throbber
USOO8129343B2
`
`(12) United States Patent
`Lau et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,129,343 B2
`Mar. 6, 2012
`
`(54) ACYLATED GLP-1 COMPOUNDS
`(75) Inventors: Jesper Lau, Farum (DK); Paw Bloch,
`Taastrup (DK); Thomas Kruse Hansen,
`Herlev (DK)
`(73) Assignee: Novo Nordisk A/S, Bagsvaerd (DK)
`(*) Notice:
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 682 days.
`11/908,834
`
`(21) Appl. No.:
`
`Mar. 20, 2006
`PCT/EP2006/060855
`
`(22) PCT Filed:
`(86). PCT No.:
`S371 (c)(1),
`Sep. 17, 2008
`(2), (4) Date:
`(87) PCT Pub. No.: WO2006/097537
`PCT Pub. Date: Sep. 21, 2006
`
`(65)
`
`Prior Publication Data
`US 2009/O156478 A1
`Jun. 18, 2009
`
`Related U.S. Application Data
`(60) Provisional application No. 60/664,497, filed on Mar.
`23, 2005.
`Foreign Application Priority Data
`
`(30)
`
`Mar. 18, 2005 (EP) ..................................... 05102171
`(51) Int. Cl.
`(2006.01)
`A6 IK38/26
`(2006.01)
`A6IP3/10
`(2006.01)
`A6IP 7/2
`(2006.01)
`C07K I4/605
`(52) U.S. Cl. ...................................................... S14/117
`(58) Field of Classification Search ........................ None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`5,545,618 A
`8/1996 Buckley et al.
`6,268,343 B1* 7/2001 Knudsen et al. ............... 514/4.8
`6,528,486 B1* 3/2003 Larsen et al. .................. 514f6.8
`2007/02O3058 A1* 8, 2007 Lau et al.
`
`EP
`EP
`RU
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`FOREIGN PATENT DOCUMENTS
`05102171
`3, 2005
`1704165
`9, 2006
`2006 107600
`10/2007
`WO91f11457
`8, 1991
`WO96,29342
`9, 1996
`WO9629342
`9, 1996
`WO 98.08871
`3, 1998
`WO98O8871
`3, 1998
`WO99.43708
`9, 1999
`WO994.3708
`9, 1999
`WOOO34331
`6, 2000
`WOOOf 69911
`11, 2000
`WOOO699.11
`11, 2000
`
`WOOO,34331
`WO
`WOO2,46227
`WO
`WOO246227
`WO
`WO O2/O98446
`WO
`WO 03/040309
`WO
`WO WO 2004/065621
`WO WO 2004/099246
`WO WO 2005/O14049
`WO
`WO2005O14049
`WO WO 2005/027978
`WO
`WO2O05O27978
`WO WO 2006/097537
`
`6, 2002
`6, 2002
`6, 2002
`12/2002
`5, 2003
`8, 2004
`11, 2004
`2, 2005
`2, 2005
`3, 2005
`3, 2005
`9, 2006
`
`OTHER PUBLICATIONS
`Simonovsky et al. Poly(ether urethane)s incorporating long alkyl
`side-chains with terminal carboxy groups as fatty acid mimics: Syn
`thesis, structural characterization and protein adsorption. Journal of
`Biomaterials Science, Polymer Edition, 2005, vol. 16, No. 12, pp.
`1463-1483.
`Green, Brian D., Biological Chemistry (2004), vol. 385, No. 2, pp.
`169-177.
`Knudsen, L.B. et al., Journal of Medicinal Chemistry, vol. 43, pp.
`1664-1669 (2000).
`Knudsen, L.B. et al., Journal of Medicinal Chemistry, vol. 47, pp.
`4128-4134 (2004).
`Deacon, C.F. et al., Diabetologia, vol. 41, pp. 271-278 (1998).
`Greenwald RB, “Peg Drugs: An Overview.” Journal of Controlled
`Release, 2001, vol. 74, p. 159-171.
`Ji et al., “Stearyl Poly(Ethylene Oxide) Grafted Surfaces for Prefer
`ential Adsorption of Albmnin.” Biomaterials, 2001, vol. 22, p. 3015
`3O23.
`Kurtzhals, P. et al., “Albumin Binding of Insulins Acylated With Fatty
`Acids: Characterization of the Ligand-Protein Interaction and Cor
`relation Between Binding Affinity and Timing of the Insulin Effect in
`Vivo.” Biochem J, 1995, vol. 312, p. 725-731.
`Simonovsky et al., “Poly(Etherurethane)s Incorporating Long Alkyl
`Side-Chains With Terminal Carboxyl Groups as Fatty Acid Mimics:
`Synthesis, Structural Characterization and Protein Adsorption.” J
`Biomat Sei Polymer EDN, 2005, vol. 16, p. 1463-1483.
`Soltero et al., “The Oral Delivery of Protein and Peptide Drugs.”
`Innovations in Pharmaceutical Technology, 2001, vol. 1, No. 9, p.
`106-110.
`Still JG, “Development of Oral Insulin: Progress and Curent Status.”
`Diabetes/Metab Res Rev, 2002, vol. 18, Suppl 1, p. S29-S37.
`Veronese FM, "Peptide and Protein Pegylation: A Review of Prob
`lems and Solutions.” Biomaterials, 2001, vol. 22, p. 405-417.
`Watanabe et al., “Structure-Activity Relationships of Glucagon-Like
`Peptide-1 (7-36) Amide: Insulinotropic Activities in Perfused Rat
`Pancreases, and Receptor Binding and Cyclic Amp Production in
`RINm.5F Cells,” Journal of Endocrinology, 1994, vol. 140, p. 45-52.
`* cited by examiner
`
`Primary Examiner — Marcela M Cordero Garcia
`(74) Attorney, Agent, or Firm — Richard W. Bork
`
`(57)
`ABSTRACT
`Protracted GLP-1 compounds and therapeutic uses thereof.
`
`6 Claims, No Drawings
`
`MPI EXHIBIT 1068 PAGE 1
`
`MPI EXHIBIT 1068 PAGE 1
`
`MPI EXHIBIT 1068 PAGE 1
`
`MPI EXHIBIT 1068 PAGE 1
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1068, p. 1 of 70
`
`

`

`1.
`ACYLATED GLP-1 COMPOUNDS
`
`US 8,129,343 B2
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a 35 U.S.C. S371 national stage appli
`cation of International Patent Application PCT/EP2006/
`060855 (published as WO 2006/097537), filed Mar. 20, 2006,
`which claimed priority of European Patent Application
`05102171.5, filed Mar. 18, 2005; this application further
`claims priority under 35 U.S.C. S 119 of U.S. Provisional
`Application 60/664,497, filed Mar. 23, 2005.
`
`FIELD OF THE INVENTION
`
`This invention relates to the field of therapeutic peptides,
`i.e. to new protracted GLP-1 compounds.
`
`BACKGROUND OF THE INVENTION
`
`10
`
`15
`
`25
`
`30
`
`35
`
`A range of different approaches have been used for modi
`fying the structure of glucagon-like peptide 1 (GLP-1) com
`pounds in order to provide a longer duration of action in vivo.
`WO 96/29342 discloses peptide hormone derivatives
`wherein the parent peptide hormone has been modified by
`introducing a lipophilic Substituent in the C-terminal amino
`acid residue or in the N-terminal amino acid residue.
`WO98/08871 discloses GLP-1 derivatives wherein at least
`one amino acid residue of the parent peptide has a lipophilic
`substituent attached.
`WO 99/43708 discloses GLP-1 (7-35) and GLP-1 (7-36)
`derivatives which have a lipophilic substituent attached to the
`C-terminal amino acid residue.
`WO 00/34331 discloses acylated GLP-1 analogs.
`WO 00/699.11 discloses activated insulinotropic peptides
`to be injected into patients where they are Supposed to react
`with blood components to form conjugates and thereby
`alledgedly providing longer duration of action in vivo.
`WO 02/46227 discloses GLP-1 and exendin-4 analogs
`fused to human serum albumin in order to extend in vivo
`half-life.
`Many diabetes patients particularly in the type 2 diabetes
`segment are subject to so-called “needle-phobia’, i.e. a Sub
`stantial fear of injecting themselves. In the type 2 diabetes
`segment most patients are treated with oral hypoglycaemic
`agents, and since GLP-1 compounds are expected to be the
`first injectable product these patients will be administered, the
`fear of injections may become a serious obstacle for the
`widespread use of the clinically very promising GLP-1 com
`pounds. Thus, there is a need to develop new GLP-1 com
`50
`pounds which can be administered less than once daily, e.g.
`once every second or third day preferably once weekly, while
`retaining an acceptable clinical profile.
`
`40
`
`45
`
`SUMMARY OF THE INVENTION
`
`55
`
`The invention provides a GLP-1 analog having a modifi
`cation of at least one non-proteogenic amino acid residue in
`positions 7 and/or 8 relative to the sequence GLP-1 (7-37)
`(SEQID No 1), which is acylated with a moiety to the lysine
`residue in position 26, and where said moiety comprises at
`least two acidic groups, wherein one acidic group is attached
`terminally.
`The present invention also provides pharmaceutical com
`positions comprising a compound according to the present
`65
`invention and the use of compounds according to the present
`invention for preparing medicaments for treating disease.
`
`60
`
`2
`The invention provides a method for increasing the time of
`action in a patient of a GLP-1 analog, characterised in acy
`lating said GLP-1 analog with a moiety B U" as disclosed in
`any of the preceding claims, on the lysine residue in position
`26 of said GLP-1 analog.
`
`DESCRIPTION OF THE INVENTION
`
`In the present specification, the following terms have the
`indicated meaning:
`The term “polypeptide' and "peptide' as used herein
`means a compound composed of at least five constituent
`amino acids connected by peptide bonds. The constituent
`amino acids may be from the group of the amino acids
`encoded by the genetic code and they may be natural amino
`acids which are not encoded by the genetic code, as well as
`synthetic amino acids. Natural amino acids which are not
`encoded by the genetic code are e.g., Y-carboxyglutamate,
`ornithine, phosphoserine, D-alanine and D-glutamine. Syn
`thetic amino acids comprise amino acids manufactured by
`chemical synthesis, i.e. D-isomers of the amino acids
`encoded by the genetic code such as D-alanine and D-leucine,
`Aib (CL-aminoisobutyric acid), Abu (CL-aminobutyric acid),
`Tle (tert-butylglycine), B-alanine, 3-aminomethyl benzoic
`acid, anthranilic acid.
`The 22 proteogenic amino acids are:
`Alanine, Arginine, Asparagine, Aspartic acid, Cysteine,
`Cystine, Glutamine, Glutamic acid, Glycine. Histidine,
`Hydroxyproline, Isoleucine, Leucine, Lysine, Methionine,
`Phenylalanine, Proline, Serine. Threonine, Tryptophan,
`Tyrosine, Valine.
`Thus a non-proteogenic amino acid is a moiety which can
`be incorporated into a peptide via peptide bonds but is not a
`proteogenic amino acid. Examples are y-carboxyglutamate,
`ornithine, phosphoserine, the D-amino acids such as D-ala
`nine and D-glutamine, Synthetic non-proteogenic amino
`acids comprise amino acids manufactured by chemical Syn
`thesis, i.e. D-isomers of the amino acids encoded by the
`genetic code such as D-alanine and D-leucine, Aib (CL-ami
`noisobutyric acid), Abu (CL-aminobutyric acid), Tle (tert-bu
`tylglycine), 3-aminomethyl benzoic acid, anthranilic acid,
`des-amino-Histidine, the beta analogs of amino acids such as
`B-alanine etc. D-histidine, desamino-histidine, 2-amino-his
`tidine, B-hydroxy-histidine, homohistidine, N-acetyl-histi
`dine, C-fluoromethyl-histidine, C.-methyl-histidine, 3-py
`ridylalanine,
`2-pyridylalanine
`or
`4-pyridylalanine,
`(1-aminocyclopropyl) carboxylic acid, (1-aminocyclobutyl)
`carboxylic acid, (1-aminocyclopentyl) carboxylic acid,
`(1-aminocyclohexyl) carboxylic acid, (1-aminocycloheptyl)
`carboxylic acid, or (1-aminocyclooctyl) carboxylic acid;
`The term “analogue' as used herein referring to a polypep
`tide means a modified peptide wherein one or more amino
`acid residues of the peptide have been substituted by other
`amino acid residues and/or wherein one or more amino acid
`residues have been deleted from the peptide and/or wherein
`one or more amino acid residues have been deleted from the
`peptide and or wherein one or more amino acid residues have
`been added to the peptide. Such addition or deletion of amino
`acid residues can take place at the N-terminal of the peptide
`and/or at the C-terminal of the peptide. A simple system is
`often used to describe analogues: For example Arg'IGLP
`1 (7-37)Lys designates a GLP-1 (7-37) analogue wherein the
`naturally occurring lysine at position 34 has been Substituted
`with arginine and wherein a lysine has been added to the
`terminal amino acid residue, i.e. to the Gly. Allamino acids
`for which the optical isomer is not stated is to be understood
`to mean the L-isomer. In embodiments of the invention a
`
`MPI EXHIBIT 1068 PAGE 2
`
`MPI EXHIBIT 1068 PAGE 2
`
`MPI EXHIBIT 1068 PAGE 2
`
`MPI EXHIBIT 1068 PAGE 2
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1068, p. 2 of 70
`
`

`

`US 8,129,343 B2
`
`10
`
`15
`
`30
`
`35
`
`25
`
`3
`maximum of 17 amino acids have been modified. In embodi
`ments of the invention a maximum of 15 amino acids have
`been modified. In embodiments of the invention a maximum
`of 10amino acids have been modified. In embodiments of the
`invention a maximum of 8amino acids have been modified. In
`embodiments of the invention a maximum of 7 amino acids
`have been modified. In embodiments of the invention a maxi
`mum of 6 amino acids have been modified. In embodiments
`of the invention a maximum of 5 amino acids have been
`modified. In embodiments of the invention a maximum of 4
`amino acids have been modified. In embodiments of the
`invention a maximum of 3 amino acids have been modified. In
`embodiments of the invention a maximum of 2 amino acids
`have been modified. In embodiments of the invention 1 amino
`acid has been modified.
`The term "derivative' as used herein in relation to a peptide
`means a chemically modified peptide oran analogue thereof,
`wherein at least one Substituent is not present in the unmodi
`fied peptide or an analogue thereof, i.e. a peptide which has
`been covalently modified. Typical modifications are amides,
`carbohydrates, alkyl groups, acyl groups, esters and the like.
`An example of a derivative of GLP-1 (7-37) is N'-((4S)-4-
`(hexadecanoylamino)-carboxy-butanoyl)|Arg,
`Lys?
`GLP-1-(7-37).
`The term “GLP-1 peptide' as used herein means GLP-1 (7-
`37) (SEQID No 1), a GLP-1 (7-37) analogue, a GLP-1 (7-37)
`derivative or a derivative of a GLP-1 (7-37) analogue. In one
`embodiment the GLP-1 peptide is an insulinotropic agent.
`The term “insulinotropic agent” as used herein means a
`compound which is an agonist of the human GLP-1 receptor,
`i.e. a compound which stimulates the formation of cAMP in
`a suitable medium containing the human GLP-1 receptor (one
`Such medium disclosed below). The potency of an insulino
`tropic agent is determined by calculating the ECso value from
`the dose-response curve as described below.
`Baby hamster kidney (BHK) cells expressing the cloned
`human GLP-1 receptor (BHK-467-12A) were grown in
`DMEM media with the addition of 100 IU/mL penicillin, 100
`ug/mL Streptomycin, 5% fetal calf serum and 0.5 mg/mL
`Geneticin G-418 (Life Technologies). The cells were washed
`twice in phosphate buffered saline and harvested with
`Versene. Plasma membranes were prepared from the cells by
`homogenisation with an Ultraturrax in buffer 1 (20 mM
`HEPES-Na, 10 mM EDTA, pH 7.4). The homogenate was
`centrifuged at 48,000xg for 15 min at 4°C. The pellet was
`45
`suspended by homogenization in buffer 2 (20 mM HEPES
`Na, 0.1 mM EDTA, pH 7.4), then centrifuged at 48,000xg for
`15 min at 4°C. The washing procedure was repeated one
`more time. The final pellet was suspended in buffer 2 and used
`immediately for assays or stored at -80° C.
`The functional receptor assay was carried out by measur
`ing cyclic AMP (cAMP) as a response to stimulation by the
`insulinotropic agent. cAMP formed was quantified by the
`AlphaScreenTM cAMP Kit (Perkin Elmer Life Sciences).
`Incubations were carried out in half-area 96-well microtiter
`plates in a total volume of 50 uL buffer 3 (50 mM Tris-HCl, 5
`mM HEPES, 10 mM MgCl, pH 7.4) and with the following
`addiditions: 1 mM ATP, 1 uM GTP, 0.5 mM 3-isobutyl-1-
`methylxanthine (IBMX), 0.01% Tween-20, 0.1% BSA, 6 ug
`membrane preparation, 15 ug/mL acceptor beads, 20 g/mL
`60
`donor beads preincubated with 6 nM biotinyl-cAMP. Com
`pounds to be tested for agonist activity were dissolved and
`diluted in buffer 3. GTP was freshly prepared for each experi
`ment. The plate was incubated in the dark with slow agitation
`for three hours at room temperature followed by counting in
`65
`the FusionTM instrument (PerkinElmer Life Sciences). Con
`centration-response curves were plotted for the individual
`
`40
`
`50
`
`55
`
`4
`compounds and ECso values estimated using a four-param
`eter logistic model with Prism v. 4.0 (GraphPad, Carlsbad,
`Calif.).
`The term “DPP-IV protected” as used herein referring to a
`polypeptide means a polypeptide which has been chemically
`modified in order to render said compound resistant to the
`plasma peptidase dipeptidyl aminopeptidase-4 (DPP-IV).
`The DPP-IV enzyme in plasma is known to be involved in the
`degradation of several peptide hormones, e.g. GLP-1, GLP-2,
`Exendin-4 etc. Thus, a considerable effort is being made to
`develop analogues and derivatives of the polypeptides Sus
`ceptible to DPP-IV mediated hydrolysis in order to reduce the
`rate of degradation by DPP-IV. In one embodiment a DPP-IV
`protected peptide is more resistant to DPP-IV than GLP-1 (7-
`37) or Exendin-4(1-39).
`Resistance of a peptide to degradation by dipeptidyl ami
`nopeptidase IV is determined by the following degradation
`assay:
`Aliquots of the peptide (5 nmol) are incubated at 37° C.
`with 1 uL of purified dipeptidyl aminopeptidase IV corre
`sponding to an enzymatic activity of 5 mU for 10-180 minutes
`in 100 uL of 0.1 M triethylamine-HCl buffer, pH 7.4. Enzy
`matic reactions are terminated by the addition of 5 uL of 10%
`trifluoroacetic acid, and the peptide degradation products are
`separated and quantified using HPLC analysis. One method
`for performing this analysis is: The mixtures are applied onto
`aVydac C18 widepore (30 nm pores, 5um particles) 250x4.6
`mm column and eluted at a flow rate of 1 ml/min with linear
`stepwise gradients of acetonitrile in 0.1% trifluoroacetic acid
`(0% acetonitrile for 3 min, 0-24% acetonitrile for 17 min,
`24-48% acetonitrile for 1 min) according to Siegel et al.,
`Regul. Pept. 1999; 79:93-102 and Mentlein et al. Eur. J.
`Biochem. 1993: 214:829-35. Peptides and their degradation
`products may be monitored by their absorbance at 220 nm
`(peptide bonds) or 280 nm (aromatic amino acids), and are
`quantified by integration of their peak areas related to those of
`standards. The rate of hydrolysis of a peptide by dipeptidyl
`aminopeptidase IV is estimated at incubation times which
`result in less than 10% of the peptide being hydrolysed.
`The term "Ce-alkyl as used herein means a Saturated,
`branched, straight or cyclic hydrocarbon group having from 1
`to 6 carbon atoms. Representative examples include, but are
`not limited to, methyl, ethyl, n-propyl, isopropyl, butyl,
`isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl,
`tert-pentyl, n-hexyl, isohexyl, cyclohexane and the like.
`The term “pharmaceutically acceptable' as used herein
`means Suited for normal pharmaceutical applications, i.e.
`giving rise to no adverse events in patients etc.
`The term “excipient as used herein means the chemical
`compounds which are normally added to pharmaceutical
`compositions, e.g. buffers, tonicity agents, preservatives and
`the like.
`The term “effective amount’ as used herein means a dosage
`which is sufficient to be effective for the treatment of the
`patient compared with no treatment.
`The term “pharmaceutical composition” as used herein
`means a product comprising an active compound or a salt
`thereof together with pharmaceutical excipients such as
`buffer, preservative, and optionally a tonicity modifier and/or
`a stabilizer. Thus a pharmaceutical composition is also known
`in the art as a pharmaceutical formulation.
`The term “treatment of a disease' as used herein means the
`management and care of a patient having developed the dis
`ease, condition or disorder. The purpose of treatment is to
`combat the disease, condition or disorder. Treatment includes
`the administration of the active compounds to eliminate or
`
`MPI EXHIBIT 1068 PAGE 3
`
`MPI EXHIBIT 1068 PAGE 3
`
`MPI EXHIBIT 1068 PAGE 3
`
`MPI EXHIBIT 1068 PAGE 3
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1068, p. 3 of 70
`
`

`

`US 8,129,343 B2
`
`6
`
`5
`control the disease, condition or disorder as well as to allevi-
`ate the symptoms or complications associated with the dis
`ease, condition or disorder.
`In another aspect the present invention relates to an acy- 5
`lated GLP-1 analogue that can bind to albuminand the GLP-1
`receptor simultaneously.
`In another aspect the present invention relates to an acy-
`HC CH
`lated GLP-1 analogue that bind to the GLP-1 receptor with an
`affinity below 100 nM, preferable below 30 nM in the pres- 10 means the HN-His-Aib-N-terminal of the GLP-1 analogue.
`ence of 2% albumin.
`In an embodiment the invention provides a GLP-1 analog
`In another aspect the present invention relates to an acy-
`acylated with a lipophilic albumin binding moiety containing
`lated GLP-1 analogue which affinity to the GLP-1 receptor is
`at least two free acidic chemical groups attached via a non
`only partly decreased when comparing the affinity in the
`natural amino acid linker to the lysine residue in position 26.
`presence of very low concentration (e.g. 0.005% to 0.2%) of
`In an embodiment, the term free acidic chemical groups is
`human albumin to the affinity in the presence of 2% human
`to be understood as having the same meaning as "acidic
`albumin. The shift in binding affinity under these conditions
`groups' as used herein.
`is less than 50 fold, preferable below 30 fold and more pref-
`In an embodiment the invention provides an acylated
`erable below 10 fold.
`GLP-1 analog where said GLP-1 analog is stabilised against
`DPP-IV by modification of at least one amino acid residue in
`The term “albumin binding moiety” as used herein means
`positions 7 and 8 relative to the sequence GLP-1 (7-37) (SEQ
`a residue which binds non-covalently to human serum albu
`ID No 1), and where said acylation is a diacid attached to the
`min. The albumin binding residue attached to the therapeutic
`lysine residue in position 26 optionally via a non natural
`polypeptide typically has an affinity below 10 uM to human
`amino acid hydrophilic linker.
`serum albumin and preferably below 1 uM. A range of albu- ?
`In an embodiment of the invention a GLP-1 analog having
`min binding residues are known among linear and branched
`a modification of at least one non-proteogenic amino acid
`lipohophillic moieties containing 4-40 carbonatoms having a
`residue in positions 7 and/or 8 relative to the sequence GLP
`distal acidic group.
`1(7-37) (SEQID No 1), which is acylated with a moiety to the
`The term “hydrophilic linker as used herein means a 30
`lysine residue in position 26, and where said moiety com
`spacer that separates a peptide and an albumin binding resi
`prises at least two acidic groups, wherein one acidic group is
`due with a chemical moiety which comprises at least 5 non
`attached terminally.
`hydrogen atoms where 30-50% of these are either N or O.
`An embodiment provides a GLP-1 analog according to the
`above embodiment, wherein the moiety attached in position
`The term "acidic groups' as used herein means organic
`chemical groups which are fully or partly negatively charged 35 26 comprises a hydrophilic linker.
`at physiological pH. The pKa value of such groups is below 7.
`An embodiment provides a GLP-1 analog according to the
`preferable below 5. This includes but is not limited to car-
`above embodiments, wherein the hydrophilic linker com
`boxylic acids, Sulphonic acids, phosphoric acids or heterocy-
`prises at least 5 non-hydrogen atoms where 30-50% of these
`clic ring systems which are fully or partly negatively charged
`are either N or O.
`at physiological pH.
`An embodiment provides a GLP-1 analog according to any
`of the above embodiments, wherein the moiety attached in
`In the below structural formula II the moiety U is a di
`position 26 comprises an albumin binding moiety separated
`radical may be attached to the terminal groups B and the
`from the peptide by the hydrophilic linker.
`aminogroup of the lysine amino acid in the peptide in two
`An embodiment provides a GLP-1 analog according to the
`different ways. In embodiments of the invention the U in 45
`above embodiment, wherein the albumin binding moiety is a
`formula II is attached with the group Battached at the end of
`linear or branched lipophilic moiety containing 4-40 carbon
`the alkyl chain and the peptide at the other end.
`atoms having a distal acidic group.
`An embodiment provides a GLP-1 analog according to any
`In the formulas below the terminal bonds from the attached
`groups are to be regarded as attachment bonds and not ending
`of the above embodiments, wherein the acylated moiety is
`in methylene groups unless stated.
`B U", where U is selected from
`
`In the formulas below
`
`O
`
`H
`NH-H-N
`
`O
`
`OH
`
`O
`
`N- in
`
`H
`
`H
`
`MPI EXHIBIT 1068 PAGE 4
`
`MPI EXHIBIT 1068 PAGE 4
`
`MPI EXHIBIT 1068 PAGE 4
`
`MPI EXHIBIT 1068 PAGE 4
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1068, p. 4 of 70
`
`

`

`US 8,129,343 B2
`
`-continued
`
`OH
`
`OH
`
`O
`
`O
`
`N
`
`N
`
`N-1-1-9
`
`N
`H
`
`H
`
`N-1N-N- p
`
`O
`
`H
`
`1Ns
`MV
`O O
`
`MPI EXHIBIT 1068 PAGE 5
`
`MPI EXHIBIT 1068 PAGE 5
`
`MPI EXHIBIT 1068 PAGE 5
`
`MPI EXHIBIT 1068 PAGE 5
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1068, p. 5 of 70
`
`

`

`US 8,129,343 B2
`
`9
`
`HO
`
`H
`HO-N
`
`10
`
`d
`
`8.
`
`O
`
`O
`
`O
`
`O
`
`H
`N
`
`o
`
`O
`
`HO
`
`O
`
`HO
`
`10
`N-formyl-histidine, C-fluoromethyl-histidine, C.-methyl
`m is 0, 1, 2, 3, 4, 5, or 6,
`histidine, 3-pyridylalanine, 2-pyridylalanine or 4-pyridylala
`n is 1, 2 or 3
`nine
`s is 0, 1, 2, or 3,
`Xaas is Ala, Gly, Val, Leu, Ile, Thr, Ser, Lys, Aib, (1-aminocy
`t is 0, 1, 2, 3, or 4
`p is 1,2,3,4,5,6,7,8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 5 clopropyl) carboxylic acid, (1-aminocyclobutyl) carboxylic
`19, 20, 21, 22, or 23;
`acid, (1-aminocyclopentyl) carboxylic acid, (1-aminocyclo
`and where B is an acidic group selected from
`hexyl) carboxylic acid, (1-aminocycloheptyl) carboxylic
`acid, or (1-aminocyclooctyl) carboxylic acid;
`Xaa is Val or Leu:
`Xaas is Ser, Lys or Arg;
`Xaao is Tyr or Gln;
`Xaao is Leu or Met;
`15 Xaa- is Gly, Glu or Aib;
`Xaa- is Gln, Glu, Lys or Arg;
`Xaas is Ala or Val;
`Xaa, is Glu or Leu:
`Xaao is Ala, Glu or Arg;
`2O Xaa- is Val or Lys;
`Xaa34 is Lys. Glu, ASnor Arg:
`Xaas is Gly or Aib;
`
`where 1 is 12, 13, 14, 15, 16, 17, 18, 19 or 20;
`An embodiment provides a GLP-1 analog according to any
`of the above embodiments, which is a compound of formula
`I (SEQID No. 2):
`
`Xaa-7-Xaa8-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Xaa16-Ser-Xaa18-Xaa19-Xaa20-Glu-Xaa22
`
`Formula I
`
`Xs usu-sur-issurplexexuxa 5-Xaa36-Xaa37-Xaa38
`
`H
`
`B-U-NH
`
`Xaa- is Arg, Gly or Lys, or is absent;
`wherein
`Xaa, is L-histidine, imidazopropionyl, c-hydroxy-histidine, 6s Xaa37 is Gly, Ala, Glu, Pro, Lys, or is absent:
`D-histidine, desamino-histidine, 2-amino-histidine, B-hy-
`and B and U" together is the acylated moiety, where U is
`droxy-histidine,
`homohistidine,
`N-acetyl-histidine,
`selected from
`
`MPI EXHIBIT 1068 PAGE 6
`
`MPI EXHIBIT 1068 PAGE 6
`
`MPI EXHIBIT 1068 PAGE 6
`
`MPI EXHIBIT 1068 PAGE 6
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1068, p. 6 of 70
`
`

`

`US 8,129,343 B2
`
`12
`
`A™
`
`11
`
`0.
`
`OH
`
`oO
`
`oO
`HOY||
`“So
`

`
`oO
`
`oO
`
`oO
`
`AL
`
`oO
`VNON , WONOR
`H
`
`HN
`
`I
`
`oO
`
`0.
`
`OH
`
`Ny
`
`0.
`
`OH
`
`NY N\A AAA
`
`H
`
`A
`oO
`
`oO
`
`ol)
`
`NTN } NONOON™
`
`H
`
`H
`
`\/
`
`7
`
`oO
`
`oO
`
`&
`
`HAIAH
`HteeeyH
`me oO
`6
`
`oO
`
`oO
`
`oO
`
`oO
`
`0
`
`oO
`0
`\
`
`Sy
`
`COOH
`
`Sy
`
`oO
`
`OH
`
`~
`
`N
`
`COOH
`
`Oo
`
`H
`
`oO
`
`oO
`
`O
`
`0
`
`COOH
`
`HSyetet
`- Rtyy5
`D.
`TOpyN

`onhak
`
`,
`
`O
`
`6
`
`4
`
`i
`
`OT,
`
`MPI EXHIBIT 1068 PAGE 7
`
`MPI EXHIBIT 1068 PAGE 7
`
`MPI EXHIBIT 1068 PAGE 7
`
`MPI EXHIBIT 1068 PAGE 7
`
`MPI EXHIBIT 1068 PAGE 7
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1068, p. 7 of 70
`
`

`

`US 8,129,343 B2
`
`13
`
`14
`acetyl-histidine, C-fluoromethyl-histidine, C.-methyl-histi
`m is 0, 1, 2, 3, 4, 5, or 6,
`dine, 3-pyridylalanine, 2-pyridylalanine or 4-pyridylalanine;
`n is 1, 2 or 3
`s is 0, 1, 2, or 3,
`Xaas is Ala, Gly, Val, Leu, Ile, Lys, Aib, (1-aminocyclopro
`t is 0, 1, 2, 3, or 4
`p is 1,2,3,4,5,6,7,8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 5 pyl) carboxylic acid, (1-aminocyclobutyl) carboxylic acid,
`19, 20, 21, 22, or 23;
`(1-aminocyclopentyl) carboxylic acid, (1-aminocyclohexyl)
`and where B is an acidic group selected from
`carboxylic acid, (1-aminocycloheptyl) carboxylic acid, or
`(1-aminocyclooctyl) carboxylic acid;
`
`HO
`
`HO
`
`s
`
`N
`
`HO
`
`and
`
`10
`
`O
`
`O
`
`O
`
`O
`
`H
`
`St.
`O
`O
`
`O
`
`O HO
`
`where 1 is 12, 13, 14, 15, 16, 17, 18, 19 or 20,
`In an embodiment the invention provides a compound
`which is a compound of formula II (SEQID No. 3):
`
`2O
`
`Xaa is Val or Leu;
`Xaas is Ser, Lys or Arg:
`Xaa, is Tyr or Gln;
`Xaao is Leu or Met;
`Xaa- is Gly, Glu or Aib;
`Xaa is Gln, Glu, Lys or Arg;
`Xaas is Ala or Val;
`Xaa, is Glu or Leu:
`
`Xaa-7-Xaa8-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Xaa16-Ser-Xaa18-Xaa19-Xaa20-Glu-Xaa22
`
`Formula II
`
`Xs usu-sur-issurplexexuxa 5-Xaa36-Xaa37-Xaa38
`
`H
`
`i-st O
`
`Xaao is Ala, Glu or Arg;
`The formula II is identical to formula I as stated in an
`embodiment above, where the moiety B. U is replaced by 60 Xaass is Val or Lys,
`B U". The difference being only the incorporation of the
`Xaa- is Lys, Glu, ASnor Arg;
`carboxy group in the U' relative to U, which is without the
`Xaas is Gly or Aib;
`attaching carboxy group.
`Xaa- is Arg, Gly or Lys, or is absent;
`Informula II each of the Xaas has the following meaning:
`Xaas, is Gly, Ala, Glu, Pro, Lys, or is absent;
`Xaa, is L-histidine, D-histidine, desamino-histidine,
`Xaass is Lys, Ser, amide or is absent;
`2-amino-histidine, B-hydroxy-histidine, homohistidine, N'-
`and where U is a spacer selected from
`
`MPI EXHIBIT 1068 PAGE 8
`
`MPI EXHIBIT 1068 PAGE 8
`
`MPI EXHIBIT 1068 PAGE 8
`
`MPI EXHIBIT 1068 PAGE 8
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1068, p. 8 of 70
`
`

`

`15
`
`O
`
`O
`
`O
`
`OH
`
`O
`
`N-
`
`O
`
`N-
`
`O
`
`OH
`
`Q O O
`\/
`N1
`
`US 8,129,343 B2
`
`16
`
`O
`
`H
`
`N-1-1-9 S -n-n-n-n
`
`H
`
`N-1-(N-N-N 1.-1.
`
`H
`
`/\,
`
`O
`
`O
`N-1N1\-1
`
`iii.
`
`O
`
`S 1n-N-1-1-
`H
`
`where n is 12, 13, 14, 15, 16, 17 or 18
`
`and where B is an acidic group selected from
`
`1 is 12, 13, 14, 15, 16, 17 or 18,
`
`m is 0, 1, 2, 3, 4, 5, or 6,
`
`s is 0, 1, 2, or 3,
`
`p is 3, 4, 5, 6, 7,8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,
`20, 21, 22, or 23;
`
`30
`
`35
`
`and
`HO
`1.
`Y HO Y
`O
`O
`
`In the embodiments below when referring to U" in formula
`I it is to be understood as also referring to formula II and U.
`with the only difference being the carboxy group.
`An embodiment provides a GLP-1 analog according to the
`embodiments above, wherein U" is selected from
`
`O
`
`O
`
`HOS so
`YN
`
`O
`N-1\o1N1
`
`O
`
`O
`
`O
`
`N
`
`N-1 no-1N1
`
`O
`
`1N1'N-1-
`
`HO
`
`O
`
`N 1n-N-1- pi
`
`O
`
`O
`
`MPI EXHIBIT 1068 PAGE 9
`
`MPI EXHIBIT 1068 PAGE 9
`
`MPI EXHIBIT 1068 PAGE 9
`
`MPI EXHIBIT 1068 PAGE 9
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1068, p. 9 of 70
`
`

`

`17
`
`O
`
`OH
`
`US 8,129,343 B2
`
`-continued
`
`O
`
`18
`
`YN
`
`O
`N-1N1\-1
`
`O
`
`OH
`
`N
`H
`
`O. O
`\/
`N- iii.
`
`O
`
`O
`
`O
`
`H
`N
`O
`N-1--6\- p
`
`O
`N-1 no-1S-1
`
`S 1n-N-1 no
`H
`
`pi
`
`s
`
`O
`
`H
`N
`1Ns
`/\
`O O
`
`O
`
`iii.
`
`O
`
`pi
`
`O
`
`1n-'N-1-
`H
`
`s
`
`O
`
`O O
`V/
`S
`
`H
`N
`
`N- N-> N-1--6\- S
`
`O
`
`O
`
`O
`
`O
`
`O
`
`N
`
`r
`
`COOH
`
`N
`
`OH
`
`O
`n
`
`N
`
`COOH
`
`O
`
`m is 2, 3, 4 or 5,
`
`n is 1 or 2
`S is 0, 1, or 2,
`
`H
`
`O
`
`s
`
`N ~ ----
`
`O
`
`S
`
`~ O N-1N
`
`COOH
`
`O
`
`S
`
`t is 0, 1, 2, or 3
`p is 1, 2, 3, 4, 7, 11 or 23
`An embodiment provides a GLP-1 analog according to the
`embodiments above, wherein B U' is
`
`45
`
`O
`
`Ho S.
`
`loos-
`
`N
`
`O
`N-1 no-1N1
`
`N 1-'N-1-~-
`
`O
`
`loos---
`
`H
`
`N-1-1-9 S ~~~~
`
`O
`
`MPI EXHIBIT 1068 PAGE 10
`
`MPI EXHIBIT 1068 PAGE 10
`
`MPI EXHIBIT 1068 PAGE 10
`
`MPI EXHIBIT 1068 PAGE 10
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1068, p. 10 of 70
`
`

`

`19
`
`O
`
`OH
`
`O
`
`loos-
`
`N
`
`O
`
`OH
`
`O
`
`loos-
`
`N
`H
`
`HOOC
`
`Ns
`MV
`O O
`
`3
`
`HOOC
`
`O O O
`VW
`-S
`N
`
`US 8,129,343 B2
`
`-continued
`
`O
`
`20
`
`N- -) O
`s
`S 1- N-1 no r
`O
`
`O
`
`O
`N-1s-ha- p
`
`O
`
`H
`N-1N1S-19
`O
`
`O
`
`O
`S 1- N-1\o
`
`O
`
`O
`
`O
`
`iii.
`
`iii.
`
`O
`
`9
`
`HOOC
`
`O
`p
`
`O O
`\/
`H N
`N1 >1. N1-a-ha
`H
`O ---,
`
`O
`
`O
`
`O
`
`O
`O
`
`loos--- N
`
`COOH
`
`O
`
`O
`
`O
`
`O
`
`OH
`
`O
`
`O
`
`O
`
`H
`N
`
`O
`
`?
`O HO
`O
`
`N
`
`N-1N1-1
`
`O
`
`O
`S 1N1 N-1\o
`H
`
`O
`
`O
`
`O
`
`O
`
`MPI EXHIBIT 1068 PAGE 11
`
`MPI EXHIBIT 1068 PAGE 11
`
`MPI EXHIBIT 1068 PAGE 11
`
`MPI EXHIBIT 1068 PAGE 11
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1068, p. 11 of 70
`
`

`

`21
`where 1 is 14, 15, 16, 17, 18, 19 or 20;
`p is 1, 2, 3, 4, 7, 8, 9, 10, 11 or 12.
`s is 0, 1 or 2
`t is 0 or 1:
`
`US 8,129,343 B2
`
`22
`An embodiment according to the above wherein
`where 1 is 14, 15, 16, 17 or 18
`p is 1, 2, 3, 4 or 11,
`s is 0, 1 or 2;
`t is 0 or 1:
`An embodiment provides a GLP-1 analog according to the
`embodiment above, wherein B U" is
`
`5
`
`O
`
`Hos
`
`so
`
`O
`
`H
`N
`
`N-1 no-1-1
`
`O
`
`O
`
`HOOC
`
`N-
`
`S 1N1'N-1N pi
`
`H
`
`O
`
`1N-1'N-1 no
`
`O
`
`H
`
`O
`
`O
`
`O
`
`O
`
`H
`N
`
`N-1 no-1N1
`
`O
`
`HOOC
`
`---,
`s
`
`O
`
`O
`O
`
`loos---
`N
`
`H
`NN-1N1-19
`O
`
`O
`
`O
`S 1- N-1\o pi
`
`O
`
`HO
`
`O
`
`H
`N
`
`O
`
`O
`
`u).
`N-1 no1N1
`s N 1N1 N-1\o
`
`O
`O
`
`H
`
`O
`
`O os N
`O
`N-
`
`HOOC
`
`OH
`
`p
`O
`
`OH
`
`O
`
`O
`
`H
`N
`
`N-n-hn
`
`O
`
`O
`
`OH
`
`O
`
`HOOC
`
`O
`
`N-
`O ---,
`
`()
`
`OH
`
`O
`
`HOOC Y& Sai YO N
`
`COOH
`
`O
`
`H
`
`O
`
`()
`
`s
`
`O
`
`MPI EXHIBIT 1068 PAGE 12
`
`MPI EXHIBIT 1068 PAGE 12
`
`MPI EXHIBIT 1068 PAGE 12
`
`MPI EXHIBIT 1068 PAGE 12
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1068, p. 12 of 70
`
`

`

`US 8,129,343 B2
`
`23
`where 1 is 14, 15, 16, 17,

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