`Journal of Medicine
`
`2
`Wfropeeight, VT, by ihe Massachusetts Medicuh Soctery
`
`
`
`
`ay,
`MAY
`Volume 292
`iO?
`
`
`Naiviher 22
`
`TREATMENT GP CARBAMYL PHOSPHATE SYNTHETASE DEFICIENCY WITH RETO
`ANALOGUES OF ESSENTIAL AMING ACIDS
`Mane Barcpnaw, M.D, Sact Beosiow,
`4D, any Macuengin Warsep MDP,
`
`Abstract Congenital cerkamy!l phosphate synthe
`tase defigiensy waa diagreasd by liver bieasy in a
`i S-yeer-cid givh a-Keis analngues of essential amino
`acids hove been shown lo spare mirogen by reduciig
`wrea formation: herse, they were given to Ins patient
`in the Nope of reducing hyperarmmonemnia and ime
`proving proidin iolerancs. After intravenous iafusion
`of the helo analogues of valine, leucine, isaeucine,
`methionine and phernylslarine, Hye morresmanding
`plauma amine acids, including aligigeleucine and ty-
`ronine, rase shanty. Twernlyines Boure ler, lasing
`
` PENITAL. disorders caused by defects in each of
`
`the five enxermed ot the Kreoba-Henselei urea.cy
`ole have Been described! The clinical and bxtierical
`
`Hinndewanons Bier
`sonmmwhas aradng dose syadfomes,
`hur
`gall arg characerizect
`by. hyperaremcniensia,
`ire.
`paired mental aed physical cevelopaunt, and exdindes
`of vorminiag, fethargy,and
`Wa.alter ‘the€
`tngeonoFof
`
`protein. Hypers:
`Henrie with dele
`yoke:
`carbamyl stlowpihitee synthetase‘nodornubiaetramecar:
`buraviase.
`‘Ereaouent.of these disorders is aasatistactory. ayvel
`
`most chdldren die ia ndamiv, Protein resiricdcon amelic
`raiessymptans burcdoce nod restore he amawnia concen:
`tration of plaare ta cormal ard may preven: adequate
`growth. Adrnmisirauian af arsenic ackP bacheca proposed,
`buna the efertivencss of his substunee isnot caablished.
`
`The
`abcarbani) phosphate svathetasc deficicacy
`described below was treated with a-Keaanalogues of five
`eaemial amine acids: valine, leucineisalencines suethic-
`nase aed chernviaiagine, Weoreasoned that these come
`penods, upon transamimaion te the corresponding sai
`
`no acids, might became incorparsied tate protein acd
`thereby promo grawth and recuce hyperarenonentia.
`
`Prom the Deparanent at Pediairics, the Tepartmnea: of Phurmacddagy
`and Bancrinerntal Therapeutics -sieed the Tetpartincnt of Medicine. the Johs
`f. Kennedy tnatinute, Johos Hopking Raspital, and dobas Haghiss awe
`sity School of Medicine tabdress vegehad requests to De. Walser athe Des
`parivicnof Pasrmacidigy, Johas Hankin laiversity Sehool of Medicine,
`
`TBA, Bidte Se., Baldmore, MATS)
`Supported by a inion Center praay Se ahs EES) ant rescurok
`
`gowns TAME SGI, S
`13) from the LE So Pubtic Heatth
`Service, 6 Program Proiecs SQnC CRY TSQ204Ny and the Ker Foundations
`
`(Dy: Bats«wae therenspientof fellowships tram the Biasiher Pourndation
`ent he Prater Fomses:
`
`
`plaame ammonia had fallen from the oreinfusion val-
`we G G.OSG to 0.026 rol. Protein intake was kent at
`0.5 9 par kunoram for two weeks. Addifion af fata
`acids by mouth reduced ghasrna aummmia arid ala
`nine to sormal or sear normal levels, Seizures and
`epaedag of vorniting and letherqy decreased in tre-
`quency. Urinary niragen deoraased, suggesting that
`nitrogen balance improved: These data indicate that
`keto acide may be useful in ihe trealment of cangeni-
`tal byperseunimemia, (8 Engl 1 Med 258. 1GB8-1080,
`
`Previons observations in adults with hyperammonemia
`
`anid pdrtabsystemeemephialopabycased bycit hacieal
`the liver providedsome support for cis approach *
`
`Gass Raewors
`
`A-P-yesr-old white girl was the proaches of an aticcaiphearssd
`1H
`ialtenn progeancy, birth and neonatal perind. Tree Funwily hile
`
`t
`:
`siding whe was siibory ag 32
`ssreralcmesof angraine, allan the maternal
`‘
`
`
`
`
`n, white ara propridary souk Liimida, che
`.
`
`patefret manesas) vomitingard Jednaegy, BOUN obwbicty ree
`nuned ona der al ciearthulds. She remaiwedasyragiomac, with
`
`nominal grmth and developroent, until £3 moutheudage when
`
`posprandhd cayisingsed leutoargy yenurred.
`At 2yearcadsee|she had an spiced transient felt hem
`
`
`
`4
`for years revealed severe mertal re
`
`wi, One year lanes, she hail an epiode af caring, fet
`lowed fa upor aud cow, which resolved over 38 hours oncinera:
` wehrigessnondh,ondeseturcsdeveloped.and
`venius Huds WHhaY one i
`sheer had another opsade. ud
`sos, Drang thie
`fall
`Hasian. She alvo coutiaucsd ty have
`
`
`persisted. ta the sao
`shies of eet,
`mori
`od isthargy/
`ulten precipioited by
`
`
`piarilyrestricted herselftvadeae pro-
`fnghor
`para ger day}.
`
`sincyroctcephakigrams ubowed
`
`babes malay with depreasedt inh: bend:
`3
`
`
`royears pobiasccal spiking i Che poste rain ces
`med age. A picnmorscephalieram showed sila.
`
`
`
`io Yaptse weeniede. Brachial artcriogvaphy demavse-
`
`navibna
`alrephy. wath aoate 08slonce A hye
`
`
`
`digonal abrormale
`HOSS Wie Hever
`
`
`eras carhan dhoside fe
`nyed feos 2018
`ad phacosc wae Tin 105 wap per LODsa.
`
`years age the pagent wayrendmaited |ofohns Hophsises
`
`
`Hospital by further invesagation. Ov physi
`:
`ead aad bead crcurmierdsce were beliveih
`
`1085
`
`The New England Journal of Medicine
`Downloaded from nejm.arg at UNIV OF PENN LIBRARY on April 18, 2015. For personal use only. No other uses without perrnission.
`From the NEJM Archive. Copyright © 2010 Massachusetts Medical Society. All rights reserved
`
`Par Pharmaceutical, Inc. Ex. 1024
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 1 of 6
`
`
`
`LOSS
`
`THE
`
`NEW EMGLAND POURNAL CF METICINE
`
`May 22.
`
`(O75
`
` had:
`
`aFads
`
`oo
`
`ia2
`
`B ‘Stithere
`Miragigne
`
`*
`&
`&
`we OF
`
`¢
`3
`
`emnnteHS
`
`Figure +. Family Pecigres of the Palenttirsicaled by the Ac-
`row) busing Silgermn Baties (SB) and Family. Members
`with Migraine (i),
`
`and heighiatche Lich perme. There was ad spans quadripare-
`Sis, whfoepereefesia ankle cio, and biktwral Babinshssig ey.
`
`Shere were ne corebollar gyms or asterixia fuscle mtass uy
`avenged, wore diminished, espociiiy on the Joh. The galt sxe
`
`herare th
`
`dikial screening of urine aad sevimino ackia showet 3
`SEDUGRRRAIE WTERIC IR Bhutasnsse, Amines Riteges Ja
`
`iantig. ve
`bleod was high: At yoper milblier by the Sele-
`
`
`aoriethad
`dard cerearasgainaldThind wmamania rose 2s
`BG
`wid 3.44 geo perliner respectively six Bours after at oral pra-
`
`tin toaat 6.5 oper Kibograns{ Pig. 2) Prosimleracce rosy
`ane
`
`
`siembers
`other tanuly bave wot yet been Completed. Urine wat
`neguiive turprinein whemioioad witli sulfosadicyle aca.
`
`Pyarbometrics revesed y ynersal age ed 19 monies on the Care
`
`
`ill Fiske. Truetigence Scale (LQ of Pi She used 9 number of
`
`
`stagie words and woral combinations that were ii ely Rem
`sized! units. anal her understanding al epuken langage WES AEB
`jevel af 1630 18 memths. She wae able. help dress herself aad
`could spirori-fowed herecd’.
`
`
`Onan noresiriged dimthe Mocd ammonia was 3.410 2b ag
`per militer. The serum ares nuirogen was $010 12 me per HG
`
`int. Liver tunedin. 2ost8 gave poreal resis. Concentrations of
`
`iduraraine, alaniseand tysing were elevated in hie Hood. Methyl
`Taslowic Agi ae nedfeud ithe wy ine. Diniacid exrredionwas
`
`withwasorral faite.
`
`perlormiod
`Aasay of liver deseBor ureanys enzymes 9
`
`
`within Asamuses
`of gorens:
`shige, Actisiies of arnichine
`
`seaud
`i acid synthetase were mca
`curedbyahe mothod al Brows and Coken Swinythe nipditivation
`af Sebinshe.® Acisiyof carbamy! heptaesyngheiuse wis mes-
`
`sured by conversion ol cartumel piosphasre famed diningjace-
`
`
`urea in an atkaline medige,? Newnal rat livers were
`used a4 sitmahaneous romirrils for dhe ax:ak. Arpinaiueningsacid
`ivan aad argina could nedbe megsured beeause the quaninyad
`
`
`
`i Results
`(Pable showed carbadrel ghee
`sthan 45 precentolnee:mal?
`
`
`
`ve
`ms
`=
`x
`a2
`x
`&:
`8
`o
`m4
`wR
`
`Z
`7
`a
`
`an
`
`“
`
`?
`
`ay
`
`x
`
`x,i
`
`%,
`‘ *4
`
`%
`
`~
`os
`.
`nevmate, LG
`ai ee aa a ed aneag tae eo oe
`
`
`
`y
`
`CH Wee Roe: she slept
`per hilngraimn perdayfinial improves
`
`
`nipare or achelp tasks
`lewes hors aie) was pore
`:
`
`cheer RegueneyseeTERS
`ORE eee pecs chy Eh ASE
`
`; anteplicate1g oheee ash vamiging
`
`
`ee Pestriciiary,
`
`i wakes «wonilaneed tes
`
`ag ammonia
`
`18Bpes$31es3Of HES. aid byt s
`seer mega
`
`
`ghatimine faiean, ffi,
`
` reeseead i
`gaa) CoM -- normal,
`HESSs st
`
`Table t, Activities of Urea-Qycie Enzymesin Liver.
`
`tary?
`Barigesy
`Nima Bassear
`
`Carbamyl chosphwe apniherass
`:
`:
`ae
`Oraithiag
`narnnaree
`
`33
`4
`F293
`
`PRBS
`ao
`28
`
`
`
`
`savaeed by
`
`
`
`ore
`5 esttinatsd
`
`homwhe er
`
`
`ta Bop
`fs obeniued eliabts faecatite 0Gh sneer:artties
`
`paaled |
`
`
`
`
`ca were Geermined with+
`Plasand eine 3
`
`WEEe MT
`
`
`.
`d.
`‘atindwe arch a
`
`
`as previa
`4
`
`suspend int
`
`Jnical Chemistry Lata
`suhomuted roethe
`
`
`
`
`xd stray the
`alle reaction! and Capric meseuprolne, |? respec:
`aeTYGa was doterained by ue Bertivlot SEAL
`weaved with a aokeayyageiS
`
`
`
`
`Driermination of Blood Ammonia, Glitamine and Alanine
`lsideh weaned aranords were made by the Self
`
`mrthiosl.? Belore the CHPEPUREnikal studies, mertiods for measur:
`
`
`
`and alanine on capillary blood were de-
`ing ammonia, ghateming
`as iB
`
`YQ imcromodiicnion of the resin
`Aumann arasadeiormined ty
`
`
`method of
`fenton? Heparined camiary ood was contee
`
`Gf md of plasma ess added 06 0.8 rel of warer, dab
`
`wt obashurrcal Biakad ats 50resin dacnd Loren),
`
`vbarban far fie
`Bw
`TRY
`sas
`washed twit with
`wiater Alzer 6.4 mol 4 M sodiumelder de was
`addedusdor wan
`
`
`devetaped bs aalddivina af edaphentl olor reagersSs to maka
`
`
`
`i
`j
`oka. Amdand wasrend at i80 am. The
`normal range
`
`
`fad (GG wath Ab ee per adlih
`slutganine:
`
`
`
`ernieas
`armoma
`ler ARUN of phaser.
`withus
`
`ghutaminase®) OF? ad of plasma way:
`Sigma
`
`singisa unitat é
`pase sotanie4
`Aion ot
`
`
`‘ieaohuion Abe,a blank come
`1 otweatesinagilace ¢
`
`
`
`susie, After the reaction mix-
`
`taining phisais but nest
`
`
`
`added and
`mrauigs, resin was
`above. The swan recoveries
`
`asia wene a8 assed 18 per
`
`
`PRA,
`
`
`
`DENS
`
`vs the Be
`
`were3
`
`
`priny, Deopee
`
` fren ketenepleasaa aeee steedont
`
`abuat 88 Berean,
`secaficylic Hiktrates
`
`sraplete,
`pagadoe oral ard
`ase prey atBiion oF ken Baal
`
`
`
`wyususe wire as previcnsly described,
`
`6
`
`4
`
`HOURS
`
`Figure 2. Changes ia Blond Ammonia (Sellgson Melted) after
`a0 Cral Protein Load of 0.8 per KHogram.
`
`The New England Journal of Medicine
`Downloaded from nejm.arg at UNIV OF PENN LIBRARY on April 18, 2015. For personal use only. No other uses without perrnission.
`From the NEJM Archive. Copyright © 2010 Massachusetts Medical Society. All rights reserved
`
`Par Pharmaceutical, Inc. Ex. 1024
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 2 of 6
`
`
`
`Val BOR Nu 2}
`
`RPO ACTS PN GONGENDTAL HYPER AMMGNEMIA — RATSHAW EP AL.
`
`LOST
`
`Snations's t-iees wan ned to examine the significwnes ed ditfer-
`EnCES.
`
`Besaes
`
`Fable 2. Dhue! Variations in Ammonia, Glutamine and Ala
`nine Convenirahions inlapilary Bind.”
`
` Peagsaty ASONtA CELAARATE PL ABSSE
`
`ar Drange
`
`
`
`THurmel Variation in Ammonia, Alanine and Ghitsmine
`
`SHAE
`
`aay
`
`ahd
`
`During an cighi-day control peried on a conser dally
`preitie iraake (h4 oper bibyorain), caguincy-tilood- «ane
`ew wermobisined ath aw, ibetore breakiaer al a cunstant
`
`vor, ison and 12 rer Considerable dag-to-
`day swindon bt soma, alanine and gintamine wasob-
`
`
`
`served (Fig. 3). Hiaddiion, shere wus a signdicant decline
`
`in all three
`concertrations frore & gm, bo Ef noon (Table
`
`
`2), When fasling vahies were compared to. posipranuital
`
`values, rhb only srarisiieallysignificant decline was ia am-
`FRU.
`
`she
`
`ea eh,LOT 20.07
`
`
`
`OSDL0.06 [0.88 1
`
`O08
`
`GLUTAMIBE,
`-ankl
`AMMONITE,mht
`
`pee BLARENE
`
`Figure 3. Surnmary of the Effect af Oral Keto Achis on Binod
`Anvnonis, Glutamine and Alanine.
`The dashed lines indicale paral ranges3.8% gad the worl
`Callines represent £5.84.
`
`intravenous Keta Ackis
`
`Yo determine the possible ality of keno acids in the
`treanmental thir child, aamixiure af 65 g ofthe o-heto
`analogues of five casermial arming acids (valine, leucine,
`scltucing, methionine and phenylalanine) was given in-
`travenoaaly as sodium aalis. Plasma value, methionine,
`leucine, iyresine, allowolencine, phenylalanine and iso-
`jeucing all increased sharply at the end of the four-hour
`infusion, with opiean dere
`eof O42 £0.84 nM ig. 4}.
`Tasting capiiary ammoom commeoiradicay wag 0.050 mM
`betorecund G:.078 mM hamedanely after infusion and
`(028 mo G0 hours let. Alanine ceacenirasan de-
`cremsed trom Joi 7 io OA ath. Gipcine and lysine also de-
`creased, whereas beudine, arginine aad ether aA
`atilsremained unchanged alter hetoe.acid intustors. Gluta-
`ISUwasn toed sharing cis spady,
`
`~ GPE be
`HS EERE
`
`ARIS
`wo GEGBee
`
`BES aE
`
`
`BOE
`oA BGO
`Gat
`
`
`
`iSignificnmiydiffersn: tram &, eal G48 one 7
`
`
`$Sigeatioantly difiesent Frogsth p ecOsR is 2 Th
`
`Grail Bete Buide
`
`After the caniral perind,teesame keto acids were given
`
`by math. Pheinigabmintre (68x 2) contaited the fab
`
`
`kwadrig: sadiur o-ketadpvaleraie, (dg: sodhurn w-he-
`iPunerbyhdwcaie, 146 @: sodium a-hetrisecapradta,
`
`£24uxiem pheavdpyrasie, 2M! g; aad saxium
`
`o-hetoeyorahyithioburvrate, 2.128 g. Aer sin chys, the
`
`
`plasmaamine acid analysis showed low phenglilanine arsd
`etarkediy elevated alloiacleucine. Accordingly, che mix-
`
`pore was changed retontain 40 wool phervipyrovate. and
`
`the kero analogue of isoleucine was discontinacd (Mix 11),
`Shoring irearmerd wih Mix 2) tapdlary ammonia and
`ae
`alanine conmoerrandens showed significant redactons 1
`
`idovels (Pip. 3). Daatsmine dell dy tose, bur ihe
`sniicanwe ai ths change ib qoestionsblesper the valae
`fell progressively during the control period. Tatal plasma
`
`Leto acts wered. diaar less.
`
`Pe tis
`
`Benne
`
`ae. I ad
`a
`ob
`#
`HOURS
`MOURY
`
`Figure 4. Changes in Girouinting Amine Acts. after infusion
`ofthe Keto Acid Miature.
`The isithend panel shows the increases in plasma arming
`ands noresonading te the infused Kete acids, and ihe right
`hand panel ihe amine acids that felt,
`
`The New England Journal of Medicine
`Downloaded from nejm.arg at UNIV OF PENN LIBRARY on April 18, 2015. For personal use only. No other uses without perrnission.
`From the NEJM Archive. Copyright © 2010 Massachusetts Medical Society. All rights reserved
`
`Par Pharmaceutical, Inc. Ex. 1024
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 3 of 6
`
`
`
`LOW RMCLANEY $008
`
` Prank Txtake Th, +
` 2B 2G
`
`foment
`
`Seas
`
`
`
`Mind
`
`SAPAS
`
`PRE |
`
`‘Tie patient im preneel chaically, She hud noepiwades of
`por vomlling arsi
`was able io complete sel scdp
`
`
`skills presiously beyond bee abilities. Smzare freausecy
`leciract-
`
`
`wsecel toneor two perweek, abhough chee
`xsep sade
`gran showedno ln praverernt,
`
`Mitragen Excretion
`
`
`YVable 3 compares the vahies far conned aud keto anid
`
`perked. Allvalues are expressed in reladion to creatinine
`nitramen tacormrent for <rrorsia codlectinn. The signiliraat
`Gecregse bh OTSWIPOged PERG Ne PALTOREN CRCLETIND 1D
`comnparicané of control with both ketoacid periods is sug-
`gesnve of improved mitrogen: balance whde the patinat
`
`wee on heto acid therapy. Nene of the other measures
`ners changed slanWinanthy, Wher hete arte Mis E was
`cosgparcd with Mix Li, there was a durther
`si
`
`cresc inunes olirogen creatinine miragen. as well aga sig-
`nifcan reduction in total nkrogen creatine airagen,
`
`supessiing further poprovwoient in -nimegen balance on
`thesecandheruand minuire,
`
`Table? SRact af Keto Acid Agmanisivation on UrinaryPartition
`of Kilragen.*
`
`cs Nk Se
`EN
`
`Pee
`
`Conga
`
`Midis
`
`ate
`BOM
`
`
`BNE
`15
`
`cet 4 20 48
`
`is
`AeSE
`
`3.58
`S63
`
`Atk HR
`
`Mordh fo
`%oP
`Sf
`2.73
`3, PRE
` ape weRAS. EE CONS deunees ereathune Siiscigen, ii urea ribeegen, AGS
`
`
`arnenms wtteges, LES
`ucie act titeges, TN amet abragen & ON sendeemived
`anc
`‘Shantz cnlsodifferent loomacatired dye, GOS.
`
`<igenss
`eatydifforainfear camming 9 1 DN
`
`SSign
`cisoibydifdecwat fran bio fg oc SUL:
`
`Table 4 opeipares calculaterivenabe wah esti
`
`geabalaace. A sivnificant inerease inchas dilicrerce is he-
`ed when che contral period is compared with bath bete
`acid ireairuen: periods. Again, chiese data suggest chat in
`proavsmentin nitrogen balance occuxved. “The smal) ite
`cPeune ie nitrogen tatiake on keto acidsherapy waa not duke
`to diet but racher ta the pitroges in the gelatin capanins
`cootaioiig ine redivatice.
`
`Pisema Free Amine d&cids
`
`Table 5 shows.dhe changes in plasma amind acid con:
`
`
`
`cenkravions
`during pro.restrictionand during traléal
`hetacd admimsiagan. foiial shoarimeliies mchuded a
`
`mid clevadon in giveine (0.313 mM, the normal range he-
`ay 3, EES to (E502 yeh) as well as marked elevaticey in
`ghitamine and alanine (measured by enayniadc methods,
`astinted shove). Phenviaisaine wap abnormally|how(LOS
`red, che porva range being 00959 wO.07T ma). Buring
`the perlod-of oral berg achd adoinisiratingn, thers was ar
`
`
`omignificaatiy d fesendthos contrat tet O03.
`
`1
`cindhe amine acids carr.
`
`
`tered heta ucids. Large quactities af atloisatenc
`peared when the keto analogue of polcucine was admis:
`wred in Mix Lbordisappeardd when this companent was
`
`spntinaaed in Mie EP
`
`
`
`phenyl pe
`3
`the admuniscation of 20 pda ad
`
`ravate br Ma1, dee placepeevylulaviresevel remained
`
`iowonthe sixth day. The plasma phenylalanine coneen+
`lation returned to porreal alter ue: dase of pheovipyriuc
`
`PRLS §
`qa ncrensed todgper day
`
`Ehscuission
`
`
`This cbid has rang of the clinical features fennd is
`
`:
`i
`hangyt phos:
`
`
`SO! Ver of the six previously reparted
`
`din children well below one yearal
`age. Furthermore, three died belare reaching the agd of
`
`i2months, and the others have nobeen follawwed beyond
`iSraontfs of age. Hencecur panernisurnenal mittghe
`has Sue
`#3
`OE
`
`protebt iuake,
`b
`‘ertheless 3ISTpotentndiv retarded
`and hentiparcic, +nh seizures and recurrent episodes of
`jechargy,
` aor oDinheriiancie Gf heperammnanemia Type
`The ps
`
`se dehielency) is ure
`iL icarbamy! phosphate ayribets
`
`
`Table S, Plaseia Aniine Acid Conmantrations {Fasting}.
`
`Skat
`DRO L
`ERA TIE DE TRATED
`NORATAR.
`
`
`AIDS
`Dax oF THrkesy (6t}
`Rawge*
`MIKEY
`MEADE
`
`TAME RS,
`
`MOREL
`
`fap
`
`at
`
`Anh
`
`erospmiding io ingested keto wold
`GSH A2
`a3 GBH
`BATA
`BONSE89
`TG Riss Rts
`HASH
`Tass DO OG O-GIRO09
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`UBL
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`
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`QUIK
`HA GMS
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`B2a
`R324
`BABS,
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`2
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`GGA ESOLTS
`ROSS
`Omndihine
`
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`OWSGB 24
`Rag
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`
`
`The New England Journal of Medicine
`Downloaded from nejm.arg at UNIV OF PENN LIBRARY on April 18, 2015. For personal use only. No other uses without perrnission.
`From the NEJM Archive. Copyright © 2010 Massachusetts Medical Society. All rights reserved
`
`Par Pharmaceutical, Inc. Ex. 1024
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 4 of 6
`
`
`
`Wed, QU) Men 21
`
`REPO? ACER 220
`
`DAL RY PERAMMUGNEMIA -- dhe
`
`
`
` AL. O89
`
`
`etiwith cecre:
`ions Of synania
`
`ases. In plaarin concerir
`
`
`edhuhe tauial rar
`Dheschic
`aitebaisoiie io netraal levels.
`
`
`Ae
`
`nore of the five
`Phe mixture was
`SETHE
`
`
`
`
`acid chromanararan ielicuncd aa
`3
`when amigo
`
`
`wikalance: We suspecr
`thai further changes bn dae nx
`ture wil be needed, poesthly incadiag the addition af
`
`threagine, Gyplaphan, husidige, fsing and arginine,
`The final miniure of Revaackts for chronic therapy will be
`determinedby moniioriog of the plasma araacids andl
`
`clinical response.
`The use of hercackis in the deerapy of ayperarn<
`PRonen
`
`
`ia representa dogical approach ta the manage.
`
`
`montal inborn errors of
`sbolisne, The adoininirati
`of a subsirate, do che form af heie ands, permits che in.
`SeoP DMRINE edithe preanuxsd firma carne, AMOS,
`
`Werinal sane, The eve
`ritual sunecesGS 3H) OT patientsAB
`
`be mcasured wrly in terns
`$etvare control, aitestion:
`de
`oo, a .
`
`
`
`% e
`
`sis.
`
`oti. However, there 13.2
`
`
`
`Type T dernnhine (rare
`
`7Apapens’s baenily histas
`paterof ihertasce distalte euler K-bahed or
`
`
`ausrecessive, There are several cases of migraine
`onthe autenialside ofcur patient's faodly, fe woudbe ol
`interest ta dwerming whether these damnly members are
`protein untcdcrasi,
`The seurplogicsequciie af itis discace, aawell as of ibe
`uther urea gale cngvme deficiencies, are though we be
`
`CORSEaces Of high arcmin devebrin blood and brain.
`‘The sauonake for osing heta nents to coduce hyperant:
`mamemia and the possible daggers may be sinteras
`fallows: kero annlogues of methionine avd phenylalanine
`reduce: ghuzamine devels by reacthag ia the Lever with
`giutarniog.’* Branchesd-chain keto aculs imay reduce ala
`nino release Pssoy oynecde 48 Thas thess comprrurads direct
`labile ttre
`on tg eseenial amino ackia, which coal tes
`
`
`
`be oped far praitin svethesis, Masiarnmonin levels
`maghiaubsequenilyJab as whaamine, alagincaral atherLa
`bile ckrogeneas campautds are reduced treard varraal,
`
`Oniheaher hand, amansientrise inammonialevels afer
`
`
`
`ries ok
`iaiwachis udphiasecdns coedlang sae folineing
`
`reactions, dP the deamidation of a- Relnglutoramate iste;
`
`
`Dy isrelauvely rapid as comparcd wathe amination af a-ke-
`togluimate (sect):
`
`ikeach + phriamine
`
`Shilarine Ginsariingss
`ze
`weeny
`
`w-herog) ucaraniae +.
`amino asid
`
`gia Reweglutaramate
`
`Quea STAS
`ete
`
`schategeiniarate + M42),
`
`phoinmate dehedrogenage
`Decbenighuiurate + WH,
`see
`
`ghnamate.
`
`
`
`
`Furthermore, onteward metabalic efiects of ih
`AY
`
`qonads might occur ai high concentrations: such: as ine
`
`hibliion of gluconeogenesis lrani certain substrates 7? in
`te anchethehain Ketoucluria, the helo anglopaes of val
`Mac, leucine aad isulencire: acciamiudate in plustua, add
`
`thereis seame evidence chat tess
`compounds are respon
`
`sibie for the symipionis pf ahis dineasc,°" Hawever, toxic
`
`
`
`side elects have-nat bern found with the cliniwal use of
`
`ketosckis iportal-sysatemin coccphalopathy, chrandcre
`
`nallabure, and starvation, 82822
`
`fay Gur pariens, che increase in plasma coneenitrationsof
`
`yale, casthionie,
`iautine, albolsoleucie, sultuciac,
`
`pheaviaieniog anclevrosing after che infusion
`(Pig. 4) pra
`aides Madence that these heia ackds are tranearmiowed to
`they corresponding aiming acids. Concentrations of ses-
`
`erabLaminc sods fell, Atransieni tise in plasma ammonia
`
`was hidecdseen bur by thencacday, Ue:level had fallen cc
`noel.
`During dhe M-day sundy of oral keto agul Lherapy:
`marked day-teaday varisdins by plasm ammanis, gine
`
`
`mlacand alanige were observed despite atovatam let,
`"The appancny nocturia rwe in a AL anergy ghaa-
`
`
`mine and alanive may reflect glucanecagenesis during the
`carh-riorinog hours,
`
` FAD RIORUES DWE ASSOC AE
`
`
`YVhe oral acdeaaimiratonof he
`
`
`We areindebank os Lr. KW. how for sesistance with che
`as-
`
`
`via Poatler dohee Garvedes, Vaheriw
`aaoal Heer eareyris cared fe
`
`
`
`endtolihe Pesligeric
`iaranond, Rober: Ward areche nurdine
`CBnival Research Line of Jokos Hopkins ‘Hosp val for techwical
`
`ASSISEATICE.
`
`Rererances
`
`aunbel disarders of the vies oyele aad sanimoms
`
`nagy Paediate 3:
`2, RTD
`
`a RO Matsuda fA case af
`cartaniyt phosminie synthetase
`
`ae
`o3 Exp i“Aa pa, ie
`
`senBiad wntine
`
`RGA, 1974:
`
`
`% By Birahark Ke The
`ries aasish plasites, :tab cha MesaSBBG5-wa,
`
`
`
`ane pis Comparative@ biechemistey Of afta aque
`of IER 4.myde SORES,
`ike REL 3
`
`
`iP Biot Chem
`Yo. Yaehpha d:
`ion GF micré amounts af caroumnyt phowphare
`
`Anal Blower32:1 54-461. 2993
`& Chow KW. Walser A> Substitution of five assmaliid secsind aide hy
`
`thelr sigha-ketansiaguas in the diet of nasa,
`ay HRLAGEES,
`14
`
`Levin B, Dadi RH, Bu
`
`
`
`foe of daticumery af
`
`hit AG ALG LORS
`
`
`i. Walser M. Lund 0: Rade
`
`6 from thaw oalxs
`
`
`iss Esswerat 5
`
`
`fH oRHasson AL,trey aie
`ior
`ase DA.
`
`a the, cupric
`anihrolkie ate
`
`
`sy. Edied te bk. Skegos Fy New
` as EL
`aisdor deternsdnistion of
`
`&sassusiessics,“ol Cheon 4 3
`f
`
`FeROS BB, “ean AS iingroved seco for the estinvated: of
`4
`PLEA, P96s
`
`monka-ia ners
`
`ammuriaspecttic
`
`aedes: ER:
`tases Butane anon yourins cones
`
`
`
`
`sh Prac See Exp Bick Med BMA
`:ie
`ip
`i
`a
`
`‘
`
`is
`tS,
`
`is,
`iF
`
`3.
`
`x
`%
`
`4.
`4,
`
`A,
`
`pig -eneymes is the
`
`The New England Journal of Medicine
`Downloaded from nejm.arg at UNIV OF PENN LIBRARY on April 18, 2015. For personal use only. No other uses without perrnission.
`From the NEJM Archive. Copyright © 2010 Massachusetts Medical Society. All rights reserved
`
`Par Pharmaceutical, Inc. Ex. 1024
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 5o0f6
`
`
`
`EORG
`
`“ORES
`
`DW BRCLAND {OURSAL OF MEDICINE
`
`May 22, 1075
`
`oR ter AW. Taeke‘s
`
`:
`sidetatn
`
`i
`
`ae
`
`nea Py. atat: Lethal nedaa-
`
`agdele grnhiqg-tey
`arbamyhae
`A
`E, Fabsan OL et al: Mensbalic 9
`
`Soumnichine transs,
`.
`
`23
`2
`
`25
`
`2h.
`
`ER.
`
`ve
`al, Theethentai &
`oo. Walker, ©
`chrwue urcmis.. £7is Tiwess
`if
`easentind pining acids iss sev
`
`SPR49G, (NTS
`
`
`
`
`IR, Saige Dh, Ownn Gh, Pasetsky S, eth Nitanee sparing induced by
`Aowdiave at vasesithal amines acids ches chielly as tivities weteanse
`figaies. churings prolonged saarvation in chess subjects, Pie Pavesi
`SAN04- 980, HBTS
`
`1. Annie BDL
`
`Bhave LEA sissdy Ot phase Fone sapesiscy aie evs
`
`
`
`1h. Nonmul vatues fir
`hildeen and wlutis,. Metubobies 22;566-569,
`23974
`if, Preonn Jo Nichohon JP, Scismke RT of ab Conpeuid hyper:
`ammImeriay
`association wh fypergiycenvia
`and decreasud
`levels ah carbadiyl phosphate syntieiase. Arch Neural 2h 49p457,
`iat
`2. Geishres TE Smuadurase Pd: Lathe asmdeficinacy oF vasteryt
`
`
`phouptme svmbhetust.
`4
`Eagt f Mod 294 8-30. p76
`
`2. Dhligers M. Charpentier O. Cathetf., otal: Myserammonidmic
`SOnsalutaannelis
`aves tiel. es catephesphar-syudkdase.
`
`
`Arch Fe Pedig iy 004-12, 1974
`22: Bormmes BA, Tetroot Cl, Wieunk OY) etal: Carkoamlpphate
`ayntiiade deficiune y jn as isfant with severe carchral damage. Arch
`ies Chas $-888-0033, $004
`
`HEMDLVIIC DREMIC SYNDROME IN FAMDLTES
`
`RCP.
`ferewarn dt. Karian, MB. Bow.
`{S.A}, Russe. W. Cressey, MD,
`
`ERCP. i}
`AND Kerr NN. Dawsons, MOD ULM,
`
`Abstract The auturrance of tha haemolytic uramic
`syadromeia tren abings prompted uate stady this tb
`neas iniamilies, Two orouns of patients could he iden-
`dfled when BG siblings with thesyndrame ind) families
`wer exemniied. Bioline whee onset occurred within
`a shorl lime ol each other had a relatively good prag-
`
`noes Sper cent murialiiyh those whose araed was
`more thn a year apart bad a poorer pragnosia (85. per
`gent morahty). We specuinie that se ervicanrncn tal
`agent may have caused the syndrome in the first grown,
`ard ial gunetic factors may have bean ioipertand inip
`sacond(N Engld Med 252770301083, 1878)
`
`
`AEMay presented 4ndTable i. Thenefonewas € characierited by
`
`WE fading of mixreengiopathic hemalyuc anemia,
`
`i
`une dewsig as
`g
`pieoniaauatoliguai.Wocet andabuse
`dhrombecytopenia and cenal faihwe, Chemalvii wre
`
`
`
`
`REsyndyonie) inthe three siblings described belowsain.
`
`
`intake arelidiy canals. and hewastried wiih heparin,
`
`
`Watcda study of howlreds wih sitilihag involvermenr
`“This
`
`
`
`
`rovitimestecowts,axa HMaogr ine and
`pay eresSRE Ageeeres, Bhevat hy
`f
`
`anaes of 41 Lamilies nawham tec orshree children hal
`arred dius aher ousetid Une dae.
`
`
`the syadrome revealed neon prouips of patients. Phe dilter-
`
`
`Case Z 4 severgetuleobswg)
`3 atENEREameeeat &sya bb wee
`
`enepswerc as toilows: the buerval betwooathe enaet af the
`asthe)
`
`svodrame within asibship: wherher thesiblings Bved inan
`ahead thatwas eaceuin ap nonendemc ler the sera ros:
`areltheoutcoardolihe lhwss.
`aOHOTERAN:
`ston andl vine ches
`
`
`Aatheore otrhe pathogenens ofthe haradlyic arene
`Sher was
`ircaied with be;
`oa
`control of Buidead olen ayae rake arash fsien
`
`
`syadrosi musraccnunt ion dillererces in ke geographic?
`
`
` ape aad racul! disuandinas.The ocencrenie in siblags
`inconpestive hurt iadace DO weeks barr,
`
`rates che possihiliey of a generic predisposition. On the
`Case 3. Aunecnamh-old buy (brother ed the neo mfients dle.
`
`basis of this analysis of lawdllal cases
`we propose. thar
`genetic actors are aulihely.io be ad primary importance in
`
`
`Lahoraary
`tbe majority af patients, However, there de appar ta be
`
`
`pres hege thse
`
`ste 3, ueineoutget wagnrormal for che firs
`apme lames bewhore there may be a ecuenc predigpost-
`len followed
`ly sevtre alignurin. Hehata aesteral
`doniothe developmencol the ines.
`
`wher pheeed sie
`
`ile, hydrals
`
`Case KReeanrs
`
`Cased, Awdighemeansh old buy owas admincd wi the fospinal
`
`
`hes: 1, SORT with a tevesday Riscary of aterexia: ip-
`eat
`
`phabiiny
`and pallor. Purparbspnwere rated. The Mord ares.
`
`anre was L1Gmon He. The daborateryvalues obtained om ad-
`
`Mission ard che mada ubnornd dovels daring the masse of his le
`
`
`Frum da feparimont of Nephruhigy, MoOUniverdiy-Monweal Chil-
`
`
`
`Hospi Reseanch Tasiine, Montreal £2), Canady Geldress seoptint
` reQurs
`
`ia Dr Kaplan alite Depatasendt of Neopheogy, Masuvest Chil
`
`dion’ s Rospital,
`2MTapper Ai, Mauss
`naviHOE (P33,
`Pyfrom the MedicaResearch Cuuiacll
`Seapspsasstend toya teres wrens ghyF-) 5
`al Casoibe,
`
`Peesenitert in part at the Third ietersaticinal Sysipevaen of Peuiasei
`phakic, Mcashingion, DAL), Semember 3) 1978,
`
`
`
`dowie ty wach
`
`grasarcsltusear
`
`sunmarizcs.,
` ferent and diferent renal arientohes were
`
`Phe humens ad che af
`
`ery
`tareby eenigoelned
`eel swelling and subendackeliat ac
`
`
`
`wetainiog maternal, Samal ihe
`of Bbrin anid a hpi
`clmplauon
`
`:
`
`
`
`The New England Journal of Medicine
`Downloaded from nejm.arg at UNIV OF PENN LIBRARY on April 18, 2015. For personal use only. No other uses without perrnission.
`From the NEJM Archive. Copyright © 2010 Massachusetts Medical Society. All rights reserved
`
`Par Pharmaceutical, Inc. Ex. 1024
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 6 of 6
`
`