`
`CP
`
`znnmA
`
`\OQ
`
`Q
`
`wherein Z is N, O or S, said ring system is optionally substituted with one or more functional
`groups selected from the group consisting of NH,, NO,, OH, loweralkyl, lower alkoxy, halogen,
`CF; andaryl;
`
`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 analogue thereof;
`
`said GLP-1 derivative or analogue comprisinga lipophilic substituent attached to at least one
`
`amino acid residue thereof.
`
`in particular, the invention relates to GLP-1 derivatives of formula II
`
`A-HN-GLP-1(8-B)-X
`
`a)
`
`wherein
`
`R3. R29
`
`0
`
`R1
`
`R3
`
`R2
`
`R3
`
`RQ
`
`wherein R’, R’ and R® are independently H, loweralkyl, optionally substituted phenyl, NH,, NH-
`CO-(ioweralkyl), -OH, lower alkoxy, halogen, SO,-(loweralkyl) or CF3, wherein said phenylis
`optionally substituted with at least one groupselected from NH, -OH,loweralkyl or loweralkoxy
`
`
`
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`

`

`WO 99/43707
`
`-4-
`
`PCT/DK99/00085
`
`having 1-6 carbon atoms, halogen, SO,-(loweralkyl), NH-CO-(loweralkyl) or CF,, or R' and R?
`
`may together form a bond; andY is a five or six membered ring system selected from the group
`
`consisting of:
`
`H
`
`H
`
`H
`
`_
`
`CcN )
`
`aN, —_
`
`Ny _
`
`a I
`
`,o
`
`ey ‘I
`
`Yo
`
`70
`
`‘J
`
`ZN
`
`‘ST
`
`wherein Z is N, O or S, and said ring system is optionally substituted with one or more functional
`
`groups selected from the group consisting of NH, NO,, OH, loweralkyl, lower alkaxy, halogen,
`
`CF, and aryl (i.e., optionally substituted phenyl, as define above), provided thatAis not histidine;
`
`B is an integerin the range of 35-45; and
`
`X is -OH, —NH,, or a C,4 alkyl amide or C,., dialkyl amide group;
`
`or an analoguethereof.
`
`whereinalipophilic substituent (optionally via a spacer) is attached to at least one amino acid
`
`residue provided that when the lipophilic substituent is an acyl group and no spaceris present,
`
`then the acyl group contains at least 12 carbon atoms.
`
`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 peptide 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, Lys*4(N*-tetradecanoyl)-GLP-1(7-37)
`
`20
`
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`

`

`WO99/43707
`
`5
`
`PCT/DK99/00085
`
`designates GLP-1(7-37) wherein the e-amino group of the Lys residue in position 34 has been
`
`tetradecanoylated. Where a reference is made to C-terminaliy extended GLP-1 analogues, the
`
`amino acid residue in position 38 is Arg unless otherwise indicated, the amino acid residue in
`
`position 39 is also Arg unless otherwise indicated and the amino acid residue in position 40 is
`
`Asp unlessotherwiseindicated. Also, if a C-terminally extended analogue extendsto position 41,
`
`42, 43, 44 or 45, the amino acid sequenceof this extension is as in the corresponding sequence
`
`in human preprogiucagon unless otherwiseindicated.
`
`The present invention relates to derivatives of native GLP-1 and derivatives of GLP-1
`
`analogs. !n a preferred embodiment, the derivatives are derivatives of GLP-1(7-45) or a fragment
`
`thereof. in a more preferred embodiment, the derivatives are derivatives of native GLP-1(7-36).
`
`in another more preferred embodiment, the derivatives are derivatives of native GLP-1(7-37). In
`
`another more preferred embodiment, the derivatives are derivatives of native GLP-1(7-38).
`
`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 Il, B is preferably 36, 37 or 38.
`
`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 o-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 o-amino acid residue which can be
`
`coded for by the genetic code.
`
`Preferred GLP-1 derivatives or analogues are those in which:
`
`B is 36, and the parent peptide comprises one or more amino acid 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®.
`In a further preferred embodiment, a parent peptide for a derivative of the invention is
`Arg**-GLP-1 (7-37); Arg*-GLP-1 (7-37); Lys*°-GLP-1(7-37);
`Arg”*Lys*°-GLP-1(7-37); Arg”*“Lys*GLP-1 (7-38):
`Arg”*™“Lys*°-GLP-1 (7-39); Arg?°“Lys*°-GLP-1 (7-40);
`
`20
`
`25
`
`30
`
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`

`

`WO 99/43707
`
`6
`
`PCT/DK99/00085
`
`Arg’Lys*®-GLP-1(7-37); Arg™Lys*°-GLP-1 (7-37);
`Arg**Lys**-GLP-1(7-39); Arg™Lys“°-GLP-1 (7-40);
`Arg”**“Lys***°.GLP-1 (7-39); Arg”**“Lys*“°-GLP-1 (7-40);
`Gly®Arg”*-GLP-1 (7-37); Gly’Arg*-GLP-1 (7-37);
`Gly®Lys*®°-GLP-1 (7-37); Gly’Arg”*™“Lys*°-GLP-1 (7-37);
`Gly*Arg®“Lys**-GLP-1(7-39); Gly*Arg”**Lys“-GLP-1 (7-40):
`Gly*Arg”Lys®-GLP-1(7-37); Gly’Arg*Lys°-GLP-1 (7-37):
`Gly®Arg*Lys*°-GLP-1 (7-39); Gly*Arg™Lys*°-GLP-1 (7-40):
`Gly®’Arg??™Lys**°-GLP-1 (7-39); or
`
`Gly’Arg”*™“Lys**“°-GLP- 1 (7-40).
`
`In a further preferred embodiment, a parent peptide for a derivative of the invention is:
`
`Arg?***Lys®®GLP-1(7-38);
`
`Arg”*™Lys*°GLP-1 (7-39);
`Arg”*™Lys“°GLP-1 (7-40);
`
`Arg**™“Lys“'GLP-1 (7-41);
`
`Arg***Lys”GLP-1 (7-42);
`Arg***Lys*GLP-1 (7-43);
`Arg”*“Lys“GLP-1 (7-44);
`Arg**™“Lys*GLP-1 (7-45);
`
`Arg”Lys*GLP-1 (7-38);
`Arg™Lys*®GLP-1 (7-38);
`Arg**™Lys®*8GLP-1(7-38):
`Arg?*“Lys®GLP-1(7-38):
`
`Arg*Lys*°GLP-1 (7-39);
`Arg™Lys*GLP-1 (7-39); or
`Arg®*Lys®**°GLP-1(7-39).
`
`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 (7-37), Arg*-GLP-
`1(7-37), Lys*-GLP-1 (7-37), Arg’*™Lys**-GLP-1 (7-37), Arg*Lys*-GLP-1(7-37), Arg“Lys®-GLP-
`1(7-37), Gly*Arg®-GLP-1(7-37), Gly*Arg*-GLP-1(7-37), Gly*Lys®-GLP-1(7-37), Gly’Arg2*“Lys®-
`GLP-1(7-37), Gly*Arg”Lys*-GLP-1(7-37) and Gly*Arg™“Lys*°-GLP-1(7-37).
`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 (7-38),
`Arg’*“Lys*-GLP-1(7-38), Arg?*™Lys*°**.GLP-1 (7-38), Gly*Arg”Lys**-GLP-1(7-38) and
`Gly*Arg”*™Lys*°GLP-1(7-38).
`
`20
`
`25
`
`30
`
`35
`
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`

`

`WO 99/43707
`
`,
`
`PCT/DK99/00085
`
`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(7-39),
`Arg***Lys*®"9-GLP-1(7-39), Gly*Arg”*Lys**-GLP-1 (7-39) and Gly®Arg”™Lys*°*°-GLP-1 (7-39).
`
`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 (7-40),
`Arg”*“Lys*°°-GLP-1 (7-40), Gly°Arg™Lys*°-GLP-1 (7-40) and Gly®Arg”*™“Lys**“°-GLP-1 (7-40).
`
`In a further preferred embodiment, the present invention relates to a GLP-1 derivative
`
`wherein the parent peptide is:
`Arg”-GLP-1(7-36); Arg*-GLP-1(7-36); Arg”*“Lys*°-GLP-1 (7-36); Arg?*-GLP-1(7-36)amide;
`Arg*-GLP-1(7-36)amide; Arg”*“Lys®-GLP-1(7-36)amide; Arg’°-GLP-1 (7-37); Arg*-GLP-1 (7-37):
`Arg”*“Lys**-GLP-1 (7-37); Arg*®-GLP-1 (7-38); Arg*-GLP-1 (7-38);
`Arg’*Lys**GLP-1 (7-38); Arg”’-GLP-1 (7-39); Arg™-GLP-1 (7-39);
`Arg?**Lys*®-GLP-1 (7-39); Gly’Arg*-GLP-1 (7-36);
`Gly®Arg*-GLP-1(7-36); Gly’Arg*™Lys**-GLP-1(7-36);
`Gly’Arg**-GLP-1(7-36)amide; Gly°Arg™-GLP-1(7-36)amide;
`Gly*Arg”*™“Lys*°-GLP-1(7-36)amide; Gly*Arg”*-GLP-1 (7-37);
`Gly*Arg*-GLP-1 (7-37); Gly*Arg?*“Lys®*-GLP-1(7-37);
`Gly’Arg”*-GLP-1(7-38); Gly’Arg*4-GLP-1 (7-38):
`Gly*Arg”™Lys**GLP-1(7-38); Gly®Arg?°-GLP-1 (7-39);
`Gly*Arg™-GLP-1 (7-39); Gly’Arg”*™Lys*°-GLP-1(7-39):
`Val®Arg”°-GLP-1 (7-36); Val®Arg™-GLP-1 (7-36);
`Val’Arg**™Lys**-GLP-1(7-36), Val’Arg?®-GLP-1 (7-36)amide;
`Val’Arg™-GLP-1(7-36)amide; Val®Arg”*“Lys*°-GLP-1(7-36)amide;
`Val’Arg’®-GLP-1 (7-37); Val®Arg™-GLP-1 (7-37);
`Val’Arg”*Lys*®-GLP-1(7-37); ValArg’°-GLP-1 (7-38);
`Val’Arg*-GLP-1 (7-38); Val®Arg**“Lys*°GLP-1 (7-38);
`Val’Arg”®-GLP-1 (7-39); Val®Arg™-GLP-1 (7-39):
`Val*Arg”*™Lys**-GLP-1(7-39); Ser’Arg”-GLP-1 (7-36);
`Ser’Arg™-GLP-1 (7-36); Ser’Arg”*“Lys*°-GLP-1 (7-36):
`Ser*Arg*-GLP-1(7-36)amide; Ser’Arg™-GLP-1(7-36)amide;
`Ser’Arg*™Lys*°-GLP-1(7-36)amide; Ser’Arg”°-GLP-1(7-37);
`Ser’Arg™-GLP-1 (7-37); Ser’Arg*™Lys*°-GLP-1 (7-37):
`Ser’Arg**-GLP-1(7-38); Ser’Arg™-GLP-1 (7-38):
`SerArg”’“Lys*GLP-1(7-38); Ser’Arg?°-GLP-1 (7-39),
`Ser’Arg™-GLP-1(7-39); Ser’Arg”*“Lys**-GLP- 1 (7-39);
`
`20
`
`25
`
`30
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`35
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` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1034, p. 9 of 63
`
`

`

`WO 99/43707
`
`PCT/DK99/00085
`
`-8-
`
`ThrArg®-GLP-1(7-36); ThrArg*-GLP-1 (7-36):
`
`ThreArg*™Lys*-GLP-1 (7-36); Thr?Arg”®-GLP-1(7-36)amide;
`
`ThrArg™-GLP-1(7-36)amide; Thr’Arg**™Lys**-GLP-1(7-36)amide;
`ThArg-GLP-1(7-37); ThrArg*-GLP-1(7-37):
`ThreArg”“Lys*°-GLP-1 (7-37); ThreArg?°-GLP-1 (7-38):
`Thr’Arg™-GLP-1 (7-38); ThreArg”*™Lys*®GLP-1 (7-38);
`Threarg’®-GLP-1(7-39); ThrArg*-GLP-1 (7-39):
`ThrArg”™Lys*-GLP-1(7-39); Val®Glu*Arg***Lys**-GLP-1 (7-36);
`Val’Glu*Arg**“Lys*°-GLP-1(7-36)amide; Val®Glu**Arg*™Lys°’GLP-1 (7-37);
`Val’Glu*”Arg”*™Lys*GLP-1 (7-38); Val®Glu**Arg”?Lys°**-GLP-1(7-39); Val®Glu**Arg*™Lys*°-GLP-
`
`1(7-36);
`Val’Glu*Arg”™Lys*-GLP-1(7-36)amide; Val’Glu“Arg*™Lys*”GLP-1(7-37);
`Val’Giu?’Arg**“Lys®GLP-1 (7-38);
`Val’Glu*Arg”*™Lys*°-GLP-1 (7-39); Val’Asp*Arg”*™Lys**-GLP-1 (7-36); Val?Asp*Arg™™Lys
`GLP-1(7-36)amide:
`Val’Asp*Arg?*™Lys*’GLP-1 (7-37); Val®Asp*’Arg*“Lys*GLP-1(7-38); Val®Asp*Arg”*™Lys*?-
`GLP-1(7-39); Val’Asp*Arg”*™Lys**-GLP-1 (7-36); Val’Asp*Arg”“Lys°*-GLP-1(7-36)amide;
`Val’Asp*Arg”“Lys*’GLP-1 (7-37); ValPAsp*’“Arg”™Lys**GLP-1(7-38); ValAsp*Arg*™Lys*?-
`GLP-1(7-39); Ser’Glu**Arg*™Lys**-GLP-1 (7-36); Ser’Glu*Arg**Lys**-GLP-1(7-36)amide;
`SerGlu*Arg*™Lys®’GLP-1 (7-37);
`Ser’Glu”’Arg**™Lys*®GLP-1 (7-38); Ser’Giu*Arg”*“Lys°*-GLP-1 (7-39); SerGlu*Arg™Lys®-
`GLP-1(7-36); Ser’Giu**Arg”*“Lys*-GLP-1 (7-36)amide; Ser’Glu**Arg*“Lys®’GLP-1 (7-37);
`Ser’Glu”’Arg*™“Lys*GLP-1 (7-38); Ser’Glu*“Arg**™Lys°°-GLP-1 (7-39); Ser’Asp*Arg™Lys*-
`GLP-1(7-36); Ser’Asp*Arg**™“Lys*-GLP-1(7-36)amide; SerPAsp*Arg””™“Lys*”’GLP-1(7-37);
`Ser’Asp*’Arg*“Lys*GLP-1(7-38); Ser’Asp*Arg”*™Lys*-GLP-1 (7-39); SersAsp*Arg”™Lys®-
`GLP-1(7-36); Ser’Asp*Arg**Lys®-GLP-1(7-36)amide; SePAsp*Arg®Lys*”GLP-1 (7-37);
`Ser’Asp”Arg”™Lys*GLP-1(7-38); Ser*Asp*Arg®™Lys®-GLP-1 (7-39); ThFeGlu*Arg2™Lys*-
`GLP-1(7-36); Thr’Glu*Arg**™Lys*°-GLP-1(7-36)amide; Thr°Glu*Arg?°“Lys*”GLP-1(7-37);
`TheGlu*Arg>™Lys*GLP-1(7-38); Thr°Glu*Arg*™Lys®-GLP-1 (7-39); ThFGluArg?™Lys®*-
`GLP-1(7-36); Thr°Glu*Arg*®“Lys®-GLP-1(7-36)amide: ThrGlu*Arg”™Lys”GLP-1 (7-37):
`ThrGlu*Arg“Lys*®GLP-1 (7-38); ThreGlu*Arg*™Lys*-GLP-1 (7-39);
`ThrAsp*Arg”*™Lys*®-GLP-1(7-36), Thr’Asp**Arg®™Lys®*-GLP-1(7-36)amide;
`ThreAsp*Arg”™“Lys*’GLP-1 (7-37);
`Thr’Asp*’Arg?*“Lys*GLP-1(7-38); Thr’Asp*Arg***Lys*-GLP-1 (7-39); ThrAsp*Arg“Lys”-
`GLP-1(7-36); ThrAsp*Arg”*“Lys**-GLP-1(7-36)amide; ThréAsp*Arg®™Lys®’GLP-1 (7-37):
`
`20
`
`25
`
`30
`
`35
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1034, p. 10 of 63
`
`

`

`WO 99/43707
`
`5
`
`PCT/DK99/00085
`
`Thr’Asp*’Arg”“Lys**GLP-1(7-38); Thr’Asp*Arg”*™Lys*-GLP-1 (7-39);
`
`Gly®Glu*Arg”**“Lys*°-GLP-1 (7-36); Gly’Glu*Arg”*™“Lys*°-GLP-1 (7-36)amide;
`
`Gly®Glu*Arg**“Lys*’GLP-1 (7-37);
`Gly®Glu*’Arg”*™Lys*°GLP-1 (7-38); Gly®Glu*Arg**™Lys*-GLP-1 (7-39); Gly®GluArg“Lys°**-
`GLP-1(7-36); Gly*Glu**Arg”™“Lys**-GLP-1(7-36)amide; Gly*Glu**Arg*™Lys°’GLP-1 (7-37);
`Gly*’Glu*’Arg**“Lys*GLP-1 (7-38); Gly®Glu*Arg”*“Lys®-GLP-1(7-39); Gly’Asp*Arg”*4Lys?
`GLP-1(7-36); Gly’Asp*Arg**™Lys**-GLP-1(7-36)amide; Gly’Asp*Arg”™Lys*”GLP-1(7-37);
`Gly*Asp*’Arg”*™Lys*GLP-1 (7-38); Gly’Asp*Arg*™“Lys**-GLP-1 (7-39); Gly’Asp*Arg”*™Lys**-
`GLP-1(7-36); Gly*Asp*Arg***Lys**-GLP-1(7-36)amide; Gly’Asp*Arg>Lys®”GLP-1(7-37):
`Gly*Asp*’Arg”*“Lys*GLP-1 (7-38); Gly’Asp*Arg”Lys®**-GLP-1 (7-39); Arg***Lys"®-GLP-1 (7-36);
`Arg”**4Lys'*-GLP-1(7-36)amide; Arg”®™Lys'®°GLP-1 (7-37); Arg”°“Lys"®GLP-1 (7-38);
`Gly*Asp“Arg”*Lys"®-GLP-1 (7-36); Gly’Asp'’Arg”*“Lys"*-GLP-1 (7-36); Gly*Asp"Arg*“Lys®-
`GLP-1(7-36)amide; Gly*Asp'’Arg”*™Lys'*-GLP-1(7-36)amide; Gly’Asp*Arg?*“Lys"°GLP-1 (7-37):
`Gly*Asp"*Arg”*“Lys"*GLP-1(7-38); Gly’Asp"’Arg”*™“Lys"®GLP-1 (7-38);
`Arg**™Lys*-GLP-1(7-36); Arg”*™Lys*-GLP-1(7-36)amide; Arg”*“Lys*°GLP-1 (7-37);
`Arg”’™“Lys*GLP-1(7-38); Gly’Asp“Arg”*™“Lys**-GLP-1 (7-36); Gly’Asp”*Arg”“Lys”*-GLP-1 (7-36);
`Gly*Asp“Arg”*“Lys**-GLP-1 (7-36)amide; Gly*Asp”Arg**'Lys?*-GLP-1(7-36)amide;
`Gly*Asp**Arg*Lys“GLP-1(7-37); Gly’Asp“Arg”*™Lys*GLP-1 (7-38); Gly’Asp”*Arg”“Lys“GLP-
`1(7-38);
`Arg’™Lys*’-GLP-1 (7-36); Arg**™Lys?’-GLP-1(7-36)amide; Arg”*“*Lys”’GLP-1 (7-37);
`Arg’*Lys’’GLP-1 (7-38); Gly*Asp*Arg*™Lys?’-GLP-1(7-36); Gly*Asp*Arg”*4Lys?”-GLP-1 (7-36);
`Gly*Asp**Arg”*“Lys*’-GLP-1(7-36)amide; Gly°Asp**Arg*™Lys”’-GLP-1(7-36)amide:
`Gly*Asp*Arg’*“Lys”’GLP-1 (7-37); Gly’Asp*Arg”“Lys””GLP-1 (7-38); Gly*Asp2*Arg2™Lys?”GLP-
`1(7-38);
`Arg**“Lys'*-GLP-1 (7-36); Arg*™“Lys'®-GLP-1 (7-36)amide; Arg’**LysGLP-1 (7-37);
`Arg**“Lys"*GLP-1(7-38); Val’Asp"*Arg”*Lys'®-GLP-1 (7-36); Val/Asp’Arg***Lys"®-GLP-1 (7-36);
`Val’AspArg*™“Lys"*-GLP-1(7-36)amide; Val@Asp'’Arg”*Lys"*-GLP-1 (7-36)amide:
`Val*Asp'*Arg”*Lys'°GLP-1 (7-37); Val°Asp"*Arg*“Lys°GLP-1(7-38); Val’Asp"7Arg”“Lys°GLP-
`4 (7-38):
`|
`Arg**™Lys®-GLP-1 (7-36); Arg”***Lys*-GLP-1(7-36)amide; Arg?*“LysGLP-1(7-37):
`Arg’***Lys*GLP-1 (7-38); Val’Asp*Arg*™Lys*°-GLP-1(7-36); Val’Asp”Arg®™“Lys®-GLP-1 (7-36):
`Val"Asp“Arg”*“Lys*-GLP-1(7-36)amide; Val’Asp”Arg”™™Lys?°-GLP-1(7-36)amide;
`Val’Asp“Arg”“Lys*GLP-1(7-37); Val*Asp“Arg*“LysGLP-1 (7-38); Val®Asp”Arg?“LysGLP-
`4(7-38);
`
`20
`
`25
`
`30
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` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1034, p. 11 of 63
`
`

`

`WO 99/43707
`
`PCT/DK99/00085
`
`-10-
`
`Arg“Lys?’~GLP-1 (7-36); Arg”°“Lys*’-GLP-1(7-36)amide; Arg**™Lys?”GLP-1 (7-37);
`Arg”*™Lys”’GLP-1(7-38); Val’Asp”Arg”*™Lys”’-GLP-1 (7-36); Val®Asp**Arg”*“Lys?’-GLP-1 (7-36);
`Val’Asp”Arg”*™Lys”’-GLP-1 (7-36)amide; Val’Asp**Arg”*™Lys*’-GLP-1 (7-36)amide;
`Val’Asp*Arg””“Lys”’GLP-1 (7-37). Val®Asp”Arg”“Lys?”GLP-1 (7-38); Val’Asp*Arg*™Lys?/GLP-
`
`1(7-38):
`Arg***Lys'*-GLP-1 (7-36); Arg”™“Lys"*-GLP-1(7-36)amide; Arg”***Lys'®GLP-1 (7-37);
`Arg?*™“Lys'*GLP-1(7-38); Ser’Asp"*Arg”***Lys"®-GLP-1(7-36); Ser’Asp"’Arg****Lys"*-GLP-1(7-
`36); Ser’Asp"*Arg”>*™Lys*-GLP-1(7-36)amide; Ser’Asp’Arg***Lys®-GLP-1(7-36)amide;
`Ser’Asp*Arg”“Lys'°GLP-1(7-37); Ser’Asp‘*Arg”™“Lys ®GLP-1 (7-38);
`Ser’Asp"’Arg”™“Lys"8GLP-1 (7-38);
`Arg***Lys”-GLP-1 (7-36); Arg”*Lys**-GLP-1(7-36)amide; Arg’®*Lys*GLP-1 (7-37);
`Arg®™“Lys*GLP-1(7-38), Ser’Asp“Arg*™Lys*-GLP-1 (7-36); Ser’Asp”Arg”?“Lys?°-GLP-1 (7-
`36); Ser’Asp“Arg”*“Lys*-GLP-1 (7-36)amide; Ser’Asp”Arg”*“Lys*-GLP-1(7-36)amide:
`Ser’Asp“Arg”LysGLP-1(7-37), Ser’Asp“Arg2“Lys2GLP-1 (7-38):
`Ser’Asp”Arg”Lys*GLP-1 (7-38):
`Arg****Lys*’-GLP-1 (7-36); Arg”*“Lys”’-GLP-1(7-36)amide; Arg?*“Lys””GLP-1 (7-37);
`Arg®™Lys*7GLP-1(7-38); Ser’Asp”Arg®Lys?’-GLP-1 (7-36); Ser’Asp**Arg?Lys”-GLP-1(7-
`36); Ser*Asp”*Arg”*™Lys”’-GLP-1 (7-36)amide; Ser*Asp”*Arg”*“Lys?”-GLP-1(7-36)amide:
`Ser’Asp*Arg**“Lys*’GLP-1 (7-37); SePrAsp*Arg”>™Lys?”GLP-1 (7-38);
`Ser’Asp*Arg”*“Lys*’GLP-1 (7-38);
`Arg®™Lys'®-GLP-1 (7-36); Arg™“Lys'®*-GLP-1 (7-36)amide; Arg?**‘Lys"®GLP-1(7-37):
`Arg”*“Lys'*GLP-1(7-38); Thr’Asp‘*Arg*™Lys"®-GLP-1 (7-36); ThrAsp’Arg”™Lys"®-GLP-1 (7-36):
`Thr’Asp"*Arg**™“Lys"*-GLP-1(7-36)amide; Thr°Asp"Arg**Lys'®-GLP-1 (7-36)amide:
`ThrAspArg*™Lys'®GLP-1 (7-37); ThrAsp*Arg*™Lys'®GLP-1(7-38); ThrAspArg2™Lys®GLP-
`1(7-38);
`Arg”™Lys*-GLP-1(7-36); Arg”*“Lys®-GLP-1 (7-36)amide; Arg”**LysGLP-1 (7-37):
`Arg*®“Lys*°GLP-1(7-38); Thr°Asp“Arg”™Lys**-GLP-1 (7-36); ThrAsp”Arg™Lys”*-GLP-1 (7-36);
`ThrAsp“Arg”*™“Lys*-GLP-1(7-36)amide; ThrAsp”Arg**Lys*-GLP-1(7-36)amide;
`Thr’Asp“Arg”™Lys*GLP-1(7-37); TheAsp“Arg”™Lys*GLP-1(7-38); ThrAsp”Arg”Lys*GLP-
`4(7-38);
`Arg”™“Lys?’-GLP-1(7-36); Arg***Lys?’-GLP-1 (7-36)amide; Arg*®*“*Lys”’"GLP-1 (7-37):
`Arg’*™“Lys*’GLP-1 (7-38); Thr°Asp*Arg”*“Lys?’-GLP-1 (7-36); Thr-AspArg”™4Lys?’-GLP-1 (7-36):
`ThrAsp*Arg*™Lys*’-GLP-1(7-36)amide; Thr’Asp*Arg”*™Lys?’-GLP-1(7-36)amide;
`Thr’Asp”Arg”™Lys”’GLP-1(7-37); ThreAsp”Arg”Lys””GLP-1(7-38); or
`ThrAsp*Arg?Lys?”“GLP-1 (7-38).
`
`20
`
`25
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`30
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`35
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` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1034, p. 12 of 63
`
`

`

`WO 99/43707
`
`PCT/DK99/00085
`
`-11-
`
`In a further preferred embodiment, the present invention relates to a GLP-1 derivative
`
`wherein the parent peptideis:
`Arg”*Lys®-GLP-1(7-36); Arg*Lys®°-GLP-1 (7-36); Arg*Lys*®-GLP-1(7-37); Arg™Lys®-GLP-1(7-
`37); Arg*Lys*’-GLP-1(7-37); Arg™Lys*’-GLP-1 (7-37); Arg”’Lys*°-GLP-1 (7-39); Arg™Lys*®-GLP-
`1(7-39); Arg”®™“Lys****-GLP-1 (7-39);
`Arg*Lys'*-GLP-1 (7-36); Arg™Lys"*-GLP-1(7-36); Arg*Lys'*GLP-1 (7-37); Arg“Lys"®GLP-1(7-37);
`Arg*Lys'"*GLP-1(7-38); Arg™Lys'*GLP-1(7-38); ArgLys"GLP-1 (7-39); Arg™Lys'®GLP-1 (7-39);
`Arg®*Lys®-GLP-1 (7-36); Arg™Lys®-GLP-1 (7-36); Arg**Lys®GLP-1(7-37); Arg™Lys@GLP-1(7-37):
`Arg*Lys*GLP-1(7-38); Arg™Lys®GLP-1 (7-38); ArgLys"GLP-1(7-39); Arg™Lys®GLP-1(7-39):
`Arg*Lys”’-GLP-1 (7-36); Arg™Lys*’-GLP-1(7-36); ArgLys?’GLP-1 (7-37); Arg*Lys”’GLP-1(7-37),
`ArgLys*’GLP-1(7-38); Arg*Lys””GLP-1(7-38); Arg”Lys?’”GLP-1(7-39); Arg™Lys?”GLP-1(7-39);
`Arg”*“Lys'**°-GLP-1(7-36); Arg”**Lys'*GLP-1 (7-37); Arg?“Lys'®°’GLP-1 (7-37);
`Arg”Lys'®°°GLP-1(7-38); Arg”“Lys"**°GLP-1 (7-39); Arg?**4Lys?°*°-GLP--1(7-36);
`Arg’*Lys*°GLP-1 (7-37); Arg?®“Lys**’GLP-1 (7-37); Arg®“Lys”""GLP-1 (7-38);
`Arg’*Lys*°°GLP-1(7-39); Arg”Lys””**-GLP-1 (7-36); Arg’°*Lys””GLP-1(7-37);
`Arg’*“Lys’”°’GLP-1(7-37); Arg”*“Lys?”*GLP-1 (7-38); Arg?*“Lys?”°GLP-1(7-39);
`Gly*GLP-1(7-36); GlySGLP-1(7-37); Gly®GLP-1(7-38): Gly®GLP-1 (7-39);
`Gly*Arg**Lys**-GLP-1 (7-36); Gly°Arg™Lys**-GLP-1 (7-36); Gly*Arg”*Lys**-GLP-1(7-37);
`Gly*Arg™Lys*°-GLP-1 (7-37); Gly®Arg”*Lys*’-GLP-1 (7-37), Gly’Arg*Lys*’-GLP-1 (7-37):
`Gly’Arg”Lys®-GLP-1(7-39); Gly’Arg™Lys®-GLP-1 (7-39); Gly*Arg?Lys®"°-GLP-1 (7-39):
`Gly*Arg”*Lys"*-GLP-1(7-36); Gly’Arg™Lys"*-GLP-1 (7-36); Gly®Arg*Lys'®GLP-1 (7-37);
`Gly*Arg*Lys"*GLP-1(7-37); Gly’Arg”Lys'®GLP-1 (7-38); Gly’Arg™Lys'®GLP-1(7-38);
`Gly*Arg*Lys*GLP-1(7-39); Gly’Arg™Lys®GLP-1 (7-39):
`Gly*Arg**Lys®-GLP-1 (7-36); Gly*Arg™Lys®-GLP-1 (7-36); Gly*Arg’Lys*GLP-1(7-37):
`Gly"Arg™Lys*GLP-1(7-37); Gly*Arg*Lys*GLP-1(7-38); Gly’Arg™Lys“GLP-1(7-38);
`Gly’Arg”*Lys*GLP-1 (7-39); Gly’Arg™Lys*GLP-1 (7-39);
`Gly*Arg**Lys”’-GLP-1 (7-36); Gly’Arg™Lys””-GLP-1(7-36); Gly*Arg8Lys””GLP-1 (7-37);
`Gly’Arg™Lys*’GLP-1(7-37); Gly*Arg*Lys”’GLP-1 (7-38); Gly’Arg™Lys?”GLP-1(7-38);
`Gly*Arg*Lys”’GLP-1(7-39); Gly°Arg“Lys*”GLP-1 (7-39);
`Gly*Arg”*“Lys"®°°-GLP-1(7-36); Gly*Arg®“Lys"*GLP-1 (7-37); Gly*Arg?Lys"®*"GLP-1 (7-37):
`Gly*Arg’*™Lys*°*GLP-1(7-38); Gly°Arg*™“Lys'®°°GLP-1(7-39); Gly*Arg®™Lys”***-GLP-1 (7-36);
`Gly*Arg***“Lys*GLP-1(7-37); Gly’Arg®®Lys®*"GLP-1 (7-37); Gly’Arg?Lys®"°GLP-1 (7-38):
`Gly*Arg”*“Lys**°°GLP-1(7-39); Gly’Arg”*Lys””°*_GLP-1 (7-36); Gly’Arg?™“Lys?”GLP-1 (7-37):
`Gly*Arg’*“Lys?”"GLP-1 (7-37); Gly*Arg®“Lys””*GLP-1 (7-38); Gly’Arg’*™Lys?”°GLP-1(7-39):
`ValGLP-1(7-36); ValSGLP-1 (7-37); Val’GLP-1(7-38); Val°GLP-1(7-39)
`
`20
`
`25
`
`30
`
`35
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1034, p. 13 of 63
`
`

`

`WO 99/43707
`
`PCT/DK99/00085
`
`-12-
`
`Val’Arg*Lys**-GLP-1 (7-36); Val’Arg™Lys*°-GLP-1(7-36); Val’Arg**Lys**-GLP-1 (7-37);
`Val’Arg™Lys**-GLP-1 (7-37); Val’Arg*Lys*’-GLP-1(7-37); Val®Arg™Lys*’-GLP-1 (7-37);
`Val’Arg**Lys**-GLP-1 (7-39); Val’Arg™Lys*°-GLP-1(7-39); Val®Arg”*™“Lys****-GLP-1 (7-39);
`ValArg*Lys'®-GLP-1(7-36); Val®Arg™Lys"®-GLP-1(7-36); Val’Arg*Lys"®GLP-1 (7-37);
`Val’Arg™Lys'*GLP-1(7-37); Val’Arg”*Lys"*GLP-1 (7-38); Val’Arg™Lys"*GLP-1 (7-38);
`Val’Arg*Lys'®GLP-1(7-39); Val’Arg™Lys®GLP-1(7-39);
`Val®Arg”*Lys**-GLP-1(7-36); Val°Arg™Lys**-GLP-1(7-36); Val’Arg*Lys*GLP-1 (7-37);
`Val’Arg™Lys?*GLP-1(7-37); Val’Arg”Lys”°GLP-1 (7-38); Val’Arg™Lys°GLP-1 (7-38);
`Val®Arg”Lys*GLP-1(7-39); Val/Arg™Lys**GLP-1(7-39);
`Val’Arg**Lys*’-GLP-1 (7-36); Val’Arg™Lys”’-GLP-1(7-36); Val’Arg*Lys?’GLP-1 (7-37);
`Val*Arg™Lys”’GLP-1(7-37); ValArg*Lys””GLP-1 (7-38); Val®Arg™Lys”’GLP-1 (7-38);
`Val’Arg”*Lys”’GLP-1(7-39); Val’Arg™Lys?’GLP-1(7-39);
`Val*Arg?*™Lys'®*°-GLP-1 (7-36); Val’Arg**™“Lys'®GLP-1(7-37); Val’Arg?**Lys"8°’GLP-1 (7-37);
`Val’Arg*™“Lys'**GLP-1 (7-38); ValPArg”*™Lys'®*°GLP-1 (7-39); Val®Arg”“Lys?***GLP-1 (7-36):
`Val’Arg**™Lys*GLP-1(7-37); Val’Arg”™Lys”**’GLP-1 (7-37); Val’Arg®“Lys*GLP-1 (7-38);
`ValtArg”**Lys”™"°GLP-1 (7-39); Val’Arg”?“Lys?”°5-GLP-1 (7-36); Val®Arg?™“Lys?”GLP-1 (7-37);
`Val’Arg”*Lys*”°’GLP-1 (7-37); Val’Arg®*“Lys?”**GLP-1 (7-38); or Val’Arg”*Lys?”GLP-1(7-39).
`
`In a most preferred embodiment, the present invention relates to derivatives of GLP-1
`
`analogues of formulaIII:
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`#15
`
`#16
`
`#17
`
`Xaa-Xaa-Xaa-Gly-Xaa-Phe-Thr-Xaa-Asp-Xaa-Xaa-
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`26
`
`27
`
`28
`
`Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-KXaa-Xaa-Xaa-Phe-
`
`29
`
`30
`
`31
`
`32
`
`33
`
`34
`
`35
`
`36
`
`37
`
`38
`
`Tle-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa
`
`39
`
`40
`
`41
`
`42
`
`43
`
`44
`
`45
`
`Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa
`
`(Ill)
`
`wherein
`
`Xaaat position 7 is any of the groups A (as defined herein),
`
`Xaaat position 8 is Ala, Gly, Ser, Thr, Leu, lle, Val, Glu, Asp, or Lys,
`
`Xaaat position 9 is Glu, Asp,or Lys,
`
`20
`
`25
`
`30
`
`35
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1034, p. 14 of 63
`
`

`

`WO 99/43707
`
`PCT/DK99/00085
`
`-13-
`
`Xaa at position 11 is Thr, Ala, Gly, Ser, Leu, lle, Val, Glu, Asp, or Lys,
`
`Xaa at position 14 is Ser, Ala, Gly, Thr, Leu, lle, Val, Glu, Asp, or Lys,
`
`Xaa at position 16 is Val, Ala, Gly, Ser, Thr, Leu, lle, Tyr, Glu, Asp, or Lys,
`
`Xaa at position 17 is Ser, Ala, Gly, Thr, Leu, ile, Val, Glu, Asp, or Lys,
`
`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, lle, Val, Glu, Asp, or Lys,
`
`Xaa at position 23 is Gin, 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, tle, Val, Glu, Asp, or Lys,
`
`Xaa at position 26 is Lys, Arg, Gln, Glu, Asp, or His,
`
`Xaa at position 27 is Glu, Asp, orLys,
`
`Xaaat 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,
`
`Xaaat 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,
`
`Xaaat position 36 is Arg, Lys, Glu, Asp,orHis,
`
`Xaa at position 37 is Gly, Ala, Ser, Thr, Leu, lle, Val, Glu, Asp, or Lys, oris deleted,
`
`Xaaat position 38 is Arg, Lys, Glu, Asp, or His, or is deleted,
`
`Xaaat 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, oris deleted,
`
`Xaa at position 42 is Pro, Lys, Glu, or Asp,oris deleted,
`
`Xaa at position 43 is Glu, Asp, or Lys, or is deleted,
`
`Xaaat 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 37, 38, 39, 40, 41, 42, 43 or 44 is deleted, then each
`
`amino acid downstream of the amino acid is also deleted,
`
`20
`
`25
`
`30
`
`35
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1034, p. 15 of 63
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`

`

`WO 99/43707
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`PCT/DK99/00085
`
`-14-
`
`(ii) a lipophilic substituent is attached optionally via a spacer to one or moreof(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 whichis part of the R group of Asp or
`
`Glu, and
`
`(iit) the total numberof different amino acids between the derivative of the GLP-1 analog
`
`and the corresponding native form o