(12) United States Patent
`Lau et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,536,122 B2
`*Sep. 17, 2013
`
`US008536122B2
`
`(54) ACYLATED GLP-1 COMPOUNDS
`
`(75) Inventors: Jesper Lau, Farum (DK); Florencio
`Zaragoza Doerwald, Smorum (DK);
`KN h E. (PThomas
`ruse Hansen, Herlev (DK)
`
`(73) Assignee: Novo Nordisk A/S, Bagsvaerd (DK)
`
`EP
`EP
`
`JP
`JP
`JP
`JP
`JP
`JP
`RU
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`W.
`Related U.S. Application Data
`(63) Continuation of application No. 1 1/908,834, filed as W
`application No. PCT/EP2006/060855 on Mar. 20,
`WO
`
`(*) Notice:
`
`Subject to any disclaimer, the term of this
`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.: 13/412.283
`
`(22) Filed:
`
`Mar. 5, 2012
`
`(65)
`
`Prior Publication Data
`
`US 2012/O295847 A1
`
`Nov. 22, 2012
`
`FOREIGN PATENT DOCUMENTS
`13294.58 A2
`T 2003
`051021715
`3, 2005
`2003 8. Al
`29:
`2002-504527 A
`2, 2002
`2002-508162 A
`3, 2002
`2003-505.347
`2, 2003
`2004-528O14 A
`9, 2004
`2004-535.442 A 11, 2004
`2010-116407. A
`5, 2010
`2006107600 A 10/2007
`90.11296
`10, 1990
`91.11457 A1
`8/1991
`96.29342
`9, 1996
`98.08871
`3, 1998
`98.08872 A1
`3/1998
`99.4334.1
`9, 1999
`99.43361 A1
`9, 1999
`99.43705 A1
`9, 1999
`99.43708
`9, 1999
`99.43707
`9, 1999
`0034331
`6, 2000
`OOf 69911
`11, 2000
`01/04156
`1, 2001
`O151071
`T 2001
`O258725
`1, 2002
`O2/46227 A2
`6, 2002
`02098.446 A1 12/2002
`99. 3. A1 58.
`99. A: 53.
`O3,O87139 A2 10, 2003
`
`(60) Provisional application No. 60/664,497, filed on Mar.
`23, 2005.
`
`(30)
`
`Foreign Application Priority Data
`
`Mar. 18, 2005 (EP) ..................................... 05102171
`
`(51) Int. Cl.
`A6 IK38/26
`A6 IK38/28
`A6IP3/10
`A6IP 7/2
`C07K I4/605
`C07K5/00
`C07K 700
`C07K 16/00
`C07K 17/00
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`- - - - - - - - - - - - - - - - - - - - - - - - - - - -
`
`eafs
`
`S14f7.2: 514f1 17:530/308
`USPG
`(58) Field of Classification Search
`None
`See application file for complete search history.
`
`•
`
`s
`
`(56)
`
`References Cited
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`
`(Continued)
`
`Primary Examiner — Marcela M Cordero Garcia
`(74) Attorney, Agent, or Firm — Richard W. Bork
`(57)
`ABSTRACT
`Protracted GLP-1 compounds and therapeutic uses thereof.
`16 Claims, No Drawings
`
`MPI EXHIBIT 1067 PAGE 1
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1067, p. 1 of 70
`
`

`

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`Makino et al., 2005, "Semisynthesis of Human Ghrelin: Condensa
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`Knudsen, L.B. et al., “Potent Derivatives of Glucagon-Like Peptide-1
`With Pharmacokinetic Properperties Suitable for Once Daily Admin
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`Deacon, C.F. et al., “Dipeptidyl peptidase IV resistant analogues of
`glucagon-like peptide-1 which have extended metabolic stability and
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`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, pp. 725-731.
`Soltero et al., “The Oral Delivery of Protein and Peptide Drugs.”
`Innovations in Pharmaceutical Technology, 2001, vol. 1, No. 9, pp.
`106-110.
`Watanabe et al., “Structure-Activity Relationships of Glucagon-Like
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`RINm.5F Cells,” Journal of Endocrinology, 1994, vol. 140, pp. 45-52.
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`Sep. 24, 2008.
`Ngo JT et al., “Computational Complexity, Protein Structure Predic
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`Green, Brian D. et al Biological Chemistry. Degradation, Receptor
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`Ji, J. et al. Biomaterials Stearyl Poly (Ethylene Oxide) Grafted Sur
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`
`MPI EXHIBIT 1067 PAGE 2
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1067, p. 2 of 70
`
`

`

`1.
`ACYLATED GLP-1 COMPOUNDS
`
`US 8,536,122 B2
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a Continuation of copending U.S. appli
`cation Ser. No. 1 1/908,834, filed Sep. 17, 2007, which is a 35
`U.S.C. S371 national stage application of International Patent
`Application PCT/EP2006/060855 (published as WO 2006/
`097537), filed Mar. 20, 2006, which claimed priority of Euro
`pean 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
`
`10
`
`15
`
`This invention relates to the field of therapeutic peptides,
`i.e. to new protracted GLP-1 compounds.
`
`BACKGROUND OF THE INVENTION
`
`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.
`25
`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 alleg
`edly 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
`50
`widespread use of the clinically very promising GLP-1 com
`pounds. Thus, there is a need to develop new GLP-1 com
`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.
`
`30
`
`35
`
`40
`
`45
`
`55
`
`SUMMARY OF THE INVENTION
`
`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.
`65
`The present invention also provides pharmaceutical com
`positions comprising a compound according to the present
`
`60
`
`2
`invention and the use of compounds according to the present
`invention for preparing medicaments for treating disease.
`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, Cys
`tine, Glutamine, Glutamic acid, Glycine. Histidine, Hydrox
`yproline, Isoleucine, Leucine, Lysine, Methionine, Phenyla
`lanine, 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
`
`MPI EXHIBIT 1067 PAGE 3
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1067, p. 3 of 70
`
`

`

`US 8,536,122 B2
`
`10
`
`15
`
`25
`
`3
`for which the optical isomer is not stated is to be understood
`to mean the L-isomer. In embodiments of the invention a
`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
`45
`HEPES-Na, 10 mM EDTA, pH 7.4). The homogenate was
`centrifuged at 48,000xg for 15 min at 4°C. The pellet was
`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
`additions: 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
`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
`
`4
`the FusionTM instrument (PerkinElmer Life Sciences). Con
`centration-response curves were plotted for the individual
`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
`
`30
`
`35
`
`40
`
`50
`
`55
`
`60
`
`65
`
`MPI EXHIBIT 1067 PAGE 4
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1067, p. 4 of 70
`
`

`

`US 8,536,122 B2
`
`10
`
`15
`
`25
`
`30
`
`5
`the administration of the active compounds to eliminate or
`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
`lated GLP-1 analogue that can bind to albuminand the GLP-1
`receptor simultaneously.
`In another aspect the present invention relates to an acy
`lated GLP-1 analogue that bind to the GLP-1 receptor with an
`affinity below 100 nM, preferable below 30 nM in the pres
`ence of 2% albumin.
`In another aspect the present invention relates to an acy
`lated GLP-1 analogue which affinity to the GLP-1 receptor is
`only partly decreased when comparing the affinity in the
`presence of very low concentration (e.g. 0.005% to 0.2%) of
`human albumin to the affinity in the presence of 2% human
`albumin. The shift in binding affinity under these conditions
`is less than 50 fold, preferable below 30 fold and more pref
`erable below 10 fold.
`The term “albumin binding moiety” as used herein means
`a residue which binds non-covalently to human serum albu
`min. The albumin binding residue attached to the therapeutic
`polypeptide typically has an affinity below 10 uM to human
`serum albumin and preferably below 1 uM. A range of albu
`min binding residues are known among linear and branched
`lipohophillic moieties containing 4-40 carbonatoms having a
`distal acidic group.
`The term “hydrophilic linker as used herein means a
`spacer that separates a peptide and an albumin binding resi
`due with a chemical moiety which comprises at least 5 non
`hydrogen atoms where 30-50% of these are either N or O.
`The term "acidic groups' as used herein means organic
`chemical groups which are fully or partly negatively charged
`at physiological pH. The pKa value of such groups is below 7.
`preferable below 5. This includes but is not limited to car
`boxylic acids, Sulphonic acids, phosphoric acids or heterocy
`clic ring systems which are fully or partly negatively charged
`at physiological pH.
`In the below structural formula II the moiety U is a di
`radical may be attached to the terminal groups B and the
`aminogroup of the lysine amino acid in the peptide in two
`different ways. In embodiments of the invention the U in
`formula II is attached with the group Battached at the end of
`the alkyl chain and the peptide at the other end.
`45
`In the formulas below the terminal bonds from the attached
`groups are to be regarded as attachment bonds and not ending
`in methylene groups unless stated.
`
`In the formulas below
`
`H
`NH-H-N
`
`HC CH
`
`means the HN-His-Aib-N-terminal of the GLP-1 analogue.
`In an embodiment the invention provides a GLP-1 analog
`acylated with a lipophillic albumin binding moiety contain
`ing at least two free acidic chemical groups attached via a non
`natural amino acid linker to the lysine residue in position 26.
`In an embodiment, the term free acidic chemical groups is
`to be understood as having the same meaning as "acidic
`groups' as used herein.
`In an embodiment the invention provides an acylated
`GLP-1 analog where said GLP-1 analog is stabilised against
`DPP-IV by modification of at least one amino acid residue in
`positions 7 and 8 relative to the sequence GLP-1 (7-37) (SEQ
`ID No 1), and where said acylation is a diacid attached to the
`lysine residue in position 26 optionally via a non natural
`amino acid hydrophilic linker.
`In an embodiment of the invention a GLP-1 analog having
`a modification 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 com
`prises at least two acidic groups, wherein one acidic group is
`attached terminally.
`An embodiment provides a GLP-1 analog according to the
`above embodiment, wherein the moiety attached in position
`26 comprises a hydrophilic linker.
`An embodiment provides a GLP-1 analog according to the
`above embodiments, wherein the hydrophilic linker com
`prises at least 5 non-hydrogen atoms where 30-50% of these
`are either N or O.
`An embodiment provides a GLP-1 analog according to any
`of the above embodiments, wherein the moiety attached in
`position 26 comprises an albumin binding moiety separated
`from the peptide by the hydrophilic linker.
`An embodiment provides a GLP-1 analog according to the
`above embodiment, wherein the albumin binding moiety is a
`linear or branched lipophilic moiety containing 4-40 carbon
`atoms having a distal acidic group.
`An embodiment provides a GLP-1 analog according to any
`of the above embodiments, wherein the acylated moiety is
`B U", where U is selected from
`
`35
`
`40
`
`O
`
`OH
`
`MPI EXHIBIT 1067 PAGE 5
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1067, p. 5 of 70
`
`

`

`7
`
`US 8,536,122 B2
`
`-continued
`O
`
`8
`
`NN
`
`N-1 no-1S-1
`
`O
`
`O
`
`S 1- n-4-
`
`HO
`
`O
`
`O
`
`O
`
`OH
`
`O
`
`YN
`
`N-1 no-1-n-1
`
`O
`
`O
`
`S 1- n-4-
`
`O
`
`O
`
`OH
`
`SN
`
`O
`
`O
`
`O
`
`N-no-kn- p &
`
`in
`
`1Ns
`
`s
`
`O 0)-N N -->
`
`O
`
`O
`
`N- iii. N-~~~4.
`N--------->
`O O
`V/
`r
`N---------------
`
`O
`
`O
`
`O O
`V/
`
`H
`
`NN
`
`COOH
`
`NN
`
`H
`
`H
`
`O
`
`O
`
`H
`
`O
`
`S H
`
`O
`
`O
`
`O
`
`OH
`
`O
`
`NN
`
`O
`
`COOH
`
`O
`
`COOH
`
`O
`
`N
`
`N1N
`O
`
`S
`
`O1Nuo
`
`s
`
`pi
`
`is 0, 1. 2. 3, 4. 5, O 6,
`n is 1, 2 or 3
`s is 0, 1, 2, or 3,
`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,
`19, 20, 21, 22, or 23;
`and where B is an acidic group selected from
`
`H
`"Ni- Ho-1
`
`s
`
`d
`
`8.
`
`55
`
`60
`
`as
`
`-continued
`
`t
`O
`O
`
`O
`
`HO
`
`O
`
`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):
`
`MPI EXHIBIT 1067 PAGE 6
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1067, p. 6 of 70
`
`

`

`US 8,536,122 B2
`
`10
`
`Formula I
`
`B-U-NH
`
`wherein
`Xaa, is L-histidine, imidazopropionyl, C.-hydroxy-histidine,
`D-histidine, desamino-histidine, 2-amino-histidine, B-hy
`droxy-histidine,
`homohistidine,
`N-acetyl-histidine,
`N-formyl-histidine, C-fluoromethyl-histidine, C.-methyl
`histidine, 3-pyridylalanine, 2-pyridylalanine or 4-pyridylala
`1.
`Xaas is Ala, Gly, Val, Leu, Ile, Thr, Ser, Lys, Aib, (1-aminocy
`clopropyl) carboxylic acid, (1-aminocyclobutyl) carboxylic
`acid, (1-aminocyclopentyl) carboxylic acid, (1-aminocyclo
`hexyl) carboxylic acid, (1-aminocycloheptyl) carboxylic
`acid, or (1-aminocyclooctyl) carboxylic acid;
`Xaa is Val or Leu;
`Xaas is Ser, Lys or Arg:
`
`15
`
`25
`
`Xaao 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- is Ala, Glu or Arg:
`Xaa- is Val or Lys;
`Xaa- is Lys, Glu, ASnor Arg;
`Xaas is Gly or Aib;
`Xaa- is Arg, Gly or Lys, or is absent;
`Xaa, is Gly, Ala, Glu, Pro, Lys, or is absent:
`and B and U" together is the acylated moiety, where U is
`selected from
`
`O
`
`OH
`
`O
`N ls
`
`s
`
`HO
`
`O
`
`N
`
`MPI EXHIBIT 1067 PAGE 7
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1067, p. 7 of 70
`
`

`

`11
`
`US 8,536,122 B2
`
`12
`
`O
`N-1 no-1N-1
`
`-continued
`O
`1- n-4-
`
`O
`
`')-->
`H
`N-no-kn- p
`in
`
`O
`
`O
`
`N-S-N-
`
`(N- N-n} --
`
`O
`
`S
`
`O
`
`O
`
`O
`
`O O
`\/
`N- iii.
`
`O O
`
`\/
`N- iii.
`
`O
`
`O
`
`NN
`
`COOH
`
`NN
`
`O
`
`OH
`
`NN
`
`COOH
`
`O
`
`COOH
`
`O
`
`&
`
`in
`
`n1n
`
`s
`
`30
`
`m is 0, 1. 2. 3, 4. 5, O 6,
`n is 1, 2 or 3
`s is 0, 1, 2, or 3,
`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, 35
`19, 20, 21, 22, or 23;
`and where B is an acidic group selected from
`
`HO
`
`-continued
`
`H
`N
`
`O HO
`
`O
`O
`
`O
`
`HO
`
`O
`
`O
`
`N
`HO N
`O
`
`and
`
`O
`
`40
`
`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):
`
`Xaa-7-Xaa8-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Xaa16-Ser-Xaa18-Xaa19Xaa20-Glu-Xaa22
`
`Formula II
`
`O
`
`MPI EXHIBIT 1067 PAGE 8
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1067, p. 8 of 70
`
`

`

`US 8,536,122 B2
`
`13
`The formula II is identical to formula I as stated in an
`embodiment above, where the moiety B. U is replaced by
`B U". The difference being only the incorporation of the
`carboxy group in the U' relative to U, which is without the
`attaching carboxy group.
`Informula II each of the Xaas has the following meaning:
`Xaa, is L-histidine, D-histidine, desamino-histidine,
`2-amino-histidine, B-hydroxy-histidine, homohistidine, N'-
`acetyl-histidine, C-fluoromethyl-histidine, C.-methyl-histi
`dine, 3-pyridylalanine, 2-pyridylalanine or 4-pyridylalanine;
`Xaas is Ala, Gly, Val, Leu, Ile, Lys, Aib, (1-aminocyclopro
`pyl) carboxylic acid, (1-aminocyclobutyl) carboxylic acid,
`(1-aminocyclopentyl) carboxylic acid, (1-aminocyclohexyl)
`carboxylic acid, (1-aminoc