Case 1:22-cv-00023-JPB Document 2-14 Filed 03/18/22 Page 1 of 26 PageID #: 358
`
`
`
`
`
`Exhibit N
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`
`
`
`
`

`

`Case 1:22-cv-00023-JPB Document 2-14 Filed 03/18/22 Page 2 of 26 PageID #: 359
`IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
`US010335462B2
`
`(12) United States Patent
`Jensen
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 105335s462 B2
`*Jnl. 2, 2019
`
`(54) USK OF I,ON&tuA&:TIN(i III.P-I PKPTI DISS
`
`(71) Applicant. Nuvu Nordish A/S, Bagsvaerd (DK)
`
`(72)
`
`Inventor: Christine Bjoern Jensen,
`ci
`Charlottenlund (DK)
`
`(73) Assignee
`
`(rove ((ordisk A/S, Bagsvaerd (DK)
`
`"'
`
`(
`
`Notice.
`
`Sublect to any disclaimer, thc term of tlus
`patent is extended or adjusted under 35
`U S (: 154(b) by 0 days
`I'his patent is subject to a terminal dis-
`'i/riser.
`
`(21) Appl No
`
`15/656,042
`
`(22)
`
`Filed:
`
`JuL 21, 2017
`
`(65)
`
`Prior Publication Data
`US 2018/008543S Al
`Mar. 29. 2018
`
`Related U.S. Application Data
`(63) Contmuation of application No. 14/409.493. file as
`apphcauon No. PCT/EP201'3,'063004 on Jun. 21,
`2013. now Pat. No. 9,764.003.
`Pmvisional application No 61/708.162, tiled on Oct.
`1. 2012, provisional application No 61.r6')4,837, filed
`on Aug 30, 2012
`
`(60)
`
`(30)
`
`I/oreign Application Priority Data
`
`JUI. I, 2012
`Ock I, 2012
`
`(Ep) ...
`(EP) ...
`
`12174S35
`12186781
`
`(51)
`
`(2006.01)
`(200G.OI)
`(200G.OI)
`(2006 01)
`
`Int. Ci.
`A 61K 38/26
`A61P 5/50
`A61P 3/04
`A 61P .3/1(/
`(sr2) U.S. CL
`CPC ............................... A6/K 38/26 (2013.01)
`(58) Field of Classificatiun Search
`None
`Scm applrcafion lilc for complete search lustory.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`8.129,343 B2
`8.(36,122 B2
`2010r0047762 Al
`2010(02r92133 Al
`21/11 113(1ltlgtl A 1
`
`3 2012 Lau et al
`Lau er al
`9"201
`2 2010 Button et al
`11 "2010 Sperfier et al
`12 2011 Bush ct al
`
`FOREIGN PATENT DOCUMENTS
`
`CN
`Rl.
`
`102229668 A
`2409 49 C2
`
`ilr/011
`Ir2011
`
`Rl.
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`2413530 f'2
`2006(097(37 A2
`2010 0921fi) AZ
`2011,(080103 Al
`2011138421 Al
`1201G419 Al
`2012080471 Al
`2012107476 Al
`12130136 Al
`1213679/tt Al
`2012177929 A2
`
`3(2011
`9(2006
`g,r2010
`7 2011
`11(2011
`2(2012
`6,201 I
`8 2(112
`10(2012
`1(i,r2012
`12 2012
`
`OTHER PUBLICATIONS
`
`Madsbad S ct al An Ovcrvicw of once-weekly glucagon-bkr
`peptide-I ieceptoi agonists avmlable encacy and safety data and
`pa spectrvcs for thr: future, 1)iabctcs. Obesity and Metabolism Year
`2011, rol 13. No 5, pp 39440
`Buse B J et al, Exenatide once rveekly versus braglutide once
`daily rn patients rvrth type 2 rhabetes (DURATION-6) a randomrsed,
`open-label study, Lancet. 2013, vol 381, pp 117-124
`"Fll'eels of r)nce-Weekly Dosing of a Long-Acimg
`Kun et al
`Release Formulation of Exentrde on Glucose Contiol and Body
`Werc it m Subi eels with Type 2 Diabetes " Diabetes care 1 20071 rol
`30 pp 1487-1493
`Bydureon NDA 022200(S-008 Package Infounarron pp 1-179 1I'eb
`2014)
`Clrntcal Trail NCT00696657 entitled "A Randonused Controlled
`I'hnmal 1rral ui
`lypc 2 l)iabctcs f'ompanng Semaglut«lc to Pla-
`cebo and Luaghrtrde" pp 1-5 Mu 2015 Accessed Sep 24. 201(
`at clmmaltnals ov archrvcraC1011696657 2011 03 25
`Lau et al "Drscoveiy of the Once-WEekly Glucagon-Like Peptide-I
`(ffi P-i) Analogue Scma lutidc '* I Mcd t'hcm (2015) vol 58 pp
`7370-73 SO
`Epei ran Asscssmcnt Rccporr Euro Med Agency pp 1-124 (2014)
`accessed Sep 24, 2015 at I/RL erne europe Mt does(en GBrdocument
`Iibraiy I'(PAR - Public asscssmcnt report(human 0(tZ73(r
`(119 pdf
`WC50016
`TnrlrcrtyAssessmenr Reporr Euro Med Agency pp 1-172 (2014)
`accessed Sep 24, 2015 at I/RL erne europe Mt does(en GBrdocument
`lrbi uy/FpAR - pubic assessment reportrhumanr002825r
`WC(00179473 pdf
`
`Mrarra et al "The Role foi GLP-I rn Regulation ol'Body Weight*'rogressin Medicine 2008 rol 28 No 8 pp 1909-1912
`
`CDC. "National Health and Nutrition Dsmnrnarron Suirey Iiealrhy
`Vimght, Ovcnvm bt and Obesity among r. 1 S adults** 03-OZ60 pp
`1-2 1/ul 2003), accessed May 10, 2016 at I.RL cdc gor,rnchsrdarar
`nhancs databncfs adultwcight pdf
`
`Primary Examiner
`Juiie Ha
`.Issistant Exarrrrncr Kristina M Hellman
`(74) Alf«raerr .48«al, «r Firra
`I cuit Y I rim
`
`(57)
`
`ABSTRACT
`
`The invention relates to use of long-acting CiLP-I peptides
`in certain doss e regin)ca for the treatment of type 2
`dnibctcs, obcsitv, ctc.
`
`10 Claims, 6 Drawing Sheets
`Specificatiun includes a Sequence Listing.
`
`

`

`Case 1:22-cv-00023-JPB Document 2-14 Filed 03/18/22 Page 3 of 26 PageID #: 360
`
`U.S. Patent
`
`Jul. 2,2019
`
`Sheet 1 of 6
`
`US 10,335,462 B2
`
`8emeglutide
`Lireglutide
`Baseline 8.1
`8.2
`8.0
`8.2
`8.2
`8.1
`8.1
`8.1
`8.1
`Placebo 0.t mg 0.2 mg 0.4 mg 0.8mg 0.8 mg 'I.8 rng 1.2 mg 1.8 mg
`T
`T
`
`0.00
`
`"p&0.05 vs. placebo
`'" p&0.001 vs. placebo
`"Semagtutide 1.8 mg T superior to liraglut:de 1.2 mg and 1.8 mg
`Data are LS means.
`
`

`

`Case 1:22-cv-00023-JPB Document 2-14 Filed 03/18/22 Page 4 of 26 PageID #: 361
`
`U.S. Patent
`
`Jul. 2,2019
`
`Sheet 2 of 6
`
`US 10,335,462 B2
`
`'C
`
`C3
`
`c
`
`1
`
`CD
`
`C&
`'
`
`I
`
`QqH Ul 95UBLIQ
`
`

`

`Case 1:22-cv-00023-JPB Document 2-14 Filed 03/18/22 Page 5 of 26 PageID #: 362
`
`U.S. Patent
`
`Jul. 2,2019
`
`Sheet 3 of 6
`
`US 10,335,462 B2
`
`

`

`Case 1:22-cv-00023-JPB Document 2-14 Filed 03/18/22 Page 6 of 26 PageID #: 363
`
`U.S. Patent
`
`Jul. 2,2019
`
`Sheet 4 of 6
`
`US 10,335,462 B2
`
`

`

`Case 1:22-cv-00023-JPB Document 2-14 Filed 03/18/22 Page 7 of 26 PageID #: 364
`
`U.S. Patent
`
`Jul. 2,2019
`
`Sheet 5 of 6
`
`US 10,335,462 B2
`
`

`

`Case 1:22-cv-00023-JPB Document 2-14 Filed 03/18/22 Page 8 of 26 PageID #: 365
`
`U.S. Patent
`
`Jul. 2,2019
`
`Sheet 6 of 6
`
`US 10,335,462 B2
`
`

`

`Case 1:22-cv-00023-JPB Document 2-14 Filed 03/18/22 Page 9 of 26 PageID #: 366
`
`US 10,335
`
`,462 B2
`
`1
`USE OF LO IIG ACTLNG GLP I PEPTIDES
`
`CROSS-REFERENCE TO RELATED
`APPI ICA'I'JONS
`
`1'his application is a contim&ation of U.). application Ser.
`No. 14/409.493, filed Dec. 19. 2014, wlfich is a 35 U.S.C. f
`371 National Stage application of International Application
`PCT/EP2013/0(i3004 (WO 2014/005858),
`filed Jun. 21,
`2013, which clmmcd puouty ol'uropean Paten& Applica-
`I, 2012 and European Patent
`tion 12174533.0. filed Jul.
`Application 12186781.6. Iilcd Oct. I, 2012, this application
`clainis Priority under 35 U S.('l 119 of U S Pn&visional
`Application 61/694,837, lilcd Aug. 30, 2012 and U.S. Pro-
`visional Application 61/708.162; filed Oct. 1. 2012.
`The present invention relates to improved uses of GLP-I
`pep&ides in therapy.
`
`S EQ U I IN('l I
`
`I . I Sl'I N(i
`
`ilia uistani appl&cauon conuiins a Scqucncc Listing wh&ch
`has been submitted &n ASCII fomiat via EFS-Web and &s
`hcrcby uicorporaicd by rcfcrencc in &ts cniirety. Said ASCH
`17. 2013 and ainended on Jul. 12,
`copy. created on .Iun
`2017, is nanuxl 8S45US02 ScqL&st.txt snd is 7,97S bytes &n
`size
`
`Sl JM MARY
`
`111
`
`&o
`
`&O
`
`less ofien, aud whcrcm snid GLP-I agon&st a&xl/or mhnin-
`istration optionally is as defined here&n.
`
`BRIEF f)ES( RIPJ JON OI'RAWIN(ig
`
`Ill(i
`I shov,s chan e in I lbAlc following subcutaneous
`administration of placebo. seniaglutide. or liraglutide to
`human subjects, *p&0.03 vs. pLscebo: sap&0.001 vs, placebo
`(based on adjusted means). Baseline values are for infor-
`mauon only: data arc model-adjusted for baschnc HbAlc.
`Dais arc model-slijusicd LS means. FAS LOCF. Tlic csii-
`mates are fmm an ANOVA niodel with treatment, country
`and previous treatnlent as fixed effects and baseline I lbAlc
`as covariate.
`FICi. 2 shov,s mean change in HbAlc from baseline
`versus time: data are mean (1.96SE). FAS LOCF. The
`treatments arc placebo (A). scmagluudc 0.1 mg (B, dilshcdI
`luic), 0.2 mg (C), 0.4 mg (D), 0.8 mg (E), 0.8 mg T (F,
`I 6 mg 1'(I); limglutide I 2 nig (I I),
`dashed line),
`I 8 mg
`(I)
`
`FICi 3A and FI(J. 3B show subjects reach&ng the AACE
`(FILI. 3A) or ADA (FILI. 3B) criteria for glycaemic control.
`The number of patients reaching the cnteria per treatment is
`u&d&calcd ui each bar. The treaimm&is arc placebo (A).
`scmagluiide 0.1 m (B). 0.2 mg (C), 04 mg (D). 0.8 mg (E).
`0 8 mg T (I'),
`I 6 mg T ((I); liraglut&de I 2 nig (11),
`I 8 mg,
`v "p&0 001
`placebo:
`"p&0.05
`vs.
`vs
`placebo;
`(I)
`cvvp&0.0001 vs, placebo (based on ad)usted means). Data
`are FAS LOCF. The estimates are from a log&stic regression
`model treatment. country and previous treatment as fixed
`clfccts and bascluie HbAlc as covuuatc. ADA, Amcricml
`D&abc&ca Assoc&ai&on, AACE. Ameucun Assoc&auon of
`('lmical Endocrinolo ists.
`l&I(i 4 shows mean body weight change versus time; data
`are mean (I 96SI I), I&AS J ()CI'I'he treatments are pLscebo
`(A): semaglutide 0.1 mg (B. dashed line). 0.2 mg (C), 0.4 mg
`(D). 0.8 m (E), 0.8 mg T (F. ILsshed line), 1.6 mg T ((i);
`liragluiulc 1.2 mg (H), 1.8 mg (I)
`FI(i 5 shows body we&ghi change from baseline at wcck
`12 v "p&0 001 vs placebo: cc "p&0 0001 vs. placebo (based
`on adjusted mern&a ": I iaseline values for information only
`data are model-adjusted for baseline weight. 1)ata are model-
`adlusted LS means, FAS LOCF. The estimates are from an
`ANOVA model lvith treatnlent. country and previous treat-
`meul as lixed cfii:cis mid baselulc wmght as covariaie.
`SE: Standard error. FAS. Full auulys&s sct. LOCF: Last
`observation carried forward
`
`DESCRIPTION
`
`Thc present uivenuon relates to an improved usc of
`GI,P-I ago&lists ill tiler'lpv. In cine cluborlllllcilt thc ulvcntlo&1
`relates to certain dosage re imes of (II,P-I agonists which
`provide improved effect in diseases or condit&ons, such as
`prevention and/or treatment of type 2 diabetes and obesity.
`In onc emboduncnt thc methods ol'hc prcscnt uivent&on
`provides surpris&ngly showed improved rcduct&on of HbAlc
`and reduci&on of body wc&ght.
`Iu onc embodiment
`thc
`(ii P-I agonist is administered in an amount winch pmvides
`an improved a) reduction in I lbAJ c or 8) reduction in body
`v e&ght compared to administration of I 8 mg liraglutide or
`less. such as 0.8 mg liraglutide or less. per day.
`In onc embodiment thc &mention rclatcs to a method lor
`rcduci&on of HbAlc or for pre& wit&ou or trcauncnt ol'ype 2
`Impaired glucose tolcmncc, or
`duibctcs, hyperglyccmia,
`non-insulin dependent diabetes, said method comprising
`administnstion of a (il P-I agonist
`to a subject
`in need
`
`In one embodiment the imention relates to a method for
`a) reduction of HbAlc: b) prevention or treatment of type 2
`lucose Iolerancc, or
`Impaired
`d&abc&as, hypcrglyccmui,
`non-insulin dependent diabetes; or c) prevention or treat-
`ment of obes&ty, rcduc&ng body weight Imd/or I'ood intake, or 31
`inducing satiety; wherein said method comprises adnliius-
`trai&on of a GLP-I agon&si
`to a subicci ui aced thereof,
`wherein sa&d (ii,p-l agon&st i) has a half-life of at least 72
`hours. wherein said half-hfe optionally is determined by so
`Assay (I I); ii) &s administered in an amount of at least 0.7 mg
`per week, such an amount equivalent to at least 0.7 mg
`semaglutide per week, and iii) is administered once weekly
`or less often.
`ilm &nvenuun relates to a GLP-I
`In onc mnboduncni
`agonist for use in a) the reduction of HbAlc: b) the preven-
`treatment of type 2 diabetes, hyperglyccmia,
`uon or
`impaired glucose tolerance, or non-insulin dependent dia-
`ihc prcvcuuon or tres&mani of obesity.
`for
`betes, or c)
`rcslucu&g body wc&ght and/or food imskc, or fi&r inducing
`satiety, wherein sa&d usc composes sdnumslmiion of sa&d
`(il P-I agonist in an amount of at least 0 7 ma per week,
`such an amount equivalent to at least 0 7 mg semaalutide per
`&seek, and wherein sa&d (JLP-I agonist and/or administration
`optionally is as defined herein.
`In onc cmboduncnt tile &live&111011 lclalcs to s colllposi! loll
`comprising a (iLP-I agonisi for use in a) the reduction of
`HbAlc: b) the prevention or treatmeni of type 2 dmbetcs,
`hyperglycemia, imps&red glucose tolerance. Or non-insulin
`dependent diabetes; or c) the prevention or treatment of Io
`obesity, for reducing body v eight and/or food intake. or for
`inducing satiety, wherein said CILP-I agonist
`i) has a
`half li fe of at least 72 hours, w hercin amd I&elf 1 if8 optionally
`is dciennincd by Assay (II), mid i&) is athmmstercd ui an
`amount of ai
`least 0.7 mg pcr wcck, such an amount
`equivalent to at least 0.7 mg semaglutide per week: and
`wherein sa&d con&position is administered once weekly or
`
`o
`
`11
`
`ss
`
`

`

`Case 1:22-cv-00023-JPB Document 2-14 Filed 03/18/22 Page 10 of 26 PageID #: 367
`
`US 10,335,462 B2
`
`thereol'i an amount ol't least 0.7 mg pcr week. such an
`amount equivalent to at least 0 7 mg semaglutide per week.
`ln one embodiment the method is for reduction of 1ibAlc.
`ln one embodiment the method is fiir prevention or treat-
`ment of type 2 diabetes. In one embodiment the method is
`treatment of hyper lycemin.
`for prevention or
`In one
`cmbodimcnt thc method is lor prcvcntion or treatment of
`impaired glucose tolerance. In one embodiment the method
`is fiir prevention or treatment of non-insulin dependent
`In one embodiment the method of the invention in
`diabetes.
`comprises delaymg or preventing diabetic disease progres-
`In one embodiment a HbAlc level below 7% is
`sion.
`achieved. In one embodiment the level of HbAlc is deter-
`mined accorduig to thc method delincd by thc Diabetes
`Control and Complicntions Tnal /DCCT). In one embodi-
`ment the level of IlbAlc is determined according to the
`method defined by the International liedemtion of (:linical
`( hemistry (Ili('(')
`In one embodiment the invention relates to n method for
`treating or preventin
`obesity, for reducing body weight
`and/or food intake, or fiir inducing satiety, wsid method
`comprising admiiustration of a GLP-I agonist to a sub)i:ct ill
`need thereof in an aniount of at least 0 7 mg per week. such
`an mnount equivalent to at least 0 7 mg semaglutide per
`week In one embodiment the method is for prevention
`
`io
`
`iii'reatmentof obesity. In one embodiment the method is for
`
`reducing body weight and/or food intake. In one embodi-
`meni the method is lhr inducuig safety.
`In onc cmbodnumit the GLP-I agonist has a half-hfc of at
`least 24 hours, such as at least 48 hours. at least 60 hours,
`or at least 72 hours, or such as at least 84 bourg at least ')6
`hours. or at least 1(yg hours, or optioimlly at least 120 lxiurs,
`least 144 hours. wherein said
`least 132 hours, or at
`at
`half-life optionally is detemiined by Assay (H),
`is aihninistercd is
`thc GLP-I a orna(
`In one cmbodunmit
`twici: weekly or less ollen, once weekly or less often. or
`once weel ly or less ol'tcn. In one embodiment thc GLP-I
`agonist is adnlmistered once every secondly week or less
`often. once every third week or less often, or once a ntonth
`or less often.
`In one enibodiment the CiLP-I agonist is administered in
`sn amount pcr week ol at least 0.8 mg, st least 0.9 mg, or at
`thc GLP-I agonist is
`least 1.0 mg. In onc mnboduncnt
`silnumstcrcd ui mi amount pcr week of at least 1.1 mg. at
`I 2 m, or at least IA mg In one embodiment the
`least
`Cil P-l a onist is adniinistered in an amount per week of at
`least 1.4 ntg. at least 1.5 m, or at least 1.6 mg.
`In one embodiment the CiLP-I a onist is arhninistered in
`an amount pcr w imk cxtutv aleut to at least 0 8 mg, at least 0 9
`mg, or st least 1.0 mg scmaglutide. In onc embodimmit the
`GLP-I sgonist w administcrcd in an mnount pcr wack
`equivalent to at least 1.1 nig, at least I 2 mg, or at least I 3
`nig sema lutide In one embodiment the (il.P-I agonist is
`adntinistered in an amount per week equivalent to at least
`1.4 ntg. at least 1.5 m . or at least 1.6 mg semaglutide
`In one cmboduncnt thc CiLP-I agonist is selimted from thc
`group consisting ol'emaglutidc, exenatule. albiglutidc. and
`dulsglutidc.
`In one enibodiment the (il,p-l agonist is administered by
`parenteral aihninistration, such as subcutaneous injection
`In one embodiment the CiLP- I agonist is a CiLP-I peptide.
`In one embodiment the CiLP-I peptide comprises no more
`than 5, such as no more than 4 or no more tluui 3. annno acid
`residues whwh lrsve bccn subsututcd, utscrtcxl or deleted as
`compared to GLP-I /7-37). In one embodiment die GLP-I
`peptide comprises no more than 4 amino acid residues which
`are not encoded by the genetic code
`
`io
`
`40
`
`o
`
`i.
`
`ro
`
`ss
`
`In onc cmboduuent thc GLP-I pepudc is a DPPIV pro-
`tected CiLP-I peptide. In one embodunent the CiLP-I pep-
`tide is DPPIV stabilisixl.
`In mie embodiment the Cil P-l agonist has an I (
`
`a ltiil'elow3000 pM. such as at or below 500 pM or at or below
`
`100 pM, optionally determined by Assay fl)
`the invention relates to a CiI P-I
`In one embodiment
`agonist for use in the reduction of I ibAI c or for use in the
`prevention or treatment of type 2 diabetes. hyperglycemia,
`impaired glucose tolerance, or non-insului dependent dia-
`betes comprising administering a CiLP-I agonist
`in an
`amount ol't least 0.7 mg pcr wccL such an tmiount
`equivalent to at least 0 7 nig semaglutide per week. In one
`embodiment thc GLP-I agonist and/or admirustration is as
`dehned herein
`the invention relates to a CiLP-I
`In one embodiment
`agonist for use in the prevention or treatment of obesity, in
`the reduction of body weight and/or food intake. or in the
`induction satiety compnsing admnusteruig a GLP-I agonist
`in an amount of at least 0.7 mg per week. such an amount
`equivalent to at least 0.7 mg semaglutnle per week In one
`embodinient the (iI,P-I agonist and/or administmtion is as
`dehned herein
`ln one embodiment the invention relates to a composition
`comprising a GLP-I a onist and one or more pharmaceuti-
`cally acceptable excipients for use in reduction of HbAlc or
`for prevention or trcatmcnt ol type 2 dinbctcs. hyperglycc-
`mia, impaired glucose tolcrancc, or uon-insulin dcpcndcnt
`diabetes, wherein said (1I.P-I aaonist is administered in an
`amouilt ot at
`least 0.7 m per week. Sucll an atliount
`equivalent to at least 0 7 mg semaglutide per week. In one
`embodiment the GLP-I agonist and/or administration is as
`dehned herein.
`In onc embodiment the mi cntiou rclatcs to a composition
`comprising a GLP-I agomst;md onc or morc phannaccuii-
`cally acceptable excipicnts Ihr usc in thc prevention or
`treatment of obesity, in the reduction of body weight and/or
`food intake, or in the induction satiety, wherein said (il.p-l
`agonist is administered in an aniount of at least 0.7 mg per
`week. such an amount equivalent to at least 0.7 mg sema-
`glutidc pcr wccl . In one embodiment the CiLP-I agonist
`and/or administranon is as dclincd hcrcin.
`In onc embodiment thc GLP-I agonist is aihnirustcrod
`v ith another therapeutic a ent Administration with another
`therapeutic agent may be carried out as administration of the
`CiLP-I agonist and the other thempeutic agent within the
`same therapeutic isindow (e.g, within a period of two weeks,
`a period ol'onc wccL or in a 96. 72, or 48 hour pened, ctc.).
`The trcauncnt with a GLP-I agonist according to thc present
`invention may be combined with one or morc adihtional
`therapeutic agents, en. selected front antidiabetic agents,
`antiobesity agents, appetite regulating agents. antihyperten-
`sive agents, agents for the treatment and/or prevention of
`complications resultin from or associated with diabetes and
`agmits for thc trcatmcnt anil/or preventiou of complications
`and disorders resultuig from or associated with obesity.
`cxiunplcs ol'hcsc Uierapcutic agents arc sulphonylureas.
`tluarolidinedimies, bi uanideg nieglitmides. glucosidase
`inhibitors, glucagon antagonists. and DPP-IV fdipeptidyl
`peptidase-IV) inhibitors.
`In one embodiment. as used herein. an "amount equiva-
`lent to*'hen used ui relation to CiLP-I agonists rcfcrs to
`amounts ol'
`lirst GLP-I agomst and a second GLP-I
`agonist liaving GLP-I receptor potmicy fi.c ECso) within
`10%. of each other
`30%, such as within 20% or ivithin
`optionally detemiined by Assay (I) descnbed herein and
`
`

`

`Case 1:22-cv-00023-JPB Document 2-14 Filed 03/18/22 Page 11 of 26 PageID #: 368
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`US 10,335,462 B2
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`hiIvlllg a Il'Ill-hh: withal
`
`i
`
`30%, stick as withlll
`
`20/oot'ithin10%, of each other optionally determined bv Assay
`
`(I I) described herein
`In one embodintent an "effective amount" of a Cil.p-l
`agonist as used herein means an amount suflicient ro cure,
`alleviate. or partially arrest the clinical manifestarions of a
`given disease or state aud IB complicauons. An amount
`adequate to accomplish Ibis is delincd as '*effectivc mnount".
`liffective amounts for each purpose will depend on the
`severity of the disease or injmy as well as the weight and io
`eneml state of the subject.
`It will be understood that
`determining an appropnate dosage may be achieved using
`routine experimentation, by constnicting a matrix of values
`and tcstuig dilli:rmit poinm ui Ihe matnx, whwh is all witlun
`the ordinary skills ol'
`trained physician or vetennary.
`In one embodiment the term "treatment" or "treating," as
`used herein means the management and care of a patient for
`the purpose of contbating a condition. such as a disease or
`the tenn "treatment** or
`a disorder. In one embodiment
`"treating*'s intended to include the full specuum of rreat-
`ments for a given condition from winch thc patient
`is
`sullering, such as athnu»strauon of Ihc acuvc compound Io
`alleviate the symptoms or complications; to delay the pro-
`ression of the disease, disorder, or condition; to alleviate or
`relieve the syntptoms and complications: and/or. to cure or
`eliminate the disease„disorder, or condition as well as to
`prevent the condition In one embodiment prevention is to be
`understood as thc management and care of a patient for thc
`purpose OI'combating thc discase, condition, or disorder and
`includes the administration of the active compounds to Io
`prevent the onset of the syniptoms or complications.
`In one embodiment the tenn "hydrophilic spacer" as used
`herein means a spacer that separates a pepride and an
`albumin binding residue v ith a chemical moiety which
`comprises at least 5 nou-hydrogen atoms where 30-50% of Ii
`thcsc are cithcr N or O.
`In onc embodiment thc tenn "analo ue" as used herein
`referring to a polypeptide means a modified peptide v herein
`one or more amino acid iesidues of the peptide have been
`substituted by other amino acid residues and/or wherein one So
`or niore amino acid residues have been delered from the
`pcpude and or wherein onc or more amino acxl residues
`luivc bccn added to thc pepudc. Such addition or delenon of
`anuno acid residues cau nike place a11hc N-Icrnunal of thc
`peptide andior at the G-termmal of the peptide A simple
`lior example
`is used to describe analogues
`systeni
`(7-37) Lys desi@tates a CII P-I analogue
`Args GLP-I
`wherein the naturally occurrin lysine at position 34 has
`been substituted with arginuie imd a lysine residue has been
`added to the C-terminal (posiuon 38).
`In one embodnueut thc term '*GLP-I pcptxlc" as used
`herein means (ii,p-l (7-37). a (II,P-I analogue. a (ii P-I
`derivative or a derivative of a Cil,p-l analogue
`In one embodunent the term "exendin-4 peptide** as used
`herein nieans exendin-4 (1-39). an exendin-4 analogue. Sn ss
`cxendui-4 derivative or a dcuvauvc of mi excndui-4 ium-
`logilc.
`In one embodimmit the tenn '*DPP-IV protected" as used
`herein referring to a polypeptide means a polypeptide which
`has been chemically modified in order to render said cont-
`pound resistant to the plasma peptidase dipeptidyl amino-
`pepticatse-4 (DPP-IV) The DPP-IV enzyme in plasma Is
`known to bc involved In thc degradation OI'everal peptide
`homiones. e.g. CILP-l. Excudut-4 etc. Thus a considerable
`clion is being IIiadc to ilcvclop GLP-I d olllsts less silsccp- Si
`tible to l)PP-IV mediated hydrolysis in order to reduce the
`rate of degradation by l)PP-IV
`
`Thc present Invention also rclatcs to a CILP-I agoiust of
`the invention, for use as a medicament. In particular embodi-
`ments, thc GLP-I agomst of the invention may bc used for
`the fitlloiving medical treatments
`(I) prevention aixl/or ireatment ol all fonna of diabetes,
`type 2 diabetes, intpaired glucose
`such as hyper lycemia.
`tolerance. type I diabetes, non-insulin dependent diabetes,
`MOI)Y (maturity onset diabetes of the young). gestational
`diabetes, and/or for reduction of HbAlc:
`(ii) delaying or prevmitmg diabetic disease progression,
`such as progression in type 2 diabetes, delaying the pro-
`gression of impaired glucose tolerance (IGT) to uisulin
`requinng type 2 diabetes. aniUor delaying the progression of
`nou-Insului rcquinng type 2 diabetes to insului requinng
`type 2 diabetes;
`(Iii) prevention and/or treatment of eating disorders. such
`as obesity, eg by decreasin
`food intake, reducing body
`v eight, suppressing appetite„ inducing satiety: treating or
`prcvmiting buige cating disorder, bulimia nervosa. muUor
`obesity induced by administration of an antipsychotic or a
`steroid, reduction of gastnc mouhty, and/or dclayuig gastnc
`cnlptylng.
`In another particular embodiment, the indicatiim is (i). In
`a furtllcr p;lrtlculai'l'llbodintcitt Illc hldicatlon Is (Il)
`01 a
`still huther particuhsr embodiment the indication is (iii). In
`one embodiment the indication is type 2 diabetes and/or
`obesity.
`the method compnscs prcventiun.
`In onc emboduncnt
`treatment, reduction aniUor induction in one or more dis-
`eases or conditions defined herein. In one embodiment the
`In one embodiment the indication
`indication is (i) and (iii)
`is (ii) and (iii). In one einbodiment the method comprises
`prevention. treatment. reduction and/or induction in one or
`more diseases or conditions selected from a) aud b). a) and
`c), b) and c), or a). b) and c) as dclined in clmm 1.
`In one embodiment thc Im ention relates to administration
`of an effective amount of a GI P-I agonist
`In one embodiment as used herein. specific values given
`in relation to numbers or intervals may be understood as the
`specific value or as about the specific value.
`Functional Properties
`tlu: CILP-I agouists of thc
`In a Iirst I'unctional aspect,
`iuvmition have a good potency. Also, or altemativcly, in a
`second hinctional aspect, the CII.P-I agonists of the inven-
`tion have a protracted pharmacokinetic pmlile Also, or
`altematii ely. in a third hinctional aspect„ the CILP-I agonists
`of the invention are stable against de radation by
`astro
`IIIICSllllill Cllzynics.
`Biological Activity (Potmicy)
`Accorduig to thc Iirst funcuonal aspect, thc CILP-I a o-
`nists of the invention are bioloaically active, or potent
`In a
`particuhtr embodiment. "potency" and/or "activity" refers to
`in vitro potency. i.e. perfonnance in a functional CILP-I
`receptor assay. more in particuLar to the capability of stimu-
`lating cAMP fomiauon m a cell linc cxprcssing the cloned
`human CILP-I rcccptor.
`Thc stinuilation ol'he fomiation ol'AMP in a mednun
`containmg the human GI P-I receptor may preferably be
`deternnned using a stable transfected cell-line such as
`BHK4fi7-12A (tk-ts13), and/or using for the determination
`of cAMP a functional receptor assay, e.g. based on compe-
`tition bctwcen endogmiously Ihnncd cAMP and cxug-
`enously adihxl biotin-labellixi cAMP, ui which assay cAMP
`is morc prep:rably captured using a spccilic anubody, and/or
`wherein mi even more preferred assay is the AlphaScreen
`cAMP Assay, such as the one described in Assay (I).
`
`Io
`
`o
`
`io
`
`

`

`Case 1:22-cv-00023-JPB Document 2-14 Filed 03/18/22 Page 12 of 26 PageID #: 369
`
`US 10,335,462 B2
`
`I i i
`
`Ic
`
`Is
`
`the tenn half maxunal ciii:(tive
`In one embodunmlt
`concentration (ECsn) genemslly refers to the concentrnrion
`winch ulduccs a rcsponsc halfway between the baseluie and
`maxinnlni. by reference to the dose resPonse curve 1(C's,i ls
`used as a measure oi'hc potency of a compound and
`represents the concentnstion where 50% of its maximal
`efl'ect is observed.
`'Hie in vitro potency of the (i),V-) agonists of the inven-
`tion may be determined as described above, and rhe ECsc of
`thc GLP-I agonist in question detcrmuied. The lower the
`EC„B the better the potency.
`In a purlieu 1 sr cmbodunentr Ihc medium has Ihc If)lowing
`composition (final in-assay concentrations) 50 mM TI(IS-
`HCI, 5 mM HEPES, 10 mM MgC)i. 6HSO; 150 mM NBC),
`'I yveen, 0 1% 13SA; 0 5 mM 113 MX; I mM Al'V, I VM
`0 01 Ac
`GTP; pH 7.4.
`In a further particular embodiment. the (il.p-l agonist of
`the invention hns an in vitro potency correspondin to nn
`EC„, at or below 3000 pM, such as below 2000 pM, below
`1000 pM. or below 500 pM. or such as below 200 pM or
`below 100 pM.
`In another particular entbodiment the (il,p-l agonist of
`the invention are potent in vivo. which may be deternuned
`as is knnyvn in the art m any suitable animal model, as well
`as in clinical trials.
`The diabetic db/db mouse ts one example of a suitable
`diurnal model, and thc blood glucose lowcruig clli:ct may bc
`dclernnncd ul such mice in vivor e.g. as described in Assay
`(III). or as described in I ixaniple 43 of WO09/030738
`Also, or alternatively, the effect on food intake in vivo
`may be determined in phanuacodynamic studies in pigs. e g.
`as described in Assay (IL')
`Protraction Half Life In Vivo in Minipi
`s
`According to ihe second liuicuonal dspectr ihe GLP-I
`agomsis of the invenuon arc prolrdctcd.
`In a particular
`cmbodimcnt protracnon may be determined as half-life
`) in vivo in mintpigs after i.v administration In addi-
`(T,
`tional embodiments. the half-hfe is at least 24 hours, such as
`at least 48 hours. at least (i0 hour~, at least 72 hours. or such dc
`as at least 84 hours, at least 96 hours, or nt least 108 hours.
`A suildblc assay I'or detcrmuung half-hii: ui vive in
`ullnlpigs dficr I.y. Bihnuustl'tinou Is chsclcisccl hl Assll)'ll).
`Dcgradalton by Gastro Intestinal Enzymes
`the Cil.p-l
`to the third functiorml aspect,
`Accordin
`agonists of the imentton are stable, or stabilised. against
`degradation by one or more gastro intestinal enzymes.
`Gastro intestinal enzymes include, without limimtion. exo
`and endo pcpttdases, such as pepsin. It)Tram, chymolrypsin,
`cldsldscs. and curboxypeptidascs. Thc suibility may bc tcstcd
`lhc fornl of
`lhcsc gdsiro lulcsllnal cnzvulcs ul
`dgtinlst
`purified enzymes. or in the fiirm of extnscts from the
`astrointesttnal system
`the GLP-I agonist of the
`In a particular embodiment,
`invention has an in vitm half-life (T,,), in an extract of rat n.
`small ultcslules, divided by thc correspondmg half-life (T,
`) of GLP-I(7-37), oi'at )cast I, such as dbove 1.0r at least
`1.2. Bt lcdsl 2 0, or such as at least 3 0. or ai least 4 0. In other
`words. a ratin (Sl) may be defined for each (il,p-l agonist,
`viz as the in vitro half-life ('I'us) of the (il.p-l agonist in cc
`question. in an extract of mst small intestines, divided by the
`corresponding half-hfe (T,,) of CiLP-I(7-37).
`A sulttibli: BssBv for clctcnnuung hl vill'ci h'dlf-life hl Bu
`cxlraci of rai small intesnncs is chsclosxxl in Assay (si).
`GLP-I Agonists
`In one enibodiment the (i),V-) peptide comprises an Aib
`residue in pnsition 8
`
`o
`
`Ss
`
`In onc emboduncnt ihc annno acid residue in position 7
`of said Cil,p-l peptide is selected from the gmup consisting,
`of l)-histidine, desamino-histidine, 2-amino-histidine, (3-hy-
`dmxv-histidine, homohistidine, N"-acetyl-histidine. a-fluo-
`ionlethyl-lfistidine. 3-pyridylalanine,
`mmethyl-histidiner
`2-pyridylalanine and 4-pyridylalanine.
`In onc cmboduneni the GLP-I peptide w aluichcd tu a
`hydroplulic spaccr via thc amino acid residue in posiuon 23,
`26, 34, 36 or 38 relative to Ihe amino acid sequence of
`Crl,p-l (7-37).
`In one embodiment the GI.P-I peptide ts exendin-4. an
`eXendln-4-analOguer Or a deriVatiVe Of eXendin-4.
`In one embodiment the GLP-I a onist peptide comprises
`thc Bnullo clclcl scclucllct: of lht: follow lug ionnillcn
`
`H-His-Gly-Glu-Oly-Tlu-Phc-Tlir-Scr-Asp-Len-Scr-
`Lys-Cilri-Viet-Glu-Glu-Glu-Ale-V(I-Ara-Lcn
`Phc-Hc-Glu-Tip-Lcu-Lis-Asn-Gly-Oly-Pm-Ser-
`ial o ui 'so
`the (iLP-I agonist comprises an
`In one embodiment
`albumin binding residue attached via a hydmplflhc spacer to
`thc C-tcmurial cmnno acnl residue of said GLP-I peptide.
`In onc embodiment thc GLP-I agonist compnscs a almond
`alblunin binding residue is attached to an anlino acid residue
`v hich is nnt the G-terniinal anitno acid residue
`In one embodiment the (iLP-I peptide is selected from
`the group consisting of semaglutide, albiglutide and duln-
`ghtide.
`In onc cmbodimcnt ihe GLP-I pcptidc lrds the lbllowulg
`struculre.
`
`(lh Oil
`Ihr c
`'I hi I'h
`kia -yil
`Cep V: I S r Sw
`Tyr I du Glu Gl Gin Ale Ale Lys Glu Phe He
`Ale Trp Leu Vil Lye A h At
`(SFQ ID NO I)
`In one embodiment the (il V-I peptide has the tiilloyving
`stnlcture
`
`(SI Q ID Iso 4)
`
`IH(s-GII-Glu-Gly-Tlu-Phc-Tlir-Scr-Asp-Vil-Scr-Scr-
`iyri
`(lh (111(llu il, Cl. Iyy(I
`Ph
`Ah IW I eu Vel
`I y. (Ily A S)
`genetically fused to human albumin.
`In one embodiment the GLP-I peptide is dula litide.
`In onc cmbochmcnt lhc GLP-I 4 otusts of the uivention
`have CiLP-I activity. In onc embodunmlt **a GLP-I agoiust"
`is understood to refi:r to;my compound, including pcptnles
`and non-peptide compounds, v hich fillly or partially acti-
`In one embodunent the
`vate the human Cil V-I receptor
`"CiLP-I a onist" is any peptide or non-peptide small mol-
`ecule that binds to a CiLP-I receptor, preferably with an
`allinity constant (Ko) or a potency (EGsrr) of below I VM,
`e g below 100 nlVI as measured by