USSN: 12/820,866
`
`paragraph [0020] of the original speclfication and therefore, the present amendment to
`
`paragraph [0020} contains no new matter.
`
`I hereby declare that all statements rnade herein of my own knowledge are true
`
`and that all statements made on information and belief are believed to be true; and
`
`further that these statements were made with the knowledge that willful false statements
`
`and the like so made are punishable by fine or imprisonment, or both, under Section
`
`1001 of Title 18 of the United States Code, and that such willful false statements may
`
`jeopardize the validity of the i359 patent.
`
`\'Respectfu!!y .. submitt~d.
`
`'\ \\ \~)""~c:2---
`
`Jonilt~&in N) Provoost
`Attorney for Applicant and Assignee
`Associate General Counsel
`lkaria
`6 R.oute 173
`Clinton, NJ 08809
`Direct phone: (908) 238-6392
`Cell: (908) 391-3440
`Fax (legal dept.).:
`(908) 238-6773
`jonathan.provoost@ lkarla.com
`
`Dated: July 7~ 2011
`
`Page 4 of 4
`
`Ex. 2024-0881
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`

`
`USSN: ·t2/820,9'8G-
`
`-EX.HI.BIT 1
`
`ONOmaxAt pt\!Scribing infbrmatkm ··· 2009)
`
`Page 5 of 5
`
`Ex. 2024-0882
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`

`
`--
`
`-
`
`INOmax® (nitric oxide) for inhalation
`100 and 800 ppm (parts per million)
`DESCRIPnON
`INO!nax (nlttfc Oldde gas) Is a drug administered by lnhalaUon. Nitric
`oxide. the act1w substance In INOmax.ls a pulmcmary vasodilatot.INOmax
`Is a gaseous blend of nitric oxide and nitrogen (0.08% and 99.112%.
`respectively for 800 ppm; 0.01% and 99.99%, respedlvely lot100 l)pm).
`INDmax Is supplied In aluminum cylinders as a compressed gas under
`high pressure (2000 paunds per square Inch gauge [pslg)).
`Tile structurallomtula Cl1 nltrtc oxide (NO) Is shown below:
`. -
`.
`• •
`• •
`N -o·
`
`CWtiCAL PlfARl'IACOLOGY
`Nitric oxide Is a eotnpaund pruduced by many cells olthe body. It relaxes
`vascular smooth muscle by lllndlng to the heme mc!ety of cylosolic
`guanylate cyclase. acUva1Jng guanylate cyclase and Increasing lntracellu·
`lar levels or cyclic guanosJne 3' .S'·monopltosphate, wlllch then leads to
`vasodllatiOIL When Inhaled, nitric oxide produces pulrngaary vasoclllatlon.
`INDmax appears to Increase the partial pressure nt arte11a1 oxygen (Palla!
`by dilating putmonery vessels In llelter ventilated areas ol the lung, redls·
`lrlbut!ng putmcnery lllood flow away from lung regions with tow ventlla·
`llon/perluslon (VIOl ratios toward regions with normal rallos.
`Effects oa Putmoaary vascurar Tone rn PPHH
`Pefslstent ~ hypertension Gl the newborn (PPIIH) occurs as a
`pfimary daveiGpmental defact or as a condition second81Y to other dis·
`eases such as meconium asplrallon syndrome (MAS), pn111111onla, sepsis,
`h)'allne memlmlne disease, congenital dlaphragmat!c lternla (CDH), and
`pulmonary hypoplasia. In these states, pulmoRa~Y vascular resistance
`(PVR) Is ttl"'- which resulls In hrPOX8JIIIa second81Y to rlghl·to-lett sttunt·
`lng ol blood through the patent ductus arlel1osus and toramen ovale. In
`neonates with Pl'tiN, INOmax Improves oxygenation (as Indicated by slg(cid:173)
`nlflcant Increases In PaOJI.
`PHARMACOIIHmCS
`Tll8 phannacoklnetlcs ol nitric Oldde has been studied In adults.
`Uptake and Dlstrlllutlon
`Nltl1c oxide Is absorbed sys!Bmlcally alter lnhalallon. Most ol It traverses
`the pulmonary capillary lied wilere It comlllnes with llemcglobln that Is
`60% to 100% oxygen-saturated. At tills level Gl oxygen saturallen, nitric
`oxide combines predomlnantlv with oxyheme!)lollln to produce methemo(cid:173)
`globin and nitrate. N.low OXVfl&n saturatlen, nitric ox[de can cnmblne with
`deoxyhemogiGbln lo trans!eniiV lerm nitrosylllemoglellln, which Is cnn·
`verted to nitrogen oxides and mall!emoglobln upan exposure to oxvgen.
`W"l1hin the pulmnn81Y system, nitric oxide can comll[no with oxygen and
`water to l)roduce nitrogen dioxide and nlll1te, respecttvelv, which Interact
`wHII oxy!lemoglebln to produce melhemaglobln and nitrate. Thus, tho end
`products of nitric oxide that enlotllte syelemlc circulation are predaml·
`nanUy metllemogtollin and nitrate.
`Metallcllsm
`Methemoglobin dlsposltlcm has been lnvesUgated as a runctlnn Gl time
`and nitric oxide exposure concentration In nennates will! resplratary tall·
`ure. The methemoglobin (MeiHb) concenlraUan-tlme profiles during tile
`flrs112 l!ours ol exposure to 0, 5, 20, and 80 ppm INOmax are sttown In
`Agure t.
`
`flfllll81
`MeiNrnogiGII!n camcnlratm • Time Profiles
`Heanates Inhaling O, 5, 20 or 80 ppm IHOmax
`
`s ... s • r ! •
`
`i
`
`"#
`
`-.,_.a.u I ... Cit • 41)
`
`............. _ ......
`
`_.,_.._.n_o-••1
`-e--..u•-o-·m
`
`I
`
`.L-~--~---L--~--~~
`I
`I
`4
`I
`I
`11
`'tl
`lhlurs ol INOmax Admlnlstratm
`Melhentoglollln concentrations Increased dul1ng tlt8 11rst 8 hours ol nitric
`oxide exposure. The mean methemoglobin level remained beloW 1% in the
`Jllaeello group and In the 5 ppm and 20 ppm iNOmax groups. but readied
`approximately 5% In the 80 ppm IHOmax group. M81hemoglollln levels
`>7% were attained on1J In patients receMng 80 ppm, w11ere they com·
`prlsed 35% ot the group. The average ume to reach peak metllemoglollln
`was 10 :1: 9 (SD) hours (mecllan, 8 hours) In these 13 patients: but one
`patient did rwt 8IC88d 7% unUI40 houra.
`Elimination
`Nitrate has been ldanUfled as the predominant nitric oxide metabolite
`excreted In tile urine, accounting for > 70% ol tile nltl1c oxide dose
`Inhaled. Nitrate Is cleared from the plasma l!y the kidney at rates
`approachlng the rate ol glemerutar flltrallon.
`curtiCAL TRIAlS
`The elflcacy oiiNOmax has been Investigated In tet111 and near-term new·
`boms with h}poxlc respiratory !allure resulting trom a v811ety Gl ettolo·
`gles. Inhalation ot INOmax reduces the oxvgenatlon Index (01, mean air·
`way pressure In em HaO x traction ol irl$lllred oxygen concentraUon [FIOzl
`x 100 divided by sys!Bmlc ~rial concentration In mm Hg [PaOiJI and
`PHARMACOLOGY).
`Increases Pa02 (See CUNI
`
`1
`
`NINOS study
`The Necnalallnha!ed Nitric Oxide Study (NINOS) group conducted a dauble·
`blbtd, randontlzed, placebo-controlled, multic:en1er tl1al In 235 neonates with
`hypoxic respiratory failure. Tll8 olljective ol the study was to determine
`wltelher Inhaled nitriC OXide WGuld reduce the OCCIIIT1lrtC8 ol death andlot
`lnltiallon Gl extracorporeal memblane oxygenation (ECMO) in a prospectlve(cid:173)
`ty deHned cohort of tet111 ot near·term neonates wlthllypoxlc respiralllly fail·
`ure unresponsive to cmventional therapy. Hypoldc respiratory failure was
`caused by meconlum aspiratian syndrGme (MAS; 49%), pii8Uill00iaisepsls
`121%), !diopatltic prirRa~Y l)ulrnonary trnJe1111nS1on of tile newborn (l'l't!N:
`17%), ot respiralllly distress syndrome (RDS: 11%).1nlants s14 days ol age
`(lllNII, 1.7 days) with a mean PaO, af 46 mm Hg and a mean oxygenation
`Index (01) of 43 em HaD I mm Hg ~initially randomized to receive 100%
`"<!with (n=114) ot w1t1tout (n=121)2.0 ppm nitric OJCicle for up to 14 days.
`Response to study drug was del!ned as a change lrum baseline in PaO, 30
`minutes alter starting treatment (lull response = >2.0 mm Hg. partial =
`11HG mm Hg. no response = <10 mm Hg). Neonates with a less than lull
`response were 8'181uated lot a response to 80 fllllll nitric Oldde ot control
`gas. The primary results lrum the NINOS study are presented In Table 1.
`Tale1
`SUmmaJy of ClilliW Results from NIHOS S1udy
`
`O;r:t(i
`(0=121)
`77 (54%)
`20 (17'1!.)
`66(55'<,)
`
`NO
`{0=114)
`
`52 (46%)
`16(14%)
`44 (39%)
`
`P~<J).l')
`
`0.006
`0.60
`0.014
`
`Cll<!Ul or ECMO".I
`Ceatta
`ECMO
`
`• EJdracolporeal membrane oxygenali0t1
`t Death or need for ECMO was the study's primary end point
`Allhaugh the lnddance of death by 120 days ol age was Similar in bCI1h
`groups (NO, 14%; control, 17%), slgnlllcantly fewer Infants In the nitric
`oxide group required ECMO compared with controls (39% vs. 55%, p =
`0.014). Tll8 eotnblned Incidence ol death and/or Initiation of ECMO showed
`a Significant advantage for the nitric oxide trealed group (46% vs. 64%, p
`= 0.006). Tll8 nitric oxide group also had significanUy greater Increases in
`Palla and gJeater decreases In tile 01 and tile alveolar-arterial oxygen gra(cid:173)
`dient than the control group (p<0.001 lot all parameters). SlgnlftcanUy
`more pallents had at least a parllal respanse to the Initial administration ol
`study drug In the nitric oxide group (66%) than the control group (ZS%,
`P<0.D01). Of the 125 Infants who d'KI not respond to 20 ppm nilric
`oxide or control, similar percentages ol NO-treated (18%) and control
`(20%1 patients had at least a partial respanse to 80 pJll11 nitric oxide
`lor inhalation ot control dru!J, suggesting a lack ol additional benefit
`tor the l!lgher dGSB ol nlll1c oxide. No Infant had study drug dlscon·
`tlnued for toxicity. Inhaled nitric oxide had no detectable effect on
`mortality. The adverse events collected in the NiNOS trial occurred at
`similar Incidence rates In bGth treatment groups (See ADVERSE
`REACTIONS). Follow-up exams were pertormed at 18-24 months lor
`tile Infants enroned in this trial. In the infants with available follow·
`up, the two treatment groups were slmilar with respect to their men·
`tal, mGtor. audlologle, or neurologic evaluations.
`CINRGI study
`This study was a double·bllnd, randomized, l)lacebo·conlrolled, mul· -
`Ucenter trial ol 186 tet111 and near-tet111 neonates with pulmonary -
`hyperlenslon and hypoxic resp!ralllly failure. The primary cbjectlve ol ~
`the study was to determine whether INOmax would reduce the receipt -
`el ECMO In these patlents.llypoldc respiratory laUure was caused by - (cid:173)
`MAS (35%), ldlopatltic PPHN (30%). pneumonia/sepSis (24%), cr RDS
`(8%}. Patients with a mean Pa02 Clf54 mm Hg and a mean 01 of 44 em
`HaD I mm Hg were randomly assigned to receive either 20 ppm
`INOmax (11=97) or nitrogen gas (placebo; n=89) in addition to their
`ventilatory support. Patients who exhillited a Pa02 >60 mm Hg and a
`pH < 7.55 were weaned to 5 ppm iNOmax or placebo. The prirRa~Y
`results from the QNRGI study are f)leSenled in Table 2.
`Tallie 2
`SUmm81Y Cl1 Clinical RaWls from CINRGI Study
`
`ecwo·.r
`Death
`
`Placello
`51189(57%)
`5189!6%)
`
`!'lOmax
`30197 (31%}
`3197 (3%1
`
`Pval.e
`<0.001
`0.48
`
`• Extracorpareal memllrane OXV!Ienation
`t ECMO was tile primary end 1J11int ol tl1is study
`SlgnlficanUy fewer neonates in the INOmax group required ECMO com·
`pared to the control group (31% vs. 57%. pdl.001). Wllile tlt8 number ol
`deaths were similar in both groups (INDmax, 3%; placebo. 6%), tile eotn·
`lllned lncldente ol death and/or receipt Cl1 ECMO was decreased In the
`INOmax group (33% vs. 511%, p<O.oot).
`In addition, the INDmax group had signl6canUy improved OxygenatiOtl as
`measured l!y Pa02- OJ, and aiYeolar·arterlal gradient (p<0.001 fer aU
`parameters). 01 the 97 patients treated wltiiiNOmax. 2 (2%} were with·
`drawn from study drug due to methemoglobin levels >4o/o. The frequency
`and number of advefse events reporled were slmilat in the two study
`groups (See ADVERSE REACTIONS).
`ARDSstudy
`In a randomized, double-blind, parallel, multicenter study, 385 patients
`with adult respiratury distress syndrome (ARDS) associated with pneumo·
`nla (46%), surgery (33%), multiple trauma (26%), aspiration (23%), pul·
`mon81Y contusion (18%), and other causes, with PaOJA02 <2SO mm Hg
`despite optimal oxygenation and ventilat!Otl, received placebo (n=193) or
`iNOmax (n=192), 5 ppm, fot41tours to 28 days ot until weaned because
`ol Improvements in oxygenation. Despite acute improvements In OJCY·
`genauon, tllere was no effect or INOmax on the primary endpoint of days
`alive end off ventilator support. These results were conslsl8nt with out·
`come data lrum a smaller dose ranging study ol nitric Oldde (1.25 to 80
`ppm). INOmax Is nGt Indicated lor use In ARDS.
`
`Ex. 2024-0883
`
`

`
`INDICAnONS
`ventilatory suppart and allier appropriate
`INOmaJC, In conjuncllon
`agents. is Indicated far lila reatment ol term and near-term (>34 weeks)
`neonates with hypoJic re plratory !allure associated with clinical or
`or pulmanary hypertenslan. where II
`ecllocanllographlc evlde
`uces the need for exlnlcorpontal membrane
`Improves oxygenation and
`oxygenation.
`CONiliAINDtCAnONS
`INDmax sllould not be used In tile treatment or neonates known to be
`dependent on rlgltt-to-leH sllunling ol blood.
`PRECADnONS
`RebGUIId
`Abrupt dlsamlinualion or INDmax may lead to worsening oxygenaUon and
`Increasing pulmonary artery III'IISSIIRI.
`Metllemqloblnemla
`Methemoglcbinemla Increases with llle dose ol nitric oxide. In lila clinical
`trials, maximum melhemoglabln levels usually were readied approxl·
`malely 8 hours after lniUauon of Inhalation, allhough methemoglab!n lev·
`els have peaked as lata as 40 hllurs lollowing Initiation oiiNDmax lllera·
`py.ln one study, 13 or 37 (35%) ol neonates treated with INDmax 80 11pm
`had melllemoglob!n levels exceecllng 7%. FoiiGwlng discontinuation er
`reduction of nill1c oJJde the methe1110!110111n levels returned to baseline
`over a pellod Clf hounl.
`Elmded NDz Lnels
`In one study. NDz le'lels wue <0.5 ppm wllen neooates were treated wilh
`l)lacebo, 5 ppm, end 20 ppm nitric OJide over tile first 48 hllurs. llle 80
`11pm group had a mean peak NDz level Clf 2.6 ppm.
`Dnlg Interactions
`No fermal drug-Interaction studies have been perlermad, and a clinically
`Signlllcantlnleradlon with ather 1118dlcauons used In the treatment or
`hypoxic respilalery !allure cannot be excllllled based on tile 8'13llable
`data. INOmax has been adntlnlsleted with tolamllne. dopamine. dolnda·
`mine, steroids, Slllfaclant. and 111gb-frequency ventilallon. Allhouglllllere
`are no study data to evaluate the possillillly, nilrlc oxide c1o110r com(cid:173)
`pounds, Including sodium nitroprusside and nltnlglycerln, may have an
`a11c1111ve effect with INOmax on the risk or developing metllemogtobine(cid:173)
`mia. All association between !111kJca1ne and an Increased risk ol mellle(cid:173)
`moglab!nemia, particularly In Infants, has Sli8Cfllcally been described In a
`literature case repott.lllls risk is present whetller the drugs are adminls·
`tered as oral, parenteral, ar topical rormulallons.
`ClrciRG!Jeaesls, Mu1agenals, lmpalrmatl of Fertility
`No evidence of a carcinogenic effed was apparent, at lnhalaUun expo(cid:173)
`sures up to tile recommended close (20 ppm), In rats lor 20 ltr/day for up
`to two years. Hlglter 8lCIJOSUI8S have not been Investigated.
`Nitric oxl1le has demonstrated genatoxlclly in Salmonella (Ames Tes1),
`human lympllocytes, and attar In 111vo exposure In ra1s. Tllent are no ani(cid:173)
`mal or 11uman studies to evaluate nitric oJJda for effects on lertillly.
`Pregnancr; cmgory c
`Alimal repnxlucllon studles ha\'8 not been conducted v.1lh INOmax. Ills nnl
`known If IOOmax can cause 1eta1 hann when admlnlstenJd to a pregnant
`woman ar can affect repnxlucllve capaclty.INOmallls not intended fer adldts.
`Nursing Motllers
`Nitric oxide Is not lml!caled klr use In the edult papulalfan, includlng nurs(cid:173)
`ing mothers. It Is not known wlletller nitric oxide Is 8lCCrlted In human milk.
`Pldlatrlc Use
`NHrlc OJlde fer Inhalation has been studied In a neonatal papulatlan (up to
`14 days or age). No lnfannauan about its elfecUYeness In other age pop(cid:173)
`ulations Is available.
`ADVERSE REACTIONS
`Controlled studies have Included 325 paUents on INOmax doses or 5to 80
`ppm and 251 patients an placebo. Total mortality In the pooled trtals was
`11% em p:lacebo and 9% on INOmax, a result adequate to exclude INOmax
`mortality being more titan 40% wcrse titan placebo.
`In both the NINOS and CINRGI studlas,llle duration olllospltallzatlon was
`similar in INOmax and placebo-troated groups.
`Fntm all controlled studies, at least 6 months ollollow-up Is available tar
`278 patients wllo recelved INOmax and 212 patients wllo received !)lace·
`llo. Among 11tese patlents,tllere was no evidence ol an adverse ellect or
`treabnent on tile need for rehospitalization, special medical semces,pul·
`monary disease, or neuntlogical sequelae.
`In the NINOS study, treatment gmups were similar with respoct to the
`incidence and severity ollntrecrenialhemerrhage, Grade IV hemor·
`rhage, perlvenlrlcular leukomalacla, cerebral lnlarclion, seizures
`requiring anuconvulsanllllerapy, pulmonary llomorrllage, or gastroln·
`tesllnal hemorrhage.
`llle table below sllows edVUfSe events with an Incidence or at least
`5% on INOmax In the CINRGI stud~. and that wero more comman on
`INOmax than on placebo.
`ADVERSE EVENTS IN THE CINRGI TRIAL
`
`Adnne Event
`HYJiolenslon
`Withdrawal
`Atelec1as1s
`Hematuria
`HYJiergtycemia
`Sepsis
`lnlection
`Stridor
`CeDulllis
`
`Placebo (no89)
`9 (10%)
`9 (10%)
`a (!Pol
`5 (6%)
`s (l~•J
`2 (2%)
`3 (3"•1
`3 (30:.}
`o (O~•J
`
`Inhaled ND (na971
`13 (13%)
`12 (12%)
`9 (!Po)
`8 rs•<>J
`8 (B••J
`7 (,.4)
`& (6•<J
`5 (5%)
`5 (S••J
`
`---
`
`OVERDOSAGE
`Overdosage with INOmax will be manliest by elevations In melllemoglo·
`bin and N01• Elevated N02 may cause acute lung InJury. Elevations in
`melhemoglcblnemla reduce the oKygen delivery capacity ar tile circula·
`Uan.ln clinical studies, NDz levals >3 Pllm or methemoglobin levels >7%
`were treated by reducing the dose or, ar dlsconllnulng,INOmax.
`Melllemogtoblnemla that does not resolve aner reducUon or disconllnua(cid:173)
`Uon ar tllorapy can be treated with lntravenaus vitamin C. intravenous
`methylene blue. or blood transfusion, based upon tile clinical situation.
`PDST·MARKmNG EXPERIENCE
`llle klllowlng adverse events have been reported as part al the post-mar·
`kellng surveillance. Tllese events have not been reparted above. Given the
`nature Clf sponteneously reported post-markeUng surveillance date, it Is
`Impossible to determine tllo actual Incidence olthe events ar deflnillvely
`esta!JIIsh their causal relallonsltlp to lite drug. 111e !!sUng Is aljdtabetical:
`dose enors associated w111t tile delivery system: lleadaclles associated
`with envlmnmental 8XIIOSUf8 or INOmaJC In llosllital staff; hypotension
`assoclaled with acute witlldrawal or the drug: hypoxemia associated with
`acule withdrawal or the drug; pulmonary edema In patients with CREST
`syndrome.
`DOSAGE AND ADMIRISTRAnON
`Dosage
`111e recommended dose oiiNOmax is 20 ppm. Treatment sllould be main·
`talned up to 14 days or until lite underlying oxygen desaturallon has
`resolved end the neonate Is ready to be weaned lntm INOmax tlleJapy.
`An lnltlal dose Clf 20 ppm was used in the NINOS and CINRGIIrlals.ln QN·
`RGI, patients wl1ose oxygenallon Improved with 20 ppm were dose·
`reduced to 5 Pllm as tolerated at the end nl4 hours ol treatment. In the
`NINOS trial, patJents w11ose oxygenation tailed to 1m11rove on 20 ppm
`could be Increased to 80 IIPm, bullhose patients did nat lllen Improve on
`the lllgher dose. As the rlslc of methemoglobinemia and elevated N01 lev·
`els Increases Significantly when INOmax Is administered at doses >20
`ppm, doses above tills level on!lnarlly should not be used.
`AdmlllistraUon
`MdlUonal therapies should be used to maJimlze oxygen de!ively. In
`patients with COllapsed alveoli, addltJonal therapies might lncluda surfac(cid:173)
`tant and high-frequency oscillatory ventilalian.
`1be safely and effectiveness af inhaled nill1c oxide have been establislted
`in a populaUun receiving otlter therapies for llypoxlc respiratory failure,
`Including vasodilators, Intravenous fluids, blcartJonate lllerapy, and
`mechanical venUiaUon. Olllerenll!ose regimens far nitric oxide were used
`In the clinical studies (see aJNICAI. TRJAI..S).
`INOmax should be administered with monitoring tor PaDz, melllernogio(cid:173)
`bln, and N01.
`1lle nill1c oJida delivery systems used in the c!lnlcallrlals provided oper(cid:173)
`ator-determined concerrtralions of nitric oldde In the breatlting gas, and
`the concentraUon was canstant thrnughoul the f'I!SIIIratery cycle. INDmax
`must be delivered througtJ a system with lllese chalactertstlcs and wltlcll
`does nat cause generation of excessive Inhaled nitrogen dioxide. Tile
`INOvent., system and otller systems meeting lltese criteria were used In
`the clinical lrlals.ln the ventilated neonate.11recise monilllling ol ii'ISilired
`nill1c oxide and NDz sllauld be instituted. using a property calibrated
`analysis device willt alarms. 111e system should be calibrated uSing a Pf8-
`clsety deflned callbrallon mixture ol nitric oxide and nitrogen dioxide, such
`as INOcaJ". Sample gas tar analysis should be drawn before the Y·11iece,
`proximal to lite patient Oxygen levels sllould also be measured.
`In the event ol a system failure or a wall-oullel power lallure. a backup
`battery power supply and reserve ni1rlc oxide delivery system sllould be
`available.
`1lle INOmax dose sllnuld not be discontinued abruptly as II may result In
`an Increase In pulmonary artery 1118S5UI8 (PAP) and/or worsening ol blood
`oxygenation (Pa02l. Deterioration In oxygenallan and etevallun in PAP may
`also occur In children with no apparent response to INOmax.
`DlsconUnuBiwean caullously.
`HDWSUPPUED
`INOmax (nllrlc oxide) Is available In the following sizes:
`Size D Portable aluminum cylinders containing 353 liters at STP of
`nitric oxide gas In 800 ppm concentration in nitrogen (delivered
`volume 344 liters) (NDC 64693·002·01 )
`Size D Porlallle aluminum cylinders cantainlng 353 liters at STP ol
`nitric oxide gas In 100 ppm concentratlan in nitrogen (delivered
`volume 344 liters) (NDC 64693-llOt -01 )
`Size 88 Aluminum cylinders containing 196311ters at STP ol nllrlc oxide
`gas In BOO ppm cnncentraUon In nitrogen (delivered volume
`191811ters) (NDC 64603·002..02)
`Size 88 Aluminum cylinders containing 1963 liters at STP of nitric oxide
`gas In 1 00 ppm concentrallan In nJtrogen (delivered volume
`19181ltors) (NOC 64693·001..02)
`Stere at 25•c C77°f) with excurslnns permitted between 15-3o•c
`(511-86°f) [see USP Controlled Room Temperatunt).
`OccupaUunal ExiiiiSUre
`Tha oxposure llmll set by tho Occupational Safety and Health
`AdmlnlstraUon (OSHA) ler nllrlc oxide Is 25 ppm, and fnr ~ lite limit is
`5ppm,
`CAUTION
`Federal law prolllblts dispensing without a III8SCriptlon.
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`Application Number
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`12820866
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`Filing Date
`2010-06-22
`First Named Inventor I James S. Baldassarre
`Art Unit
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`I Ernst V. Arnold
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`INFORMATION DISCLOSURE
`STATEMENT BY APPLICANT
`( Not for submission under 37 CFR 1.99)
`
`Application Number
`
`12820866
`
`Filing Date
`2010-06-22
`First Named Inventor I James S. Baldassarre
`Art Unit
`1613
`I Ernst V. Arnold
`Attorney Docket Number
`1001-0002USC1
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`Examiner Name
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`1
`
`Barst, et al. "Vasodilator Testing with Nitric Oxide and/or Oxygen in Pediatric
`Pulmonary Hypertension" Received: 14 September 2009 I Accepted: 19 January 2010 Springer Science+Business
`Media, LLC 201 0, 9 pages
`
`2
`
`Bates, Inhaled Nitric Oxide: A Selective Pulmonary Vasodilator, 2004, 9 pages
`
`D
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`D
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`3
`
`4
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`5
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`6
`
`Beggs, et al., "Cardiac Failure in Children" 17th Expert Committee on the Selection and Use of Essential Medicines,
`Geneva, March 2009, 31 pages
`
`D
`
`Copy of the Canadian Office Action mailed May 31, 2011 for Canadian patent application No. 2671029, a counterpart D
`foreign application of US patent application No. 12/494,598
`
`Douwes, et al. "The Maze of Vasodilator Response Criteria" Published online: 26 November 2010, Pediatr Cardiel
`(2011) 32: pp. 245-246
`
`D
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`Fraisse, et al., "Acute pulmonary hypertension in infants and children: cGMP-related drugs" Pediatric Crit Care Med
`2010, Vol11, No.2 (Suppl.), 4 pages
`
`D
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`7
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`INOmax (nitric oxide) for inhalation 100 and 800 ppm (parts per million), drug label insert, 2007, 2 pages
`
`D
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`8
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`9
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`Kay, et al. "Congestive heart failure in pediatric patients," From the Department of Pediatrics, Duke University Medical D
`Center, 2001 by Mosby, Inc., 6 pages
`
`Definition of Contraindication on Medicine.net.com; http://www.medterms.com/scriptlmain/art.asp?articlekey=17824; D
`retrieved 3/14/2011; 2 pages
`
`10
`
`Murray, Angiotensin Converting Enzyme Inhibitory Peptides Derived from Food Proteins: Biochemistry, Bioactivity and D
`Production; Current Pharmaceutical Design, 2007, 773-791
`
`11
`
`Non-Final Office Action for US Patent Application 12/820,980, mailed on June 10, 2011, James Baldassarre,
`"METHODS OF TREATING TERM AND NEAR-TERM NEONATES HAVING HYPOXIC RESPIRATORY FAILURE
`ASSOCIATED WITH CLINICAL OR ECHOCARDIOGRAPHIC EVIDENCE OF PULMONARY HYPERTENSION"
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`INFORMATION DISCLOSURE
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`Application Number
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`12820866
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`Filing Date
`2010-06-22
`First Named Inventor I James S. Baldassarre
`Art Unit
`1613
`I Ernst V. Arnold
`Attorney Docket Number
`1001-0002USC1
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`Examiner Name
`
`12
`
`UCI General Clinical Research Center, Federal Regulations 21 CFR Part 312,
`«http://www.gcrc.uci.edu/rsa/aer.cfm», retrieved 9/13/201 0, 2 pages
`
`13
`
`NIH CC: Critical Care Services, http://www.cc.nih.gov/ccmd/clinical_services.html; retrieved 3/10/2011, 3 pages
`
`Guidelines for Industry: Clinical Safety Data Management
`«www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatorylnformation/Guidance/ucm073087.pdf>>,
`March 1995, 17 pages
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`15
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`INFORMATION DISCLOSURE
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`( Not for submission under 37 CFR 1.99)
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`Application Number
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`12820866
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`Filing Date
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`I Ernst V. Arnold
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`/David A. Divine, Reg. No. 51,275/
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`2011-07-08
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`David D. Divine
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`Application Number:
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`12820866
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`22-Jun-201 0
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`Title of Invention:
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`METHODS OF TREATING TERM AND NEAR-TERM NEONATES HAVING
`HYPOXIC RESPIRATORY FAILURE ASSOCIATED WITH CLINICAL OR
`ECHOCARDIOGRAPHIC EVIDENCE OF PULMONARY HYPERTENSION
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`Title of Invention:
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`METHODS OF TREATING TERM AND NEAR-TERM NEONATES HAVING
`HYPOXIC RESPIRATORY FAILURE ASSOCIATED WITH CLINICAL OR
`ECHOCARDIOGRAPHIC EVIDENCE OF PULMONARY HYPERTENSION
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