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`homohistidine , a -fluoromethyl-histidine or a-methyl-
`histidine;
`Xaa at position 8 is : Gly, Ala, Val, Leu , Ile , Ser, or Thr ;
`Xaa at positi on 12 is : His, Trp , Phe, or Tyr;
`5 Xaa at position 16 is: Leu, Ser, Thr, Trp , His, Phe, Asp,
`Val, Glu, or Ala ;
`Xaa at position 22 is : Gly, Asp, Glu, Gln, Asn, Lys, Arg, or
`Cys;
`Xaa at position 23 is : His , Asp, Lys, Glu, or Gln;
`10 Xaa at position 26 is: Asp, Lys, Glu, or His ;
`Xaa at position 30 is: Ala, Glu, Asp, Ser, or His;
`Xaa at posi t ion 35 is: Thr , Ser , Lys , Arg, Trp, Tyr, Phe,
`Asp, Gly, Pro, His, or Glu;
`Xaa at position 37 is: Lys, Arg, Thr, Ser , Glu, Asp, Trp,
`Tyr, Phe, His, -NH2, Gly, Gly-Pro, or Gly-Pro-NH2, or is
`deleted.
`
`15
`
`The heterologous fusion protein of Claims 1 , 2 , or 3
`8 .
`wherein the GLP-1 compound comprises the sequence of formula
`2 0 V ( SEQ ID NO : 6)
`
`25
`
`10 11 12 13 14 15 16 17
`7
`8
`9
`Xaa-Xaa- Glu-Gly- Thr-Phe-Thr-Ser-Asp- Val - Ser-
`18 19 20 21 22 23
`24 25
`26 27
`28
`Ser-Tyr-Leu- Glu-Xaa-Xaa-Ala-Ala-Lys-Xaa-Phe-
`29 30 31 32 33
`34 35 36 37
`Ile-Xaa-Trp-Leu-Val-Lys-Gly-Arg-Xaa
`formula V (SEQ I D NO : 6)
`
`30 wherein:
`Xaa at position 7 is : L-histidine, D-histidi ne , desamino(cid:173)
`histidine , 2-amino-histidine, ~-hydroxy-histidine,
`h omohistidine, a -fluorornethyl-histidine or a-methyl(cid:173)
`histidine ;
`35 Xaa at position 8 ts: Gly, Ala, Val, Leu, I l e, Ser, or Thr;
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`homohistidine , a -fluoromethyl-histidine or a-methyl-
`histidine;
`Xaa at position 8 is : Gly, Ala, Val, Leu , Ile , Ser, or Thr ;
`Xaa at positi on 12 is : His, Trp , Phe, or Tyr;
`5 Xaa at position 16 is: Leu, Ser, Thr, Trp , His, Phe, Asp,
`Val, Glu, or Ala ;
`Xaa at position 22 is : Gly, Asp, Glu, Gln, Asn, Lys, Arg, or
`Cys;
`Xaa at position 23 is : His , Asp, Lys, Glu, or Gln;
`10 Xaa at position 26 is: Asp, Lys, Glu, or His ;
`Xaa at position 30 is: Ala, Glu, Asp, Ser, or His;
`Xaa at posi t ion 35 is: Thr , Ser , Lys , Arg, Trp, Tyr, Phe,
`Asp, Gly, Pro, His, or Glu;
`Xaa at position 37 is: Lys, Arg, Thr, Ser , Glu, Asp, Trp,
`Tyr, Phe, His, -NH2, Gly, Gly-Pro, or Gly-Pro-NH2, or is
`deleted.
`
`15
`
`The heterologous fusion protein of Claims 1 , 2 , or 3
`8 .
`wherein the GLP-1 compound comprises the sequence of formula
`2 0 V ( SEQ ID NO : 6)
`
`25
`
`10 11 12 13 14 15 16 17
`7
`8
`9
`Xaa-Xaa- Glu-Gly- Thr-Phe-Thr-Ser-Asp- Val - Ser-
`18 19 20 21 22 23
`24 25
`26 27
`28
`Ser-Tyr-Leu- Glu-Xaa-Xaa-Ala-Ala-Lys-Xaa-Phe-
`29 30 31 32 33
`34 35 36 37
`Ile-Xaa-Trp-Leu-Val-Lys-Gly-Arg-Xaa
`formula V (SEQ I D NO : 6)
`
`30 wherein:
`Xaa at position 7 is : L-histidine, D-histidi ne , desamino(cid:173)
`histidine , 2-amino-histidine, ~-hydroxy-histidine,
`h omohistidine, a -fluorornethyl-histidine or a-methyl(cid:173)
`histidine ;
`35 Xaa at position 8 ts: Gly, Ala, Val, Leu, I l e, Ser, or Thr;
`
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`Xaa at position 22 is: Gly, Asp, Glu , Gln, Asn, Lys, Arg,
`Cys;
`Xaa at position 23 is :. His, Asp, Lys , Glu, or Gln;
`Xaa at position 24 is: Ala, Glu, His, Phe, Tyr, Trp, Arg,
`or Lys
`Xaa at position 30 is: Ala , Glu, Asp , Ser , or His;
`Xaa at position 37 is : Lys, Ar g, Thr, Ser , Glu , Asp, Tr p,
`Ty r , Phe, His, Gly, Gly-Pro, or is deleted .
`
`or
`
`5
`
`10
`
`9 . The heterologous fusion protein of Claims 1, 2, or 3
`wherein the GLP- 1 compound comprises the sequence of formula
`VIII (SEQ ID NO : 11) .
`
`10 11 12 13 14 15 16 17
`7
`9
`8
`Xaa-Xaa-Glu-Gly-Thr- Phe-Thr-Ser-Asp-Xaa-Ser-
`18 19 20 21 22 23 24 25 26 27 28
`Xaa- Xaa - Xaa-Glu-Xaa-Xaa-Ala-Xaa-Xaa-Xaa-Phe-
`29 30 31 32 33 34 35 36 37
`I le-Xaa- Trp-Leu-Xaa-Xa a-Gly-Xaa-Xaa
`formula VIII (SEQ ID NO: 11)
`
`wherein :
`Xaa at position 7 is : L- histidine, D-histidine , desamino-
`h i stidine, 2-amino-histidine, ~-hydroxy-histidine,
`homohistidine, a -fluoromethyl- histidine or a-methyl-
`histidine;
`Xaa at position 8 is : Gly , Ala, or Val;
`Xaa at position 16 is: Leu or Val;
`Xaa at position 18 is Lys or Ser;
`Xaa at position 19 is: Gln or Tyr;
`Xaa at position 20 is: Met or Leu;
`Xaa a t position 22 is : Glu or Gln ;
`Xaa at position 23 is : Glu, or Gln ;
`Xaa at position 25 is : Val or Ala;
`Xaa at positi on 26 is: Arg or Lys;
`
`15
`
`20
`
`25
`
`30
`
`35
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`Xaa at position 27 is Leu or Glu;
`Xaa at position 30 is: Glu or Ala;
`Xaa at position 33 is: Val or Lys;
`Xaa at position 34 is : Asn or Lys;
`5 Xaa at position 36 is: Gly or Arg; and
`Xaa at position 37 is: Gly, Pro, Pro-Ser- Ser-Gly-Ala-Pro-
`Pro-Pro-Ser, or is absent.
`
`10. The heterologous fusion protein of claims 1 through 9
`10 wherein the GLP- 1 compound has no more than 6 amino acids
`that are different from the corresponding amino acid in GLP-
`1(7 - 37)OH, GLP-1(7-36)OH, or Exendin-4.
`
`11. The heterologous fusion protein of Claim 10 wherein the
`15 GLP-1 compound has no more than 5 amino acids t h at differ
`from the corresponding amino acid in GLP -1 (7 - 37)OH, GLP- 1(7 -
`36)OH, or Exendin- 4 .
`
`12 . The heterologous fusion pro t ein o f Cla im 11 wherein the
`20 GLP-1 compound has no more than 4 amino acids that differ
`from the corresponding amino acid in GLP-1(7-37)OH, GLP- 1(7-
`36)OH, or Exendin-4.
`
`13. The heterologous fusion protein of Claim 12 wherein the
`25 GLP-1 compound has no more than 3 amino acids that differ
`from the corresponding amino acid in GLP-1(7-37)OH, GLP-1(7-
`36)OH, or Exendin-4 .
`
`14.The heterol ogous fusion protein of Claim 13 wher ein the
`30 GLP-1 compound has no mor e than 2 amino acid s that differ
`from t he corresponding amino acid in GLP-1(7-37)OH, GLP-1(7-
`36)OH, or Exendin-4 .
`
`15 . The heterologous fusion protein of any one of Claims 1
`through 14 wherein Xaa at position 8 is glycine or valine.
`
`35
`
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`16. The heterologou s fusion protein of Claim 8 wherein the
`GLP-1 compound has no more than 2 amino acids that differ
`from the corresponding amino acid in GLP-1(7-37)0H or GLP-
`1 (7-36)0H and Xaa at position 8 is glycine or valine and xaa
`at position 30 is alanine, glutamic acid , aspartic acid,
`serine, or histidine .
`
`5
`
`17. The heterologous fusion protein of Claim 16 wherein Xaa
`10 at position 30 is Glutamic acid .
`
`15
`
`18 . The heterologous fusion protein of Claim 8 wherein the
`GLP-1 compound has no more than 2 amino acids that differ
`from the corresponding amino acid in GLP-1(7-37 ) 0H or GLP-
`1(7-36)0H and Xaa at position 8 is glycine or valine and Xaa
`at position 37 is histidine, phenylalanine, tyrosine,
`tryptophan, aspartic acid, glutamic acid, serine, threonine,
`arginine, or lys i ne .
`
`20
`
`19 . The heterologous fusion protein of Claim 18 wherein Xaa
`at position 37 is histidine.
`
`25
`
`30
`
`20 . The heterologous fusion protein of Claim 8 wherein the
`GLP-1 compound has no more than 2 amino acids that differ
`from the corresponding amino acid in GLP-1(7-37)0H or GLP-
`1(7-36)0H and Xaa at position 8 is glycine , valine , leucine,
`isoleucine , serine, threonine, or methionine and Xaa at
`position 22 i ·s aspartic acid, glutamic acid, lysine ,
`arginine, asparagine , glutamine or histidine .
`
`21 . The heterologous fusion p r otein of Claim 20 wherein Xaa
`at position 22 is lysine or glutamic acid.
`
`22. The heterologous fusion protein of Claim 8 wherein the
`35 GLP-1 compound is Va1 8-GLP-1 (7-37).
`
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`23. The heterologous fusion protein of Claim 8 wherein the
`GLP-1 compound is Gly8 -GLP-1(7-37) .
`
`5
`
`24. The heterologous fusion protein of any one of Claims 1
`through 23 wherein the second polypeptide is human albumin .
`
`25. The heterologous fusion protein of Claim 24 wherein the
`second polypeptide has the sequence of SEQ ID NO: 34 .
`
`26. The heterologous fusion protein of any one of Claims 1
`through 23 wherein the second polypeptide is an N-terminal
`fragment of albumin.
`
`27. A heterologous fusion protein comprising a first
`polypeptide with a N-terminus and a C-terminus fused to a
`second polypeptide with a N-terminus and a C-terminus
`wherein the first polypeptide is a GLP-1 compound and the
`second polypeptide is selected from the group consisting of
`a) the Fe portion of an immunoglobulin;
`b) an analog of the Fe portion of an immunoglobulin;
`and
`c) fragments of the Fe portion of an immunoglobulin,
`and wherein the C-terminus of the first polypeptide is fused
`to the N-terminus of the second polypeptide .
`
`10
`
`15
`
`20
`
`25
`
`28. ~ heterologous fusion protein comprising a first
`polypeptide with a N-terminus and a C-terminus fused to
`a second polypeptide with a N-terminus and a C-terminus
`30 wherein the first polypeptide is a GLP-1 compound and the
`second polypeptide is sele~ted from the group consisting of
`a) the Fe portion of an immunoglobulin;
`b) an analog of the Fe portion of an immu noglobulin;
`and
`
`35
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`c) fragments of the Fe portion of an immunoglobulin,
`and wherein the C-terminus of the first polypeptide is
`fused to the N-terminus of the second polypeptide via a
`5 peptide linker.
`
`29 . The heterologous fusion protein of the Claim 28 wherein
`the peptide linker is selected from the group consisting of :
`a) a glycine rich peptide;
`b) a peptide having the sequence [Gly-Gly-Gly-Gly-Ser]n
`where n is 1, 2, 3, 4, 5, or 6; and
`c) a peptide having the sequence [Gly- Gly-Gly- Gly- Ser] 3 •
`
`10
`
`15
`
`30 . The heterologous fusion protein of any one of Claims
`27, 28, or 29 wherein the GLP-1 compound comprises the
`sequence of formula 1
`[SEQ ID NO : 2].
`
`10 11 12 13 14 15 16 17
`7
`8
`9
`His - Xaa-Xaa-Gly-Xaa-Phe-Thr-Xaa-Asp-Xaa-Xaa-
`18 1 9 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 39
`Ile-xaa-Xaa-Xaa-Xaa-Xaa-xaa-Xaa-Xaa-Xaa-Xaa-
`40 41 42
`43
`44
`45
`Xaa-Xaa-Xaa-Xaa-Xaa-Xaa
`Formula I
`(SEQ ID NO: 2)
`
`wherein:
`Xaa at position 8 is Ala, Gly, Ser, Thr, Leu, Ile, Val,
`Glu, Asp, or Lys;
`Xaa at position 9 is Glu, Asp, or Lys;
`Xaa at position 11 is Thr, Ala, Gly, Ser, Leu, Ile, Val,
`Glu, Asp, or Lys;
`Xaa at . position 14 is Ser, Ala, Gly, Thr , Leu, Ile, Val,
`Glu, Asp, or Lys;
`
`20
`
`25
`
`30
`
`35
`
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`
`15
`
`Xaa at position 16 is Val, Ala, Gly, Ser, Thr, Leu, Ile,
`Tyr, Glu, Asp, Trp, or Lys;
`Xaa at position 17 is Ser, Ala, Gly, Thr, Leu, Ile, Val ,
`Glu, Asp, or Lys;
`5 Xaa at position 18 is Ser, Ala, Gly, Thr, Leu, I l e, Val,
`Glu, Asp, Trp, Tyr, or Lys ;
`Xaa at position 19 is Tyr, Phe, Trp, Glu, Asp, Gln, or Lys;
`Xaa at position 20 is Leu, Ala, Gly, Ser , Thr, Ile , Val,
`Gl u, Asp, Met , Trp, Tyr, or Lys;
`10 Xaa at position 21 is Glu, Asp, or Lys;
`Xaa at position 22 is Gly, Ala, Ser, Thr, Leu, Ile, Val,
`Gl u, 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, I le, 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 Leu, Glu, Asp, or Lys;
`20 Xaa at position 30 is Ala, Gly, Ser, Thr, Leu, Ile, Val,
`Glu, Asp, or Lys;
`Xaa at position 31 is Trp, Phe, Tyr, Glu, Asp, or Lys;
`Xaa at posi t ion 32 is Leu, Gly, Ala, Ser, Thr , Ile, Val,
`Glu, Asp, or Lys;
`25 Xaa at position 33 is Val, Gly, Ala, Ser, Thr, Leu, Ile,
`Glu, Asp, or Lys;
`Xaa at position 34 is Asn, Lys, Arg, Glu, Asp , or His;
`Xaa at position 35 is Gly, Ala, Ser,- Thr , Leu, Ile, Val,
`Glu, Asp, or Lys;
`30 Xaa at position 36 is Gly, Arg, Lys, Glu, Asp, or His;
`Xaa at position 37 is Pro, Gly, Al a, Ser, Thr, Leu, Ile,
`Val, Glu, Asp, or Lys, or is deleted;
`Xaa at position 38 is Ser, Arg, Lys, Glu, Asp , or His, or
`is deleted;
`35 Xaa at position 39 is Ser, Arg, Lys, Glu, Asp, or His, or
`
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`is deleted;
`Xaa at position 40 is Gly, Asp, Glu, or Lys , or is deleted ;
`Xaa at position 41 is Ala, Phe, Trp, Tyr , Glu, Asp , or Lys,
`o r is delet ed;
`5 Xaa at position 42 is Ser, Pro, Lys, Glu, or Asp , or is
`deleted;
`Xaa at position 43 is Ser, Pro, Glu, Asp, or Lys , or is
`deleted ;
`Xaa at position 44 is Gl y , Pro , Glu, Asp, or Lys, or is
`de l eted;
`and
`Xaa at position 45 is Ala, Ser, Val, Glu, Asp, or Lys, or is
`deleted;
`provided that when the amino acid at posi t ion 37, 38, 39,
`40, 41, 42, 4 3, or 44 is delet ed, then each amino acid
`downstream of tha t amino acid is also deleted.
`
`1 0
`
`15
`
`20
`
`25
`
`31. The heterologous fusion protein of Claims 27, 28, or 29
`wherein the GLP-1 compound comprises the sequence of formula
`II (SEQ ID NO: 3) :
`
`10 11 12 13 14 15 16 17
`.9
`7
`8
`Xaa-Xaa - Xaa- Gly- Xaa - Xaa - Thr- Ser- Asp- Xaa- Ser-
`18 19 20 21 22
`23 24 25 26 27 28
`Xaa-Tyr - Leu-Glu-Xaa-Xaa-Xaa-Ala-Xaa-Xaa-Phe-
`29 30 31 32 33
`34 ~5 36 37
`Ile-Xaa -Xaa-Leu-Xaa-Xaa-xaa-Xaa-Xaa
`Formula II (SEQ ID NO : 3)
`
`30 wherein :
`Xaa at position 7 is : L-his t idine, D-histidine, desamino(cid:173)
`histidine, 2-amino-histidine, ~-hydroxy-histidine,
`homohistidine, a- fluoromethyl-histidine or a-methyl (cid:173)
`histidine;
`35 Xaa at position 8 is : Gly, Ala, Val , Leu, Ile , Ser, or Thr;
`
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`
`10
`
`15
`
`Xaa at position 9 is: Thr, ?er, Arg, Lys, Trp, Phe, Tyr,
`Glu, or His;
`Xaa at position 11 is: Asp, Glu, Arg, Thr, Ala, Lys, or His;
`Xaa at position 12 is: His, Trp, Phe, or Tyr;
`5 Xaa at position 16 is: Leu, Ser, Thr, Trp, His, Ph e, Asp,
`Val, Tyr, Glu, or Ala;
`Xaa at position 18 is: His, Pro, Asp, Glu, Arg, Ser, Ala, or
`Lys;
`Xaa at position 19 is: Gly, Asp, Glu, Gln, Asn, Lys, Arg, or
`Cys;
`Xaa at position 23 is: His, Asp, Lys, G~u, Gln, or Arg;
`Xaa at position 24 is: Glu, Arg, Ala, or Lys;
`Xaa at position 26 is: Trp, Tyr, Phe, Asp, Lys, Glu, or His;
`Xaa at position 27 is: Ala, Glu, His, Phe, Tyr, Trp, Arg, or
`Lys ;
`· Xaa at pos ition 30 is: Ala, Glu, Asp, Ser, or His;
`Xaa at position 31 is: Asp, Glu, Ser, Thr, Arg, Trp, or Lys;
`Xaa at position 33 is: Asp, Arg, Val, Lys, Ala, Gly, or Glu;
`Xaa at position 34 is: Glu, Lys, or Asp;
`20 Xaa at position 35 is: Thr, Ser, Lys, Arg, Trp, Tyr, Phe,
`Asp, Gl y, Pro, His, or Glu;
`Xaa at position 36 is: Thr, Ser, Asp, Trp , Tyr, Phe, Arg,
`Glu, or His;
`Xaa at position 37 is: Lys, Arg, Thr, Ser, Glu, Asp, Trp ,
`Tyr, Phe, His, Gly, Gly-Pro, or is deleted.
`
`25
`
`32. The heterologous fusion protein of Claims 27, 28, or 29
`wherein the GLP-1 compound comprises the sequence of formula
`III (SEQ ID NO: 4):
`7
`8
`10 11 12 13 14 15 16 17
`9
`Xaa-Xaa-Glu-Gly-Xaa-Xaa-Thr-Ser-Asp-Xaa-Ser-
`18 19 20 21 22
`23
`24 25 26 · 27 28
`Ser-Tyr-Leu-Glu-Xaa-Xaa-Xaa-Ala-Xaa-Xaa-Phe-
`29 30 31 32 33 34 35 36 37
`Ile- Ala-Xaa- Leu - Xaa- Xaa-Xaa - Xaa - R
`
`30
`
`35
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`f ormula III (SEQ ID NO : 4)
`
`5
`
`wherein :
`Xaa at position 7 is : L-histidine, D-histi dine, desamino-
`his tidine, 2-amino-his t idine, P- hydroxy-h istidine,
`homohistidine, a -fluoromethyl-histidine or a - methyl (cid:173)
`histidine ;
`Xaa at position 8 is : Gly, Ala, Val, Leu, Ile, Ser, or Thr ;
`Xaa at position 11 is : Asp, Glu , Arg, Thr, Ala, Lys, or His;
`10 Xaa at position 12 is: His, Tr p, Phe, or Tyr;
`Xaa at position 16 is : Leu, Ser, Thr, Trp, His , Ph e, Asp,
`Val, Glu, or Ala;
`Xaa at position 22: Gly, Asp , Glu, Gln, Asn , Lys, Arg , or
`Cys ;
`Xaa at position 23 i s : Hi s, Asp, Lys, Glu , or Gln;
`Xaa at position 24 is: Glu, His, Al a, or Lys;
`Xaa a t position 25 is : Asp, Lys, Gl u, or His;
`Xaa a t position 27 is: Ala, Glu, His, Phe, Tyr, Trp, Arg ,
`or Lys;
`Xaa at position 30 i s: Ala, Glu, Asp, Ser , or His ;
`Xaa at position 33 is : Asp, Arg , Val, Lys , Ala, Gl y, or
`Glu ;
`Xaa at position 34 is: Glu, Lys, or Asp ;
`Xaa at position 35 is : Thr, Ser, Lys , Arg , Trp, Tyr, Phe,
`Asp , Gly , Pro, His , or Glu;
`Xaa at position 36 is : Arg, Glu , or Hi s;
`Xaa at position 37 is : Lys, Arg , Thr, Ser, Glu, Asp, Trp ,
`Tyr, Phe, His , Gly , Gly-Pro, or is deleted .
`
`15
`
`20
`
`25
`
`30
`
`35
`
`33 . The heterologous fusion protein of Claim 27, 28 , or 29
`wherein the GLP- 1 compound c ompri ses t he sequence of f ormula
`IV (SEQ ID NO : 5) :
`7
`10 11 12 13 14 15 16 17
`8
`9
`Xaa-Xaa-Glu-Gly-Thr-Xaa -Thr-Ser-Asp- Xaa- Ser-
`19 20
`21 22
`23
`24 25
`26
`27 28
`1 8
`
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`
`Ser- Tyr- Leu- Glu- Xaa-Xaa- Ala-Ala-Xaa-Glu-Phe-
`29 30 31 32
`33 34 35 36 37
`Ile-Xaa-Trp-Leu-Val-Lys-Xaa-Arg-Xaa
`formula IV (SEQ ID NO: 5}
`
`5
`
`10
`
`15
`
`20
`
`wherein:
`Xaa at position 7 is: L-histidine, D-histidine, desamino(cid:173)
`histidine, 2-amino-histidine, ~-hydroxy-histidine,
`homohistidine, a -fluoromethyl-histidine or a -methyl(cid:173)
`histidine ;
`Xaa at position 8 is: Gly , Ala, Val, Leu, Ile, Ser, or Thr ;
`Xaa at position 12 is: His, Trp, Phe, or Tyr ;
`Xaa at position 16 is: Leu, Ser, Thr, Trp, His, Phe, Asp,
`Val, Glu, or Ala ;
`Xaa at position 22 is : Gly, Asp, Gl u, Gln, Asn, Lys, Arg , or
`Cys ;
`Xaa at posit;i.on 23 is: His, Asp, Lys, Glu, o r Gln;
`Xaa at position 26 is: Asp, Lys, Glu, or His ;
`Xaa at posi t ion 30 is: Ala, Glu, Asp, Ser, or His;
`Xa a at position 35 is: Thr, Ser, Lys, Arg, Trp, Tyr, Phe,
`Asp, Gly, Pro , His, or Glu;
`Xaa at position 37 is : Lys, Arg, Thr , Ser, Glu, Asp, Trp,
`Tyr, Phe, His, Gly, Gly-Pro, or i s deleted .
`
`25
`
`34. The heterologou s fusion p r otein of Claims 27, 28 , o r 29
`wherein the GLP- 1 compound comprises the sequence of formula
`V (SEQ I D NO : 6}
`
`30
`
`35
`
`10 11 12 13 14 15 16 17
`7
`8
`9
`Xaa-Xaa-Glu-Gly-Thr -Phe-Thr-Ser-Asp-Val-Ser-
`18 19 20 21 21
`23
`2 4 25 26 27
`28
`Ser-Tyr- Leu - Glu-Xaa-Xaa- Ala- Ala- Lys - Xaa- Phe-
`29 30 31 32 33 34 35
`36 37
`Ile-Xaa-Trp-Leu-Val-Lys-Gly-Arg-Xaa
`formula V (SEQ ID NO: 6)
`
`FRESENIUS EXHIBIT 1036
`Page 111 of 200
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`
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`PCT/US0l/43165
`
`- 111 -
`
`Xaa
`Xaa
`
`wherein:
`Xaa at position 7 is: L-histidine, D-histidine, desamino(cid:173)
`histidine, 2-amino-histidine, ~-hydroxy-histidine,
`homohistidine, a-fluoromethyl-histidine or a-methyl(cid:173)
`histidine;
`at position 8 is: Gly, Ala, Val, Leu, Ile, Ser, or Thr;
`at position 22 is: Gly, Asp, Glu, Gln, Asn, Lys, Arg, or
`Cys;
`at position 23 is: His, Asp, Lys, Glu, or Gln;
`at position 24 is: Ala, Glu, His, Phe, Tyr, Trp, Arg,
`or Lys
`at position 30 is: Ala, Glu, Asp, Ser, or His;
`at position 37 is: Lys, Arg, Thr, Ser, Glu, Asp, Trp,
`Tyr, Phe, His, Gly, Gly-Pro, or is deleted.
`
`Xaa
`Xaa
`
`Xaa
`Xaa
`
`5
`
`10
`
`15
`
`20
`
`25
`
`35 . The heterologous fusi.on protein of Claims 27, 28, or 29
`wherein the GLP - 1 compound comprises the sequence of formula
`VIII (SEQ ID NO:11) .
`
`8
`10 11 12 13 14 15 16 17
`7
`9
`Xaa-Xaa-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Xaa-Ser-
`18 19 20
`21 22
`23 24 25
`26
`27 28
`Xaa - Xaa- Xaa-Glu-Xaa-Xaa-Ala- Xaa-Xaa-Xaa-Phe-
`29
`30 31 32 33 34 35 36 37
`Ile-Xaa-Trp-Leu-Xaa-Xaa-Gly-Xaa-R
`formula VIII (SEQ ID NO : 11)
`
`wherein:
`30 Xaa at position 7 is: L-histidine, D-histidine, desamino(cid:173)
`histidine, 2-amino-histidine, ~-hydroxy-histidine,
`homohistidine , a-fluoromethyl-histidine or a-methyl(cid:173)
`histidine;
`Xaa at position 8 is : Gly, Ala, or Val;
`35 Xaa at posi tion 16 is: Leu or Val;
`
`FRESENIUS EXHIBIT 1036
`Page 112 of 200
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`
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`PCT/US0l/43165
`
`- 112 -
`
`Xaa at position 18 is Lys or Ser;
`Xaa at position 19 is: Gln or Tyr;
`Xaa at position 20 is : Met or Leu;
`Xaa at positi on 22 i s: Glu o r Gln ;
`Xaa at position 23 is : Glu , or Gln;
`Xaa at position 25 is : Val or Ala ;
`Xaa at position 26 is : Arg or Lys;
`Xaa at position 27 is Leu or Glu;
`Xaa a t position 30 is: Glu o r Ala ;
`Xaa at pos i tion 33 is : Val or Lys;
`Xaa at position 34 is : Asn or Lys;
`Xaa at position 36 is: Gly or Arg ; and
`Xaa at position 37 is: Gl y, Pro, Pro-Ser-Ser- Gly- Ala- Pro-
`Pro-Pro-Ser, or is absent .
`
`36. The heterologous fusion protein of claims 27 through 35
`wherein the GLP-1 compound has no more than 6 amino acids
`that are different from the corresponding amino acid in GLP-
`1(7-37)OH, GLP-1(7-36)OH, or Exendin-4 .
`
`37 . The heterologous fusion protein of Claim 36 wherein the
`GLP-1 compou nd has no more than 5 amino acids that differ
`from the corresponding amino acid in GLP-1(7-37)OH , GLP-1(7-
`36)OH, or Exendin-4 .
`
`38 . The heterologous fusion p r otein of Cl aim 37 wherein the
`GLP-1 compound has no more than 4 amino acids that differ
`from the .corresponding amino acid in GLP-1(7-37)OH , GLP-1(7 -
`36)OH, or Exendin- 4 .
`
`39. The heterologous fusion protei n o f Claim 38 wherein the
`GLP-1 compound has no more than 3 amino acids that differ
`from the corresponding amino acid in GLP-1(7-37)OH, GLP-1(7-
`36)OH, or Exendin- 4 .
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`FRESENIUS EXHIBIT 1036
`Page 113 of 200
`
`
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`PCT/US0l/43165
`
`- 113 -
`
`40. The heterol?gous fusion protein of Claim 39 wherein the
`GLP-1 compound has no more than 2 amino acids that differ
`from the corresponding amino acid in GLP-1(7 - 37)OH, GLP-1(7-
`36)OH, or Exendin-4 .
`
`5
`
`41. The heterologous fusion protein of any one of Claims 27
`through 40 wherein Xaa at position 8 is glycine or valine.
`
`42. The heterologous fusion protein of Claim 34 wherein the
`10 GLP-1 compound has no more than 2 amino acids that differ
`from the corresponding amino acid in GLP-1(7-37)OH or GLP-
`1(7-36)OH and Xaa at position 8 is g l ycine or valine and Xaa
`at posi ti on 30 is alani ne, g lutamic acid, aspartic acid,
`serine, or histidine .
`
`15
`
`20
`
`25
`
`43. The heterologous fusion protein of Claim 42 wherein Xaa
`at position 30 is Glutamic acid .
`
`The heterologous fusion protein of Claim 34 wherein
`44 .
`the GLP-1 compound has no more than 2 amino aci ds t hat
`differ from the corresponding amino acid in GLP-1(7-37)OH or
`GLP- 1(7 - 36)OH and Xaa at position 8 is glycine or valine and
`Xaa at position 37 is histidine, phenylal anine, tyrosine,
`tryptophan, aspartic acid, glutamic acid, serine, t hreonine,
`arginine, or lysine .
`
`45 . The heterologous fusion protein of Claim 44 wherein Xaa
`at position 37 is histidine.
`
`FRESENIUS EXHIBIT 1036
`Page 114 of 200
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`
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`PCT/US0l/43165
`
`- 114 -
`
`5
`
`46 . The heterologous fusion protein of Claim 34 wherein the
`GLP - 1 compound 'has no more than 2 amino acids that differ
`from the corresponding amino aci d in GLP-1(7-37)OH or GLP-
`1(7-36)OH and Xaa at position 8 is glyci ne, valine, leucine,
`isoleucine, serine, threonine, or methionine and Xaa at
`position 22 is aspartic acid, glutamic acid, lysine,
`arginine, asparagine, glutamine or histidine.
`
`10
`
`47. The heterologous fusion protein of Claim 46 wherein Xaa
`a t position 22 is lysine or glutamic aci d.
`
`15
`
`20
`
`25
`
`48. The heterologous fusion protein of Claim 34 wherein the
`GLP- 1 compound is Val-8-GLP-1(7-37) .
`
`49 . The heterologous fusion protein of Claim 34 wherein the
`GLP -1 compound is Gly- 8-GLP- 1(7-37) .
`
`50. The heterologous fusion protein of any one of Claims 27
`through 49 wherein the second polypeptide i 9 the Fe portion
`of a n Ig selected from the group consisting of: IgGl, IgG2,
`IgG3, IgG4, IgE, IgA, IgD, or IgM .
`
`51. The heterologous fusion protein of any one of Claims 27
`through 50 wherein the second polypeptide is the Fe portion
`of an Ig selected from the group consisting of: IgGl, IgG2,
`IgG3, and IgG4.
`
`30
`
`52 . The heterologous fusion protein of Claim 51 wherein the
`second polypeptide is the Fe portion of an IgGl
`immunogl obulin .
`
`53. The heterologous fusion protein of Claim 51 wherein the
`second polypeptide is the Fe portion of an I gG4
`immunogl obulin .
`
`35
`
`FRESENIUS EXHIBIT 1036
`Page 115 of 200
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`
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`WO 02/46227
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`PCT/US0l/43165
`
`- 115 -
`
`54 . The heterologous fusion protein of Claims 50 through 53
`wherein the IgG is human .
`
`5
`
`55 . The het erol ogous fusion protein of any one of Claims 27
`through 54 wherein the Fe portion comprises the hinge, CH2,
`and CH3 domains .
`
`56. The heterologous fusion protein of Claim 52 wherein the
`second polypept i de has the sequence o f SEQ ID NO : 32.
`
`10
`
`57 . A polynucleotide encoding a heterologous fusion protein
`of any one of Claims 1 through 56 .
`
`15
`
`58. A vector comprising the polynucleotide of Claim 57 .
`
`59 . A hos t cell comprising the vect or of Claim 58 .
`
`60 . A host cell expressing at least one heterologous fusion
`20 protei n of any one of Claims 1 thr ough 56 .
`
`61. The host cell of Claim 60 wherein said host cell is a
`CHO cell .
`
`62 . A process for producing a heter ologous fusion protein
`comprising the steps of transcribing and translating a
`polynucleotide of Claim 57 under conditions wherein the
`heterologous fu s ion protein is expressed in detectable
`amounts.
`
`63 . A method for normali zing blood glucose levels i n a
`mammal in need thereof comprising t he administration of a
`therapeutically ef f ective amount of the heterologous fusion
`protein of any one of Claims 1 through 56.
`
`25
`
`30
`
`35
`
`FRESENIUS EXHIBIT 1036
`Page 116 of 200
`
`
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`WO 02/46227
`
`PCT/US0l/43165
`
`- 116 -
`
`64 . A method of treating a patient with non- insulin
`dependent diabetes mellitus comprising the administration of
`a therapeutically effective amount of the heterologous
`f us ion pro t ein of a ny one of Claims 1 through 56.
`
`65. A method of treating obesity comprising the
`administration of a therapeutically effective amount of the
`heterologous fusion protein of any one of Claims 1 through
`56 .
`
`66. The use of a heterologous fusion protein as c l aimed in
`any one o f Claims 1 through 56 for the manufacture of a
`medicament for the treatment of patients with non-insulin
`dependent diabetes melli tus.
`
`67. The use of a heterologous fusion protein as claimed in
`any one of Claims 1 through 56 for the manufacture of a
`medicament for the treatment of patients with obesity.
`
`68.A pharmaceuti cal formulation adapted for the treatment of
`patients with non-insulin dependent diabetes comprising a
`heterologous fusion protein of any one of Claims 1
`through 56.
`
`69 . The het erologous fusion protein of Claims 1, 2, or 3
`wherein the GLP-1 compound comprises the sequence of
`formula IX [SEQ ID NO: 12]
`
`Xaa1-Xaa8-Glu-Gly-Thr-Xaa12- Thr- Ser- Asp-Xaa16- Ser(cid:173)
`Xaa1a-Xaa19-Xaa20-Glu-Xaa22-Gln-Ala-Xaa25-Lys-Xaa27-
`Phe-Ile-Xaa30- Trp-Leu-Xaa33 -Lys - Gly- Arg-Xaa31
`Formula IX (SEQ ID NO: 12)
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`wherein:
`
`35 Xaa1
`
`is: L-histidine, D-histidine, desamino-histidine, 2 -
`
`FRESENIUS EXHIBIT 1036
`Page 117 of 200
`
`
`
`WO 02/46227
`
`PCT/US0l/43165
`
`- 117 -
`
`amino-histidine, ~-hydroxy-histidine,
`
`homohistidine, a-fluoromethyl-histidine, or a-
`methyl-histidine ;
`is : Ala, Gly , Val , Leu, Ile, Ser, or Thr;
`Xaa8
`Xaa12 is: Phe, Trp , or Tyr ;
`Xaa16 is: Val, Trp , Ile , Leu, Phe, or Tyr ;
`Xaa1s is: Ser, .Trp , Tyr, Phe, Lys, Ile, Leu, Val ;
`Xaa19 is : Tyr, Trp, or Phe;
`Xaa20 is: Leu, Phe , Tyr, or Trp;
`Xaa22 is : Gly, Glu, Asp, or Lys;
`Xaa25 is : Ala, Val, Ile, or Leu;
`Xaa27 is : Glu , Ile, or Ala ;
`Xaa30 is : Ala or Glu
`Xaa33 is : Val, or .Ile ; and
`Xaa37 is : Gly , His , NH2, or is absent.
`
`5
`
`10
`
`15
`
`70 . The heterologous fus i on protein of Claim 69 wherein the
`second polypeptide is human albumin .
`
`20
`
`71. The heterologous fusion p r otein of Claim 70 wherein the
`second polypeptide has the sequence of SEQ ID NO : 34 .
`
`25
`
`30
`
`72 . The heterologou s fusion protein of Claim 69 wherein the
`second polypeptide is an N-terminal fragment of albumin.
`
`73 . The heterologous fusion protein of any one of Claims
`27, 28, or 29 wher ein the GLP-1 compound comprises the
`sequence of formula IX [SEQ ID NO: 12]
`
`Xaa7-Xaas-Glu-Gly-Thr-Xaa12-Thr -Ser-Asp-Xaa1 rSer-
`Xaa1s-Xaa19-Xaa20- Glu-Xaa22 - Gln- Ala - Xaa2s - LYS-Xaa27-
`Phe- I le-Xaa30-Trp-Leu-Xa a 33-Lys-Gly-Arg-Xaa37
`Formu la IX {SEQ ID NO : 12)
`
`FRESENIUS EXHIBIT 1036
`Page 118 of 200
`
`
`
`WO 02/46227
`
`PCT/US0l/43165
`
`- 118 -
`
`wherein:
`is : L-histidine, D-histidine, desamino-histidine, 2 -
`
`Xaa7
`
`amino-histidine, ~ - hydroxy- histidine,
`
`5
`
`homohistidine , a -fluoromethyl -histidine, or a -
`methyl - histidine ;
`is : Ala , Gly , Val, Leu, Ile, Ser , or Thr ;
`Xaa8
`Xaa12 is: Phe , Trp, or Tyr ;
`Xaa16 is: Val, Trp, Ile, Leu, Phe , or Tyr;
`10 Xaa18 is : Ser, Trp, Tyr , Phe, Lys, Ile, Leu, Val;
`Xaa19 is : Tyr , Trp, or Phe ;
`Xaa20 is : Leu , Phe, Tyr, or Trp ;
`Xaa22 is : Gly , Glu , Asp, or Lys ;
`Xaa25 is : Ala , Val , I le, or Leu ;
`15 Xaa21 is : Glu, I l e , or Ala ;
`Xaa30 is : Ala or Glu
`Xaa33 is : Val, o r
`
`I l e; and
`
`Xaa37 is: Gly, His, NH2, or is absent .
`
`20
`
`25
`
`74 . The heterologous fusion protein of Claim 73 wherein the
`second polypeptide is t h e Fe portion of an Ig selected from
`the group consisting of : IgGl, IgG2, IgG3, I gG4, IgE, IgA ,
`IgD, or I gM.
`
`75. The heterologous fusion protein of Cl aim 73 or 7 4
`where i n the second polypepti de is the Fe portion of an Ig
`selected from the group consis t ing of: IgGl , IgG2 , IgG3, and
`IgG4.
`
`30
`
`76. The heterologous fusion protein o f Clai m 75 wherein t he
`second polypep t ide is the Fe portion o f an I gGl
`immunoglobulin .
`
`FRESENIUS EXHIBIT 1036
`Page 119 of 200
`
`
`
`WO 02/46227
`
`PCT/US0l/43165
`
`- 119 -
`
`77 . The heterologous fusion protein of Claim 75 wherein
`the second polypeptide is the Fe portion of an IgG4
`immunoglobulin.
`
`5
`
`78. The heterol ogous fusion protein of Claims 73 t hrough
`78 wherein the IgG is human.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`79. The heterologous fusion protein of Claim 75 wherein
`the second polypeptide has .the sequence of SEQ ID NO:
`32.
`
`80. The heterologous fusion protein of any one of Claims
`69 through 79 wherein the GLP- 1 compound is selected
`from the group consisting of Gly8-GLP- 1(7 - 37), Val8-
`Tyr12-GLP-1(7-37), Val8-Tyr12-GLP-1(7-36), Val 8-Trp12-
`GLP-1 (7-37), Val8-Leu16-GLP-1 (7-37), Val 8-Val16-GLP-1 (7-
`37), Val8-Tyr16-GLP-1(7-37), Gly8-Glu22 -GLP-1(7-37),
`Val 8-Glu22 - GLP-1(7-37) ,Val 8-Leu25 -GLP-1(7-37), Val 8 -
`·Tyr12-Tyr16-GLP-1(7-37), Val 8-Trp12- Glu22 - GLP- 1(7 - 37),
`Val 8-Tyr12-Glu22 -GLP-1 (7-37) , Val 8-Tyr16-Phe19-GLP-1 (7-
`37), Val 8-Tyr16-Glu22 -GLP-1 (7-37), Val 8-Trp16-Glu22 -GLP-
`1 (7-37), Val 8-Leu16-Glu22 -GLP-1(7-37), .Val8-Ile16-Glu22 -
`GLP-1 (7.-37) , Val8-Phe16 -Glu22-GLP-l (7-37), Val 8-Trp18-
`Glu22- GLP- 1 (7 - 37), Val 8-Tyr18- Glu22 - GLP- 1(7 - 37), Val8-
`Phe18 - Glu22-GLP-1 (7-37) , Val 8-I le18- Glu22 - GLP- 1 ( 7 - 3 7) ,
`Val 8-Lys18-Glu22 -GLP-1 (7-37) , Val 8-Trp19-Glu22-GLP-1 ( 7-
`37), Val 8-Phe19-Glu22-GLP-1(7-37) , Val8-Phe20 -Glu22 -GLP-
`1(7-37), Va1 8-Glu22 -Leu25 -GLP-1(7-37), Val8-Glu22-Ile25 -
`GLP-l (7-37), Val8-Glu22 -Val 25-GLP-1 (7-37), Val8-Glu22 -
`Ile27 - GLP- l (7-37), Val8-Glu22 -Ala27- GLP-1(7 - 37), Val8-
`Glu22 -Ile33-GLP-1 (7-3 7), Val 8-Asp9-Ile11-Tyr16-Glu22 -GLP-
`1 ( 7-37), Val8-Tyr16-Trp19-Glu22 -GLP-1(7-37), Val 8-Trp16-
`Glu22-Val 25-Ile33-GLP-1 ( 7-37) , Val 8- Trp 16-Glu22-Ile33-GLP(cid:173)
`l ( 7-37), Val8-Glu22 -Val25 -Ile33-GLP-1(7-37), Val8-Trp16-
`
`FRESENIUS EXHIBIT 1036
`Page 120 of 200
`
`
`
`WO 02/46227
`
`PCT/US0l/43165
`
`- 120 -
`
`Glu 22 -Val25 - GLP-1( 7- 37),
`37) .
`
`and Val 8-Cys16-Lys26 - GLP-1(7 -
`
`FRESENIUS EXHIBIT 1036
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`
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`PCT/US0l/43165
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`1 / 17
`
`Fi g. l
`
`5
`10
`15
`Ala Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
`20
`25
`30
`Pro Ala Pro Glu Lys Gly Gl y Pro Ser Val Phe Leu Phe Pro Pro
`35
`40
`45
`Lys Pro Lys Asp Thr Lys Met Ile Ser Arg Thr Pro Glu Val Thr
`50
`55
`60
`Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
`65
`70
`75
`Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
`80
`85
`90
`Pro Arg Gl u Glu Gln Tyr Asn Ser Thr Tyr Arg Va l Val Ser Val
`95
`100
`105
`Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
`11 0
`115
`120
`Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Th r
`125
`130
`1 35
`Ile Ser Lys Al a Lys Gly Gln Pr o Arg Glu Pro Gln Val Tyr Thr
`140
`145
`150
`Leu Pr o Pro Ser Arg Glu Glu Me t Thr Lys Asn Gl n Val Ser Leu
`155
`160
`165
`Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
`170
`175
`180
`Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
`185
`190
`1 95
`Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
`200
`205
`210
`Thr Val Asp Lys Ser Arg Tr p Gln Gln Gly Asn Val Phe Ser Cys
`215
`220
`225
`Ser Val Met His Glu Ala Leu His Asn Hi s Tyr Thr Gln Lys Ser
`230
`Leu Ser Leu Ser Pro Gly Lys
`
`[SEQ ID NO: 32 ]
`
`FRESENIUS EXHIBIT 1036
`Page 122 of 200
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`
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`PCT/US0l/43165
`
`2 /17
`
`Fig. 2
`
`15
`10
`5
`Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu Glu Asn
`20
`25
`30
`35
`Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe
`40
`45
`50
`Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val
`55
`60
`65
`70
`Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp
`75
`80
`85
`90
`Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys
`95
`100
`105
`Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp
`110
`115
`120
`125
`Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala
`130
`140
`135
`Phe His Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg
`145
`150
`155
`160
`Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys
`165
`170
`175
`18 0
`Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro
`185
`190
`195
`Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu
`200
`205
`210
`215
`Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val
`220
`225
`230
`Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser Lys Leu
`235
`240
`245
`250
`Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly Asp Leu Le
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