Case 1:22-cv-00023-JPB Document 2-1 Filed 03/18/22 Page 1 of 23 PageID #: 28
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`
`
`Exhibit A
`
`
`
`
`
`

`

`Case 1:22-cv-00023-JPB Document 2-1 Filed 03/18/22 Page 2 of 23 PageID #: 29
`
`IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
`US008)14833B2
`
`(») United States Patent
`Pedersen et al.
`
`(loj Patent No.:
`(45) Date of Patent:
`
`US 8&114&833 $2
`6Feb. 14, 2012
`
`(54) PROPYLENE GLYCOL-&'(EV IAINLVG
`PEPTIDE FORVIUI YTIONS VVHICH ARK
`OPTIMAL FOR PRODUCTIOV AND FOR USK
`IN INJECTION DKVICICS
`
`(75)
`
`Imentors: Tine njeldskovPedersen.Smonim
`(DK): Claude Bonde. Lyngby (DK):
`Dorthe Kot Kngelund, Hoite (DK)
`
`(73) Assignee:
`
`!Vovo Vordisk A/S. Bagsvaerd (DK)
`
`( '
`
`Notice
`
`Sublect to any d&sclaimer. the tenn of tlus
`patent is extended or adjusted under 3(
`U S C. 154(b) by 663 days
`
`Tlus pateni is sublect to a terminal dis-
`claimer.
`
`(21) Appl. Nos li/435,977
`
`(22)
`
`Filed:
`
`.'41ay 17, ZUU6
`
`(65)
`
`Prior Publication Data
`IJS 2007/0010424 Al
`
`Jan. 11. 2007
`
`Related U.S. Application Data
`
`of
`(63) Cont&nuation
`appl&cation
`PC T/DK2004/000792. Iiled on Nov. 18. 2004
`
`No.
`
`(60)
`
`(30)
`
`Prov&sionul applimit&on No C&0/524,65'3, liled on Nov
`24. 2003.
`
`Foreign Application Priority Data
`
`Nov. 20, 2003
`
`(DK) ....
`
`... 2003 01719
`
`(51)
`
`Int. CI.
`A 6/Ã.3/I/26
`(52) U.S. Cl.
`514/2, 530/308
`(58) Field uf ClassiTication Search .................... None
`See application file for complete search lustory.
`
`(zoo&.o»
`
`((6)
`
`References Cited
`
`A
`A
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`2001s0014666 Al
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`F.P
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`
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`
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`
`let &ons.
`C'hnstuia Bradley
`Pr&mon K&amiaer
`(74) .4//ornei;.Igea/, orFirai Michael J Brignati
`
`ABSTIIA&.'T
`
`((7)
`The present invention relates to pharmaceutical formulations
`compos&n a pept&de and propylene glycol. to methods of
`and to uses of such formulations
`preparing such fonna
`in the treatment of d&seases and conditions fiir uhich usc of
`the peptide contained u& such formulauons is ind&cuted. The
`present invention fiuther relates to methods for reducing the
`cloggutg ofinjection devices by a peptide f0nmdation and for
`reduc&ng deposits on product&on eqiupment during produc-
`tion of a peptide Ilonnulation.
`
`31 Claim~, 7 Drmving Sheets
`
`

`

`Case 1:22-cv-00023-JPB Document 2-1 Filed 03/18/22 Page 3 of 23 PageID #: 30
`
`1js 8,114,833 $2
`Page 2
`
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`FC)RL'I(JN PATENT DOCUMEN'I'S
`6 iool
`)00101010
`3 '2002
`2180218
`l(1990
`'&YO WQ0200
`I I 'IW2
`92'19260
`9(1993
`9311178(
`V'0 93 18785
`9 '1993
`11 '1993
`93 23010
`2'1995
`95 22560
`3'199s
`9S05848
`W 0 i) 51060(
`4 1995
`5'199(
`9« I 182(
`WO 96'2000(
`7 1%)6
`9624369
`8 1996
`W'0 963846i)
`12 19')6
`WO 98 08871
`3 1998
`7 '1998
`WO 98 31386
`12 '1998
`98(fr406
`99 ICi41'1
`4 19W
`5't9W
`%0 9r) 21889
`IYO 9ij 29336
`6 1999
`V(0 99 30731
`Ci't999
`WO 9ij 43341
`9 1999
`V'0 99 43708
`9 1999
`%0 &)943707
`9 1999
`V'0 00 15224
`3 2000
`%0 00 '37098
`Ci 2000
`9&0 00'41546
`7 2000
`%0 00 5(119
`9 2000
`0100223
`I 2001
`WO 01 43762
`6 2001
`0151071
`7 2001
`WO 01 49314
`7 2001
`(VO 0 I 4 1071
`7 2001
`IVO 0152937
`7 2001
`iV0015(213
`8 2001
`YYO 01'77141
`10 '2001
`1(2002
`02&67989
`6 '2002
`0247716
`%0 tlg&47715
`6(2002
`V'0 02 48183
`6'soos
`WO 02411 183
`6(2002
`11 2002
`02098445
`03'013(89
`2 '2003
`WO 03 '020201
`3i2003
`4 '2003
`WO 0:I 002136
`%0 03 03509(j
`5 2003
`iYO 2004 029076
`4 2004
`%0 2004105781
`12 2004
`I 200(
`iYO 2005 000222
`5 '2005
`2005 '04fi716
`iVO 2006 02(882
`3 2006
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`OTHER PUBI,IOATIONS
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`Non-I mal Office Action muled Dec. 9, 2009 in (,.S. Appl No
`12 184 531 filcri Aug I, 2008 by Moitcnsen ct at
`Srgrm& C.'ustom Peptide Synthesis. 2004, pp
`1-2, http
`SIGM(GFr osys(DMFFpriDF, DrslcN(sp
`Bailey ei al The Kinetics of Icnzyme-('atalysed Reactions 13&ochemi-
`cal Engtn&enng Fundmnentals, 2nd Ld.. pp, 129-148 (1986)
`Entry for Cilycenn in Dmgs Com (usvsv Dm s Com&PPA:glyccnn-
`glyceiol html), Pnn(ed Aug 04, 2009
`Luropean Pharmacopoeui. 2W7, vol. 1. p 730. Councd of Liurope-
`Strasbourg
`S E Bondos A A Bicknefl Detecuon and Pie&en(ion of Piotein
`Aggr& ation Bcforc During and Aflcr Punfication. Analyttcal Bio-
`chemistry, 2003. 223-231, vol 316. Academic Press
`Slunotesuto, Patent Absuacts ol Japan, of JP1010169)6
`Skovgaard &s al, "fjsm Fvoiutionary Information and Anccstial
`Sequences to Lndeistand the Sequence-Function Relationslup in
`GLP-I Agon)stay J. Viol Bio, 2006, vol. 363. p, 977 988.
`Tsoka ct al. Sclcctivc Flocculation Ands Prcmpitation tbr tho
`Improvement of Virus-I ike Particle Recovery horn Yeast
`Homo enat&, Biotechnol Piog, vol, 16(4), pp. 661-7 Ooooi
`Non-FinalOfficcAction in L' Appl No lo 185923. Filed Iunc 27.
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`Non hn d OtliceAmion in U S. Appl No. 10 185,923, hied Jun. 27,
`2002, Imentors I link et el Sent Oct 9, 2007
`Non-hnal Otlice Action in L S. Appl No. 11 786,095. hied Api
`11.2007, inventors Funk et al Sent Feb 24, 2009
`Non I inid OfficeA&tioninU S Appl No 12'343 722. FdrstDe&.24,
`2008, Inventors I unkel sf Sent May 22, 2009
`Non I inalOfficeActionmU S.Appl.bo 10 719601,1iledbov 21,
`2003, Inventors Maikussen et al Sent Miu 4, 200(
`Non-I inal Oflice Acbon in Ll S Appl Vo I I '220,266. I sled Sep 6,
`200(, Imentors Mmkussen et al Sent Sep 14, 200Ci
`Non-I inal (jflice Action in Ll S Appl No 11,'220,266. I iled Sep 6,
`2005, Inventors Mmkussen et al Sent feb 11. 2008
`Non-Fin)0 Oflice Action in Ll S Appl No i I '220,266. I sled Sep 6,
`l. 2007
`2005, Inventors Ivfarkussen et al Sent Oct
`Non-I inalOfficeActioninU S Appl No ll 290.634,liledboi 30,
`2005, 1mentors Juul-Mortensen et ai Sent.lun 30. 2008
`Non hnal OfficeAction mf' Appl No I I'290 634, hied Noi 30,
`200(, lmentors .Iuul Moitensenet el Sent No& 9. 2007
`Non I inslOfliceActioninU S Appl No IL29063(,iile&INov .0,
`2005, Inventors Juul-Mortensen et al Sent I'eb 2 2007
`Non-I inal Otfice Action m U.S Appl. No. 11'290.635, I iled Noi 30,
`2005, 1mentms .Iuul-Moitensen et al Sent Feb 2. 2007
`Non Final OtTice Action mf: S (ppl No 11'3(i( 274, hie&I Mar
`2006, Inventors Schlmn ct al Sent Aug 20. 2007
`Non FinalOtliceAction inUS Appl No 11,36R274,FiledMai
`2006, Inventors. Schlein et al. Sent I'eb 5, 200'I.
`Non FinalOfficeActioninU S Appl No IL'36(274, FiledMm I,
`200t&, Imentms Schlein et el Sent.lan 28,2009
`hnal OtTice Action in L'
`Appl. Vo. 10(18(,923, hied Jun. 27,
`2002, Inventors Funk ct al Sent Dm 12. 2006
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`Final Olhce Action in US Appl Vo 10'185,923, Filed.lun 27,
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`Inventors S&hlein el el Sent Apr 4, 2008
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`Inventors Schism et al Sent Zuig 12, 2009
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`Inventors Funk ct al Sent Nov 24, 2009
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`2008, Inventors I unk et al Sent Feb 18. 2009.
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`tion 8, pp. 124-128.
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`Pep(ides anil Piofems, 200f), pp. 14(-148:md l(0-1(1
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`Dated Feb I I, 2010
`
`

`

`Case 1:22-cv-00023-JPB Document 2-1 Filed 03/18/22 Page 4 of 23 PageID #: 31
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`US 8,114,833 $2
`Page 3
`
`Luropean Phanmuopocia, 3rd L'dition, 2 2 .', 199i, pp. 17-8. Co unml
`of Lurope-Strasbourg
`Fiokiaei & Hovgaaiif Phaimaceutical Fnnnnlarion Dmulopment of.
`2000, pp. 145-148 & ISO-1(l,
`I'urther Experuncntal Data Dated Jun 22. 2009
`Gonzales, Johnny C.', Declaration of (Includin Curncuhun Viia)
`Dated Vov l. 2010 fiom Patent L'P14123tld.
`Knudsen,l B etal,PotentDenvativesofGlucogon-likePeptide-l,
`Journal ol'Vleiticmal Chemssuy. 2000, vol 43, pp ICi64-9
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`Mack Pubiishmg C'o . Remington*s Pharmaceuiical Smences,
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`the Pharmaceutical Sciences. 198.', 3rd Fdnion, p i32
`
`ICith
`
`M u tin A, ei al.. Phyucal Pharmacy. Physical Chemical Pnnciples m
`Ihe Phmmaceulical Sciences, 198M . rd Lilition. p 323
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`Lnited States Pharnncopoeui. 24th L'drtion, 1999, pp, 1977-8
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`vol 1. 2nd Ldition,p 20
`'ited by examiner
`
`

`

`Case 1:22-cv-00023-JPB Document 2-1 Filed 03/18/22 Page 5 of 23 PageID #: 32
`
`U.S. Patent
`
`Feb. 14,2012
`
`Sheet I of 7
`
`US 8,114,833 B2
`
`FIGURE 1
`
`

`

`Case 1:22-cv-00023-JPB Document 2-1 Filed 03/18/22 Page 6 of 23 PageID #: 33
`
`U.S. Patent
`
`Feb. 14,2012
`
`Sheet 2 of 7
`
`US 8,114,833 B2
`
`FIGURE 2
`
`Mannitol
`
`&'rgi-
`
`InosI-
`
`Glyce-
`
`

`

`Case 1:22-cv-00023-JPB Document 2-1 Filed 03/18/22 Page 7 of 23 PageID #: 34
`
`U.S. Patent
`
`Feb. 14,2012
`
`Sheet 3 of 7
`
`US 8,114,833 B2
`
`Myo-inositol
`
`Maltose
`
`Glycerol
`
`

`

`Case 1:22-cv-00023-JPB Document 2-1 Filed 03/18/22 Page 8 of 23 PageID #: 35
`
`U.S. Patent
`
`Feb. 14,2012
`
`Sheet 4 of 7
`
`US 8,114,833 B2
`
`Glycine
`
`Lactose
`
`Mannitol
`
`

`

`Case 1:22-cv-00023-JPB Document 2-1 Filed 03/18/22 Page 9 of 23 PageID #: 36
`
`U.S. Patent
`
`Feb. 14,2012
`
`Sheet 5 of 7
`
`US 8,114,833 B2
`
`FIGURE 5
`
`

`

`Case 1:22-cv-00023-JPB Document 2-1 Filed 03/18/22 Page 10 of 23 PageID #: 37
`
`U.S. Patent
`
`Feb. 14,2012
`
`Sheet 6 of 7
`
`US 8,114,833 B2
`
`FIGURE 6
`
`

`

`Case 1:22-cv-00023-JPB Document 2-1 Filed 03/18/22 Page 11 of 23 PageID #: 38
`
`U.S. Patent
`
`Feb. 14,2012
`
`Sheet 7 of 7
`
`US 8,114,833 B2
`
`FIGURE 7
`
`

`

`Case 1:22-cv-00023-JPB Document 2-1 Filed 03/18/22 Page 12 of 23 PageID #: 39
`
`1jS 8,114,833 B2
`
`I
`
`I.YCOIA.'ONTAIVIVC'KPTIDE
`
`PROPYI,ENlr I
`FORYIULATIONS TYHICH ARK
`OPTIMAL FOR PRODUC."I'IOV AVD FOR USK
`IN IV JECTIOVU DKVIC.'FS
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`5
`
`This Application is a continuation of International Appli-
`cation serml no. PCT/DK2004/000792 filed Nov. Ig, 2004
`and claims pn ority from U.S. apphcatton Ser. No. 60'524,653
`tiled Nov. 24, 2003 and iroin Danish Application
`serial no PA
`2003 01719 filed Nov. 20. 2003.
`
`FIEI.D OF Tl Ill INVFNTION
`
`11ie present invention relates to pharmaceutical formula-
`tions comprismg a peptide and propylene glycol. to methods
`of prepanng such lormulations, and to uses ol such formula-,ii
`tions in thc treatment ofdiseases and conditions for which usc
`of the peptide contmned in such formulations is indicated.
`The present invention further relates to methods for reducuig
`the cloggut of injectiim devices by a peptide fomiul ation and
`for reducing deposits on production equipment during pro-
`duction of a peptide fornnilation.
`
`"
`
`BACKGROUND OF THL'NVENTION
`
`The inclusion of isotonicity agents in peptide-containing ""
`pharmaceutical fiinnulatiwis is widely Hiow n md onc ol'lhc
`nuire common isotonic agents used in such iiinnulations is
`mamfitol. However, tlm present inventors liave observed tliat
`mannitol causes problems during the production ol'peptide
`formulauons as it crystallizes resulung in deposits in the ""
`production equipnwnt and in the final product. Such deposits
`uicrease the need lo clean the filing equipment during pro-
`duction ofthe formulation mtd this results in reduced produc-
`tion capability In addition, such deposits niay also result in
`reduced yield of the iinal product suice vials/cartndges con- so
`taining the peptide fomiulation may need to be discarded if
`particles are prcscnt Finally.
`thc present
`inventors have
`observed that ui peptide formulations to be administered by
`injection, the presence of mannitol results in clogging of
`iiiieclion devices.
`Accordingly, it is desirable to identify an alternative iso-
`tonic a cnt to mannitol for inclusion in peptide-cont mung
`formulauons and ui particular. for uiclusion ui peptide for-
`mulations which are acbninistered by injection.
`
`s.
`
`(i
`
`SUMIYLARY OF THE INVL'NTION
`
`s
`
`The present inventors have discovered that peptide formu-
`lations ramtaining propylene glycol at certain concentrations
`exhibit reductnl deposits ut production equipment and in the
`final product and also exhibit reduced clogging of injection
`devices The present conipositiwis nuiy bc formulated with
`anypeptideandarealsophysmally midchemically stable thus
`rendering them shelf-stable and suitable for invasive (e.g
`uficction, subculancxius injection. intmmuscular, intravenous ai
`or infusion) as well as non-invasive (e.g. nasal. oral, pulmo-
`nary, transdennal or transmucosal c.g buccal) mwns of
`arlitiiiiistmtioil.
`'Ilie present invention therefore relates to a phamiaceutica1
`fonmilation comprising a peptide and propyleim glycol,
`where the propylene glycol is present ui a concentration of
`1-100 mg!ml and the pH of the fomiulation is fmm 7-10. In a
`
`r
`
`preferred embodiment, the plbarmaceutical fiirmulations of
`the invention further contain a buffi:r mid a preservative.
`The present invention also relates to methods for producin
`the pharnmccutical Rinnulatiwis of the invention
`In onc embodiment, thc method for preparing a peptide
`formulatioll cotliprises:
`a) prepanng a first solution by dissolving preservative,
`propylene glycol and buffer in ~ster,
`b) preparing a second solution by dissolving the peptide in
`water:
`c) nuxing the first and second solutions; and
`d) adjusting the plHif fiie niixture in c) to tbc desired pll.
`In another embodiment. the method for preparing a peptide
`formulation comprises:
`a) prepanng a iirst solution by dissolving preservative and
`bufi'cr in water:
`b) adding propylene glycol to the fimt solution;
`c) mixing the first solution vs ith a second solution contain-
`ino pepude dissolved ui ~ster; uid
`d) adiusting the pl I of the mixture in c) to the desired pl I.
`In yct another embodiment, the method for preparing a
`pepnde formulation compnses:
`a) preparing a solution by dissolving preservative. buflbr
`and propylene glycol in water;
`b) addin the peptide to the solution of step a); and
`c) adiusting the pH of the solution of step b) to the desired
`pH
`The present uivention fiirther relotes to methods of treat-
`ment using the pharmaceutical formulations of tlm invention
`where lhe cnimposilioos are aibninislered in an ainount eilec-
`tive to combat the disease, condition. or disorder for wluch
`aihmnislration of the peptide contained in the formulation is
`uidicated
`In addition the present invention also relates to a method
`fiir reducing deposits on production cquipmenl during pro-
`duction of a peptide formulation, ~here the method com-
`prises replacing the isotonicity agent previously utilized in
`said I'onnulaliwi ivitb propylmie glycol al a concentration
`
`oi'envseen1-100 mg/ml.
`
`In one cmbodimcnt, tlm reduction in deposits on the pro-
`duction equipment dunng production by the propylene gly-
`col-containing formulation relative to that observed for the
`fornnilation contmning the previously utilized isotonicity
`agent is measured by a sinmlated filling experiment.
`The present invmition also relates to a method fiir rsxlucing
`deposits in the iinal product duruig producnon of a peptide
`formulation. where the method comprises replacing the iso-
`toniwty agent previously utilizexI in said fomnilation ivith
`propylene glycol at a concentration of between 1-100 ntg 'ml.
`In one embodiment, tlie reduction in deposits in the final
`pmduct is measured by a reduction in lite number of vials
`and/or cartrid es of the propylene lycol-contmiung formu-
`lation that niust be discarded due to deposits relative to num-
`ber of vials and'or cartndges of the formulation containing
`the previously utilized isotonicity agent tlmt must be dis-
`carded duc to deposits
`The present invenuon further relates to a method for reduc-
`ing tlm clogging of injection dhx ices by a peptide fiirmula-
`tion. where the metluxl comprises replacing the isotoniciiy
`agent previously utihzed in said formulation v;ith propylene
`glycol at a concentration of between 1-100 mgiml
`In one embodunent. the reduction in clo ging of the uilec-
`tiiill device by the propylene glycol-containing fomiulation
`relative to tlmt observed for the formulation containing the
`pre~iously utilized isotomcity agent is measured in a sunu-
`lated in use study.
`
`

`

`Case 1:22-cv-00023-JPB Document 2-1 Filed 03/18/22 Page 13 of 23 PageID #: 40
`
`(js 8,1
`
`14,833 B2
`
`3
`BRIFF Dl',S('RIPTION OF I'Hii FICIURFS
`
`FIG. I shows a photograph ofdried droplets on microscope
`slides of froin lcli to righk placebo (no peptide) I'ormulotimls
`containing lm iaotOnic agent (e only water. prcservativc and
`buffer), mmuiitol. sorbitol, xylitol. sucrose or glycerol as the
`isotonic ageni u.1th the far nght slide contaiiung maniutol
`with peptide Arg'
`I.ys'"(N'-(/-Cilu(N"-hexadecanoyl)))-
`CII,P-I (7-37)
`FIG. 2 shows light microscopy pictures of from left to
`right, some of the dned droplets of placebo fornullations
`contaming mmuiitol. uginin. inositol or glycerol as thc iso-
`tolllc age&'lt
`FIG. 3 shows fivjit microscopy pictures of clogged needles
`dosed with placebo formulations cont uning myoinositol.
`mnlklse or glycerol as the isotonic agent
`FI(i. 4 shov's light microscopy pictures of deposits on
`needles dosed with placebo fomiulat&ons contmning glycuie.
`lactose or nlaunl toi os &he. Isotonic 'Igelit.
`shou s Iillul equipment aller 24 hours simulated
`FICI'
`filling with Arg",
`I.ys '(N'-(/-Glu(N"-hexadecmioyl)))-
`GLP-1(7-37) medium containing myo-inositol.
`FIG. 6 shows deposits on filling equipment after 24 hours
`sinuiloted filling with a mannitol-containing placebo formu-
`lation.
`I'IG. 7 shows deposits on needles dosed with matuutol (top
`(bottom panel)-containing
`panel) mid propylene glycol
`Ar '",
`I,ys v(N'-(7-Glu(N'Chexadectutoyl)))-GI,P-I(7-37)
`formulations.
`DI:SCRIPTION Ol'I IL'NVL&NTION
`
`The present ulvention relates to a pharmaceutical formula-
`tion comprising a peptide or a mixtnre of peptides and pro-
`pylene glycol uhcrc thc linol concmltration of pmpylenc
`glycol in the formulation &s 1-100 mg/ml and the pll of the
`fonnulntion is in the range of from 7-10.
`lilmlulations ol'he i&Ivan&loll al'0
`The pharmaceutical
`found to be optimal for production becmlse they exhibit
`rcduccd deposits in production equipnwnt rdativc to formu-
`lat i o co ntainulg other & sotonicity agents as measured by the
`simulated filling studies describsxI in the I'ixamples. In addi-
`&lou, thc pharmaceutical formulations of thc invention are
`found to be optimal for use ui injection devices becmlse they
`exhibit reduced clogging of the injection devices relative to
`formulauons containing other isoionicity agents as measured
`by the sinn&lated &n use studies described in the L'xamples.
`The Ilormulotums ol'lm present invenuon may be I'ormu-
`lated uith any pepude ~here exmnples of such peptides
`include. but are not limited to, glucagon. Inunan growth hor-
`mone (h(ill). ulsulin. aprotin&n. FoctorVIL tissue plasmino-
`en activator (TPA). I'actorVIIa, ITR-I'octorVIR&. hepon-
`nasc, A('TH, Heparin Binding Protein.
`corticotropin-
`calciton&n. glues on-like
`releasing linc&or, anglo-tensin,
`peptide-l, glucagon-like peptide-2. insulin-like growth fac-
`tor-l, insulin-like grolsth I'actor-2, libroblast gmv,th factors.
`gastnc ulhibitory peptide. growih hormone-releasing fi&ctor,
`pituitary adenylate cyclose activating peptide,
`secretin,
`entcrogastrin. somatostatin, somntomedin, parathyroid hor-
`mone, tluombopoietin, erytlrmlpOieti, hypothalamic releas-
`ing facton„prolactin, thyroid stimulating hormones, endor-
`pluns. enkephaluls. vasopressin, oxytocin, op&ods. DPP IV,
`complement
`interleukins,
`immmioglobulins.
`inlfibitors,
`scrinc promase inhibitorw cytokincs. cytokinc rcccptors.
`PDCI', mmor necrosis factors, nunor necmsis factors recep-
`tors, growth factors and analogues as well as derivatives
`
`0
`
`thereofu here each ofthese peptidcs constituws an alteniative
`mnbodiment of the present invention.
`In the present ap pi cat & on. the designation "on analogue" is
`used to designate o peptide u harem one or more muino acid
`residues ol'he parent peptide Imvc been substituted by
`another amino acid residue and/or wherein one or noire
`amulo acid residues of the p uent pepiide have been deleted
`and/or wherein one or more un&no acid residues have been
`added to thc parent peptide Such addition can take place
`10 either at the ¹erminal end or at the C-ternunol end of the
`parent peptide or both. Typically "an analogue" &s a peptide
`v, herein 6 or less mmno acids have hemi substitutcsl and/or
`added and/or deleted frnm the parent peptide, more prefer-
`„ably a peptide wherein 3 or less amino acids bove been sub-
`stitute) and/or added and/or deleted from the parent peptide,
`and tmlst prefcmbly. a peptide wherein one mnino acid lms
`Scen substituted and/or added Imd/or deleted from tlm pare&it
`pepnde.
`In the present application, "o denvative*'s used to desig-
`nate a peptide or airalogue ther&xi f ls hich is chem&willy modi-
`fied by introducing an orgmiic substituent e.g. ester, allyl or
`1&popluhc functionaht&es. on one or more anuno acid residues
`of the peptide or analogue thereof.
`In oiw. embodiment, thc peptide to be included in thc for-
`nullation ofthe invention is a GLP-I agon&st where "a GLP-I
`agonist's understood to refer to any peptide wluch filliy or
`p u &i ally act&votes the human GI P- I receptor In a preli:rred
`embodiment, the "GLP-I agon&st" is any peptide that binds to
`"0 a Cii P-I rcccptor, prefl rably with nn afiinity wmstnnt
`(Ko) or
`a potency (BC„,) of below I PM. e.g. below 100 nM as
`measured by methods known in the art
`(see e.vg. WO
`98/OSS71) mid cxhibiis illsulinotropic activity. where insuli-
`notropic activity may be measured In v&vo or ul vitm essays
`"» known to those of ordinary skill in the art For example. thc
`O'I,P-I agonist may be luhuinistcrcd to an mlimal and the
`ulsulin concentration measured over ume.
`Methods f&sr identifying C)I,P-I ogonists arc described in
`WO 93/19)75 (Novo Nordisk A!S) and exumplcs of suitable
`40 GLIu1 analogues and derivatives wliich cmi be used accord-
`ing to the presvnt invention includes those rcl'erred to in WO
`99/43705 (Novo Nord&sk A/S). WO 99/43706 (Novo Nordisk
`A/S), WO 9/9//43707 (Novo Nordisk A/S), WO 98/08871
`(analogues with lipophilic substituent) and in WO 02/46227
`(analogues fused to serum albunun or to ilc portion of an
`Ig) (N&1vo Nordisk A/S). WO &999/43708 (Novo Nordisk A/S),
`WO 99/43341 (Novo Nordisk A/S). WO 87/06941 (The Gen-
`em1 I 1o spital Corporation), WO 90/11296 (The (ienera1 Hos-
`(Sorpomfion). WO 91/11457 (Bucklev et al.), WO
`pital
`50 98/43658(fili Lilly & Co j. BP 0708179A2 (Bh LIIly & Co),
`LP 0699686-A2 (Bli Lilly & Co.), WO 01/98331 (L'li L illy &
`Co)
`In one emboduuent, the GLP- I ago mat is selected 1roni the
`group consisting of GI,P-I(7-36)-amide. GI.P-I(7-37), a
`I GI,P-I(7-36)-amide uialogue, o Cii.P-I(7-37) analogue, or a
`derivative of any of these.
`In one mnbodimcnt, thc (iI.P-I ogonist is a derivatilm
`ol'II.P-I(7-36)-anude. GI,P-)(7-37), a GI.P-I(7-36)-amide
`analogue or a CiI.P-I(7-37) analogue. which comprises 0
`ro hpophilic substituent
`In this embodiment of the invention. the GLI'-I derivative
`prel'erably lms three lipophilic substituents, more preferably
`nvo hpoplulic subst&tuents. and most prefemsbly one lipo-
`plu lie substituent ottached to the parent peptide (ie GLP-1(7-
`36)-amide, GI.P-I(7-37), a ()I,P-I(7-36)-amide amdogue or
`o GLP-1(7-37) analogue), where each lipophdic substituent
`(s) preferably has 4-40 carbon atoms, more preferably S-30
`
`

`

`Case 1:22-cv-00023-JPB Document 2-1 Filed 03/18/22 Page 14 of 23 PageID #: 41
`
`US 8,114,833 B2
`
`5
`carbon atimis, even morc preferably 8-25 carbon atoms, even
`more preferably 12-25 carbon atoms, and most preferably
`14-18 carbon atoms.
`In onc embodimait, thc 1ipophi lie substituent coniprises a
`partially or completely hydrogenated cyclopentanophenath-
`rene skeleton.
`In another embodiment.
`the lipophdic substituent
`straight-chain or branched afk31 group.
`Inyet another crnbodiment, thc lipophilic substitumit is an
`acyl gmup of a straight-chaui or bmnched fatty acid. Prefer-
`ably. the lipoplulic substituent is an acyl group having the
`formula C:Il,(C:H,)„(.0, uherhsn n is an integer I'rom 4 ui
`38. preferably an uiteger from 12 to 38. and most preferably
`
`is a
`
`is CHi(( Hc),s( 0, C'Hs(('H ), ('O,C'H (('Hi),,('0
`CHs(C'Hi),"C'0, CH.,(CH,)„CO
`a'xl
`C'11.,(CHsj
`ii('0
`In a more prefetrhxf embodiment. the lipophilic sub-
`stituent is tctradccnnoyl. In a most ptcfcsrsxf enibodimmit, thc
`lipophilic substituent is hexadecmioyl
`In a further embodiment of the present invention. the lipo-
`philic substituent hms a group which is negatii'Hy charged
`such as a carboxylic acid group, For example, the lipoplulic
`substituent may be an acyl gmup of a stmight-chain or
`branched alkane a n&diearboxyl ic acid ofthe formula I IOOC
`(CHs)„CO . wherein m is an integer from 4 to 38, prefer-
`ably mi integer from 12 to 38, and most preferably is
`
`HOO('Clii)„CO. IIOOC(CIIi),„CO, IIOOC(CII,),sCO
`
`HOOC(CHi)„,CO or HOC80(CIIjisCO
`In the C)LP-I derivatives of the invention. the lipophilic
`substituent(s) contain a functional group which can be
`attached to onc of the followinn functional groups of an
`anuno acid of'he parent CiLP- I peptide:
`(a) the amino youp attached to the alpha-carbon of the
`N-terminal nmino acid,
`(b) the carboxy group auached to the alpha-carbon of the
`('-terminal amino acid,
`(c) thc epsilon-mnino grmip of'any I ys residue,
`(d) the carboxy youp of the R group of any Asp and Cilu
`I'i:Sitlith,
`(c) tbc hydroxy group of thc R ~coup of miy Tyr. Scr and
`Tlu residue.
`(I) the amino grnup ofthe R group ol'any Trp, Asn,(iln,
`Arg. and Ilia residue, or
`(n) the thiol group of the R group of any ('ys residue.
`In ono cmbodinwm, n lipophilic substituent is attnclmd to
`the carboxy group ofthe R gmup of any Asp and Cilu residue.
`In another embodiment, a lipophilic substituent is attached
`to the carboxy group attached to the alpha-carbon of the
`0-ternunal amino acid.
`In a imist preferred eniboduuent a lipophilic subsiituent is
`attached to the epsilon-amino roup of any Lys residue.
`In a preferred embodiment of the invention, the lipoplfilic
`substituent is attached to the parcnt Crl,P-I peptide by means
`of a spucer. A spacer must contain at least two functional
`gl(llips. olio to 'itt'scil io a filuctlilltal gl(iilp of ilii'. Ilpophl lie
`substituent uid the other to a fiuictional group of the permit
`(iLP-I peptide.
`In one embodiment. thc spaccr is an amino ncid residue
`except Cys or Met, or a dipeptide such as Cily-l.ys I'or pur-
`poses ofthe present invention. thc pluase "a dipeptide such as
`Ci ly-I ys*'enus any combiimtion of'v,o mmno acids cxchqu
`Cys or Met. prefembly a ihpeptide wherein the 0-terminal
`mnino acid residue is I.ys, His or Trp, prcfi.rabfy I,ys, and the
`N-ternunal muino amd residue is Als. Arg. Asp, Asn, Gly,
`Glu, (kin. He, Leu, Vaf. Pire. I'ro, Ser, Tyr. Tlu: Lys, His and
`I'rp. Preferably, nn amimi group of the parmit peptide fiirms
`an amide bond iiith a carboxylic group of the mnino acid
`residue or dipeptide specer, and an amino youp of the amino
`
`s
`
`ui
`
`acid residue or dipeptide spacer fiirms mi amide bond with a
`carboxyl group of the lipoplu lie substituent.
`Preferred spacers are lysyl, glutamyl, asparagyl, glycyl,
`beta-alanyl nnd gamma-aniinobutanoyl, cack of which con-
`stitutes an individual embodiment. Most preferred spacers are
`gluts myl and beta-el any l. When the spacar is Lys. Cilu or Asp,
`the carboxyl gmup thereof may form m muide bond with mi
`amino group of the amino acid residue. and the amino p'oup
`thereof may fiorm mi mnidc bond with a airboxyl group of the
`lipopluhc substituent. When Lys is used as the spacer. a
`further spacer may in some instances be insened benveen the
`euunino group of Lys and the lipophibc substituent. In one
`embodiment, such a fiirther spacer is succinic acid wluch
`forms an aniidc bond with thee-amino group of I ys and widi
`in the lipoplulic subsutuent. In
`an unino group present
`another embodiment such a further spacer is (ilu or Asp
`which forms mi nmidc bond with thc e-nniino group of I ys
`and another amide bond u ith a carboxyl group present ui thc
`lipophilic substituent. that is, the lipophilic substituent is a
`in N"-acylated lysitm residue
`In another embodiment. the spacer is an unbranched afkane
`a,in-dicarboxylic acid group having from I to 7 methylene
`gmups. wluch spacer forms a badge between ui amino group
`of the parent peptide and an amino youp of the lipoplulic
`substituent. Prefi:rably. the spacer is succinic acid.
`In a further embodiment. the upophilic substituent with the
`attached spacer is a group of the formula Clio(Cllc)„NH
`C'0(CIIs),CO, whereui p is an integer from 8 to 33, pref-
`erably front 12 to 28 and q is an uiteger from I to 6, preferably
`s(i 2
`
`In a lurther embodiment the hpophilic subsutuent v ith the
`attached spacer is a group of the fornnila CHs(CHi),CO
`NHC:H(C'OOH)(C'.H,)sC:0, v, hi:rein r is an iiitcger from 4
`to 24, preferably from 10 to 24.
`In a further embodiment the lipophilic substituent with the
`auached spacer is a group of thc forinula CHs(C'Ha),C'0
`NI ICI 1((CII,),COOI I)CO, u herein s is an integer fmm 4
`to 24, preferably from 10 to 24.
`In a further cnibodiment. the lipophilic substituent is a
`sn group of the formula COOH(( Hi),CO whereui t
`is mi
`integer from 6 to 24
`In a further embodiment. the hpophilic substituent with the
`attached spacer is a group of the formula NHCH(('OOH