`Kim et al.
`
`USOO6284727B1
`(10) Patent No.:
`US 6,284,727 B1
`(45) Date of Patent:
`Sep. 4, 2001
`
`(54) PROLONGED DELIVERY OF PEPTIDES
`(75) Inventors: Yesook Kim; William J. Lambert;
`Hong Qi; Robert A Gelfand; Kieran
`F. Geoghegan; Dennis E. Danley, all
`of New York, NY (US)
`(73) Assignee: Scios, Inc., Sunnyvale, CA (US)
`(*) Notice:
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`OTHER PUBLICATIONS
`Kreymann et al, Laneef Dec. 5, 1987 p. 1300.*
`Conn's Current Therapy p. 483. (1989).*
`Remington's Pharmaceutical Sciences, 16th ed. p. 1555,
`1467, 1453, 1451, 1450, 1448, CH 91, 1980.*
`CroSS et al., “Subcutaneous Absorption Kinetics And Local
`Tissue Distribution Of Interferon And Other Solutes,” J.
`Pharm. Pharmacol., 1993, 45, pp. 606–609.
`Hirano et al., “Studies on the Absorption of Practically
`Water-Insolable Drugs Following Injection VIII: Compari
`Son of the Subcutaneous Absorption Rates From Aqueous
`Suspensions in the Mouse, Rat and Rabbit,” J. Pharm. Sci.,
`(21) Appl. No.: 08/472,349
`1993, 72(6), pp. 608–612.
`Nara et al., “A New Method for Assessment of Drug
`(22) Filed:
`Jun. 7, 1995
`Absorption From Muscle: Application of a Local Perfusion
`System,” J. Pharm. Pharmacol, 1991, 43, pp. 272-274.
`Related U.S. Application Data
`Dickert et al., “Absorption of NPH-Insulin from Subcuta
`neous Tissue: A Methodological Study in Pigs,” ACTA
`(63) Continuation of application No. 08/181,655, filed on Jan. 25,
`1994, now abandoned, which is a continuation-in-part of
`Pharmacolet Toxicol, 1982, 51, pp. 30–37.
`application No. 08/044,133, filed on Apr. 7, 1993, now
`SuperSaxo et al., “Effects of Molecular Weight on the
`abandoned.
`Lymphatic Absorption of Water-Soluble Compounds Fol
`(51) Int. Cl." - A61K 38/00
`lowing Subcutanous Administration,
`Pharmaceutical
`(52) U.S. Cl. ............
`... 514/12; 530/324
`Research, 1990, 7(2), pp. 167–169.
`(58) Field of Search ................................ 514/12; 530/324
`Mosjov, “Structural Requirements for Biological Activity of
`Glucagon-Like Peptide-1, ” Int. J. Peptide Protein Res.,
`1992, 40, pp. 333–343.
`Suzuki et al., “Comparison of the Effects of Various C-Ter
`minal and N-Terminal Fragment Peptide of Glucogen-Like
`Peptide-1 or Insulin and Glucagon Release from the Isolated
`Perfused Rat Pancreas,” Endocrinology, 1989, 125(6), pp.
`3109-3113.
`Krówczyfiski, Leszek, “Technologia postaci lekow (Tech
`nology of the drug forms)", Paristwowy Zaklad
`Wydawnictw Lekarskich Warszawa, 1969, pp. 220,
`463-464, 490, 502.
`Gennaro, Alfonso R., Chapter 23 in Remington's Pharma
`ceutical Sciences, 16th edition, A. OSol Editor, Mack Pub
`lishing Company, Easton, PA, 1980, pp. 343-363.
`Gill, I. J. et al., “Cyclodextrins as protection agents against
`enhancer damage in nasal delivery Systems II. Effect on in
`Vivo absorption of insulin and histopathology of nasal
`membrane,” European Journal of Pharmaceutical Sciences
`1:237-248, Jun. 1994.
`Hendrick, G.K. et al., “Glucagon-like Peptide-I-(7–37)
`Suppresses Hyperglycemia in Rats,” Metabolism 42(1):1-6,
`Jan. 1993.
`
`3/1987 Chance et al. ......................... 514/12
`4,654,324
`4,857,505 * 8/1989 Ardent .......
`... 514/2
`4,985,404 * 1/1991 Mitchell .....
`... 514/6
`5,118,666 * 6/1992 Habener .....
`... 514/12
`5,120,712 * 6/1992 Habener .....
`... 514/12
`5,175,145
`12/1992 Cooper ...
`... 514/4
`5,424,286
`6/1995 Eng ................
`... 514/2
`5,545,618
`8/1996 Buckley et al.
`... 514/2
`5,574,008
`11/1996 Johnson et al.
`... 514/12
`5,614,492
`3/1997 Habener ................................. 514/12
`5,631,224
`5/1997 Efendic .................................. 514/12
`
`FOREIGN PATENT DOCUMENTS
`
`2/1997 (DE).
`1953O865 A1
`4/1986 (EP).
`O 177478
`O 343 696 A2 11/1989 (EP).
`O 442 671 A2
`8/1991 (EP).
`O 473268 A3
`3/1992 (EP).
`O 526 862 A1
`2/1993 (EP).
`O 619 322 A2 10/1994 (EP).
`O 658 568 A1
`6/1995 (EP).
`O 733 644 A1
`9/1996 (EP).
`2732 894
`10/1996 (FR).
`06941 * 11/1987 (WO) .............................. CO7K/7/10
`WO 88/07366
`10/1988 (WO).
`WO 90/02835
`3/1990 (WO).
`11296 - 10/1990 (WO)
`11457 - 8/1991 (WO)
`WO 93/18785
`9/1993 (WO).
`WO 93/18786
`9/1993 (WO).
`WO 93/19175
`9/1993 (WO).
`WO 93/25579
`12/1993 (WO).
`WO95/05848
`3/1995 (WO).
`WO95/07098
`3/1995 (WO).
`WO95/17510
`6/1995 (WO).
`WO95/31214 11/1995 (WO).
`WO 96/20005
`4/1996 (WO).
`
`
`
`... CO7K/7/10
`
`- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - CO7K/7/34
`
`(List continued on next page.)
`Primary Examiner. Sheela Huff
`(74) Attorney, Agent, or Firm-Sterne, Kessler, Goldstein
`& Fox PL.L.C.
`ABSTRACT
`(57)
`There are disclosed methods for the treatment of non-insulin
`dependent diabetes mellitus in a mammal comprising the
`prolonged administration of GLP-1 (7-37), and related
`peptides. Also disclosed are compositions to prolong the
`administration of the peptides.
`
`37 Claims, 10 Drawing Sheets
`
`MPI EXHIBIT 1071 PAGE 1
`
`MPI EXHIBIT 1071 PAGE 1
`
`
`
`US 6,284,727 B1
`Page 2
`
`OTHER PUBLICATIONS
`Holst, J.J. et al., “Truncated glucago-like peptide I, an
`insulin-releasing hormone for the distal gut,” FEBS Letters
`211(2):169–174, Jan. 1987.
`Remington Pharmaceutical Sciences, 16th ed. pp. 1555,
`1467, 1453, 1451, 1450, 1448, Ch. 91, 1980.*
`CrOSS et al., "Subcutaneous Absorption Kinetics and Local
`Tissue Distribution of Interferon and other Soluter, J.
`Pharm. Pharmacol., 1993, 45, pp. 606–609;.
`Hirano et al., “Studies on the Absorption of Practically
`Water-Insoluble Drugs following Injection VIII: Compari
`Son of the Subcutaneous Absorption Rates from Aqueous
`Suspensions in the Mouse, Rat, and Rabbit,” J. Pharm. Sci.,
`1993, 72(6), pp. 608–612;.
`Nara et al., “A New Method for Assessment of Drug
`Absorption from Muscle: Application of a Local Perfusion
`System,” J. Pharm. Pharmacol, 1991, 43, pp. 272-274;.
`
`Dickert et al., “Absorption of NPH-Insulin from Subcuta
`neous Tissue: A Methodological Study in Pigs.” Acta Phar
`macol et Toxicol, 1982, 51, pp. 30-37;.
`SuperSaxo et al., “Effects of Molecular Weight on the
`Lymphatic Absorption of Water-Soluble Compounds fol
`lowing Subcutaneoud Administration,
`Pharmaceutical
`Research, 1990, 7(2), pp. 167–169;.
`Mosjov, “Structural requiremtns for Biological Activity of
`Glucagon-like Peptide-1.” Int. J. Peptide Protein Res.,
`1992, 40, pp. 333-343;.
`Suzuki et al., “Comparison of the Effects of various C-Ter
`minal and N-Terminal Fragment Peptide of Glucogen-like
`Peptide-1 or Insulin and Glucagon Release from the Isolated
`Perfused Rat Pancreas,” endocrinology, 1989, 125(6), pp.
`3109-3113.
`
`* cited by examiner
`
`MPI EXHIBIT 1071 PAGE 2
`
`MPI EXHIBIT 1071 PAGE 2
`
`
`
`U.S. Patent
`
`Sep. 4, 2001
`
`Sheet 1 of 10
`
`US 6,284,727 B1
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`MPI EXHIBIT 1071 PAGE 3
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`MPI EXHIBIT 1071 PAGE 3
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`MPI EXHIBIT 1071 PAGE 4
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`MPI EXHIBIT 1071 PAGE 4
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`U.S. Patent
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`Sep. 4, 2001
`
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`US 6,284,727 B1
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`U.S. Patent
`
`Sep. 4, 2001
`
`Sheet 4 of 10
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`US 6,284,727 B1
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`Sep. 4, 2001
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`US 6,284,727 B1
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`Sep. 4, 2001
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`Sep. 4, 2001
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`Sep. 4, 2001
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`Sheet 8 of 10
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`US 6,284,727 B1
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`MPI EXHIBIT 1071 PAGE 10
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`Sep. 4, 2001
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`Sheet 9 of 10
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`US 6,284,727 B1
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`MPI EXHIBIT 1071 PAGE 11
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`Sep. 4, 2001
`Sep. 4, 2001
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`US 6,284,727 B1
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`
`1
`PROLONGED DELIVERY OF PEPTIDES
`
`US 6,284,727 B1
`
`This application is a continuation of application Ser. No.
`08/181,655, filed Jan. 25, 1994, now abandoned, which is a
`continuation-in-part of application Ser. No. 08/044,133,
`filed Apr. 7, 1993, now abandoned.
`BACKGROUND OF THE INVENTION
`The present invention relates to compositions and meth
`ods for the treatment of Diabetes Mellitus. More specifically,
`the present invention relates to compositions to prolong the
`administration of glucagon-like peptide 1 (GLP-1), and
`derivatives thereof. These compositions are useful in treat
`ment of Non-Insulin Dependent Diabetes Mellitus
`(NIDDM).
`The amino acid Sequence of GLP-1 is known as:
`His-Asp-Glu-Phe-Glu-Arg-His-Ala-Glu-Gly-Thr-Phe-Thr
`Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys
`Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly
`(SEQUENCE ID NO: 1)
`GLP-1 is disclosed by Lopez, L. C., et al., P.N.A.S., USA
`80: 5485-5489 (1983); Bell, G. I., et al., Nature 302:
`716–718 (1983); Heinrich, G. et al., Endocrinol. 115:
`2176-2181 (1984) and Ghiglione, M., et al., Diabetologia
`27: 599–600 (1984).
`During processing in the pancreas and intestine, GLP-1 is
`converted to a 31 amino acid peptide having amino acids
`7-37 of GLP-1, hereinafter this peptide is referred to as
`GLP-1 (7–37).
`This peptide has been shown to have insulinotropic
`activity, that is, it is able to Stimulate, or cause to be
`Stimulated, the Synthesis or expression of the hormone
`insulin. Because of this insulinotropic activity, GLP-1
`(7–37) is alternatively referred to as insulinotropin.
`GLP-1 (7-37) has the following amino acid sequence:
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys-Gly-Arg-Gly (SEQUENCE ID NO: 2).
`GLP-1 (7-37), certain derivatives thereof and the use
`thereof to treat Diabetes mellitus in a mammal are disclosed
`in U.S. Pat. Nos. 5,118,666 (666 patent) and 5,120,712
`(712 patent), the disclosures of these patents being incor
`porated herein by reference. The derivatives of GLP-1
`(7–37) disclosed in the 666 and 712 patents include
`polypeptides which contain or lack one of more amino acids
`that may not be present in the naturally occurring Sequence.
`Further derivatives of GLP-1 (7–37) disclosed in the 666
`and 712 patents include certain C-terminal Salts, esters and
`amides where the salts and esters are defined as OM where
`M is a pharmaceutically acceptable cation or a lower
`(C-C) branched or unbranched alkyl group and the amides
`are defined as -NRR where R and R are the same or
`different and are Selected from the group consisting of
`hydrogen and a lower (C-C) branched or unbranched alkyl
`grOup.
`Certain other polypeptides, alternatively referred to as
`truncated GLP-1 or truncated insulinotropin, having insuli
`notropic activity and the derivatives thereof are disclosed in
`PCT/US 89/01121 (WO 90/11296). Those polypeptides,
`referred to therein as GLP-1 (7-36), GLP-1 (7–35) and
`GLP-1 (7-34) have the following amino acid sequences,
`respectively.
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys-Gly-Arg (SEQUENCE ID NO:3);
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys-Gly (SEQUENCE ID NO: 4); and
`
`5
`
`15
`
`25
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys (SEQUENCE ID NO: 5);
`Derivatives of the polypeptides disclosed in PCT/US89/
`01121 include polypeptides having inconsequential amino
`acid Substitutions, or additional amino acids to enhance
`coupling to carrier protein or to enhance the insulinotropic
`effect thereof. Further derivatives of insulinotropin disclosed
`in PCT/US89/01121 include certain C-terminal Salts, esters
`and amides where the salts and esters are defined as OM
`where M is a pharmaceutically acceptable cation or a lower
`branched or unbranched alkyl group and the amides are
`defined as -NRR where R and R are the same or
`different and are Selected from the group consisting of
`hydrogen and a lower branched or unbranched alkyl group.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`FIG. 1 shows the effect of a prolonged infusion (7 hours)
`of 4 ng/kg/min insulinotropin on plasma glucose levels in
`patients with NIDDM.
`FIG. 2 shows the effect of a short infusion (60 minutes)
`of 10 ng/kg/min insulinotropin on plasma glucose levels in
`patients with NIDDM.
`FIG. 3 shows the effect of a prolonged infusion (7 hours)
`of 2 ng/kg/min and 4 ng/kg/min of insulinotropin on plasma
`glucose levels in patients with NIDDM.
`FIG. 4. Mean (n=3) Plasma Concentration of Insulinotro
`pin in Rats. After Subcutaneous Administration of Single 0.5
`mg/0.5 ml Doses in Different Aqueous Suspensions (AS).
`FIG. 5. Mean (n=3) Plasma Concentration of Insulinotro
`pin in Rats. After Subcutaneous Administration of Single 0.5
`mg/0.5 ml Doses in Different Aqueous Suspensions (AS).
`FIG. 6. Mean (n=3) Plasma Concentration of Insulinotro
`pin in Rats. After Subcutaneous Administration of Single 0.5
`mg/0.5 ml Doses in Different Aqueous Suspensions (AS).
`FIG. 7. Mean (n=3) Plasma Concentration of Insulinotro
`pin in Rats. After Subcutaneous Administration of Single 0.5
`mg/0.5 ml Doses in Different Aqueous Suspensions (AS).
`FIG.8. Mean (n=3) Plasma Concentration of Insulinotro
`pin in Rats. After Subcutaneous Administration of Single 0.5
`mg/0.13 ml Doses in Different Aqueous Suspensions (AS).
`FIG. 9. Mean (n=3) Plasma Concentration of Insulinotro
`pin in Rats. After Subcutaneous Administration of Single 0.5
`mg/0.13 ml Doses in Different Aqueous Suspensions (AS).
`FIG. 10 shows pharmacokinetic studies of an insulinotro
`pin Zinc precipitate.
`
`SUMMARY OF THE INVENTION
`In one embodiment, the present invention is directed to a
`method for the treatment of non-insulin dependent diabetes
`mellitus in a mammal in need of Such treatment comprising
`the repeated administration over an extended period of time
`of a compound with prolonged action after each
`administration, Said prolonged action necessary to achieve
`Sustained glycemic control in Such mammals, Said com
`pound Selected from the group consisting of:
`(a) a peptide having the amino acid sequence:
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys-Gly-Arg-Gly; (SEQUENCE ID NO: 2)
`(b) a peptide having the amino acid Sequence:
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-X (SEQUENCE ID NO: 7)
`
`MPI EXHIBIT 1071 PAGE 13
`
`MPI EXHIBIT 1071 PAGE 13
`
`
`
`3
`wherein X is Selected from the group consisting of:
`(A) LyS,
`(B) Lys-Gly, and
`(C) Lys-Gly-Arg;
`(c) a derivative of a polypeptide comprising the primary 5
`Structure
`
`HN-W-COOH
`wherein W is an amino acid Sequence Selected from the
`group consisting of
`His-Asp-Glu-Phe-Glu-Arg-His-Ala-Glu-Gly-Thr-Phe-Thr
`Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys
`Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly
`(SEQUENCE ID NO: 1) and
`His-Asp-Glu-Phe-Glu-Arg-His-Ala-Glu-Gly-Thr-Phe-Thr
`Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys
`Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg
`(SEQUENCE ID NO: 6)
`which derivative when processed in a mammal results in a
`polypeptide derivative having an insulinotropic activity;
`(d) a derivative of a polypeptide comprising the primary
`Structure
`
`15
`
`HN-R-COOH
`wherein R is an amino acid Sequence Selected from the
`group consisting of
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys-Gly-Arg-Gly; (SEQUENCE ID NO: 2)
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys-Gly-Arg; (SEQUENCE ID NO:3)
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys-Gly; (SEQUENCE ID NO: 4) and
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys; (SEQUENCE ID NO: 5) and
`(e) a derivative of Said peptides (a) through (d) wherein
`Said derivative is Selected from the group consisting of:
`(1) a pharmaceutically acceptable acid addition Salt of
`Said peptides;
`(2) a pharmaceutically acceptable carboxylate Salt of said
`peptides;
`(3) a pharmaceutically acceptable alkali addition Salt of
`Said peptides;
`(4) a pharmaceutically acceptable lower alkyl ester of said
`peptides, and
`(5) a pharmaceutically acceptable amide of Said peptides
`wherein Said pharmaceutically acceptable amide is
`Selected from the group consisting of amide, lower
`alkyl amide and lower dialkyl amide.
`Preferred is the method wherein said administration is
`Subcutaneous.
`Also preferred is the method wherein Said administration
`is intramuscular.
`Also preferred is the method wherein Said administration
`is transdermal.
`Also especially preferred is the method wherein Said
`administration is by an infusion pump.
`Also preferred is the method wherein Said administration
`is by oral inhalation.
`Also preferred is the method wherein Said administration
`is by nasal inhalation.
`Also preferred is the method wherein Said administration
`is gastrointestinal.
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`In another embodiment, the present invention is directed
`to a composition of matter comprising;
`(i) a compound Selected from the group consisting of:
`(a) a peptide having the amino acid sequence:
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys-Gly-Arg-Gly; (SEQUENCE ID NO: 2)
`(b) a peptide having the amino acid Sequence:
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-X (SEQUENCE ID NO: 7)
`wherein X is Selected from the group consisting of:
`(A) LyS,
`(B) Lys-Gly, and
`(C) Lys-Gly-Arg;
`(c) a derivative of a polypeptide comprising the primary
`Structure
`
`HN-W-COOH
`wherein W is an amino acid Sequence Selected from the
`group consisting of
`His-Asp-Glu-Phe-Glu-Arg-His-Ala-Glu-Gly-Thr-Phe-Thr
`Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys
`Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly
`(SEQUENCE ID NO: 1) and
`His-Asp-Glu-Phe-Glu-Arg-His-Ala-Glu-Gly-Thr-Phe-Thr
`Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys
`Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg
`(SEQUENCE ID NO: 6)
`which derivative when processed in a mammal results in a
`polypeptide derivative having an insulinotropic activity;
`(d) a derivative of a polypeptide comprising the primary
`Structure
`
`HN-R-COOH
`wherein R is an amino acid Sequence Selected from the
`group consisting of
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys-Gly-Arg-Gly (SEQUENCE ID NO: 2)
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys-Gly-Arg (SEQUENCE ID NO:3)
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys-Gly (SEQUENCE ID NO: 4) and
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys (SEQUENCE ID NO: 5);
`a derivative of Said peptides (a) through (d) wherein said
`derivative is Selected from the group consisting of:
`(1) a pharmaceutically acceptable acid addition Salt of
`Said peptides;
`(2) a pharmaceutically acceptable carboxylate Salt of Said
`peptides,
`(3) a pharmaceutically acceptable alkali addition Salt of
`Said peptides;
`(4) a pharmaceutically acceptable lower alkyl ester of said
`peptides, and
`(5) a pharmaceutically acceptable amide of Said peptides
`wherein Said pharmaceutically acceptable amide is
`Selected from the group consisting of amide, lower
`alkyl amide and lower dialkyl amide, and
`(ii) a polymer capable of prolonging the action of Said
`compound to achieve Sustained glycemic control.
`
`MPI EXHIBIT 1071 PAGE 14
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`MPI EXHIBIT 1071 PAGE 14
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`
`
`S
`Especially preferred is the composition wherein Said
`polymer is a low molecular weight polymer.
`Further especially preferred is a composition wherein Said
`polymer is Selected from the group consisting of polyeth
`ylene glycol, polyvinylpyrrolidone, polyvinylalcohol,
`polyoxyethylene-polyoxypropylene copolymers, polysac
`charides Selected from the group consisting of cellulose,
`cellulose derivatives, chitosan, acacia gum, karaya gum,
`guar gum, Xanthan gum, tragacanth, alginic acid,
`carrageenan, agarose, and furcellarans, dextran, Starch,
`Starch derivatives, hyaluronic acid, polyesters, polyamides,
`polyanhydrides, and polyortho esters, with especially pre
`ferred polymerS Selected from the group consisting of poly
`ethylene glycol and polyvinylpyrrollidone.
`In another embodiment, the present invention is directed
`to a composition of matter comprising;
`(i) a compound Selected from the group consisting of:
`(a) a peptide having the amino acid sequence:
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys-Gly-Arg-Gly (SEQUENCE ID NO: 2);
`(b) a peptide having the amino acid Sequence:
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-X (SEQUENCE ID NO: 7)
`wherein X is Selected from the group consisting of:
`(A) LyS,
`(B) Lys-Gly, and
`(C) Lys-Gly-Arg;
`(c) a derivative of a polypeptide comprising the primary
`Structure
`
`HN-W-COOH
`wherein W is an amino acid Sequence Selected from the
`group consisting of
`His-Asp-Glu-Phe-Glu-Arg-His-Ala-Glu-Gly-Thr-Phe-Thr
`Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys
`Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly
`(SEQUENCE ID NO: 1) and
`His-Asp-Glu-Phe-Glu-Arg-His-Ala-Glu-Gly-Thr-Phe-Thr
`Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys
`Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg
`(SEQUENCE ID NO: 6)
`which derivative when processed in a mammal results in a
`polypeptide derivative having an insulinotropic activity;
`(d) a derivative of a polypeptide comprising the primary
`Structure
`
`HN-R-COOH
`wherein R is an amino acid Sequence Selected from the
`group consisting of
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys-Gly-Arg-Gly (SEQUENCE ID NO:2);
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys-Gly-Arg (SEQUENCE ID NO:3);
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys-Gly (SEQUENCE ID NO: 4); and
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys (SEQUENCE ID NO: 5); and
`a derivative of Said peptides (a) through (d) wherein said
`derivative is Selected from the group consisting of:
`
`1O
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`US 6,284,727 B1
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`(1) a pharmaceutically acceptable acid addition Salt of
`Said peptides;
`(2) a pharmaceutically acceptable carboxylate Salt of Said
`peptides,
`(3) a pharmaceutically acceptable alkali addition Salt of
`Said peptides;
`(4) a pharmaceutically acceptable lower alkyl ester of said
`peptides, and
`(5) a pharmaceutically acceptable amide of Said peptides
`wherein Said pharmaceutically acceptable amide is
`Selected from the group consisting of amide, lower
`alkyl amide and lower dialkyl amide, and
`(ii) a pharmaceutically acceptable water-immiscible oil
`Suspension capable of prolonging administration of
`Said compound.
`Especially preferred is the composition wherein Said oil is
`Selected from the group consisting of peanut oil, Sesame oil,
`almond oil, castor oil, camellia oil, cotton Seed oil, olive oil,
`corn oil, Soy oil, Safflower oil, coconut oil, esters of fatty
`acids, and esters of fatty alcohols.
`Further especially preferred is the composition further
`comprising a Wetting agent, especially a nonionic Surfactant.
`More further especially preferred is the composition fur
`ther comprising a Suspending agent.
`In another embodiment, the present invention is directed
`to a composition of matter comprising;
`(i) a compound Selected from the group consisting of:
`(a) a peptide having the amino acid sequence:
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys-Gly-Arg-Gly (SEQUENCE ID NO: 2);
`(b) a peptide having the amino acid Sequence:
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-X (SEQUENCE ID NO: 7)
`wherein X is Selected from the group consisting of:
`(A) LyS,
`(B) Lys-Gly, and
`(C) Lys-Gly-Arg;
`(c) a derivative of a polypeptide comprising the primary
`Structure
`
`HN-W-COOH
`wherein W is an amino acid Sequence Selected from the
`group consisting of
`His-Asp-Glu-Phe-Glu-Arg-His-Ala-Glu-Gly-Thr-Phe-Thr
`Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys
`Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly
`(SEQUENCE ID NO: 1) and
`His-Asp-Glu-Phe-Glu-Arg-His-Ala-Glu-Gly-Thr-Phe-Thr
`Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys
`Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg
`(SEQUENCE ID NO: 6)
`which derivative when processed in a mammal results in a
`polypeptide derivative having an insulinotropic activity;
`(d) a derivative of a polypeptide comprising the primary
`Structure
`
`HN-R-COOH
`wherein R is an amino acid Sequence Selected from the
`group consisting of
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys-Gly-Arg-Gly (SEQUENCE ID NO: 2)
`
`MPI EXHIBIT 1071 PAGE 15
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`MPI EXHIBIT 1071 PAGE 15
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`
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`US 6,284,727 B1
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`7
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys-Gly-Arg (SEQUENCE ID NO:3)
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys-Gly (SEQUENCE ID NO: 4) and
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys (SEQUENCE ID NO: 5); and
`a derivative of Said peptides (a) through (d) wherein said
`derivative is Selected from the group consisting of:
`(1) a pharmaceutically acceptable acid addition Salt of
`Said peptides;
`(2) a pharmaceutically acceptable carboxylate Salt of said
`peptides;
`(3) a pharmaceutically acceptable alkali addition Salt of
`Said peptides;
`(4) a pharmaceutically acceptable lower alkyl ester of said
`peptides, and
`(5) a pharmaceutically acceptable amide of Said peptides
`wherein Said pharmaceutically acceptable amide is
`Selected from the group consisting of amide, lower
`alkyl amide and lower dialkyl amide, and
`(ii) Zinc (II), which is complexed with the peptide.
`Preferred is the composition capable of Sustained glyce
`mic action.
`Especially preferred is the composition wherein the Zinc
`product is amorphous.
`Also especially preferred is the composition wherein the
`Zinc product is crystalline.
`In yet another embodiment, the present invention is
`directed to a composition of matter comprising,
`(i) a compound Selected from the group consisting of:
`(a) a peptide having the amino acid sequence:
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys-Gly-Arg-Gly (SEQUENCE ID NO: 2);
`(b) a peptide having the amino acid Sequence:
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gin-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-X (SEQUENCE ID NO: 7)
`wherein X is Selected from the group consisting of:
`(A) LyS,
`(B) Lys-Gly, and
`(C) Lys-Gly-Arg;
`(c) a derivative of a polypeptide comprising the primary
`Structure
`
`HN-W-COOH
`wherein W is an amino acid Sequence Selected from the
`group consisting of
`His-Asp-Glu-Phe-Glu-Arg-His-Ala-Glu-Gly-Thr-Phe-Thr
`Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys
`Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly
`(SEQUENCE ID NO: 1) and
`His-Asp-Glu-Phe-Glu-Arg-His-Ala-Glu-Gly-Thr-Phe-Thr
`Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys
`Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg
`(SEQUENCE ID NO: 6)
`and which derivative when processed in a mammal results in
`a polypeptide derivative having an insulinotropic activity;
`(d) a derivative of a polypeptide comprising the primary
`Structure
`
`HN-R-COOH
`
`8
`wherein R is an amino acid Sequence Selected from the
`group consisting of
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys-Gly-Arg-Gly (SEQUENCE ID NO: 2)
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys-Gly-Arg (SEQUENCE ID NO:3)
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys-Gly (SEQUENCE ID NO: 4) and
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys (SEQUENCE ID NO: 5); and
`a derivative of Said peptides (a) through (d) wherein said
`derivative is Selected from the group consisting of:
`(1) a pharmaceutically acceptable acid addition Salt of
`Said peptides;
`(2) a pharmaceutically acceptable carboxylate Salt of Said
`peptides,
`(3) a pharmaceutically acceptable alkali addition Salt of
`Said peptides;
`(4) a pharmaceutically acceptable lower alkyl ester of said
`peptides, and
`(5) a pharmaceutically acceptable amide of Said peptides
`wherein Said pharmaceutically acceptable amide is
`Selected from the group consisting of amide, lower
`alkyl amide and lower dialkyl amide, and
`(ii) a metal Selected from the group consisting of Ni(II),
`Co (II), Mg (II), Ca (II), K (I), Mn (II), Fe(II), and
`Cu(II).
`In yet another embodiment, the present invention is
`directed to a composition of matter comprising,
`(i) a compound Selected from the group consisting of:
`(a) a peptide having the amino acid sequence:
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys-Gly-Arg-Gly (SEQUENCE ID NO: 2);
`(b) a peptide having the amino acid Sequence:
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-X (SEQUENCE ID NO: 7)
`wherein X is Selected from the group consisting of:
`(A) LyS,
`(B) Lys-Gly-,
`(C) Lys-Gly-Arg;
`(c) a derivative of a polypeptide comprising the primary
`Structure
`
`HN-W-COOH
`
`wherein W is an amino acid Sequence Selected from the
`group consisting of
`His-Asp-Glu-Phe-Glu-Arg-His-Ala-Glu-Gly-Thr-Phe-Thr
`Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys
`Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly
`(SEQUENCE ID NO: 1) and
`His-Asp-Glu-Phe-Glu-Arg-His-Ala-Glu-Gly-Thr-Phe-Thr
`Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys
`Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg
`(SEQUENCE ID NO: 6)
`which derivative when processed in a mammal results in a
`polypeptide derivative having an insulinotropic activity;
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`MPI EXHIBIT 1071 PAGE 16
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`MPI EXHIBIT 1071 PAGE 16
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`US 6,284,727 B1
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`9
`(d) a derivative of a polypeptide comprising the primary
`Structure
`
`HN-R-COOH
`wherein R is an amino acid Sequence Selected from the
`group consisting of
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp
`Leu-Val-Lys-Gly-Arg-Gly (SEQUENCE ID NO: 2);
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-S