throbber
\\_/I
`
`1
`
`253/204
`Patent
`
`DESCRIPTION
`
`MODIFIED EXENDINS AND EXENDIN AGONISTS
`
`RELATED APPLICATIONS
`
`This application claims priority to, and the benefit
`
`of, United States provisional patent application serial
`
`no. 60/132,018, filed April 30, 1999, which application is
`
`hereby incorporated by reference in its entirity.
`
`FIELD OF THE INVENTION
`
`The present
`
`invention relates to novel modified
`
`exendins and exendin agonists having an exendin or exendin
`
`agonist peptide linked to one or more polyethylene glycol
`
`5
`
`10
`
` i
`
`
`
`IKZIIT'.‘.I'.l|.. ......
`
`
`
`
`
`II"‘si||‘"H‘B212?‘.2331!~B-ufl'"'.|"‘
`
`
`
`
`
`
`
`15
`
`polymers (or other molecular weight increasing agents),
`
`nI.-
`
`
`
`
`
`IA...-4Wait4...]!I4.-.
`
`and related products and methods that are useful,
`
`for
`
`example,
`
`in the treatment of diabetes,
`
`including Type 1
`
`and 2 diabetes,
`
`in the treatment of disorders which would
`
`be benefited by agents which modulate plasma glucose
`
`20
`
`levels, and in the treatment of disorders which would be
`
`benefited by the administration of agents useful in
`
`modulating glucagon or triglyceride levels, or the rate of
`
`gastric emptying or food intake,
`
`including obesity, eating
`
`disorders, and insulin—resistance syndrome.
`
`25
`
`BACKGROUND
`
`The following description includes information that
`
`may be useful
`SD-149563.!
`
`in understanding the present
`
`invention.
`
`It
`
`SANOFI-AVENTIS Exhibit 1015 - Page 1
`IPR for Patent No. 8,951,962
`
`

`
`I
`
`•
`
`253/204
`Patent
`
`2
`
`is not an admission that any of the information provided
`herein is prior art to the presently claimed invention,
`nor that any of the publications specifically or
`implicitly referenced are prior art to that invention.
`The exendins are peptides that are found in the
`salivary secretions of the Gila monster and the Mexican
`Bearded Lizard, reptiles that are endogenous to Arizona
`and Northern Mexico. Exendin-3 [SEQ. ID. NO. 1] is
`present in the salivary secretions of Heloderma horridum
`(Mexican Beaded Lizard), and exendin-4 [SEQ. ID. NO. 2] is
`present in the salivary secretions of Heloderm suspectum
`(Gila monster) (Eng, J., et al., J. Biol. Chem., 265:20259-
`62, 1990; Eng, J., et al., J. Biol. Chem., 267:7402-05,
`1992). The amino acid sequence of exendin-3 is shown in
`Figure 1. The amino acid sequence of exendin-4 is shown
`in Figure 2. Exendin-4 was first thought to be a
`(potentially toxic) component of the venom.
`It now
`appears that exendin-4 is devoid of toxicity, and that it
`instead is made in salivary glands in the Gila monster.
`The exendins have some sequence similarity to several
`members of the glucagon-like peptide family, with the
`highest homology, 53%, being to GLP-1[7-36]NH2 [SEQ. ID.
`NO. 3]
`(Goke, et al., J. Biol. Chem., 268:19650-55, 1993).
`GLP-1[7-36]NH2, also sometimes referred to as
`proglucagon[78 107] or simply "GLP-1", has an
`insulinotropic effect, stimulating insulin secretion from
`pancreatic beta-cells; GLP-1 has also been reported to
`
`5
`
`10
`
`15
`
`20
`
`25
`
`SD-149563.1
`
`SANOFI-AVENTIS Exhibit 1015 - Page 2
`
`IPR for Patent No. 8,951,962
`
`

`
`3
`
`253/204
`Patent
`
`
`
`E,
`
`we
`
`FE
`
`:3
`
`x:...uu.....
`5'":H-::'.u2E.»-I‘'<...l
`
`
`inhibit glucagon secretion from pancreatic a1pha—cells
`
`(flrsov, et al., Diabetes, 42:658-61, 1993; D’Alessio, et
`
`al., J. Clin. Invest., 972133-38, 1996).
`
`GLP—1 has been
`
`reported to inhibit gastric emptying (willms B, et al., J.
`
`5 Clin. Endocrinol. Metab. 81 (1): 327-32, 1996; Wettergren
`
`A, et al., Dig. Dis. Sci. 38
`
`(4): 665-73, 1993), and
`
`gastric acid secretion (Schjoldager BT, et al., Dig. Dis.
`
`Sci. 34
`
`(5): 703-8, 1989; O'Halloran DJ, et al., J.
`
`Endocrinol. 126 (1): 169-73, 1990; Wettergren A, et al.,
`
`10 Dig. Dis. Sci. 38
`
`(4): 665-73, 1993)). GLP—1[7—37], which
`
`has an additional glycine residue at its carboxy terminus,
`
`is reported to stimulate insulin secretion in humans
`
`(flrsov, et al., Diabetes, 42:658-61, 1993). Other reports
`
`relate to the inhibition of glucagon secretion
`
`I5
`
`(Creutzfeldt WOC, et al., Glucagonostatic actions and
`
`reduction of fasting hyperglycemia by exogenous glucagon-
`
`like peptide I(7-36) amide in Type 1 diabetic patients,
`
`Diabetes Care 1996;19(6):580—6), and a purported role in
`
`appetite control
`
`(Turton MD, et al., A role for glucagon-
`
`20
`
`like peptide-1 in the central regulation of feeding,
`
`Nature 1996 Jan;379(6560):69—72).A transmembrane G—protein
`
`adenylate-cyclase-coupled receptor, said to be responsible
`
`at least in part for the insulinotropic effect of GLP-1,
`
`has reportedly been cloned from a beta-cell line (Thorens,
`
`25
`
`Proc. Natl. Acad. Sci. USA 89:8641-45, 1992). GLP-1 has
`
`been the focus of significant investigation in recent
`
`years due to its reported action on the amplification of
`
`SD-l49563.l
`
`SANOFI-AVENTIS Exhibit 1015 - Page 3
`IPR for Patent No. 8,951 ,962
`
`

`
`
`
`
`
`
`
`vllilhIL’?'.Z‘.nr.‘.,,IV"):i‘..nl'.-muIlu-Vll-nix
`
`
`
`
`-...u'L...vim.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`IS"!IT"!‘ITS?-I-..W“!"''l3‘.lI‘I181fill"IIl4..l'mu!‘'3...”‘In-.I’‘IWu.“
`
`4
`
`253/204
`Patent
`
`stimulated insulin production (Byrne MM, Goke B. Lessons
`
`from human studies with glucagon—like_peptide~1: Potential
`
`of the gut hormone for clinical use.
`
`In:
`
`Fehmann HC, Goke
`
`B.
`
`Insulinotropic Gut Hormone Glucagon-Like Peptide 1.
`
`Basel, Switzerland: Karger, 1997:2l9—33).
`
`GLP-1 has also been reported to restore islet glucose
`
`sensitivity in aging rats,
`
`restoring their glucose
`
`tolerance to that of younger rats (Egan JM, et al.,
`
`Diabetologia 1997 Jun;40(Suppl l):Al30). However,
`
`the
`
`short duration of biological action of GLP-1 in vivo is
`
`one feature of the peptide that has hampered its
`
`development as a therapeutic agent. Various methods have
`
`been tried to prolong the half~life of GLP—l or GLP—1(7-
`
`37),
`
`including attempts to alter their amino acid
`
`sequences and to deliver them using certain formulations
`
`(see, e.g., European Patent Application, entitled
`
`“Prolonged Delivery of Peptides,” by Darley, et al.,
`
`publication number 0 619 322 A2,
`
`regarding the inclusion
`
`of polyethylene glycol
`
`in formulations containing GLP-1
`
`(7-37)).
`
`Pharmacological studies have led to reports that
`
`exendin—4 can act at GLP~l receptors 33 vitro on certain
`
`insulin-secreting cells, at dispersed acinar cells from
`
`guinea pig pancreas, and at parietal cells from stomach;
`
`the peptide is also reported to stimulate somatostatin
`
`release and inhibit gastrin release in isolated stomachs
`
`(Goke, et al., J. Biol. Chem. 268:l9650-S5, 1993; Schepp,
`
`SD-149563. I
`
`SANOFI-AVENTIS Exhibit 1015 - Page 4
`IPR for Patent No. 8,951,962
`
`

`
`253/204
`Patent
`
`et al., Eur. J. Pharmacol., 69:183—91, 1994; Eissele, et
`
`al., Life Sci., 55:629-34, 1994). Exendin-3 and exendin~4
`
`were reportedly found to stimulate CAMP production in, and
`
`amylase release from, pancreatic acinar cells (Malhotra,
`
`R., et al., Regulatory Peptides, 4l:l49-56, 1992: Raufman,
`
`et al., J. Biol. Chem. 267:2l432-37, 1992; Singh, et a1.,
`
`Regul. Pept. 53:47-59, 1994). Exendin-4 has a
`
`significantly longer duration of action than GLP-1.
`
`For
`
`example,
`
`in one experiment, glucose lowering by exendin—4
`
`in diabetic mice was reported to persist for several
`
`hours, and, depending on dose,
`
`for up to 24 hours (Eng, J.
`
`Prolonged effect of exendin—4 on hyperglycemia of db/db
`
`mice, Diabetes 1996 May; 45(Suppl 2):152A (abstract 554)).
`
`Based on their insulinotropic activities,
`
`the use of
`
`exendin-3 and exendin-4 for the treatment of diabetes
`
`mellitus and the prevention of hyperglycemia has been
`
`proposed (Eng, U.S. Patent No. 5,424,286).
`
`The results of an investigation which showed that
`
`exendins are not
`
`the species homolog of mammalian GLP-1
`
`was reported by Chen and Drucker who cloned the exendin
`
`gene from the Gila monster
`
`(J. Biol. Chem. 272(7):4l08-15
`
`(1997)).
`
`The observation that the Gila monster also has
`
`separate genes for proglucagons (from which GLP-1 is
`
`processed),
`
`that are more similar to mammalian proglucagon
`
`than exendin,
`
`indicated that exendins are not merely
`
`species homologs of GLP—1.
`
`SD-l49563.l
`
`SANOFI-AVENTIS Exhibit 1015 - Page 5
`IPR for Patent No. 8,951,962
`
`

`
`6
`
`253/204
`Patent
`
`Methods for regulating gastrointestinal motility
`
`using exendin agonists are described in commonly owned
`
`U.S. Patent Application Serial No. 08/908,867, filed
`
`August 8, 1997 entitled "Methods for Regulating
`
`5 Gastrointestinal Motility," which application is a
`
`continuation-in-part of U.S. Patent Application Serial
`
`No. 08/694,954, filed August 8, 1996.
`
`Methods for reducing food intake using exendin
`
`agonists are described in commonly owned U.S. Patent
`
`10 Application Serial No. 09/003,869, filed January 7, 1998,
`
`entitled "Use of Exendin and Agonists Thereof for the
`
`Reduction of Food Intake," which claims the benefit of
`
`U.S. Provisional Application Nos. 60/034,905 filed January
`
`7, 1997 1 60/055,404 filed August 7 1 1997 1 60/065 1 442 filed
`
`15 November 14 1 1997 and 60/066,029 filed November 14 1 1997.
`
`Novel exendin agonist compounds are described in
`
`commonly owned PCT Application Serial No. PCT/US98/16387
`
`filed August 6 1 1998, entitled "Novel Exendin Agonist
`
`Compounds," which claims the benefit of U.S. Patent
`
`20 Application Serial No. 60/055 1 404 1 filed August 8, 1997.
`
`Other novel exendin agonists are described in
`
`commonly owned PCT Application Serial No. PCT/US98/24210,
`
`filed November 13, 1998 1 entitled "Novel Exendin Agonist
`
`Compounds," which claims the benefit of U.S. Provisional
`
`25 Application No. 60/065,442 filed November 14, 1997.
`
`Still other novel exendin agonists are described in
`
`commonly owned PCT Application Serial No. PCT/US98/24273,
`
`SD-149563.1
`
`SANOFI-AVENTIS Exhibit 1015 - Page 6
`
`IPR for Patent No. 8,951,962
`
`

`
`7
`
`253/204
`Patent
`
`5
`
`15
`
`filed November 13, 1998, entitled "Novel Exendin Agonist
`Compounds," which claims the benefit of U.S. Provisional
`Application No. 60/066,029 filed November 14, 1997.
`Other recent advances in exendin related technology
`are described in U.S. Provisional Patent Application
`Serial No. 60/075,122, filed February 13, 1998, entitled
`"Inotropic and Diuretic Effects of Exendin and GLP-1" and
`in U.S. Provisional Patent Application Serial
`No. 60/116,380, filed January 14, 1998, entitled "Novel
`10 Exendin Agonist Formulations and Methods of Administration
`Thereof".
`Polyethylene glycol (PEG) modification of therapeutic
`peptides and proteins may yield both advantages and
`disadvantages. While PEG modification may lead to
`improved circulation time, reduced antigenicity and
`immunogenicity, improved solubility, resistance to
`proteolysis, improved bioavailability, reduced toxicity,
`improved stability, and easier formulation of peptides
`(See, Francis et al., International Journal of Hematology,
`68:1-18, 1998) problems with PEGylation in most cases is
`substantial reduction in bioactivity.
`In addition,
`Id.
`most methods involve use of linkers that have several
`types of adverse effects including immunogenicity,
`instability, toxicity, and reactivity.
`Id.
`Modified exendins and exendin agonists and related
`formulations, dosage formulations, and methods that solve
`these problems and that are useful in the delivery of
`
`20
`
`25
`
`SD-149563.1
`
`SANOFI-AVENTIS Exhibit 1015 - Page 7
`
`IPR for Patent No. 8,951,962
`
`

`
`
`
`
`
`
`
`:-.PEI‘:"’‘.‘I-1‘"E57‘E3!!§’.‘;::!!'.I'.!!
`
`
`
`
`
`
`
`8
`
`253/204
`Patent
`
`therapeutically effective amounts of exendins and exendin
`
`agonists are described and claimed herein.
`
`The contents of the above-identified articles,
`
`patents, and patent applications, and all other documents
`
`mentioned or cited herein, are hereby incorporated by
`
`reference in their entirety.
`
`The inventors reserve the
`
`right to physically incorporate into this application any
`
`and all materials and information from any such articles,
`
`patents, patent applications, or other documents mentioned
`
`or cited herein.
`
`SUMMARY OF THE INVENTION
`
`The present
`
`invention relates to novel modified
`
`exendins and exendin agonists having an exendin or exendin
`
`agonist linked to one or more molecular weight
`
`increasing
`
`compounds, of which polyethylene glycol polymers (or other
`
`molecular weight
`
`increasing agents), and related products
`
`and methods.
`
`Such products and methods that are useful
`
`for many applications,
`
`including,
`
`for example,
`
`in the
`
`treatment of diabetes,
`
`including Type 1 and 2 diabetes,
`
`gestational diabetes (see U.S. patent application serial
`
`no. 09/323,867, entitled, “Use of Exendins and Agonists
`
`Thereof For The Treatment of Gestational Diabetes
`
`Mellitus,” filed June 1, 1999),
`
`in the treatment of
`
`disorders which would be benefited by agents which
`
`modulate plasma glucose levels,
`
`in the treatment of
`
`disorders which would be benefited by the administration
`
`of agents useful
`SD-M95611
`
`in modulating the rate of gastric
`
`SANOFI-AVENTIS Exhibit 1015 - Page 8
`IPR for Patent No. 8,951,962
`
`

`
`9
`
`253/204
`Patent
`
`emptying or food intake, including obesity, eating
`
`disorders, and insulin-resistance syndrome, and to
`
`modulate triglyceride levels and to treat subjects
`
`suffering from dyslipidemia (i.e., increased LDL
`
`5
`
`cholesterol, increased VLDL cholesterol, and/or decreased
`
`HDL cholesterol) (see U.S. provisonal patent application
`
`serial no. 60/175,365, entitled, "Use of Exendins and
`
`Agonists Thereof for Modulation of Triglyceride Levels and
`
`Treatment of Dyslipidemia," filed January 10, 2000). The
`
`10 methods are also useful for lowering plasma lipid levels,
`
`reducing cardiac risk, reducing the appetite, and reducing
`
`the weight of subjects. Still other embodiments concern
`
`methods for suppressing glucagon secretion (see U.S.
`
`provisonal patent application serial no. 60/132,017,
`
`15
`
`entitled, "Methods for Glucagon Suppression," filed April
`
`30, 1999, which is commonly owned). Pharmaceutical
`
`compositions for use in the methods of the invention are
`
`also disclosed.
`
`The present invention is related to the surprising
`
`20
`
`discovery that exendin is cleared from the plasma almost
`
`entirely by renal filtration, and not primarily by
`
`proteolytic degradation, as occurs for many other
`
`biologically active peptides, for example, GLP-1. This
`
`surprising discovery supports the determination that
`
`25
`
`PEGylation or other modification of exendin or exendin
`
`agonists to increase molecular size, will have
`
`pharmaceutical benefit.
`
`SD-149563.1
`
`SANOFI-AVENTIS Exhibit 1015 - Page 9
`
`IPR for Patent No. 8,951,962
`
`

`
`10
`
`253/204
`Patent
`
`5
`
`Thus, the present invention provides a modified
`exendin or exendin agonist having an exendin or exendin
`agonist linked to one or more polyethylene glycol polymers
`or other molecular weight increasing compounds. A
`"molecular weight increasing compound" is one that can be
`conjugated to an exendin or exendin agonist and thereby
`increase the molecular weight of the resulting conjugate.
`Representative examples of molecular weight increasing
`compounds, in addition to PEG, are polyamine acids (e.g.,
`10 poly-lysine, poly-glutamic acid, and poly-aspartic acid;
`see Gombotz, et al. (1995), Bioconjugate Chern., vol. 6:
`332-351; Hudecz, et al. (1992), Bioconjugate Chern., vol.
`3, 49 57; Tsukada, et al. (1984), J. Natl. Cancer Inst.,
`vol 73,: 721-729; Pratesi, et al. (1985), Br. J. Cancer,
`vol. 52: 841-848), particularly those of the L
`conformation, pharmacologically inactive proteins (e.g.,
`albumin; see Gombotz, et al. (1995) and the references
`cited therein), gelatin (see Gombotz, et al. (1995) and
`the references cited therein), succinyl-gelatin (see
`20 Gombotz, et al.
`(1995) and the references cited therein),
`(hydroxypropyl)-methacrylamide (see Gombotz, et al. (1995)
`and the references cited therein), a fatty acid, a
`olysaccaride, a lipid amino acid, and dextran.
`In preferred embodiments, the modified exendin or
`exendin agonist has a molecular weight that is greater
`than the molecular weight of the exendin or exendin
`agonist (preferably about 10%, 50% or 90% greater), the
`
`15
`
`25
`
`SD·I49563.1
`
`SANOFI-AVENTIS Exhibit 1015 - Page 10
`
`IPR for Patent No. 8,951,962
`
`

`
`11
`
`253/204
`Patent
`
`modified exendin or exendin agonist has a negative charge
`
`that is greater than the negative charge of the exendin or
`
`exendin agonist (preferably about 10%, 50% or 90%
`
`greater), the modified exendin or exendin agonist has a
`
`5
`
`kidney clearance that is less than the kidney clearance of
`
`the exendin or exendin agonist (preferably about 10%, 50%
`
`or 90% less), the modified exendin or exendin agonist has
`
`a half-life that is greater than the half-life of the
`
`exendin or exendin agonist (preferably about 10%, 50% or
`
`10
`
`90% greater), the modified exendin or exendin agonist has
`
`a immunogenicity/antigenicity that is less than the
`
`immunogenicity/antigenicity of the exendin or exendin
`
`agonist, the modified exendin or exendin agonist has a
`
`solubility that is greater than the solubility of the
`
`15
`
`exendin or exendin agonist (preferably about 10%, 50% or
`
`90% greater), the modified exendin or exendin agonist has
`
`a proteolysis rate that is less than the proteolysis rate
`
`of the exendin or exendin agonist (preferably about 10%,
`
`50% or 90% less), the modified exendin or exendin agonist
`
`20
`
`has a toxicity that is less than the toxicity of the
`
`exendin or exendin agonist, the modified exendin or
`
`exendin agonist has a stability that is greater than the
`
`stability of the exendin or exendin agonist, and/or the
`
`modified exendin or exendin agonist has a
`
`25
`
`permeability/biological function that is greater or less
`
`than the permeability/biological function of the exendin
`
`SD-149563.1
`
`SANOFI-AVENTIS Exhibit 1015 - Page 11
`
`IPR for Patent No. 8,951,962
`
`

`
`12
`
`253/204
`Patent
`
`or exendin agonist (preferably about 10%, 50% or 90%
`
`greater or less).
`
`The exendin or exendin agonist may be linked to one,
`
`two or three polyethylene glycol polymers or other
`
`5 molecular weight increasing agents. The polyethylene
`
`glycol polymers (or other molecular weight increasing
`
`agents) may preferably have molecular weights between 500
`
`and 20,000.
`
`In a preferred embodiment, the modified
`
`exendin or exendin agonist is one of compounds 201-230,
`
`10 more preferably one of compounds 209, 210 and 213, or one
`
`of compounds 201 and 202, or one of compounds 216 and 217
`
`(See Example 4 below) .
`
`The polyethylene glycol polymers (or other molecular
`
`weight increasing agents) are preferably linked to an
`
`15
`
`amino, carboxyl, or thio group, and may be linked by N or
`
`C termini of side chains of lysine, aspartic acid,
`
`glutamic acid, or cysteine, or alternatively, the
`
`polyethylene glycol polymers or other molecular weight
`
`increasing agents may be linked with diamine and
`
`20
`
`dicarboxylic groups. The exendin or exendin agonist is
`
`preferably linked to the polyethylene glycol polymers or
`
`other molecular weight increasing agents through an
`
`epsilon amino group on a lysine amino acid of the exendin
`
`or exendin agonist.
`
`25·
`
`The present invention also features a method of
`
`making a modified exendin or exendin agonist. The method
`
`involves linking one or more polyethylene glycol polymers
`
`SD-149563.1
`
`SANOFI-AVENTIS Exhibit 1015 - Page 12
`
`IPR for Patent No. 8,951,962
`
`

`
`253/204
`Patent
`
`or other molecular weight increasing agents to an exendin
`
`or exendin agonist.
`
`In preferred embodiments,
`
`the linking
`
`is performed by solid-phase synthesis.
`
`The present
`
`invention also provides a method of
`
`treating a disease benefited by administration of an
`
`exendin or exendin agonist.
`
`The method involves providing
`
`a modified exendin or exendin agonist of the invention to
`
`a patient having such a disease and thereby treating the
`
`disease.
`
`Exemplary diseases include postprandial dumping
`
`syndrome, postprandial hyperglycemia,
`
`impaired glucose
`
`tolerance, a condition or disorder which can be alleviated
`
`by reducing food intake, obesity, an eating disorder,
`
`insulin—resistance syndrome, diabetes mellitus, and a
`
`hyperglycemic condition.
`
`In a preferred embodiment,
`
`the
`
`postprandial hyperglycemia is a consequence of Type 2
`
`diabetes mellitus.
`
`In other preferred embodiments,
`
`the
`
`postprandial hyperglycemia is a consequence of Type 1
`
`diabetes mellitus or impaired glucose tolerance.
`
`Also featured in the present
`
`invention is a
`
`pharmaceutical composition.
`
`The composition contains a
`
`modified exendin or exendin agonist and a pharmaceutically
`
`acceptable carrier.
`
`The invention also provides a kit.
`
`The kit contains
`
`a modified exendin or exendin agonist and instructions
`
`and/or packaging for use.
`
`The kit may also include a
`
`document
`
`indicating that the kit,
`
`its components, or the
`
`methods of using them, has received regulatory approval.
`
`SD-149563.!
`
`SANOFI-AVENTIS Exhibit 1015 - Page 13
`IPR for Patent No. 8,951 ,962
`
`

`
`14
`
`253/204
`Patent
`
`The present invention also provides a method of
`
`beneficially regulating gastro-intestinal motility in a
`
`subject. The method involves administering to the subject
`
`a therapeutically effective amount of a modified exendin
`
`5
`
`or exendin agonist of the present invention.
`
`Also featured are methods of treatment for ingestion
`
`of a toxin. The methods involve:
`
`(a) administering an
`
`amount of a modified exendin or exendin agonist of the
`
`present invention effective to prevent or reduce the
`
`10
`
`passage of stomach contents to the intestines; and (b)
`
`aspirating the contents of the stomach.
`
`The invention also provides methods for reducing the
`
`appetite or weight, or lowering plasma lipids, of a
`
`subject, as well as methods for treating gestational
`
`15
`
`diabetes. The invention also provides methods for
`
`reducing the appetite or weight, or lowering plasma
`
`lipids, of a subject, as well as methods for treating
`
`gestational diabetes. Additional methods include
`
`modulating triglyceride levels, and treating subjects
`
`20
`
`suffering from dyslipidemia, as well as suppressing
`
`glucagon levels. These and other methods of the invention
`
`involve administering to the subject a therapeutically
`
`effective amount of a modified exendin or exendin agonist
`
`of the present invention.
`
`25
`
`Modified exendins and exendin agonists are useful,
`
`for example, as inhibitors of gastric emptying for the
`
`treatment of, for example, diabetes mellitus, and obesity.
`
`SD-149563.1
`
`SANOFI-AVENTIS Exhibit 1015 - Page 14
`
`IPR for Patent No. 8,951,962
`
`

`
`15
`
`253/204
`Patent
`
`Thus, the present invention is also directed to novel
`
`methods for reducing gastric motility and slowing gastric
`
`emptying. The methods involve the administration of a
`
`modified exendin or exendin agonist, for example one or
`
`5 more PEG polymers linked to exendin-3 [SEQ ID NO. 1],
`
`exendin-4 [SEQ ID NO. 2], or other compounds which
`
`effectively bind to the receptor at which exendins exert
`
`their action on gastric motility and gastric emptying.
`
`These methods will be useful in the treatment of, for
`
`10
`
`example, pos
`
`1 hyperglycemia, a complication
`
`associated with type 1 (insulin dependent) and type 2
`
`(non-insulin dependent) diabetes mellitus, as well as
`
`gestational diabetes, dyslipidemia, to modulate
`
`triglyceride levels, and to suppress glucagon secretion.
`
`15
`
`By "exendin agonistn is meant a compound which mimics
`
`the effects of exendins, e.g., on gastric motility and
`
`gastric emptying (namely, a compound which effectively
`
`binds to the receptor at which exendins exert their action
`
`on gastric motility and gastric emptying, preferably an
`analog or derivative of an exendin) or a compound, e.g.,
`
`20
`
`that mimics the effects of exendin on the reduction of
`
`food intake by binding to the receptor or receptors where
`
`exendin causes this effect. Preferred exendin agonist
`
`compounds include those described in United States Patent
`
`25 Application Serial No. 90/003,869, entitled, "Use of
`
`Exendin And Agonists Thereof For The Reduction of Food
`
`Intaken, filed January 7, 1998,
`
`(and the priority
`
`SD-149563.1
`
`SANOFI-AVENTIS Exhibit 1015 - Page 15
`
`IPR for Patent No. 8,951,962
`
`

`
`16
`
`253/204
`Patent
`
`applications thereto) which enjoys common ownership with
`
`the present application and which is incorporated by this
`
`reference into the present application as though fully set
`
`forth herein. Effects of exendins or exendin agonists on
`
`5
`
`reducing food intake can be identified, evaluated, or
`
`screened for, using the methods described herein, or other
`
`methods known in the art for determining exendin effects,
`
`e.g., on food intake or appetite.
`
`In another aspect, a therapeutically effective amount
`
`10
`
`of an amylin agonist is also administered to the subject.
`
`In a preferred aspect, the amylin agonist is an amylin or
`28
`an amylin agonist analog such as 25
`29 Pro-human-amylin.
`
`'
`
`'
`
`The use of amylin agonists to treat post-prandial
`
`hyperglycemia, as well as to beneficially regulate
`
`15 gastrointestinal motility, is described in International
`
`Application No. PCT/US94/10225, published March 16, 1995
`
`which has been incorporated by reference herein.
`
`In yet another aspect, a therapeutically effective
`
`amount of an insulin or insulin analog is also
`
`20
`
`administered, separately or together with a modified
`
`exendin or exendin agonist, to the subject.
`
`Preferably, the subject is a vertebrate, more
`
`preferably a mammal, and most preferably a human.
`
`In
`
`preferred aspects, the modified exendin or exendin agonist
`
`25
`
`of the invention is administered parenterally, more
`
`preferably by injection.
`
`In a most preferred aspect, the
`
`injection is a peripheral injection. Preferably, about 1
`
`SD-149563.1
`
`SANOFI-AVENTIS Exhibit 1015 - Page 16
`
`IPR for Patent No. 8,951,962
`
`

`
`17
`
`253/204
`Patent
`
`~g-30 ~g to about 5 mg of the modified exendin or exendin
`
`agonist of the invention is administered per day. More
`
`preferably, about 1-30 ~g to about 2mg, or about 1-30 ~g
`
`to about 1mg of the modified exendin or exendin agonist of
`
`5
`
`the invention is administered per day. Most preferably,
`
`about 3 ~g to about 500 ~g of the modified exendin or
`
`exendin agonist of the invention is administered per day.
`
`Preferred exendins or exendin agonists for
`
`modification and use include:
`
`10
`
`exendin-4 (1-30)
`
`[SEQ ID NO 4: His Gly Glu Gly Thr
`
`Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val
`
`Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly];
`
`exendin-4 (1 30) amide [SEQ ID NO 5: His Gly Glu Gly
`
`Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala
`
`15 Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly-NH 2 ];
`
`exendin-4 (1-28) amide [SEQ ID NO 6: His Gly Glu Gly
`
`Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala
`
`Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH 2 ];
`14 Leu, 25 Phe exendin-4 amide [SEQ ID NO 7: His Gly Glu
`
`20 Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu
`
`Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro
`
`Ser Ser Gly Ala Pro Pro Pro Ser-NH 2 ];
`14Leu, 25 Phe exendin-4 (1-28) amide [SEQ ID NO 8: His
`
`Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu
`
`25 Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH 2 ];
`and
`
`SD- I 49563.1
`
`SANOFI-AVENTIS Exhibit 1015 - Page 17
`
`IPR for Patent No. 8,951,962
`
`

`
`18
`
`253/204
`Patent
`
`14 Leu, 22Ala, 25 Phe exendin-4 (1-28) amide [SEQ ID NO 9:
`
`His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu
`
`Glu Glu Glu Ala Val Arg Leu Ala Ile Glu Phe Leu Lys Asn(cid:173)
`
`NH2] .
`
`5
`
`In the methods of the present invention, the modified
`
`exendins or exendin agonists may be administered
`
`separately or together with one or more other compounds
`
`and compositions that exhibit a long term or short-term
`
`satiety action, including, but not limited to other
`
`10
`
`compounds and compositions that include an amylin agonist,
`
`cholecystokinin (CCK), or a leptin (ob protein). Suitable
`28
`[ 25
`29 Pro-] -human
`
`amylin agonists include, for example,
`
`'
`
`'
`
`amylin (also known as "pramlintide," and previously
`
`referred to as "AC-137") as described in "Amylin Agonist
`
`15
`
`Peptides and Uses Therefor," U.S. Patent No. 5,686,511,
`
`issued November 11, 1997, and salmon calcitonin. The CCK
`
`used is preferably CCK octapeptide (CCK-8). Leptin is
`
`discussed in, for example, Pelleymounter, M.A., et al.
`
`20
`
`Science 269:540-43 (1995); Halaas, J.L., et al. Science
`269:543-46 (1995); and Campfield, L.A., et al. Eur. J.
`Pharmac. 262:133-41 (1994).
`
`The invention also provides compositions and methods
`
`for providing therapeutically effective amounts of the
`
`modified exendins or exendin agonists of the invention in
`
`25
`
`order to increase urine flow in an individual, decrease
`
`the amount of potassium in the urine of an individual,
`
`prevent or alleviate a condition or disorder associated
`
`SD-149563.1
`
`SANOFI-AVENTIS Exhibit 1015 - Page 18
`
`IPR for Patent No. 8,951,962
`
`

`
`•
`
`253/204
`Patent
`
`19
`
`with hypervolemia or toxic hypervolemia in an individual,
`
`induce rapid diuresis, prepare an individual for a
`
`surgical procedure, increase renal plasma flow and
`
`glomerular filtration rates, or treat pre-eclampsia or
`
`5
`
`eclampsia of pregnancy.
`
`Definitions
`
`In accordance with the present invention and as used
`
`herein, the following terms are defined to have the
`
`10
`
`following meanings, unless explicitly stated otherwise.
`
`The term "amino acid" refers to natural amino acids,
`
`unnatural amino acids, and amino acid analogs, all in
`
`their D and L stereoisomers if their structure allow such
`
`stereoisomeric forms. Natural amino acids include alanine
`
`15
`
`(Ala), arginine (Arg), asparagine (Asn), aspartic acid
`
`(Asp), cysteine (Cys), glutamine (Gln), glutamic acid
`
`(Glu), glycine (Gly), histidine (His), isoleucine (Ile),
`
`leucine (Leu), Lysine (Lys), methionine (Met),
`
`phenylalanine (Phe), proline (Pro), serine (Ser),
`
`20
`
`threonine (Thr), typtophan (Trp), tyrosine (Tyr) and
`
`valine (Val). Unnatural amino acids include, but are not
`
`limited to azetidinecarboxylic acid, 2-aminoadipic acid,
`
`3-aminoadipic acid, beta-alanine, aminopropionic acid, 2-
`
`aminobutyric acid, 4-aminobutyric acid, 6-aminocaproic
`
`25
`
`acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-
`
`aminoisbutyric acid, 2-aminopimelic acid, tertiary(cid:173)
`
`butylglycine, 2,4-diaminoisobutyric acid, desmosine, 2,2'-
`
`SD-149563.1
`
`SANOFI-AVENTIS Exhibit 1015 - Page 19
`
`IPR for Patent No. 8,951,962
`
`

`
`20
`
`253/204
`Patent
`
`diaminopimelic acid, 2,3-diaminopropionic acid, N(cid:173)
`
`ethylglycine, N-ethylasparagine, homoproline,
`
`hydroxylysine, allo-hydroxylysine, 3-hydroxyproline, 4-
`
`hydroxyproline, isodesmosine, allo-isoleucine, N-
`
`5 methylalanine, N-methylglycine, N-methylisoleucine, N(cid:173)
`
`methylpentylglycine, N-methylvaline, naphthalanine,
`
`norvaline, norleucine, ornithine, pentylglycine, pipecolic
`
`acid and thioproline. Amino acid analogs include the
`
`natural and unnatural amino acids which are chemically
`
`10
`
`blocked, reversibly or irreversibly, or modified on their
`
`N-terminal amino group or their side chain groups, as for
`
`example, methionine sulfoxide, methionine sulfone, S(cid:173)
`
`(carboxymethyl)-cysteine, S-(carboxymethyl)-cysteine
`
`sulfoxide and S-(carboxymethyl)-cysteine sulfone.
`
`15
`
`The term "amino acid analogu refers to an amino acid
`
`wherein either the C-terminal carboxy group, the N(cid:173)
`
`terminal amino group or side chain functional group has
`
`been chemically codified to another functional group. For
`
`example, aspartic acid-(beta-methyl ester) is an amino
`
`20
`
`acid analog of aspartic acid; N-ethylglycine is·an amino
`
`acid analog of glycine; or alanine carboxamide is an amino
`
`acid analog of alanine.
`
`The term "amino acid residueu refers to radicals
`
`having the structure:
`
`(1) -C(O)-R-NH-, wherein R typically
`
`25
`
`is -CH(R' )-, wherein R' is an amino acid side chain,
`
`typically H or a carbon containing substitutent;
`
`SD-149563.1
`
`SANOFI-AVENTIS Exhibit 1015 - Page 20
`
`IPR for Patent No. 8,951,962
`
`

`
`21
`
`253/204
`Patent
`
`or (2)
`
`(CH)p
`
`C(~O)­
`
`o--
`
`N
`
`I
`
`5
`
`, wherein p is 1, 2, or 3 representing the
`
`azetidinecarboxylic acid, proline, or pipecolic acid
`
`residues,
`
`ively.
`
`The term "lower" referred to herein in connection
`
`10 with organic radicals such as alkyl groups defines such
`
`groups with up to and including about 6, preferably up to
`
`and including 4 and advantageously one or two carbon
`
`atoms. Such groups may be straight chain or branched
`
`chain.
`
`15
`
`"Pharmaceutically acceptable salt" includes salts of
`
`the compounds of the present invention derived from the
`
`combination of such compounds and an organic or inorganic
`
`acid.
`
`In practice the use of the salt form amounts to use
`
`of the base form. The compounds of the present invention
`
`20
`
`a

This document is available on Docket Alarm but you must sign up to view it.


Or .

Accessing this document will incur an additional charge of $.

After purchase, you can access this document again without charge.

Accept $ Charge
throbber

Still Working On It

This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.

Give it another minute or two to complete, and then try the refresh button.

throbber

A few More Minutes ... Still Working

It can take up to 5 minutes for us to download a document if the court servers are running slowly.

Thank you for your continued patience.

This document could not be displayed.

We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.

Your account does not support viewing this document.

You need a Paid Account to view this document. Click here to change your account type.

Your account does not support viewing this document.

Set your membership status to view this document.

With a Docket Alarm membership, you'll get a whole lot more, including:

  • Up-to-date information for this case.
  • Email alerts whenever there is an update.
  • Full text search for other cases.
  • Get email alerts whenever a new case matches your search.

Become a Member

One Moment Please

The filing “” is large (MB) and is being downloaded.

Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.

Your document is on its way!

If you do not receive the document in five minutes, contact support at support@docketalarm.com.

Sealed Document

We are unable to display this document, it may be under a court ordered seal.

If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.


Access Government Site

We are redirecting you
to a mobile optimized page.





Document Unreadable or Corrupt

Refresh this Document
Go to the Docket

We are unable to display this document.

Refresh this Document
Go to the Docket