(12) United States Patent
`Knudsen et al.
`
`USOO6458924B2
`US 6,458,924 B2
`(10) Patent No.:
`*Oct. 1, 2002
`(45) Date of Patent:
`
`(54) DERIVATIVES OF GLP-1ANALOGS
`(75) Inventors: Liselotte Bjerre Knudsen, Valby (DK);
`Per Olaf Huusfeldt, Kobenhavn K
`(DK); Per Franklin Nielsen, Vaerløse
`(DK)
`(73) Assignee: Novo Nordisk A/S, Bagsvaerd (DK)
`Subject to any disclaimer, the term of this
`(*) Notice:
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`This patent is Subject to a terminal dis
`claimer.
`
`(21) Appl. No.: 09/398,111
`(22) Filed:
`Sep. 16, 1999
`Related U.S. Application Data
`(63) Continuation-in-part of application No. 09/265,141, filed on
`Mar. 8, 1999, now Pat. No. 6,384,016, and a continuation
`in-part of application No. 09/258,750, filed on Feb. 26,
`1999, now Pat. No. 6,268,343, which is a continuation-in
`part of application No. 09/038,432, filed on Mar. 11, 1998,
`now abandoned, which is a continuation-in-part of applica
`tion No. 08/918,810, filed as application No. PCT/DK97/
`00340 on Aug. 22, 1997, now abandoned.
`(60) Provisional application No. 60/035,904, filed on Jan. 24,
`1997, provisional application No. 60/036,226, filed on Jan.
`25, 1997, provisional application No. 60/036,255, filed on
`Jan. 24, 1997, provisional application No. 60/078,422, filed
`on Mar. 18, 1998, provisional application No. 60/082,478,
`filed on Apr. 21, 1998, provisional application No. 60/082,
`479, filed on Apr. 21, 1998, provisional application No.
`60/082,480, filed on Apr. 21, 1998, provisional application
`No. 60/082,802, filed on Apr. 23, 1998, and provisional
`application No. 60/084,357, filed on May 5, 1998.
`Foreign Application Priority Data
`(30)
`Aug. 30, 1996
`(DK) .............................................. O931/96
`Nov. 8, 1996 (DK) ......
`... 1259/96
`Dec. 20, 1996
`(DK)......
`... 1470/96
`Feb. 27, 1998
`(DK)......
`... 0263/98
`Feb. 27, 1998
`(DK)......
`... 0264/98
`Feb. 27, 1998
`(DK)......
`... 0268/98
`Feb. 27, 1998
`(DK)......
`... 0272/98
`Feb. 27, 1998 (DK).
`... 0274/98
`Mar. 13, 1998 (EP).
`986 10006
`Apr. 8, 1998 (DK) ...
`... 0508/98
`Apr. 8, 1998 (DK) .............................................. 0509/98
`Apr. 8, 1998 (DK) ........................................ 1998 OOSO7
`
`(51) Int. Cl." ......................... A61K 38/16; A61K 38/26
`(52) U.S. Cl. ........................... 530/324; 530/345; 514/2;
`514/12
`(58) Field of Search ....................... 514/2, 12; 530/324,
`530/345
`
`(56)
`
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`Broderick, Diabetologia (1995) vol. 38, No. Suppl. 1, pp.
`A171. Meeting Info.: 31st Annual Meeting of the European
`Association for the Study of Diabetes Stockholm, Sweden
`Sep. 12–16, 1995.*
`M. Gutniak et al., Antidiabetogenic Effect of Glucagon-Like
`Peptide (7-36) Amide in Normal Subjects and Patients with
`Diabetes with Diabetes Mellitus.
`M. Navarro et al., Changes in Food Intake Induced by
`GLP-1(7–36) Amide In the Rat, Abstracts of the 15'
`International Diabetes Federation Congress, Nov. 6-11,
`1194 Kobe, poster presentation 11A5PP1295 Issued 1994.
`R. Schick et al., “Glucagon-like peptide 1-a novel brain
`peptide Involved in feeding regulation 'Obesity in Europe
`1993, Chapter 53, pp. 363-367.
`P.D. Lambert et al., “A Role for GLP-1(7–36)NH in the
`Central Control Of Feeding Behavior” Digestion 1994; vol.
`54. pp. 360–361.
`B. Wilms et al., “Gastric Emptying, Glucose Responses,
`and Insulin Secretion after a Liquid Test Meal:Effects of
`Exogenous Glucagon-Like Peptide-1 (GLP-1) (7–36)
`Amide in Type 2 (Noninsulin-Dependent) Diabetic
`Patients” Journal of Clinical Endocrinology and Metabolism
`vol. 8 No. 1 (1996) pp. 327–332.
`(List continued on next page.)
`Primary Examiner-Christopher S. F. Low
`ASSistant Examiner David Lukton
`(74) Attorney, Agent, or Firm-Reza Green, Esq.; Richard
`Bork, Esq.
`ABSTRACT
`(57)
`The present invention relates to a pharmaceutical composi
`tion comprising a GLP-1 derivative having a lipophilic
`Substituent; and a Surfactant.
`
`20 Claims, 1 Drawing Sheet
`
`MPI EXHIBIT 1073 PAGE 1
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1073, p. 1 of 129
`
`

`

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`Page 2
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`entero-insular Axis' Diabetologia vol. 35:pp. 701-711
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`physiologic regulator of food intake in human Gastroen
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`obesity:cause or con-Sequence” Gur vol. 38: pp. 916-919
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`Marx J. “Obesity gene discover may help solve weighty
`problem” news). Science, (Dec. 2, 1994) 266 (5190) pp.
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`its human Homologue”. Nature, (Dec. 1, 1994) 372 (6505)
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`Rink T.J., “In search of a satiety factor”. Nature, (Dec. 1,
`1994) 372 (6505) pp. 406-407.
`Woods et al., “Signals that regulate food intake and energy
`Homeostasis”. Science, 280:1378–1383, May 29, 1998.
`Thorens T. “Glucagon-like peptide-1 and control of insulin
`secretion”. Diabete & Metabolisme (Paris). 1995, 21, pp.
`311-318.
`Henriksen et al. Peptide amidation by chemical protein
`engineering A combination of encymic and photochemical
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`Wang et al. “Glucagon-like peptide-1 is a physiological
`incretin in rat”. J. Clin. Invest., (Jan 1995) (1) 417-21.
`Bell et al. “Exon duplication and divergence in the human
`Preproglucagon gene”. Nature, (Jul. 28-Aug. 3, 1983).
`Wettergren et
`al. “Truncated GLP-1 (proglucagon
`78-107-amide) inhibits gastric and pancreatic functions in
`man”. Digest. Dis. Sci., (Apr. 1993) 38 (4) 665–73.
`Suzuki et al. “Comparison of the effects of various C-ter
`minal and N-terminal fragment peptides of glucagons-like
`peptide-1 on insulin and glucagons release from the isolat
`edcx perfused rat pancreas”. Endocrinology, (Dec. 1989)
`125(6) 3109–14.
`
`Navarro et al., Journal of Neurochemistry, vol. 67, No. 5, pp.
`1982–1991 (Nov. 1996).
`Turton et al., Nature, vol. 379, pp. 69–72 (Jan. 4, 1996).
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`Clodfelter et al., (1998) Pharmaceutical Res. 15(2):254-262.
`W.B. Gratzer et al., “Relation Between Conformation and
`Association State'. The Journal of Biological Chemistry,
`244, No. 24, Dec. 25, 1969, pp. 6675–6679.
`Sasaki et al., "X-Ray Analysis of Glucagon and Its Rela
`tionship to Receptor Binding”, Nature Vo. 257, Oct. 30,
`1975, pp. 751–757.
`Wagman et al., “Proton NMR Studies Of The Association
`And Folding of Glucagon In Solution’, Elsevier/North-Hol
`land Biomedical Press, vol. 119, No. 2, Oct. 1980, pp.
`265-27O.
`Epand et al., “Molecular Interactions. In The Model Lipo
`protein Complex Formed Between Glucagon and Dimyris
`toylglycerophosphocholine”, Biochemistry vol. 16, No. 20,
`1977.
`Schneider et al., “Polypeptide Hormone Interaction” (Glu
`cagon Binding To LySolecithin), The Journal of Biological
`Chemistry, Vo. 247, No. 16, Aug. 25, 1972, pp. 4986-4991.
`Schneider et al., “Polypeptide Hormone Interaction” (Con
`formational Changes of Glucagon Bound To LySolecithin),
`The Journal of Biological Chemistry, Vo. 247, No. 16, Aug.
`25, 1972, pp. 4992-4995.
`Robinson et al., “Lipid-Induced Conformational Changes in
`Glucagon, Secretin, and Vasoactive Intestinal Peptide',
`Biopolymers, vol. 21, 1982, pp. 1217-1228.
`Hamed et al., “Bahavior of Amphipathic Helices on Analysis
`Via Matrix Methods, With Application to Glucagon, Secre
`tin, and Vasoactive Intestinal Peptide', Biopolymers, vol.
`22, 1983, pp. 1003-1021.
`Wu et al., “Helical Conformation of Glucagon in Surfactant
`Solutions”, Americal Chemical Society, 1980, pp.
`2117-2122.
`Bösch et al., “Physicochemical Characterization of Glu
`cagon-Containing Lipid Micelles' Biochimic et Biophysica
`Acta, 603 (1980) pp. 298–312.
`Thornton et al., Structure of Glucagon-Like Peptide(7–36)
`Amide in a Dodecylphosphocholine Micelle as Determined
`by 2D NMR, Biochemistry 1994, 33, pp. 3532-3539.
`* cited by examiner
`
`MPI EXHIBIT 1073 PAGE 2
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1073, p. 2 of 129
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`

`

`U.S. Patent
`
`Oct. 1, 2002
`
`US 6,458,924 B2
`
`
`
`O. 1
`
`1
`
`1 O
`
`1 OO
`
`1 OOO
`
`(peptide? (u M)
`
`FIG. 1
`
`MPI EXHIBIT 1073 PAGE 3
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`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1073, p. 3 of 129
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`

`

`1
`DERVATIVES OF GLP-1. ANALOGS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`This application is a continuation-in-part of Ser. No.
`09/265,141 filed Mar. 8, 1999 now U.S. Pat. No. 6,384,016
`and of Ser. No. 09/258,750 filed Feb. 26, 1999 now U.S. Pat.
`No. 6,268,343 which is a continuation-in-part of Ser. No.
`09/038,432 filed Mar. 11, 1998 now abandoned which is a
`continuation-in-part of Ser. No. 08/918,810 filed Aug. 26,
`1997 now abandoned, which is a 371 and of PCT application
`Ser. No. PCT/DK97/00340 filed Aug. 22, 1997, and claims
`priority of U.S. provisional application Ser. Nos. 60/035,
`904, 60/036,226, 60/036,255, 60/078,422, 60/082,478,
`60/082,479, 60/082,480, 60/082,802, and 60/084.357 filed
`Jan. 24, 1997, Jan. 25, 1997, Jan. 24, 1997, Mar. 18, 1998,
`Apr. 21, 1998, Apr. 21, 1998, Apr. 21, 1998, Apr. 23, 1998,
`and May 5, 1998, respectively, and of Danish application
`serial nos. 0931/96, 1259/96, 1470/96, 0263/98, 0264/98,
`0268/98, 0272/98, 0274/98,0507/98, 0508/98, and 0509/98
`filed Aug. 30, 1996, Nov. 8, 1996, Dec. 20, 1996, Feb. 27,
`1998, Feb. 27, 1998, Feb. 27, 1998, Feb. 27, 1998, Feb. 27,
`1998, Apr. 8, 1998, Apr. 8, 1998 and Apr. 8, 1998,
`respectively, and of European application no. 98.610006.3
`filed Mar. 13, 1998, the contents of each of which is fully
`incorporated herein by reference.
`FIELD OF THE INVENTION
`The present invention relates to novel derivatives of
`human glucagon-like peptide-1 (GLP-1) and fragments and/
`or analogues thereof which have a protracted profile of
`action and to methods of making and using them.
`BACKGROUND OF THE INVENTION
`Peptides are widely used in medical practice, and Since
`they can be produced by recombinant DNA technology it
`can be expected that their importance will increase also in
`the years to come. When native peptides or analogues
`thereof are used in therapy it is generally found that they
`have a high clearance. A high clearance of a therapeutic
`agent is inconvenient in cases where it is desired to maintain
`a high blood level thereof over a prolonged period of time
`Since repeated administrations will then be necessary.
`Examples of peptides which have a high clearance are:
`ACTH, corticotropin-releasing factor, angiotensin,
`calcitonin, insulin, glucagon, glucagon-like peptide-1,
`glucagon-like peptide-2, insulin-like growth factor-1,
`insulin-like growth factor-2, gastric inhibitory peptide,
`growth hormone-releasing factor, pituitary adenylate
`cyclase activating peptide, Secretin, enterogastrin,
`Somatostatin, Somatotropin, Somatomedin, parathyroid
`hormone, thrombopoietin, erythropoietin, hypothalamic
`releasing factors, prolactin, thyroid Stimulating hormones,
`endorphins, enkephalins, vasopressin, oxytocin, opiods and
`analogues thereof, Superoxide dismutase, interferon,
`asparaginase, arginase, arginine deaminase, adenosine
`deaminase and ribonuclease. In Some cases it is possible to
`influence the release profile of peptides by applying Suitable
`pharmaceutical compositions, but this approach has various
`Shortcomings and is not generally applicable.
`The hormones regulating insulin Secretion belong to the
`So-called enteroinsular axis, designating a group of
`hormones, released from the gastrointestinal mucosa in
`response to the presence and absorption of nutrients in the
`gut, which promote an early and potentiated release of
`insulin. The enhancing effect on insulin Secretion, the
`
`5
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`15
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`35
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`40
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`US 6,458,924 B2
`
`2
`So-called incretin effect, is probably essential for a normal
`glucose tolerance. Many of the gastrointestinal hormones,
`including gastrin and Secretin (cholecystokinin is not insuli
`notropic in man), are insulinotropic, but the only physiologi
`cally important ones, those that are responsible for the
`incretin effect, are the glucose-dependent insulinotropic
`polypeptide, GIP, and glucagon-like peptide-1 (GLP-1).
`Because of its insulinotropic effect, GIP, isolated in 1973 (1)
`immediately attracted considerable interest among diabe
`tologists. However, numerous investigations carried out
`during the following years clearly indicated that a defective
`secretion of GIP was not involved in the pathogenesis of
`insulin dependent diabetes mellitus (IDDM) or non insulin
`dependent diabetes mellitus (NIDDM) (2). Furthermore, as
`an insulinotropic hormone, GIP was found to be almost
`ineffective in NIDDM (2). The other incretin hormone,
`GLP-1 is the most potent insulinotropic Substance known
`(3). Unlike GIP, it is surprisingly effective in stimulating
`insulin secretion in NIDDM patients. In addition, and in
`contrast to the other insulinotropic hormones (perhaps with
`the exception of Secretin) it also potently inhibits glucagon
`Secretion. Because of these actions it has pronounced blood
`glucose lowering effects particularly in patients with
`NIDDM.
`GLP-1, a product of the proglucagon (4), is one of the
`youngest members of the secretin-VIP family of peptides,
`but is already established as an important gut hormone with
`regulatory function in glucose metabolism and gastrointes
`tinal Secretion and metabolism (5). The glucagon gene is
`processed differently in the pancreas and in the intestine. In
`the pancreas (9), the processing leads to the formation and
`parallel Secretion of 1) glucagon itself, occupying positions
`33-61 of proglucagon (PG); 2) an N-terminal peptide of 30
`amino acids (PG (1-30)) often called glicentin-related pan
`creatic peptide, GRPP (10,11); 3) a hexapeptide correspond
`ing to PG (64–69); 4) and, finally, the so-called major
`proglucagon fragment (PG (72-158)), in which the two
`glucagon-like sequences are buried (9). Glucagon seems to
`be the only biologically active product. In contrast, in the
`intestinal mucosa, it is glucagon that is buried in a larger
`molecule, while the two glucagon-like peptides are formed
`Separately (8). The following products are formed and
`Secreted in parallel: 1) glicentin, corresponding to PG
`(1-69), with the glucagon Sequence occupying residues Nos.
`33–61 (12); 2) GLP-1(7–36)amide (PG (78-107))amide
`(13), not as originally believed PG (72-107)amide or 108,
`which is inactive). Small amounts of C-terminally glycine
`extended but equally bioactive GLP-1(7–37), (PG (78–108))
`are also formed (14); 3) intervening peptide-2 (PG
`(111-122)amide) (15); and 4) GLP-2 (PG (126–158)) (15,
`16). A fraction of glicentin is cleaved further into GRPP (PG
`(1–30)) and oxyntomodulin (PG (33–69)) (17, 18). Of these
`peptides, GLP-1, has the most conspicuous biological activi
`ties.
`Being Secreted in parallel with glicentin/enteroglucagon,
`it follows that the many Studies of enteroglucagon Secretion
`(6, 7) to some extent also apply to GLP-1 secretion, but
`GLP-1 is metabolised more quickly with a plasma half-life
`in humans of 2 min (19). Carbohydrate or fat-rich meals
`Stimulate Secretion (20), presumably as a result of direct
`interaction of yet unabsorbed nutrients with the microVilli of
`the open-type L-cells of the gut mucosa. Endocrine or neural
`mechanisms promoting GLP-1. Secretion may exist but have
`not yet been demonstrated in humans.
`The incretin function of GLP-1(29-31) has been clearly
`illustrated in experiments with the GLP-1 receptor
`antagonist, exendin 9-39, which dramatically reduces the
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`US 6,458,924 B2
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`3
`incretin effect elicited by oral glucose in rats (21, 22). The
`hormone interacts directly with the cells via the GLP-1
`receptor (23) which belongs to the glucagon/VIP/calcitonin
`family of G-protein-coupled 7-transmembrane Spanning
`receptors. The importance of the GLP-1 receptor in regu
`lating insulin Secretion was illustrated in recent experiments
`in which a targeted disruption of the GLP-1 receptor gene
`was carried out in mice. Animals homozygous for the
`disruption had greatly deteriorated glucose tolerance and
`fasting hyperglycaemia, and even heterozygous animals
`were glucose intolerant (24). The signal transduction mecha
`nism (25) primarily involves activation of adenylate cyclase,
`but elevations of intracellular Ca" are also essential (25,
`26). The action of the hormone is best described as a
`potentiation of glucose Stimulated insulin release (25), but
`the mechanism that couples glucose and GLP-1 Stimulation
`is not known. It may involve a calcium-induced calcium
`release (26, 27). AS already mentioned, the insulinotropic
`action of GLP-1 is preserved in diabetic f-cells. The relation
`of the latter to its ability to convey "glucose competence' to
`isolated insulin-Secreting cells (26, 28), which respond
`poorly to glucose or GLP-1 alone, but fully to a combination
`of the two, is also not known. Equally importantly, however,
`the hormone also potently inhibits glucagon Secretion (29).
`The mechanism is not known, but seems to be paracrine, Via
`neighbouring insulin or Somatostatin cells (25). Also the
`glucagonostatic action is glucose-dependent, So that the
`inhibitory effect decreases as blood glucose decreases.
`Because of this dual effect, if the plasma GLP-1 concentra
`tions increase either by increased Secretion or by exogenous
`infusion the molar ratio of insulin to glucagon in the blood
`that reaches the liver via the portal circulation is greatly
`increased, whereby hepatic glucose production decreases
`(30). As a result blood glucose concentrations decrease.
`Because of the glucose dependency of the insulinotropic and
`glucagonostatic actions, the glucose lowering effect is Self
`limiting, and the hormone, therefore, does not cause
`hypoglycaemia regardless of dose (31). The effects are
`preserved in patients with diabetes mellitus (32), in whom
`infusions of Slightly Supraphysiological doses of GLP-1 may
`completely normalise blood glucose values in Spite of poor
`metabolic control and Secondary failure to Sulphonylurea
`(33). The importance of the glucagonostatic effect is illus
`trated by the finding that GLP-1 also lowers blood glucose
`in type-i diabetic patients without residual B-cell Secretory
`capacity (34).
`In addition to its effects on the pancreatic islets, GLP-1
`has powerful actions on the gastrointestinal tract. Infused in
`physiological amounts, GLP-1 potently inhibits
`pentagastrin-induced as well as meal-induced gastric acid
`Secretion (35, 36). It also inhibits gastric emptying rate and
`pancreatic enzyme Secretion (36). Similar inhibitory effects
`on gastric and pancreatic Secretion and motility may be
`elicited in humans upon perfusion of the ileum with
`carbohydrate- or lipid-containing solutions (37, 38).
`Concomitantly, GLP-1. Secretion is greatly Stimulated, and it
`has been speculated that GLP-1 may be at least partly
`responsible for this so-called “ileal-brake' effect (38). In
`fact, recent Studies Suggest that, physiologically, the ileal
`brake effects of GLP-1 may be more important than its
`effects on the pancreatic islets. Thus, in dose response
`Studies GLP-1 influences gastric emptying rate at infusion
`rates at least as low as those required to influence islet
`secretion (39).
`GLP-1 seems to have an effect on food intake. Intraven
`tricular administration of GLP-1 profoundly inhibits food
`intake in rats (40, 42). This effect seems to be highly
`
`15
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`25
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`35
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`40
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`45
`
`50
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`4
`specific. Thus, N-terminally extended GLP-1(PG 72-107)
`amide is inactive and appropriate doses of the GLP-1
`antagonist, exendin 9-39, abolish the effects of GLP-1(41).
`Acute, peripheral administration of GLP-1 does not inhibit
`food intake acutely in rats (41, 42). However, it remains
`possible that GLP-1 secreted from the intestinal L-cells may
`also act as a Satiety signal.
`Not only the insulinotropic effects but also the effects of
`GLP-1 on the gastrointestinal tract are preserved in diabetic
`patients (43), and may help curtailing meal-induced glucose
`excursions, but, more importantly, may also influence food
`intake. Administered intravenously, continuously for one
`week, GLP-1 at 4 ng/kg/min has been demonstrated to
`dramatically improve glycaemic control in NIDDM patients
`without significant side effects (44). The peptide is fully
`active after Subcutaneous administration (45), but is rapidly
`degraded mainly due to degradation by dipeptidyl peptidase
`IV-like enzymes (46, 47).
`The amino acid Sequence of GLP-1 is given i.a. by
`Schmidt et al. (Diabetologia 28 704–707 (1985). Human
`GLP-1 is a 37 amino acid residue peptide originating from
`preproglucagon which is Synthesised, i.a. in the L-cells in
`the distal ileum, in the pancreas and in the brain. Processing
`of preproglucagon to GLP-1 (7-36)amide, GLP-1(7–37) and
`GLP-2 occurs mainly in the L-cells. Although the interesting
`pharmacological properties of GLP-1 (7-37) and analogues
`thereof have attracted much attention in recent years only
`little is known about the structure of these molecules. The
`secondary structure of GLP-1 in micelles has been described
`by Thorton et al. (Biochemistry 33 3532-3539 (1994)), but
`in normal solution, GLP-1 is considered a very flexible
`molecule. Surprisingly, we found that derivatisation of this
`relatively small and very flexible molecule resulted in com
`pounds whose plasma profile were highly protracted and Still
`had retained activity.
`GLP-1 and analogues of GLP-1 and fragments thereof are
`useful i.a. in the treatment of Type 1 and Type 2 diabetes and
`obesity.
`WO 87/06941 discloses GLP-1 fragments, including
`GLP-1 (7-37), and functional derivatives thereof and to their
`use as an insulinotropic agent.
`WO 90/11296 discloses GLP-1 fragments, including
`GLP-1 (7-36), and functional derivatives thereof which have
`an insulinotropic activity which exceeds the insulinotropic
`activity of GLP-1(1-36) or GLP-1(1-37) and to their use as
`insulinotropic agents.
`The amino acid sequence of GLP-1 (7-36) and GLP-1
`(7–37) is (SEQ ID NO: 1):
`
`9 10 11 12 13 14 15 16 17
`8
`7
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser
`
`(I)
`
`18 19 20 21 22 23 24 25 26 27 28
`Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe
`
`55
`
`29 30 31. 32 33 34 35 36
`Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-X
`wherein X is NH for GLP-1(7–36) and X is Gly for
`GLP-1(7–37).
`WO 91/11457 discloses analogues of the active GLP-1
`peptides 7-34, 7-35, 7-36, and 7-37 which can also be
`useful as GLP-1 moieties.
`EP 0708179-A2 (Eli Lilly & Co.) discloses GLP-1 ana
`logues and derivatives that include an N-terminal imidazole
`group and optionally an unbranched Co-Co acyl group in
`attached to the lysine residue in position 34.
`
`60
`
`65
`
`MPI EXHIBIT 1073 PAGE 5
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1073, p. 5 of 129
`
`

`

`US 6,458,924 B2
`
`S
`EP 06996.86-A2 (Eli Lilly & Co.) discloses certain
`N-terminal truncated fragments of GLP-1 that are reported
`to be biologically active.
`Unfortunately, the high clearance limits the usefulness of
`these compounds. Thus there still is a need for improve
`ments in this field.
`Accordingly, it is an object of the present invention to
`provide derivatives of GLP-1 and analogues thereof which
`have a protracted profile of action relative to GLP-1(7–37).
`It is a further object of the invention to provide derivatives
`of GLP-1 and analogues thereof which have a lower clear
`ance than GLP-1(7–37).
`It is a further object of the invention to provide a phar
`maceutical composition with improved Solubility and Sta
`bility.
`
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`MPI EXHIBIT 1073 PAGE 6
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`

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