'
`
`66/DE/I70
`
`PROVISIONAL APPLICATION COVER SHEET
`. This is a request for filing a PROVISIONAL APPLICATION under 37 C.F.R. l.53(b)(2).
`‘
`'
`
`Docket Number
`242/040
`
`Type a plus sign
`(+) inside ‘his box
`
`FIRST NAME
`
`MIDDLE INITIAL
`
`RESIDENCE (CITY AND EITHER STATE OR FOREIGN
`COUNTRY)
`
`OE
`
`--
`
`3“ ‘’“’g°= 0‘
`San Diego, CA
`
`Young
`
`Andrew
`
`A
`
`TITLE or THE INVENTION (280 characters max)
`
`MODIFIED EXENDIN S AND EXENDIN AGONISTS
`
`Bradford J. Duft, Esq.
`LYON & LYON LLP
`
`633 West Fifth Street, Suite 4700, Los Angeles,
`
`92024 _——
`
`ENCLOSED APPLICATION PARTS‘(check all that apply)
`
`Specification
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`
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`
`81
`I
`18
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`Small Entity Statement (1 sheet)
`
`X
`
`Other (specify)
`
`Return Postcard and Express Mail Label
`No. EL08859233 IUS
`
`METHOD OF PAYMENT (check mic)
`
`A check or money order is enclosed to cover the Provisional filing fees
`The Commissioner is hereby authorized to charge
`filing fees and credit Deposit Account Number:
`
`12-2475
`
`PROVISIONAL
`FILING FEE
`AMOUNTISI
`
`The invention was made by an agency of the United States Government or under a contract with an agency of the United States
`Government.
`No.
`
`Yes, the name of the U.S. Government agency and the
`Government contract number are:
`
`Respectfully submitted,
`SIGNATURE 0 4‘-/T
`TYPED or PRINTED NAME
`Charles S. Berkman
`
`Date: AQriI30, I299
`REGISTRATION N0. 38 077
`
`for Richard .1. Warburg, Registration No. 32,327
`
`Additional inventors are being named on separately numbered sheets attached hereto
`
`PROVISIONAL APPLICA TION FILING ONLY
`Burden Hour Statement: This fonn is estimated to take 2 hours to complete. Time will vary depending upon the needs of the
`individual case. Any comments on the amount oftime you are required to complete this form should be sent to the Office of
`Assistance Quality and Enhancement Division, Patent Trademark Office, Washington, DC 2023], and to the Office of Infonnation
`and Regulatory Affairs, Office of Management and Budget (Project 0651-OOXX), Washington, DC 20503. DO NOT SEND FEES
`OR COMPLETED FORMS TO THIS ADDRESS. SEND TO: Commissioner of Patents and Trademarks, Washington, DC 20231.
`
`0 - MA IN(.r
`RTIF CA
`I hereby certify that this paper (along with any referred to as being attached or enclosed) is being deposited with the United States Postal Service on the date shown below
`with sufficient postage as Express Mail in an envelope addressed to the Assistant Commissioner for Patents, Washington, D.C. 20231.
`
`EL08859233l [IS
`Express Mail mailing no.
`
`April 30, 1999
`date of deposit
`
`SD-113534.!
`
`SANOFI-AVENTIS Exhibit 1003 - Page i
`IPR for Patent No. 8,951,962
`
`

`
`PROVISIONAL APPLICATION
`
`
`
`TO THE COMMISSIONER OF PATENTS AND TRADEMARKS:
`
`BE IT KNOWN that we, Kathryn S. Prickett and Andrew A. Young, have invented
`certain new and useful improvements in MODIFIED EXENDINS AND EXENDIN AGONISTS
`
`CERTIFICATE OF MAILING
`(37 C.F.R. §1.1o)
`
`I hereby certify that this paper (along with any referred to as being attached or enclosed) is being deposited with the United States Postal Service
`on the date shown below with sufficient postage as ‘Express Mail Post Office To Addressce‘ in an envelope addressed to the Assistant
`Commissioner for Parents, Washington, D.C. 20231.
`
`EL08859233lUS
`Express Mail Label No.
`
`April 30, 1999
`Date of Deposit
`
`SD-113537.]
`
`Irene Grimes Betke
`
`
`
`SANOFI-AVENTIS Exhibit 1003 - Page ii
`IPR for Patent No. 8,951 ,962
`
`

`
`DE§QRIPIION
`
`MODIFIED EXENDINS AND EXENDIN AGONISTS
`
`242/040
`
`FIELD OF T E I
`
`ION
`
`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
`
`polymers (or other molecular weight increasing agent), and
`
`related products and methods that are useful, for example,
`
`in the treatment of diabetes,
`
`including Type I and II
`
`diabetes,
`
`in the treatment of disorders which would be
`
`benefited by agents which modulate plasma glucose levels,
`
`and in the treatment of disorders which would be benefited
`
`by the administration of agents useful in modulating the
`
`rate of gastric emptying or food intake,
`
`including obesity,
`
`eating disorders, and insulin—resistance syndrome.
`
`BACKGROUND
`
`The following description includes information that
`
`may be useful
`
`in understanding the present invention.
`
`It
`
`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
`
`Beaded 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 Heloderma suspectum (Gila
`
`SD-I 12400.5
`
`x
`
`I-’
`
`'37?
`§'''’';
`.5:
`
`._....
`
`SANOFI-AVENTIS Exhibit 1003 - Page 1
`IPR for Patent No. 8,951,962
`
`

`
`242/O40
`
`monster)(Eng, J., et al., J. Biol. Chem., 265:202S9-62,
`
`1990; Eng, J., et al., J. Biol. Chem., 267:7402-O5, 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" as used most often
`
`herein, has an insulinotropic effect, stimulating insulin
`
`secretion from pancreatic beta—cells; GLP-1 has also been
`
`reported to inhibit glucagon secretion from pancreatic
`
`alpha-cells (0rsov, et al., Diabetes, 42:658-61, 1993;
`
`D’Alessio, et al., J. Clin, Invest., 97:l33—38, 1996).
`
`GLP—1 has been reported to inhibit gastric emptying (Willms
`
`B, et al.,
`
`Q Clin Endgcrinol 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
`
`_S__(g 34 (5): 703-8, 1989; O'Halloran DJ, et al., J
`
`Endocrinol 126 (1): 169-73, 1990; Wettergren A, et al., 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
`
`(wrsov,
`
`et al., Diabetes, 42:658-61, 1993).
`
`A transmembrane G-
`
`protein adenylate-cyclase—coupled receptor said to be
`
`responsible at least in part for the insulinotropic effect
`
`SD-1124005
`
`SANOFI-AVENTIS Exhibit 1003 - Page 2
`IPR for Patent No. 8,951,962
`
`

`
`mm.
`
`miltg
`
`mimmflm
`
`.:..»..
`
`3 ‘E.3.‘
`F
`E
`E
`ifi
`=2?
`
`..u..
`
`242/040
`
`of GLP-1 has reportedly been cloned from a beta—cell line
`
`(Thorens, Prog. Natl, Agag. §ci. QSA 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 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 l. Basel, Switzerland: Karger,
`
`1997:219—33).
`
`Other reports relate to the inhibition of gastric
`
`emptying (Wettergren A, et al., Truncated GLP-1
`
`(proglucagon 78-107-amide)
`
`inhibits gastric and pancreatic
`
`functions in man, Dig. Dis. Sci. 1993 Apr;38(4):665—73),
`
`inhibition of glucagon secretion (Creutzfeldt WOC, et al.,
`
`Glucagonostatic actions and reduction of fasting
`
`hyperglycemia by exogenous glucagon—like peptide I(7—36)
`
`amide in type I diabetic patients, Diabetes Care
`
`l996;19(6):580-6), and a purported role in appetite control
`
`(Turton MD, et al., A role for glucagon—like peptide-1 in
`
`the central regulation of feeding, Nature 1996
`
`Jan;379(6560):69—72).
`
`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.,
`
`Glucagon-like peptide-1 restores acute-phase insulin
`
`release to aged rats, Diabetologia 1997 Jun;40(Suppl
`
`1):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-1
`
`SD-1124005
`
`SANOFI-AVENTIS Exhibit 1003 - Page 3
`IPR for Patent No. 8,951 ,962
`
`

`
`‘filflfifi
`
`mmmmmmmm
`
`fimfiflfififl
`
`242/040
`
`or GLP—1(7—37),
`
`including attempts to alter their amino
`
`acid sequence 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-1 receptors 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. 268:19650-55, 1993; Schepp, et al., Eur, Q,
`
`Pharmacgl., 69:183-91, 1994; Eissele, et al., gife 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 Peptig§s,41:149-56, 1992; Raufman, et al., Q;
`
`Biol. Chem. 267:21432-37, 1992; Singh, et al., Regul. Pept.
`
`53:47-59, 1994). Additionally, 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).
`
`SD-I 12400.5
`
`SANOFI-AVENTIS Exhibit 1003 - Page 4
`IPR for Patent No. 8,951,962
`
`

`
`242/040
`
`The results of an investigation of whether exendins
`
`are 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):4108—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,
`
`indicates that exendins are not merely species homologs of
`
`GLP-1.
`
`To date, agents that serve to delay gastric emptying
`
`have generally found a place in medicine as diagnostic aids
`
`in gastrointestinal radiological examinations.
`
`For
`
`example, glucagon is a polypeptide hormone that is produced
`
`by the alpha cells of the pancreatic islets of Langerhans.
`
`It is a hyperglycemic agent that mobilizes glucose by
`
`activating hepatic glycogenolysis.
`
`It can to a lesser
`
`extent stimulate the secretion of pancreatic insulin.
`
`Glucagon is used in the treatment of insulin—induced
`
`hypoglycemia, for example, when administration of glucose
`
`intravenously is not possible. However, as glucagon
`
`reduces the motility of the gastro—intestinal tract it is
`
`also used as a diagnostic aid in gastrointestinal
`
`radiological examinations. Glucagon has also been used in
`
`several studies to treat various painful gastrointestinal
`
`disorders associated with spasm. Daniel, et al.
`
`(Br. Med.
`
`J., 3:720, 1974) reported quicker symptomatic relief of
`
`acute diverticulitis in patients treated with glucagon
`
`compared with those who had been treated with analgesics or
`
`antispasmodics.
`
`A review by Glauser, et al.
`
`(J, Am. C911,
`
`Emergency Physns, 8:228, 1979) described relief of acute
`
`esophageal food obstruction following glucagon therapy.
`
`In
`
`SD-1 1 2400.5
`
`SANOFI-AVENTIS Exhibit 1003 - Page 5
`IPR for Patent No. 8,951 ,962
`
`

`
`'11:,“ififi;i§:'?f!'ii}?‘E33533
`
`
`
`
`§mfi$fifl§'
`
`ES
`.‘=‘E
`
`Ft:
`:52:
`
`242/040
`
`another study, glucagon significantly relieved pain and
`
`tenderness in 21 patients with biliary tract disease
`
`compared with 22 patients treated with placebo (M.J.
`
`Stower, et al., Br. J. Surg., 69:59l—2, 1982).
`
`Methods for regulating gastrointestinal motility using
`
`amylin agonists are described in commonly owned
`
`International Application No. PCT/US94/10225, published
`
`March 16, 1995.
`
`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 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
`
`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, 60/055,404 filed August 7, 1997, 60/065,442 filed
`
`November 14, 1997 and 60/066,029 filed November 14, 1997.
`
`Novel exendin agonist compounds are described in
`
`commonly owned PCT Application Serial No. PCT/US98/16387
`
`filed August 6, 1998, entitled “Novel Exendin Agonist
`
`Compounds,” which claims the benefit of U.S. Patent
`
`Application Serial No. 60/055,404, filed August 8, 1997.
`
`Other novel exendin agonists are described in commonly
`
`30
`
`owned PCT Application Serial No. PCT/US98/24210, filed
`
`November 13, 1998, entitled “Novel Exendin Agonist
`
`SD-1124005
`
`SANOFI-AVENTIS Exhibit 1003 - Page 6
`IPR for Patent No. 8,951 ,962
`
`

`
`W.in
`
`"ii-'5'iii?!’
`
`Eififfififififii
`
`5"":
`
`‘E
`=s
`
`in‘?5.3:?
`
`ig
`-w
`
`242/040
`
`Compounds," which claims the benefit of U.S. Provisional
`
`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,
`
`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—l” and
`
`in U.S. Provisional Patent Application Serial No.
`
`60/116,380, filed January 14, 1998, entitled “Novel Exendin
`
`Agonist Formulations and Methods of Administration
`
`—- LII Thereof”.
`
`Obesity, excess adipose tissue,
`
`is becoming
`
`increasingly prevalent in developed societies.
`
`For
`
`example, approximately 30% of adults in the U.S. were
`
`estimated to be 20 percent above desirable body weight --
`
`an accepted measure of obesity sufficient to impact a
`
`health risk (Harrison's Principles of Internal Medicine
`
`12th Edition, MCGraw Hill, Inc.
`
`(1991) p. 411).
`
`The
`
`pathogenesis of obesity is believed to be multifactorial
`
`but the basic problem is that in obese subjects food intake
`
`and energy expenditure do not come into balance until there
`
`is excess adipose tissue. Attempts to reduce food intake,
`
`or hypernutrition, are usually fruitless in the medium term
`
`because the weight loss induced by dieting results in both
`
`increased appetite and decreased energy expenditure (Leibel
`
`g;_g1.,
`
`(1995) New England Jburnal of Medicine 322: 621-
`
`628).
`
`The intensity of physical exercise required to
`
`SD-l 124005
`
`SANOFI-AVENTIS Exhibit 1003 - Page 7
`IPR for Patent No. 8,951 ,962
`
`

`
`242/040
`
`expend enough energy to materially lose adipose mass is too
`
`great for most people to undertake on a sufficiently
`
`frequent basis. Thus, obesity
`
`currently a poorly
`
`treatable, chronic, essentially intractable metabolic
`
`5 disorder. Not only is obesity itself believed by some to
`
`be undesirable for cosmetic reasons, but obesity also
`
`carries serious risk of co-morbidities including, Type 2
`
`diabetes, increased cardiac risk, hypertension,
`
`atherosclerosis/ degenerative arthritis, and increased
`
`10
`
`incidence of complications of surgery involving general
`
`anesthesia. Obesity due to hypernutrition is also a risk
`
`factor for the group of conditions called insulin
`
`resistance syndrome, or "syndrome X. 11
`
`In syndrome X,
`
`has been reported that there is a linkage between insulin
`
`15
`
`:;i
`
`resistance and hypertension.
`(Watson N. and Sandler M.,
`Curr. Med. Res. Opin., 12(6) :374-378 (1991); Kodama J. et
`al. 1 Diabetes Care, 13(11) :1109-1111 (1990); Lithell et
`al. 1 J. Cardiovasc. Pharmacol. 1 15 Suppl. 5:846-852
`
`(1990)) .
`
`20
`
`In those few subjects who do succeed in losing weight,
`
`by about 10 percent of body weight, there can be striking
`
`improvements in co-morbid conditions, most especially Type
`
`2 diabetes in which dieting and weight loss are the primary
`
`therapeutic modality, albeit relatively ineffective in many
`25 patients for the reasons stated above. Reducing food
`
`intake in obese subjects would decrease'the plasma glucose
`
`levelr the plasma lipid level, and the cardiac risk in
`
`these subjects. Hypernutrition is also the result of, and
`
`the psychological cause of, many eating disorders.
`
`30 Reducing food intake would also be beneficial in the
`
`treatment of such disorders. Thus, it can be appreciated
`
`SD-112400.5
`
`8
`
`SANOFI-AVENTIS Exhibit 1003 - Page 8
`
`IPR for Patent No. 8,951,962
`
`

`
`242/040
`
`that an effective means to reduce food intake is a major
`
`challenge and a superior method of treatment would be of
`
`great utility.
`
`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 (fiee, Francis et al.,
`
`International Journal of Hematology, 68:1—18, 1998)
`
`problems with PEGylation in most cases is substantial
`
`reduction in bioactivity.
`
`;g.
`
`In addition, most methods
`
`involve use of linkers that have several types of adverse
`
`effects including immunogenicity,
`
`instability,
`
`toxicity,
`
`and reactivity. Lg.
`
`Modified exendins and exendin agonists and related
`
`formulations, dosage formulations, and methods that solve
`
`these problems and that are useful in the delivery of
`
`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. Applicants 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.
`
`SD-I 12400.5
`
`SANOFI-AVENTIS Exhibit 1003 - Page 9
`IPR for Patent No. 8,951 ,962
`
`

`
`242/040
`
`SUMARY 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 polyethylene glycol polymers
`
`(or other molecular weight increasing agents), and related
`
`products and methods that are useful, for example,
`
`in the
`
`treatment of diabetes,
`
`including Type I and II diabetes,
`
`in
`
`the treatment of disorders which would be benefited by
`
`agents which modulate plasma glucose levels, and in the
`
`treatment of disorders which would be benefited by the
`
`administration of agents useful in modulating the rate of
`
`gastric emptying or food intake,
`
`including obesity, eating
`
`disorders, and insulin—resistance syndrome.
`
`The methods
`
`are also useful for lowering plasma lipid levels,
`
`reducing
`
`cardiac risk, reducing the appetite, and reducing the
`
`weight of subjects. Pharmaceutical compositions for use in
`
`the methods of the invention are also disclosed.
`
`The present
`
`invention is related to the surprising
`
`observation 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,
`
`including GLP-l with which
`
`exendin shares many potentially therapeutic actions.
`
`Related to this observation, it appears that exendin
`
`persists in the plasma as an intact bioactive molecule,
`
`in
`
`contrast to GLP—l, for example,
`
`that is rapidly cleaved
`
`into smaller biologically inactive peptides. The presence
`
`of a molecule in the plasma can be usefully prolonged by
`
`reducing its rate of filtration at the kidney, only if
`
`kidney filtration is a major mode of elimination of the
`
`molecule, and this can only be expected to be effective if
`
`SD-1124005
`
`10
`
`ifilflfifi
`
`5%.
`izé
`
`; 2 E.
`='=-*2
`
`=5
`.=
`33.3
`
`SANOFI-AVENTIS Exhibit 1003 - Page 10
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`

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`242/040
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`the non-filtered moiety is also biologically active. While
`
`PEGylation has been used to increase molecular size and
`reduce glomerular (kidney) filtration, it is not obvious
`
`that such chemical modification will necessarily produce a
`5 pharmacokinetic benefit. It is the surprising result,
`atypical of similar proteins, that exendin is not degraded
`proteolytically, and is eliminated almost entirely by
`
`glomerular filtration, that supports the detarmination that
`PEGylation or other modification of exendin or exendin
`agonists to increase molecular size, will have
`pharmaceutical benefit.
`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 agents) .
`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 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 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 90% greater),
`the modified exendin or exendin agonist has a
`immunogenicity/antigenicity that is less than the
`immunogenicity/antigenicity of the exendin or exendin
`
`10
`
`15
`
`20
`
`25
`
`30
`
`SD-112400.5
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`11
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`

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`242/040
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`agonist 1
`
`the modified exendin or exendin agonist has a
`
`solubility that
`
`greater than the solubility of the
`
`exendin or exendin agonist (preferably about 10% 1 50% or
`
`90% greater) , the modified exendin or exendin agonist has a
`
`5 proteolys
`
`rate that is
`
`than the proteolysis rate of
`
`the exendin or exendin agonist (preferably about 10%r 50%
`
`or 90% less) 1
`
`the modified exendin or exendin agonist has a
`
`toxicity that is less than the toxicity of the exendin or
`
`exendin agonist, the modified exendin or exendin agonist
`
`10
`
`has a stability that is greater than the stability of the
`
`exendin or exendin agonist, and the modified exendin or
`
`exendin agonist has a permeability/biological function that
`
`is greater or less than the permeability/biological
`
`function of the exendin or exendin agonist (preferably
`
`15
`
`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
`
`molecular weight increasing agents) . The polyethylene
`
`glycol polymers (or other molecular weight increasing
`
`20
`
`agents) may preferably have molecular weights between 500
`
`and 20 1 000.
`
`In a preferred embodiment/ the modified
`
`exendin or exendin agonist is one of compounds 201-217 1
`
`more preferably one of compounds 209 1 210 and 213 1 or one
`
`of compounds 201 and 202 1 or one of compounds 216 and 217
`
`25
`
`(See Example 4 below) .
`
`The polyethylene glycol polymers (or other molecular
`
`weight increasing agents) are preferably linked to an
`
`amino 1 carboxyl 1 or thio group, and may be linked by N or C
`
`termini of side chains of lysiner aspartic acid, glutamic
`
`30
`
`acid, or cysteine, or alternatively, the polyethylene
`
`glycol polymers (or other molecular weight increasing
`
`SD-112400.5
`
`12
`
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`

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`242/040
`
`agents) may be linked with diamine and 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
`
`5
`
`lysine amino acid of the exendin or exendin agonist.
`
`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 (or other
`
`molecular weight increasing agents) to an exendin or
`
`10
`
`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
`
`15
`
`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
`
`20
`
`by reducing food intake, obesity, an eating disorder,
`
`insulin-resistance syndrome, diabetes mellitus, and a
`
`hyperglycemic condition.
`
`In a preferred embodiment, the
`
`post-prandial hyperglycemia is a consequence of Type 2
`
`diabetes mellitus.
`
`In other preferred embodiments, the
`
`25
`
`post-prandial 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
`
`30
`
`acceptable carrier.
`
`SD-112400.5
`
`13
`
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`242/040
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`The invention also provides a kit. The kit contains a
`
`modified exendin or exendin agonist and instructions and/or
`packaging for use.
`
`The present invention also provides a method of
`5 beneficially regulating gastrointestinal motility in a
`subject. The method involves administering to the subject
`a therapeutically effective amount of a modified exendin or
`exendin agonist.of the present invention.
`
`10
`
`Also featured is a method of treatment for ingestion
`of a toxin. The method involves:
`(a) administering an
`amount of a modified exendin or exendin agonist of the
`present invention effective to prevent or reduce the
`passage of stomach contents to the intestines; and (b)
`
`15
`
`aspirating the contents of the stomach.
`invention also provides a method for reducing the
`appetite or weight, or lowering plasma lipids, of a subject.
`The method involves administering to the subject a
`therapeutically effect'ive amount of a modified exendin or
`exendin agonist of the present invention.
`Modified exendins and exendin agonists are useful as
`inhibitors of gastric emptying for the treatment of, for
`example, diabetes mellitus and obesity. 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 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
`30 gastric emptying. These methods will be useful in the
`treatment of, for example, post-prandial hyperglycemia, a
`
`20
`
`25
`
`SD-112400.5
`
`14
`
`SANOFI-AVENTIS Exhibit 1003 - Page 14
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`
`

`
`complication associated with type 1 (insulin dependent) and
`
`type 2 (non-insulin dependent) diabetes mellitus.
`By "exendin agonist" is meant a compound which mimics
`
`242/040
`
`'
`
`'
`
`SD-112400.5
`
`15
`
`the effects of exendins, e.g., on gastric motility and
`5 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.,
`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 Application
`Serial No. 90/003,869, entitled, "Use of Exendin And Agonists
`Thereof For The Reduction of Foof Intake", filed January 7 1
`1998, (and the priority 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 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
`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
`29Pro-human-amylin.
`The use of amylin agonists to treat post-prandial
`hyperglycemia, as well as to beneficially regulate
`gastrointestinal motility, is described in International
`30 Application No. PCT/US94/10225, published March 16, 1995
`which has been incorporated by reference herein.
`
`10
`
`15
`
`20
`
`25
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`SANOFI-AVENTIS Exhibit 1003 - Page 15
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`

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`242/040
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`In yet another aspect, a therapeutically effective
`
`amount of an insulin or insulin analog is also
`
`administered, separately or together with a modified
`
`exendin or exendin agonist,
`
`to the subject.
`
`5
`
`Preferably,
`
`the subject is a vertebrate, more preferably
`
`a mammal, and most preferably a human.
`
`In preferred aspects,
`
`the modified exendin or exendin agonist of the invention is
`
`administered parenterally, more preferably by injection.
`
`In
`
`a most preferred aspect,
`
`the injection is a peripheral
`
`10
`
`injection. Preferably, about 1 pg—3O pg to about 5 mg of the
`
`modified exendin or exendin agonist of the invention is
`
`22
`
`administered per day. More preferably, about 1-30 pg to
`
`about 2mg, or about 1-30 pg to about 1mg of the modified
`
`exendin or exendin agonist of the invention is administered
`
`15
`
`per day. Most preferably, about 3 pg to about 500 pg of the
`
`gr
`
`modified exendin Or exendin agonist of the invention is
`
`administered per day.
`
` exendin—4 (1-30)
`
`Preferred exendins or exendin agonists for modification
`
`and use include:
`
`[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 Val Arg
`
`25
`
`Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly—NHfl;
`
`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-NHfl;
`
`“Leu,25Phe exendin-4 amide [SEQ ID NO 7; His Gly Glu Gly
`
`30
`
`Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val
`
`SD-1 12400.5
`
`SANOFI-AVENTIS Exhibit 1003 - Page 16
`IPR for Patent No. 8,951,962
`
`

`
`.
`
`:-.
`
`;.?
`
`
`
`‘
`
`;
`
`5=.')
`
`:i—..
`
`gé
`EE
`
`242/O40
`
`Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser Ser Gly
`
`Ala Pro Pro Pro Ser-NH2];
`
`“Leu,“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 Glu Glu
`
`5 Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn—NH2]; and
`
`“Leu