Coalition for Affordable Drugs II LLC
`v. NPS Pharmaceuticals, Inc.
`
`IPR2015-00990 & IPR2015-01093
`Patent No. 7,056,886
`
`Counsel for Petitioner
`Merchant & Gould
`June 23, 2016
`
`CFAD Exhibit 1091
`CFAD v. NPS
`IPR2015-00990
`IPR2015-01093
`
`

`
`Merchant & Gould
`
`.-\111n1cl1cc1u;1| Pmpcrly 1.21\-V lilrm
`
`my United States Patent
`lsaacs
`
`Exhibit 1003
`’886 patent
`
`[54] GL1’-2 l*"()R_‘|-'IUI.A'I'IU NS
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`[75]
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`Indu .1. Iuaaus. .-‘u1dJ;m:1'. MA {[15}
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`Exhibit 1003
`
`’886 patent
`
`um Patent No.:
`[45] Date of Patent:
`
`US 7,056,886 B2
`Jun. 6, 2006
`
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`See :ipp1jt:zIIi-am file for cflnlpluln: scztrch 11j::1ur1»'.
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`£531
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`11.3. I‘.-'(1'1".N'I' DE]-C'T.J.‘vI1EN'['S
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`Buhl or al.. Nnmrally Gccinrrlilg Pmducts of Pm-glL1cago11
`11 I
`1151] in lhc 1’nrc:inL' and [Iu1nu11 E":.a1n11 ]111c51ir1c_ 1. Biol.
`(‘In-nu. 263. 81121 81124 119881.‘
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`.-‘k1L§_g.14.:r['L'.-:11 I51I.:1 1-’II.: pn:g1LIL;ugu1I [1. D\'us:1v;;miI.14.:
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`and cnrrcspnnding amino acid !~‘n:q11c'n1nn::e of the c1'1N:1.,
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`1571
`
`'1‘11ci|1ucnI1m1is rdiru-c1u(i to l'ormu1:nIj-.ms. of {;'L£‘—2 peptides
`and wiulugs l11¢.:rvI.11‘ L:.1a11i|:Ii1iI1g supcrmr siubilily iiullmh-'i11g.
`:4lnr*ag1:
`.:1nriu"ur cxpuxttrc tn EJ1.L"\.-'a|.L‘Il'.1.
`temperatures. The
`GT.P—2 o::uIn]sm:1'1im'::-; r.5nnmr'1.t::: 2| GT1"-2 ]1upI1':1+.-nr:an :|11:a1ng
`tl1ur<:m°. 2: plmsplmtc buffer, I.-11isti-:1i11c. and um1mitn|.
`
`2
`
`4.935.244 .-\
`
`“
`
`l-1991 Ma]-Linuel a1.
`
`............. .. 424.39
`
`75 Claims, I’: Drawing SIM-Hts
`
`

`
`Merchant & Gould
`
`.'\11ll11L‘llCL'lLl21l l’roper1)'
`
`l.21\-V lilrm
`
`l
`
`GLP-2 F0-Rl'trlULATIDl"'~"S
`
`FIELD OF ]l*J‘v'ENTION
`
`The present invention provides fonnulations for GLP-2 5
`peptides and analogs thereof. In particular_.
`tl1e invention
`provides formulations of GLP-2 peptides and GLP—2 ana-
`logs with improved stability.
`
`BACKGROUND OF THE II“-T‘v'ENTI{Jl*l
`
`.fi.dn1inistration of therapeutic peptides requires peptide
`formulations tl1at ren1ai11 stable during storage. In general.
`parenteral administration is used with peptides because of
`tl1eir increased size and subsequent dillicultgr in crossing
`biological membranes. Peptides can be particularly difficult
`to formulate because of their tendency to degrade over time
`andfor undergo aggregation and precipitation. Degradation.
`aggregation, and precipitation are all
`indicative of an
`unstable fonnulation. Such an unstable formulation is not
`
`coinniercially viable. as it cannot pass l_l.S. Food and Dntg
`Adininistration approval.
`
`the degradation of
`Formulation variables which al]'ect
`peptides during storage include, but are not limited to. pH.
`the quantity of salts present. and the type and quantity of
`cxcipients. ln addition, tenipcraturcs. pressures. and time for
`freezing and dr_ving cycles can affect
`the stability of a
`lyophilized peptide formulation. The role of most of these
`variables has been studied; however, the synergistic effect of
`the variables is still poorly understood.
`
`_
`1*’
`
`in
`
`1-:
`
`Exhibit 1003
`’886 patent
`
`Col. 1, ll. 5-55
`
`Exhibit 1003
`
`’886 patent
`
`Col. 1, 11. 5-55
`
`Glucagon-like peptide-2 (GLP-2} is a 33 amino acid i
`peptide having therapeutic applications in the treatment of
`diseases of tlie gastrointestinal tract. In particular. it has been
`determined that GLP—2 and analogs thereof act as trophic
`agents to enhance and maintain the functioning oli the 35
`gastrointestinal tract and to promote growth of intestinal
`tissue. See e.g., US. Pat. Nos. 5,334,428: ."S,'r'89.3T9'. and
`5.95"tl.tl?T: and lnteniational Publication No. WC) asrsasoe.
`
`44]
`
`Conunercial exploitation of GLP—2 or an analog thereof
`requires a stable Cil.P-2 lorinulation that can be readil}-'
`prepared using a L‘LlI11fl1t:%l'ClHll}' acceptable process. Because
`(il.l’-2 is a protein, and thus far Inorc labile than traditional
`small molecular weight dnlgs. the formulation of GLP-2 or
`an analog thereof presents challenges not ECIlI1l'I1Dl1l}'
`encountered by the pharniaceutical industry. For example.
`lnethioniuc oxidation at position It] and asparginc dca1ni-
`nation at position 11. 16, andfor 24 of GLP-2 are potential
`routes of degradation. Furthenuore. GLP-2 or an analog
`thereof LDEI}-' also be adsorbed to surfaces to form aggregates
`and-“or precipitate. which would then render the fonnulation 51;.
`unstable.
`
`4_.—_
`
`'lhere is a need in the art for stable tbnnttlations ofiil .l’-2
`
`peptides and analogs thereof which can be prepared using a
`eonimercially acceptable process. The present
`invention
`satislies these needs.
`
`3
`
`

`
`Merchant & Gould
`
`.-\111nIcllccIu;1| l’ropcrI)' L21\-V l’ll‘l11
`
`Oran e Book: Approved Drug Products with Thera eutic Equivalence Evaluations
`Searc results from the "DB_Rx ' table for query on "1 3441."
`
`Exhibit 1039
`Orange Book, Gattex
`
`Active Ingredient:
`Dosage Form;Route:
`
`Proprietary Name:
`
`Applicant:
`strw
`Application Number:
`
`"'"“"”“”‘“'""“"‘
`
`Approval Date:
`
`Reference Listed Drug
`RXIOTCIDISCN:
`TE Code:
`
`TEDUGLUTIDE RECDMBINANT
`PDW'DER;SUBCUTANEDUS
`
`GAT|'E){ I(]T
`
`NP5 PHARI-IS INC
`swam
`N2 03441
`
`"'31
`
`Dec 21, 2012
`
`Yes
`RX
`
`Patent and Exclusivitv Info for this product: View
`
`Exhibit 1039
`
`Orange Book, Gattex
`
`Patent Data
`
`“'9' "°
`NEDS4-41
`
`NEDS4-41
`
`NEDS4-41
`
`N2[l3-'-M1
`
`Exclusivitv Data
`
`Appl No
`
`Drug Stlnstalce
`claim
`
`Dmg Product
`claim
`
`‘I’
`
`‘I’
`
`‘I’
`
`Exclusivitv Code
`
`Exclusivitv Exuiraliun
`
`Dec 21, 2019
`
`Dec 21, 201?
`
`4
`
`

`
`Merchant & Gould
`
`.'\11]l11L‘liCL'lLl21| l’mpcr1)' L21\-V Iilrm
`
`5
`
`His —i.La— .Iu.g—G1y—s.-_r—1=iu—:su— .Iuap—GIn— Hr.-i—.na.n—
`In
`|_
`1
`11u—n.—L..u—i-.s.p-4.-u.—L.¢u-—.-sh—.xIs—.-ug—:.sp—n.c-—
`L5
`2::
`11¢:.i.s...—'ri-p—|gu:1i.s—iaIn —1'i.r—|_,3g.—- ri.e—--'r|u—.i,sp In-:n;,i_u In r~nc1:2|
`15
`II
`
`In an: aspect oi l|1.c invcutiun. lb: imcsllnntropiiil: un-
`loas of 513-2 nonir-rm tnfiic finqucncc nf Formula I {SEQ
`ID ND:1} as fnllnws:
`
`R I -(Yl2un-X1 -II{'2-X_'i-‘X-1-—Str 5—l‘hi:fi-ScrT-AspS-:[PI )-
`Lcul-1-Asplfi -AsrLlI5.LeuI”."-.A.]a]S -Xl'§I-X2If,'I-A.sp21-
`P1'ic2Z-{P2 J—TI;I25 -Lsu 2Ei-lJr:2TI'-Eln-2Ii--Thr2"J- L}'s3-|J-
`{P7-H‘1'5!}fl-R2.
`
`whnn:i.n
`
`3L‘-
`
`1-5
`
`Exhibit 1029
`Drucker ’379
`
`Exhibit 1029
`
`Drucker ’379
`
`Col. 4, ll. 26-67
`Col. 5, ll. 1-55
`
`C01. 4, 11. 26-67
`
`C01. 5,11. 1-55
`
`El!
`
`X1 is IE5 at 'I'_'rr
`3{2Js.Ji..Liu:ru1 Ala-rqilancrncnt amine: mid maids-ins: on
`said Inning Iissisllum: In DPP-IV cnsyruni
`X3 is Asp nr I3-Ju:
`X4 is G-ly nt Ala;
`PI is Gin-Klfilrhsn-'l'lu'-Ila ar'I‘§rr-Sc:-1.;-,rs—'I'.'IT{5l‘-Q ID
`NCK3}:
`KIEI
`is Mat at an nxidativtly suhlc li-'l::t.replau::n:¢i'it
`aininfi arid‘.
`1119 is Al: on‘ Thi".
`R20 is mg, Lys. His L‘: Ma.
`['2 is Iln-A511. lln-Ala or Val-I'.iLn;
`F3 is 1 -cuvalcut bond. D1.‘ is 111:. 1].¢-'1'|u' or 1|-c-'I‘hr-Asp-.
`R11: H as an N-bcnruinal blocking group:
`R2 is U-H -Us I C‘-hurrnilril blanking grtup:
`‘fl is one nr two basic aniiiiu acids sdncltd frnin mi:
`grnup Arg. Lys. and His:
`Ylis nun nrhi-'abasin:'a.11Ii.i1n acids s-ducind [1'on11:tI»:
`gtudp Arg. L3-5. and His‘. and
`I11 and n.in.d:pcnI]v:.a1l]}'. I: ill or 1; and
`-.I.-I1».-Jcin at lca.-it nu: nff-{L I-E11-i3. R-1. P1. Xlfl. XI9. X20.
`PI and F3 is och: Ih:|.n 3 wild Int, m.-munalian -[‘iLP.1
`1'csi'.duI:.
`Wild-type nususnaiian £31.?‘-2 Icsidu-:s wI:Li.ch occur at a
`specific pclsilliuu u'cdI:lI:'.rmi.u1:I1l5:i' iLi.gnI'ng firs. '§uI||.lEl'l|.5¢$ of
`65 ELF-2‘: Esnlaind from n:1.i.|&'u'cuI: marruulinn spncii-.'.s and
`n::nrrI;Iariug1hi: 5Dl2|llE2l1!;E1D 11:: hum.II1 slsqucncvz. rnprnducnd
`hclnw. for nn|1w:ni:|1.eI.-1SEQ ID NC!-:2):
`
`for pulpnscs of this
`The a.r|1.i|1n- acid scsi-zhl.-s which.
`app1inaLi.o.I1. arc k.rin=Arn In oncu: at spc::'i.fIn pnsitions in wild
`t_Irp-I: rnasnsnflial GLP-2's an: Inn: fnltowing: position 3-[13
`may b: 11:13: Val: Fhzvsitinn Klfi rruy bu: Asn or Err;
`K15! n1:I.y be Alzuinc -:r'l'1u'couinr.po5iI:i-I:q1 X.2.‘£| may bnfirg
`Ins Lys: p-n-sjLi4:Iu X27 nay be El: E0’ Lve.u'. and position X211
`miur ht Gln nr Ilis.
`'|‘hc pt-cscrit ['rLP-2 a.I1.ai::»gs may ilinnrpinranc :1-esircii
`ainiln arid sitlstirutinlis into a "|:Iau:tgraI.md"' wI1.i.eh is an
`N-Ii-.':|111iua]l;.-‘II C-tutrninally I'I'HH1ifidi'CH.'.|'II|.UI'I mammalian
`GLP-2 pa.-prim. Such Innings ate. rqxeasriisd ui I-‘manila J
`as Ilmse in which RI cuusnmtes III N-lamina] blasting
`yDU[r.3.|1'I1I"I:>I' -I-hen in is I diet: 'l'1i.5flII."BI' twn basicainine
`said: such as mg or T_.:.Is-. audio: R2 is a C-I:u‘1ni.u.IJ blotting
`g1-oup:atL-:I.-'-¢u- wlmn n is] then Yzisin-1epe.ru1enuy.une at
`ru-:: bash: amino aci-is su-:Ii as mg or Lys.
`In ;rcfI:n'nd c of 11: i.m.rcnLi.u:irL Iii: ('_i]..F-2
`analog is an Inning, vnflull lcngjli. f':LP-}.i.:..GLP-1i[1—33l
`and P3 is accordingly‘
`I'D:
`sI.'.ql.I¢I:In.*-I.= J1:-Thr-Asa.
`AlE1‘rbal.i.'-'t]’;.'. me:
`-ELI‘-2 analugs may he Ii‘-u:nnina.1I:.-
`tluncnbcd. 1n grinld GLP-2u[1—E|'2J
`focnis
`in which P3 is
`fl:—'[1I:. DI’ {'iL.P-2I{1—31:I [mm in. which P3 L5 11:. I:
`ULP-2t I-313] fnrms in which F3 is J -nuuluit band.
`This "b.|.n-sting g'o1q:Is" rc]:rcsa:-mud by R] and. RE E1:
`chenucalginupnmal an: lIZI|fliD¢I}' use-ciin ihctnnlpeptidc
`-EhI!'J:lIIIi5El.']." tn -nnI1.fi:r binchnnsical s1a'ba'Jil3' and resistance In
`rligtfitiirn by I::I:I;1Iq:flIEl-I-'I:. Suillahis N-ls:rrm'.riu] prnlhcling
`group-3 includs. fir Exasnplc. D.__3H.bI|.':|:f'EgI'|:l.1pfi such as ..
`mctyl. Also suilahlc I5 N—tr.rrn.i|aJ ]:I1'nlc::'LLn3 gmups are
`uniln acid analngncs 1.u:'k:ing flit aminn functinn. Suiublt
`C‘-1Et'rIu'ruI1 pruning pimps include pimps which mrm
`k:II:InI:i DI.’ insidcs :1: In: cutrnn I.lnn1 -of lh: I.‘-tnrmiuil
`caIbnJ;rl.ntgrnu|1sv.-!1idifonnc.sI.:rsltE1cn13.~gensimnnf
`1h: cube:-wl. Know and esI.e:'-I-:-rming groups inelud-: nl.‘s)'1
`growls. pu1rr.i.i:ula.t|g.r hmnnhnd or In‘h1'a.n.c|1-til CH..I1l:_I.r1
`groups. c.g.. madly]. r.'.1I:I)'l ud pttlpyl gmups. w1u].c unide-
`fnrming grnuprs [m::|.I.I::ii: amino linicti-ans sud: as ]1|.'i.I'I13.l‘_|||'
`1n1i.n:. EB.’ ilkylaminn functions. v.'..g._ nsnnn-C,_,a1k_I.rl.|min.o
`and di-El salkyrlamjnn groups such as In-cthylamjiin.
`uhylamln-:-. dimnihylaminn. d.'u-.iI:,1.Ila:'njno.
`rm:IJ1:.r1<-.l11:.'-
`1a.I'n.I'.n.-n and the llht. Arm'ni:>a.i:i::l mflngns we also sililahln
`fnr ]:u'-iiincting rlu: (_'.'-h:L1niIi.a] cud nflhn prts-:I1I: compounds.
`for ='.l:=I1'q'IJ:. -I.lcI:.a.rhnI}'Ial.vusI a.m.in-0 a¢.:iI1 aniogucs such as
`:g:rr|al.ils.
`E.mb-n-d.i.ri1.cnL-2 nf flit Lni-Icnflnn spccificafly iii:J uni: such
`alflflfifi in '-I-'Jiir:I1. In B D and RI is I blocking gm-up such as
`.u:u:j.-'1'. ud analogs in which in is El and R2 is a C-u:I1:nina1
`blanking gr-cup sud: as an a.nxin-r.. e.g.. —J"«'H2.
`
`5
`
`

`
`Merchant & Gould
`
`.-\11ln1cllc:c1u;1| l’roper1)' Law lilrm
`
`Exhibit 1003
`’886 patent
`
`Exhibit 1003
`
`Col. 4, ll. 18-50
`’886 patent
`
`C01. 4, 11. 18-50
`
`GLF-2 aiialegs petentially tlselhl i11 tl1e present inventien
`include agenists and antagonists ef the GLP-2 reeepter.
`GLP-2 agenisls activate ll1e GLP-2 recepler by lirsl lzninding
`te the receptor. fellewed hy stimulating an intracellular
`secend inessenger system eeupled tn the recepter. In ene
`einhedinient ef the inventien. the GLP-2 agenists act selec-
`tively at the (El ..lr‘-2 recepter_ Selectively-acting (ll .l-'-2 agn-
`nists are eenipeunds that. in the E01119}-it ef a suitable GLP-2
`reeeptnr hinding er funetinnal assay, hind tn the {i|.]’-2
`recepter with greater aflinity. Such greater aflinity is pref-
`erahly at
`least an nrder nf magnitude greater relative te
`dilferent recepter types, such as ll1e GLP-1 recepter. In ether
`enihediinents. the GLP—2 analegs hind Ie the GLP—2 recep-
`ter with an aflinity at
`least equivalent
`tn the aflinity eli
`naturally eccurring GLP—2.
`
`In ether enibedinients ef the inventien, the GLP—2 peptide
`is a11 analeg elinatural GLP-2 that incerperates ene er niere
`amine acid sutzrstitutiens, additiens. deletiens. er inedifica-
`
`liens and retains hielegical acitivity.
`
`The agenist activity el" human GLP-2 and rat GLP-2 is
`believed te require an intact N-tenninus, hut varieus dele-
`liens ef up te several residues at the C-terniinus are luleraled
`witheut less efagenist activity. Suhstitutiens are telerated at
`sites eutside regiens censerved acress the varieus GLP-2
`species henielegs. Similarly. suhstitutiens are alse telerated
`at sites within regiens ceuserved acress til .1’-2 species. In
`preferred enihediinents. the amine acid substitutions are
`censcrvative suhstitutiens. 1-‘er example: ene rnernher ef an
`amine acid class can be substituted by anether nieniher, e. g.,
`the substitution ef alanine hy glycine,
`the suhstitutinn nt”
`asparagine hy glutainine, the suhstitutieu ef inethienine hy
`leucine er iseleuciiic, and the like.
`
`6
`
`

`
`Exhibit 1043
`Carpenter Deposition Transcript
`
`p. 111, l. 22-p. 112, l. 16
`
`7
`
`

`
`Merchant & Gould
`
`.-\n ln1cil<.'L‘ELI;1|
`
`|’mpcrl\
`
`l;1\\'l'I|’m
`
`W. Structures of GLPs and Family of G1ueagon-
`Related Peptides
`
`Exhibit 1018
`Kieffer & Habener
`
`Exhibit 101 8
`
`p. 879
`
`Kieffer & Habener
`
`p. 879
`
`GL1"-'—1{?—3?] and —['.5'—3Er}amide, GIP, e:~:endin—3
`and -41, secretin, peptide histidine—methiorIine amide {PHM},
`-he1ospectin—1 and -2, helodermin, pituitary adenyl
`cyclase—activating polypeptides
`[PACi'3LP}—3B, and -23’,
`P.#LCA.P—t'elated peptide {PEP}, C.H—re1easing factor [GEE],
`and vasoactive intestinal polypeptide [VIP] {Fig. 3}. These
`peptide hormones are produced in the gut, pancreas, and the
`central and peripheral nervous systems and exhibit a wide
`variety of biological actions in whidt several act as neuro-
`transmitters. hlotat:-ly, even peptide hormones that are co-
`encoded within the same precursor, such as the peptide
`hormones derived from the cleavages of preproglucagon,
`differ significandy in the physiological processes that they
`regulate. For example, the major function of glucagnn is to
`maintain blood glucose levelsduring fasting, whereas {3LP—1
`functions primarily during feeding to stimulate insulin re-
`lease and to lower blood glucose levels. On the other hand,
`GLP—2 appears to regulate the growth of intestinal epithelial
`cells.
`
`8
`
`

`
`Merchant {St Gould
`
`An lmccllccluzll Property Law Firm
`
`Exhibit 1018
`Kieffer & Habener
`
`Exhibit 101 8
`
`p. 879
`
`Kieffer & Habener
`
`p. 879
`
`flLLl|2i|I.|!.-'nlIIP<I-------
`|3l.P-‘Ii?’-3Ti""'““'
`flI..F"-1li'-3IiIHI‘|i-
`gp............. ..
`ExEHD!".3_ .... ..
`EIEI~lE|'|H-II----
`
`Members of the Super Family of Giucagnri-Related Peptides
`5
`
`EDDDDHHHZU-'Ii'||'|'|M.'I'3I7|El
`
`]rriirrrrr:I-TlI11-—fifl:_:_:-
`
`llIfl|'.l!|ll3lll3lll1'lu[|‘fl3l-RI‘-I:'h'-H1I'.'§'l:'l=
`
`l'l"l"g|"|="E.'fl‘ 3i|FflIlIF:-IIIHHRIIJP-'.i|l|‘|":
`
`HIE-RH
`
`-{l'_'I-I.--I-III-I-I.
`
`HIFUUMI-I*U_
`
`=II'|'3PH"lI'|'|'|'||'I|'|'||'I-
`
`1:
`'F~EH:lnI3EEhlf3EFIl3.l.IlA.HLHH2
`I L‘-It-Ii
`
`FIG. 3. Aminuacidsequenue-sefttiememhers effliesuperfamilynfglucagmi-rela1.ed peptides. Sequeiiuesiuclude human glucagun, human GLPs,
`human GIP, exendiusffleiadermaharfidmlil, huJnansecretiJLhumanpe|;rtide]1istidiJ1emet]:iunine{PI-Ilulii, heluspectinsffleiedernm Iiarriciiimi,
`heludermin ffleiiicirriria , humaii PACAP, human PACAP-related peptide {PEP}, h1.u1:IaJi GRF, and human ‘VIP. Residues identical
`tn these efglumgun in the same position are shmieii Smndurd singfie letter abbreuiciiiens are used fur amino acids {IU'P.FiC—IU'B Cumilzlissiun
`an Eiuchelnical Neu1eni:]atu1'e]I: 1'1, Ma; C, C35; D, Asp; E, Glu; F, Phe; G, G11; H, His; I, De; K, Lye; L, Lei]; M, Met; P, Pro; 421, G111; R, iirg; 5,
`Ser, T, Tim V, 1:731; W, Trp; and "1', ‘T31.
`
`9
`
`

`
`Merchant & Gould
`
`.-\111n1cllc:c1LI;1l
`
`l’mpL‘r1)' Law lilrm
`
`Exhibit 1022
`Munroe et al.
`
`EXhflflt1O22
`
`p. 1573
`
`Munroe et al.
`
`p.1573
`
`lrt 'l-'1-'l-‘I5
`
`aetivit:,r§
`Ftetiue
`
`Partially aetive
`Inaetive
`Ftetive
`fitetive
`Inaetive
`Inaetive
`
`Partially aetive
`Inaetive
`Ftetive
`Ftetive
`Inaetive
`Inaetive
`Inaetive
`
`3 3:9 ill?
`gr-
`
`[I
`
`T 2
`
`ID
`
`5 E 5 E 4 6
`
`ha
`
`ID
`
`D-
`
`I I I I 1 1 1 I I I I A A A
`
`22
`2
`
`Table 2.
`
`In titre and in tire flfllltflljf profiles nf selected peptide—
`
`K,-, n1":-‘P’
`
`Peptide
`
`Higl1—a[finit}r
`
`L.~:Jw—alinit'_I,'
`
`E1355, nlhll
`
`I1Dfi:[I.[I]
`_
`NA
`ND
`I15fi:[I.3
`
`reLP.2u-33;r|
`N—r*Le—rGLF—E{]—33}
`[Arg-1]rG LF—2{— 1.33;.
`[Arg—3=1-|r~GLP—2{]—34-}
`[Tyr—3-=l]ht'3LF—2
`reLP.2.[233;.
`rC'.]_P—2{3—33;u
`reLP.2u-29;.
`[Thr-Tinsertiun|
`[eI;.r.2]eLr-.2.;1.22;
`
`hG-LP‘-EH l-33)‘
`
`t']LP-1[?-Sfijamide
`err
`
`2591 4::
`14:21
`2
`m
`E In!
`
`§§§E§§E§E'l'l'l'l'l'
`
`l‘l'l'l'l'l'l'l'l'l'l'l'
`
`1th--.1-.1
`
`I—lE\.D'-.|'|§E5£I
`
`"ms in = 1;.
`
`1.001 -12
`20.3 1 -11
`9411
`1 41
`3.1 1 0.3
`1.4 1 :11
`210
`122
`1-12 1 -12
`3.501 -14
`um 12::
`2.0 1 -12
`
`1.3 I I121]
`
`NA
`
`NA
`NA
`
`NFL, not aetit-e—ne deteetah-le binding; ND. net determined.
`‘H = 2, except where indicated.
`fr! = 3-.
`iflelatitre tn Ill] nM rG-LP-2[l-33). n = 3.
`§Relati'I.re tn vehicle-treated e-nntrul animals. at = 4 or greater. In n‘-L-r:-I aetivity is based on ehangts in small lxmrel wet weight after 14-day treatment
`as deseribed in Medioztt and Materials.
`
`‘rGLF-2111-33] is native rat GLF-2 peptide; hGLF-21.1-33] is native human GLF-2 peptide.
`
`10
`
`

`
`Merchant & Gould
`
`.-\n ]nlcllcc1LI'.1|
`
`l’mpcr1}'
`
`l.;1\\* Firm
`
`Exhibit 1027
`Kornfelt
`
`Exhibit 1027
`
`Col. 2, ll. 20-57
`
`Kornfelt
`
`DETAJIED DESCRIPTION OF THE
`
`]1'~i‘ir'Ei‘*~Tl"IflI‘~i
`
`C01. 2, 11. 20-57
`
`The invention relates to a stabilized phannaceltietl
`preparation comprising glucagon andastahfliring amountof
`a pltarrnaceuticaliy acceptable arnpholyte. especially an
`amino acid or dipeptide or a rniltalre thereof and optionally
`an BIt'.‘.i.pit:lJI. Eucit preparations retain the glucagon activity
`at room temperature. e.g. 25° C.. for extended periods of
`time.
`
`all
`
`45
`
`A pharrnacentically acceptable alnpholyte to he used in
`accordance with the invention may he selected from the
`g;l‘I.':IIl]‘.I consisting of amino acids or derivations thereof such
`as glycine, cthylglycinc [saroosinc].
`tziimcthylglycine
`ioetaine). alanine. 13-alanine. saline, lcucine, nor-leucine.
`isolencine. serine. threooine. aspartic acid. glutarnic acid.
`hydroztyglutarnic acid.
`lysine. hydronylysine. omithine.
`argininc. histidinc. methionine. asparagine and glutamine;
`dipeplides such as glycylglycine; pharmaceuticaily accept-
`ahle sulfonic acids or derivatives thereof such as taurine;
`creatinine. and ethylenediantinetetraaoetic acid {EDTA]-
`
`An amino acid to be used in accordance ~..1.:'it11 the present
`invention is preferably a naturally occurring alpha amino
`acid. Such amino acids may he 1 or d amino acids or a
`mixture thereof.
`
`Preferably glycine. glycylglycine. histidine or a mixture
`of two or more of these is used.
`
`A pharnlaceatical preparation of the invention in 1yo-
`philizod foorn preferably also comprises an e:I;cipient. e.g. for
`facilitating Lht: |y't2:]:|hiii?..s.titJn and rapid and coruplete redis-
`soiution thereof when reconstituting the preparation before
`use.
`
`an eltcipient may be selected from disaccharides such as
`lactose. trehalose. and sucrose. sugar alcohols such as sor-
`bitol or rnannitol. polysaccharides such as the polymers
`commercialized as Dentranlfll products such as DEIEEDQ ill].
`Destrsniil Tfl or Dcxtraniii T5. and Ficolllil and polytralent
`alcohols such as polyethylene glycol or polyvinyl alcohol or
`a combination of two or more of these.
`
`11
`
`

`
`Merchant & Gould
`
`.-\n ]nts:llcc1Lu1|
`
`l’mpcr1}'
`
`l.;1\\* I"Irm
`
`The pH ef the prepsrstiens ssesrdiug ten the imrentiuu in
`the form of s sulutien is prel'e1s,h1}r adjusted tu I111.-.inter1.-s1 m
`Exhibit 1027
`1-1’. Prefetshly. The pH is adjusted to: the interval 2-4, and
`Kornfelt
`must preferred te she-tit 2.3.
`
`Tite inventien else relates tn :1 meflmd fer the preparslieu
`-of 3 pI1a11'I1s|r:et.I1J'.I1:-ti preparation cumprising glucagfln and a
`stabilizing sttteunt
`emf
`ti phannneeutiealifr acceptable
`Col. 3, ll. 9-29
`1 2
`-fi.TIII]Ji'iDij."I.'IE wherein 1gi1IE.Elgt2I]1I15‘{i.I sseltred .111 :1 ._fi_!Iil.'I12I-If.‘J-ll
`the
`b t O 7
`mp-I1el3-Tte an-:1 epttuusi exetptent and ijfflpitllflfltl. uphea-
`ally -flflflf SI-BIJIE: fIiL'fi1i.L-E.'rII.
`The dissolution of the glueageu is preferably es.1'ried nut
`at s tempersliure of from 4“ tn 3” C.
`
`CO1‘ 3 9
`
`_
`
`9
`
`A me-st pcreferrenzl preparstinn seeetdiug to the in‘-renliun
`cumprises glueagell, laetese IZ.'tl' rnsuitlitei as eiseipient and
`glycine. histidiite er g1jFC]flgi}?t2i_'EIE es:
`.1 n:Ii:I;tt1re of two er
`mere {If these as s stai:Iiii:;ing agent. Such s prepsrstitm
`shows a buffer eifeet at pH shunt 13 giving s It'til:tiJ:|:tl.lt'n [hr
`the rate ef deeeiupesilien ei glue-sgen. Thus, the imrentisn
`enables the fermtllatien «sf :1 prepsratien in which gluesgenn
`is stable at Iflfllfl temperature.
`
`12
`
`

`
`Exhibit 1029
`Drucker ’379
`
`Col. 9, ll. 25-56
`
`Exhibit 1029
`Drucker ’379
`
`Col. 10, ll. 25-33
`
`13
`
`

`
`Merchant & Gould
`
`.-\n ]n1cllcc1LI;1| l’mpcr1}' l.;1\\'I*'Irm
`
`15
`
`For use in stimulating growth of the upper
`
`Exhibit 1028
`Drucker ’600
`
`IPR2015-00990
`
`gastrointestinal tract, andior enhancing upper
`
`gastrointestinal tract functioning in a mammal
`
`including a
`
`_
`
`_
`
`p. 21, ll. 15-30
`the present invention provides in one of its aspects a
`human,
`package,
`in the form of a sterile—fi11ed vial or ampoule,
`
`,
`Drucker 600
`IPR2015-00990
`
`p. 21,
`
`20 that contains a tissue growth promoting amount of the GLP-2
`
`in either unit dose or multiwdose amounts,
`or GLP—2 analog,
`.
`.
`.
`.
`wherein the package incorporates a label instructing use of
`
`its contents for the promotion of such growth.
`
`In one
`
`embodiment of the invention,
`
`the package contains the GLP—2
`
`or GLP-2 analog and the desired carrier, as an
`
`administration-ready formulation. Alternatively, and
`
`according to another embodiment of the invention,
`
`the package
`
`provides the GLP-2 or GLP-2 analog in a form.
`
`such as a
`
`lvophilized form, suitable for reconstitution in a suitable
`
`3D carrier,
`
`such as phosphate-buffered saline.
`
`14
`
`

`
`Exhibit 1030
`Osterberg
`
`Merchant & Gould
`pp. 301, 304, 305
`
`.-\11]n1clIcc1u;1| Pmpcrly l.21\-V l"Irm
`
`Exhibit 1 03 0
`
`Osterberg
`
`pp.3o1,3o4,3o5
`
`storage. Sugars and amino acids protect the protein by
`
`preferential eitclusion during freezing and by glass :Eorrua—
`
`***
`
`tion and!’ or by functioning as a water substitute in the
`
`dried state {Carpenter and Crowe, 1939; Franks et al.,
`
`1991; Aralcawa et al., 1992). In contrast to sugars, amino
`
`>I<>I<>I<
`
`if the product temperature is increased by ti—'I|"°C. Thus, the
`increased T; of the L-histidinef sucrose mixtures is of
`economic and practical
`importance. Another irnportant
`observation was that the addition of sucrose abolished the
`
`***
`
`crystallisation of L—hist:idine. The reduced tendency for
`
`>I<>I<>I<
`
`and wit:I1out a thermal cycle. Freeze—drj.ring of L—histidine
`
`zliom solutions having a pH in the range 4-3 showed that
`
`L—histidine has a rather low tendency to C1'jf5tflll.i5E' during
`
`freeze-dr3.ring {Table 1]. The samples freezodried at pH 3
`
`Exhibit 1030
`Osterberg
`
`p. 307
`
`Exhibit 1030
`
`Osterberg
`
`p. 307
`
`4. Conclusions
`
`L—Histidine may be regarded as a multifimctional protein
`stabiliser since it can function as a buffer and a metal ion
`
`scavenger and stabilise the protein in an amorphous phase-
`
`‘When formulating proteins wit:I1 L—histidine, it is important
`
`to consider the pH value with regard to both possible
`crystallisation of L—histidine and its influence on the T;.
`Metal
`ions such as Ca“ and Mg“ can be added to
`L—histidine without significant depression of T;. The risk of
`crystallisation of amorphous L—hcistidine is low as long as
`
`the fiirmulation is protected fiorn moisture contact. The
`
`addition of sucrose reduces the risk of crystallisation and
`increases the I‘; of the freeze-concentrated mixture.
`
`15
`
`

`
`Merchant & Gould
`
`.'\11]l11L‘HCL'lLl21| l’mpcr1)' L21\-V Firm
`
`Exhibit 1024
`Cleland et al.
`
`Exhibit 1024
`
`Cleland er al.
`
`p. 6
`
`p' 6
`
`sun-an ----a--------------a E-state
`
`-Illnillnnlll-I-I-'5.
`
`F:llu.r:2I. Eirn;I]iJ':-ad.|n'v.'||:-us:-diagrlan‘finr En1.1:I1u.1II.i.n:In d-u1I':L:I]:-u'|:nI! [.'ifl=Tfl'bI|: II and
`lust Eu: |isI.IiIn'.| Ilil|:I.|::i-Ln:I}I.
`
`16
`
`

`
`Exhibit 1043
`Carpenter Deposition Transcript
`
`p. 121, ll. 17-24
`
`17
`
`

`
`Merchant & Gould
`
`.'\11llllL‘llCL'lLl11l l’mpt‘r1)' Law lilrm
`
`Rational Design of Stable Lyophilized Protein Formulations:
`Some Practical Advice
`
`John F. Carpenter,"3'5 Nlichael J. Pikalj’ Byeong S. Chang,‘ and Theodore W. Randolph”
`
`***
`
`***
`All of these difficulties theoretically can be avoided with
`a properly prepared lyophilized formulation. to the dried solid.
`degradafivg reactions can her avoided or slowed Sufficiflnfly.
`such that the protein product remains stable for months or
`years at ambient temperatures (3+fr). Furthermore. shorbterrn
`
`* * *
`
`***
`
`not damaging to a lvophilized protein (6). Even in cases where
`two‘ or mm-E‘ degmdafive parhways fizquifgg diffg1'efl[cundi|'_iQn5
`for maximum thennodynamie stabilization, the reduced reaction
`rates in a dried product can allow for long-term stability. Thus,
`>l<>l<>l<
`***
`
`drying (6.l5.lt3}. Thus, at primary focus of formulation design
`should he protecting the protein during these steps, so that the
`dried formulation immobilizes the native protein in a chemically
`incrt solid matrix having both high Tg and low residual rnois-
`{UTE (5-5.14115}
`
`***
`
`** *
`
`Phosphate or potassium phosphate t,uffBm_ Buffers that havfl
`minimal pH change upon freezing include citrate, histidinc and
`T115 (2234; T”]_ Anchgfdpquy and J_}'-‘_ Carpenter‘ unpub-
`fished cih5erI.ra[ions)_
`* * *
`
`Fortunately, appropriate excipients can prevent or at least
`minimize unfolding, and the success of the formulation can
`be judged immfidiately by Examining the Pmiei" 5°‘3°“d3"l"
`Structure
`in the drlfid 3°11“ with i“f”'“'-"d _-“P'5‘“'°5_':°P3’
`(l5.l6.25-23). More importantly, in the few Slttlilits published
`***
`***
`***
`
`After this review of all of the dangers of lyophilization
`and all the factors to be considered it might seem that rapid
`development of a stable Iyophilized formulation would be an
`imF055ibll3 [‘15ik— F0“""9lEll" with 3 mliflnal 3PF'|‘03'-'-‘h “J f'31'"l11'
`lation design, most fonnulalion problems are quickly resolved.
`>x< >x< >x<
`***
`Rational Choice of stabilizing Emipiems
`>l<>l<>l<
`
`examined for each formulation. 4} Sucrose is commonly used
`in parenteral products that are approved by the Food and Drug
`Administration [33].
`in contrast, trchalose has not yet been
`
`* * *
`For many proteins the advice given above will probably
`lead to :1 sucuessful lyopltilizcd founulatiun. However, every
`protein has unique pi1}fSiCCICl'|{:mi.Cfll properties and, hence.
`Exhibit 1050, Carpenter 1997, pp. 969-974
`unique stabilization requirements. Thus, the fonnulation will
`ham *0 bl? "‘3U5'+‘3l""l1-3'3" fill‘ WETY illm’-7i“ di'”E- Cwnblfllng 3
`detailed knowledge of the protein properties with the rational
`choice of exciptenta should allow rapid development of a stable
`I yophil ized formulation.
`
`18
`
`

`
`Merchant & Gould
`
`.-‘tn lnttsllcscttlul l’mpt:rt)' Law Firm
`
`Rational Design of Stable Lyophilized Protein Formulations:
`Some Practical Advice
`
`***
`
`configuration (3-10). As the formulation is being developed, the
`pharmaceutical scientist should work closely with the process
`engineers. who will be designing the lyophilization cycles. It
`
`***
`
`product temperature during the process may be greater. Finally.
`input from a researcher knowledgeable in the physics of freeze-
`drying will help prevent the forrttulation scientist from arbi-
`trarily rejecting useful formulations. There are ways [see
`
`>l<>l<>l<
`
`>l<>l<>l<
`
`***
`
`Before choosing the appropriate "general" stabilizers.
`which are efiective at protecting most proteins. it is absolutely
`essential
`that the formulation be optimized for the specific
`factors that increase the physical and chemical stability of a
`given protein. For example, simply avoiding extremes in pH
`
`>l<>l<>l<
`
`***
`
`all solutes (5.fi,9,19}. The persons responsible for bulk drug
`purification and pharmaceutical prefonnulation often already
`have insight into these issues. Thus, it is imperative that the
`formulation scientist confer with these people, prior
`to
`embarking of design of a lyophilizetl fennulation.
`
`>l<>l<>l<
`
`are disrtccharides (2,5,-5,l1.l5,l6,?.5—28]. However. one group
`of compounds that should be avoided are the reducing sugars.
`These compounds may effectively inhibit protein unfolding
`during the lyophilization cycle. but during storage in the dried
`solid they have the propensity to degrade proteins via the Mail-
`lard reaction between carbonyls of the sugar and free amino
`groups on the protein [31]. The result can he at brown syrup
`containing degraded protein instead of a white cake containing
`active protein drug. Usually. the only way to slow this process
`significantly is to store the product at suhzcro temperatures.
`which defeats the purpose of a lyophili:-zed product. Compounds
`in this undesirable category include glucose. lactose, maltose
`and rnaltodextrins.
`
`***
`
`>l<>l<>l<
`
`At this point, the major component missing is a nonreduc-
`ing disaccharide, which fonns an amorphous phase with the
`protein in the dried solid and serves as the primary stabilizer.
`The main choices are sucrose or trehalose {5,t5). These com-
`pounds are relatively effective at protecting proteins during
`freezing and usually excellent at inhibiting unfolding during
`dehydration (545, I5. lI5.2.‘E-‘-231 Freezing protection depends on
`Exhibit 1050, Carpenter 1997, pp. 969-974
`
`19
`
`

`
`Merchant & Gould
`
`.-\t1 lnlcllcsclutil l’mpt:r1)' Law liirm
`
`4
`
`LYOPHILIZATION OF PROTEIN
`
`PHARMACEUTICALS
`
`Joint It Carpenter
`Department of Pharmaceutical. Scientzes, University of Colorado
`
`Byetmg 3. Chang
`Anzgtan, Inc.
`
`***
`
`***
`
`'iJptiJILizi.1'rg the [i|1'I2Itt.“]'.1'J.lr-il:I1{.I cake staI:tiJ.it1.r during the 13.rnphiIi-ra-
`fifllt Ejrtlu appears and can be a daunting, txrrnplitatod process.
`HflWt."-'-"Er. as 1o|'iJ1l.'It! dtimmented, achievirtg these goals ean be rela-
`fl"-"?[i-' Slflighfiorward if the underlying |ih].r.|ti‘r_‘ai principles are un-
`derfitood and it rational approach is taken. In genera], for [t.:II'ii.;_—l.l,';'flI|
`storage sta|:tiiit_g.- oi tirietl proteins. it appears that only iiaur t‘.I‘iteria
`must he met:
`
`1. Acute l}.I'ti-]:nJ'I.1|.1'z.='t1.1'I:III-i.I1-£l1.1t‘it€:I.1 uttfiolding must he mininti-.::ed
`and, ideally. the proton: should be Ii-ttti‘-*1.’ in the dried solid.
`
`The dried powder must have it glass I.rar1=iit'rL1Ii teirtpetnttttrl:
`that is 1'l.'i_fil.'.l1'.‘Il' dun the desired storage 1-Eitlpertilttre.
`
`***
`
`The residual moisture must I:-: re|ari'treI}.r low ti.t.-., -'=- -':.I.'II.tII] 5
`H34) per g dried so|'|d]-
`
`Specliit ii:-i'n.1uiation conditions t:t:.g,, pH] must he t:it:1.'eioped
`to i.ni1il:-it -:ht:n:t'I:a| degradation padswag.-'s,whitJ't might arise
`E1-‘en i.11 native proteilts
`>l< >l< >l<
`I
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