UNITED STAlLS PA (cid:9) LENT AND TRADEMARK OFFICE
`
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`Address: COMMISSIONER FOR PATENTS
`P.O. Box 1450
`Alexandria, Virginia 22313-1450
`www uspnigov
`
`APPLICATION NO. (cid:9)
`
`12/821,020
`
`FILING DATE
`
`06/22/2010
`
`FIRST NAMED INVENTOR (cid:9)
`
`I ATTORNEY DOCKET NO. I CONFIRMATION NO.
`
`James S. Baldassarre
`
`26047-0003004
`
`3179
`
`94169 (cid:9)
`7590
`Fish & Richardson PC
`P.O.Box 1022
`minneapolis, MN 55440
`
`01/31/2012
`
`EXAMINER
`
`ARNOLD, ERNST V
`
`ART UNTT
`
`PAPER NUMBER
`
`1613
`
`MAIL DATE
`
`DELIVERY MODE
`
`01/31/2012
`
`PAPER
`
`Please find below and/or attached an Office communication concerning this application or proceeding.
`
`The time period for reply, if any, is set in the attached communication.
`
`PTOL-90A (Rev. 04/07)
`
`1
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`IKARIA EXHIBIT 2002
`Praxair v. INO Therapeutics
`IPR2015-00529
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`Office Action Summary
`
`Application No.
`
`Applicant(s)
`
`12/821,020
`
`Examiner
`
`BALDASSARRE ET AL.
`
`Art Unit
`
`ERNST ARNOLD
`1613
`-- The MAILING DATE of this communication appears on the cover sheet with the correspondence address --
`Period for Reply
`
`A SHORTENED STATUTORY PERIOD FOR REPLY IS SET TO EXPIRE 3 MONTH(S) OR THIRTY (30) DAYS,
`WHICHEVER IS LONGER, FROM THE MAILING DATE OF THIS COMMUNICATION.
`Extensions of time may be available under the provisions of 37 CFR 1.136(a). In no event, however, may a reply be timely filed
`after SIX (6) MONTHS from the mailing date of this communication.
`If NO period for reply is specified above, the maximum statutory period will apply and will expire SIX (6) MONTHS from the mailing date of this communication.
`Failure to reply within the set or extended period for reply will, by statute, cause the application to become ABANDONED (35 U.S.C. § 133).
`Any reply received by the Office later than three months after the mailing date of this communication, even if timely filed, may reduce any
`earned patent term adjustment. See 37 CFR 1.704(b).
`
`Status
`
`1)Z Responsive to communication(s) filed on 27 December 2011.
`2a)q This action is FINAL. (cid:9)
`2b)Z This action is non-final.
`3)q An election was made by the applicant in response to a restriction requirement set forth during the interview on
`; the restriction requirement and election have been incorporated into this action.
`4)q Since this application is in condition for allowance except for formal matters, prosecution as to the merits is
`closed in accordance with the practice under Ex parte Quayle, 1935 C.D. 11, 453 O.G. 213.
`
`Disposition of Claims
`
`5)E1 Claim(s) 31-45 is/are pending in the application.
`5a) Of the above claim(s) (cid:9)
` is/are withdrawn from consideration.
`6)q Claim(s) (cid:9)
`is/are allowed.
`7)Z Claim(s) 31-45 is/are rejected.
`8)q Claim(s) (cid:9)
`is/are objected to.
`9)q Claim(s) (cid:9)
`are subject to restriction and/or election requirement.
`
`Application Papers
`
`10)q The specification is objected to by the Examiner.
`11)q The drawing(s) filed on (cid:9)
`is/are: a)q accepted or b)q objected to by the Examiner.
`Applicant may not request that any objection to the drawing(s) be held in abeyance. See 37 CFR 1.85(a).
`Replacement drawing sheet(s) including the correction is required if the drawing(s) is objected to. See 37 CFR 1.121(d).
`12)q The oath or declaration is objected to by the Examiner. Note the attached Office Action or form PTO-152.
`
`Priority under 35 U.S.C. § 119
`
`13)q Acknowledgment is made of a claim for foreign priority under 35 U.S.C. § 119(a)-(d) or (f).
`a)q All b)q Some * c)q None of:
`1.q Certified copies of the priority documents have been received.
`2.q Certified copies of the priority documents have been received in Application No. (cid:9)
`
`3.q Copies of the certified copies of the priority documents have been received in this National Stage
`application from the International Bureau (PCT Rule 17.2(a)).
`* See the attached detailed Office action for a list of the certified copies not received.
`
`Attachment(s)
`
`1) Z Notice of References Cited (PTO-892)
`2) q Notice of Draftsperson's Patent Drawing Review (P10-948)
`3) Z Information Disclosure Statement(s) (PTO/SIB/08)
`Paper No(s)/Mail Date 1/10/12.
`
`4) q Interview Summary (PTO-413)
`Paper No(s)/Mail Date.
`5) q Notice of Informal Patent Application
`6) q Other:
`
`U.S Patent and Trademark Office
`PTOL-326 (Rev. 03-11)
`
`Office Action Summary
`
`Part of Paper No./Mail Date 20120123A
`
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`IKARIA EXHIBIT 2002
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`Application/Control Number: 12/821,020 (cid:9)
`Art Unit: 1613
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`Page 2
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`DETAILED ACTION
`
`Continued Examination Under 37 CFR 1.114
`
`A request for continued examination under 37 CFR 1.114, including the fee set forth in
`
`37 CFR 1.17(e), was filed in this application after final rejection. Since this application is
`
`eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e)
`
`has been timely paid, the finality of the previous Office action has been withdrawn pursuant to
`
`37 CFR 1.114. Applicant's submission filed on 12/27/11 has been entered.
`
`Claims 1-30 have been cancelled and claims 31-45 are new.
`
`Information Disclosure Statement
`
`The information disclosure statement (IDS) submitted on 1/10/12 was filed after the
`
`mailing date of the Office Action on 6/27/11. The submission is in compliance with the
`
`provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being
`
`considered by the examiner.
`
`Withdrawn rejections:
`
`Applicant's amendments and arguments filed 12/27/11 are acknowledged and have been
`
`fully considered. Any rejection and/or objection not specifically addressed below is herein
`
`withdrawn. The following rejections and/or objections are either reiterated or newly applied.
`
`They constitute the complete set of rejections and/or objections presently being applied to the
`
`instant application.
`
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`Application/Control Number: 12/821,020 (cid:9)
`Art Unit: 1613
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`Page 3
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`Claim Rejections - 35 USC § 103
`
`The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all
`
`obviousness rejections set forth in this Office action:
`
`(a) A patent may not be obtained though the invention is not identically disclosed or
`described as set forth in section 102 of this title, if the differences between the subject matter
`sought to be patented and the prior art are such that the subject matter as a whole would have
`been obvious at the time the invention was made to a person having ordinary skill in the art
`to which said subject matter pertains. Patentability shall not be negatived by the manner in
`which the invention was made.
`
`The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459
`
`(1966), that are applied for establishing a background for determining obviousness under 35
`
`U.S.C. 103(a) are summarized as follows:
`
`1.
`2.
`3.
`4.
`
`Determining the scope and contents of the prior art.
`Ascertaining the differences between the prior art and the claims at issue.
`Resolving the level of ordinary skill in the pertinent art.
`Considering objective evidence present in the application indicating obviousness
`or nonobviousness.
`
`Claims 31-45 are rejected under 35 U.S.C. 103(a) as being unpatentable over Fraisse et
`
`al. (Cardiol Young 2004; 14: 277-283 IDS filed on 12/27/11) and Atz et al. (Seminars in
`
`Perinatology 1997, 21(5), pp 441-455) and Kinsella et al. (The Lancet 1999, 354, 1061-1065)
`
`and Loh et al. (Circulation 1994, 90, 2780-2785) and Beghetti et al. (the Journal of Pediatrics
`
`1997 page 844) and Ichinose et al. (Circulation 2004; 109:3106-3111: IDS filed on 1/10/12) and
`
`INOmax insert (IDS filed on 1/19/12).
`
`This application currently names joint inventors. In considering patentability of the
`
`claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various
`
`claims was commonly owned at the time any inventions covered therein were made absent any
`
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`evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out
`
`the inventor and invention dates of each claim that was not commonly owned at the time a later
`
`invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c)
`
`and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
`
`Applicants claims, for example:
`
`(Nn'') A madnxi (cid:9) minnitig (cid:9)
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`axicia inn:1nm, wl-wsnia the
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`i3thate'd 33itiC
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`innalcd aarin naidn
`
`Determination of the scope and content of the prior art
`
`(MPEP 2141.01)
`
`Fraisse et al. sought to identify the predictors of extracorporeal membrane oxygenation
`
`therapy, death and response to iNO by performing detailed diagnostic screening with Doppler
`
`echocardiographic screening of the patient, neonates, with suspected pulmonary hypertension
`
`(Abstract; page 278 Patients and methods). The non-invasive technique allows for measurement
`
`of ventricular function and estimates both the direction and degree of shunting including bi-
`
`directional shunting (page 277 right column; page 278, right column; and pages 279-280. Tables
`
`1 and 2 and appropriate text). Fraisse et al. teach that right to left ductal shunting of blood was
`
`found to be an independent predictor of death (Abstract). Fraisse et al. teach that a left to right
`
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`Application/Control Number: 12/821,020 (cid:9)
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`shunting of blood increases the risk of failing to respond to iNO including a patient with severe
`
`left ventricular dysfunction (Abstract and page 281 upper left column). Thus the patient is not
`
`known to be dependent on right to left shunting of blood and the patient had pre-existing left
`
`ventricular dysfunction before administration of iNO was performed. Furthermore, patients
`
`without LVD were provided the iNO therapy (see Tables 1 and 2).
`
`Fraisse et al. teach that 44 neonates started iNO therapy at 40-80 ppm and the clinical
`
`data and hemodynamic characteristics are in Table 2 (page 280 right column).
`
`Fraisse et al. teach on page 281:
`
`A comprehensive echocardiographic examination is
`an integral element of the initial evaluation of new-
`borns with persistent pulmonary hypertension, both
`in order to exclude structural congenital heart disease,
`and to assess cardiac function)1 Echocardiography is
`also a valuable non-invasive method for evaluating
`the degree of pulmonary hypertension, the extrapul-
`monary shunt, and ventricular function.3'"3-12 in
`the present study, the majority of the patients had
`either normal, or only mildly depressed, left and
`right ventricular systolic function. Several factors
`can cause biventricular dysfunction in newborns with
`persistent pulmonary hypertension. These include
`pulmonary hypertension by itself, an alteration in the
`left ventricular geometry due to the pressure over-
`loaded right ventricle, hypoxaemia causing generalised
`myocardial ischeamia, and metabolic acidemia.13 As
`in our study, however, others have found significant
`depression of left ventricular function in less than
`one-fifth of patients with persistent pulmonary hyper-
`tension of the newl3ortL''11 Right ventricular dys-
`
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`Application/Control Number: 12/821,020 (cid:9)
`Art Unit: 1613
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`And on page 282:
`
`Page 6
`
`The results of our present study, however, indicate
`that an exclusively left-to-right shunt across the
`atrial septum increases the risk of failing to respond
`to nitric oxide, with an odds ratio of 7.46, and a
`p value equal to 0.028. Left-to-right shunting across
`the atrial. septum is usual ire newborns with a patent
`oval foramen and normally compliant ventricles, In
`persistent pulmonary hypertension of the newborn, a
`left-to-right atrial shunt associated with a predomi-
`nantly left-to-right ductal shunt and a normal biven-
`tricular function may reflect intrapulmonary shunting.
`in this subgroup of patients, systemic oxygenation is
`significantly less improved by inhalation of nitric
`oxide.' Another potential pathophysiologic mecha-
`nism that underlies this finding may involve reduced
`left ventricular compliance, leading to increased left
`atrial pressure, with a resultant left-to-right shunt
`across the oval foramen. Decreased left ventricular
`compliance may occur in persistent pulmonary
`hypertension of the newborn due to adverse interac-
`tion between the ventricles, a leftward shift of the
`ventricular septum secondary to right ventricular
`hypertension, decreased left ventricular diastolic fill-
`ing, and left ventricular systolic dysfunction due to
`decreased preload, hypoxaemia, and acidosis. Even
`when left ventricular systolic function is severely
`depressed in these patients, the right ventricle can
`maintain systemic output through the patent arterial
`duct. Selective pulmonary vasodilation with inhalation
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`Application/Control Number: 12/821,020 (cid:9)
`Art Unit: 1613
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`Page 7
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`of nitric oxide in this circumstance may not give the
`desired clinical response, because the blood flowing
`across the duct is redistributed away from the sys-
`temic circulation towards the lungs, decreasing post--
`ductal systemic output, and increasing the left atrial
`pressure."
`
`And...
`
`ate at increased risk ofdeath. A pure ith-to-right duc-
`tal shunt tends to be associated with greater need for
`extracorporeal membrane oxygenation, and should
`prompt cautious re-evaluation of the indication for
`further treatment aimed at increasing pulmonary
`vasodilation. The direction of flow across the atrial
`
`The Examiner interprets "reduced left ventricular compliance" to be a dysfunction of the
`
`left ventricle such that compliance is reduced.
`
`Atz et al. teach methods using inhaled nitric oxide in the neonate, which is a child, with
`
`cardiac disease, hence an identified patient in need of nitric oxide treatment, (title and Abstract)
`
`which intrinsically provides pharmaceutically acceptable NO gas for inhalation to a medical
`
`provider to provide to the patient. Atz et al. warn that sudden pulmonary vasodilation may
`
`produce pulmonary edema (page 452, left column). Atz et al. teach that: "Caution should be
`
`exercised when administering NO to patients with severe left ventricular dysfunction and
`
`pulmonary hypertension." (page 452, left column). Since the patients have pulmonary
`
`hypertension as claimed in instant claim 25 then they also intrinsically have hypoxic respiratory
`
`failure in the absence of evidence to the contrary. It is irrelevant how the hypoxic respiratory
`
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`Application/Control Number: 12/821,020 (cid:9)
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`Page 8
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`failure is associated with clinical or echocardiographic evidence of pulmonary hypertension
`
`because the hypoxia is intimately tied to the pulmonary hypertension regardless of how it is
`
`evidenced. Atz et al. continues with: "Therefore, in newborns with severe left ventricular
`
`dysfunction, predominantly left to right shunting at the foramen ovale and exclusively right to
`
`left shunting at the ductus arteriosus, NO should be used with extreme caution, if at all. We and
`
`others have reported adverse outcomes in this circumstance." (page 452, left column) (Examiner
`
`added emphasis). Therefore, it is known in the art that patients who had pre-existing LVD treated
`
`with NO for any duration may experience adverse outcomes. Artz et al. thus identify conditions
`
`in the patients which is screening of the patient. Thus, Atz et al. fairly teaches excluding patients
`
`which include pediatric patients with left ventricular dysfunction from inhaled NO treatment
`
`because the Examiner interprets "if at all" to mean no treatment and hence exclusion from
`
`treatment. The left ventricular dysfunction is intrinsically pre-existing.
`
`To summarize, the methods disclosed by Atz et al. are interpreted to mean:
`
`• identifying a patient eligible for NO treatment;
`
`• diagnosing/identifying if the patient has left ventricular dysfunction;
`
`• excluding that patient with left ventricular dysfunction from treatment with NO
`
`but treating the patient with NO for other conditions discussed by Atz et al. with
`
`inhalation of NO thereby reducing the risk of adverse events associated with the
`
`medical treatment.
`
`Atz et al. teach neonates with pulmonary hypertension (Abstract and page 442, left
`
`column to right column) thus the hypertension is diagnosed in the patient population.
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`Application/Control Number: 12/821,020 (cid:9)
`Art Unit: 1613
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`Page 9
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`Kinsella et al. teach excluding patients (premature neonates) from inhaled nitric oxide
`
`treatment if they have fatal congenital anomalies or congenital heart disease (Abstract and page
`
`1062, Methods). Since left ventricular dysfunction is a congenital heart disease, as acknowledged
`
`by Applicant, (see specification [00281), and it would be pre-existing, then the methods of
`
`Kinsella et al. intrinsically exclude this patient population from the method. The patients also had
`
`pulmonary hypertension which would be associated with the cardiac function (Abstract). Thus,
`
`one or more adverse events are reduced in the neonates excluded from the method. The neonate
`
`must breathe oxygen to survive. Furthermore, if the patients are already excluded then any
`
`further limitations on the treatment are truly irrelevant. The intended patient population is
`
`intrinsically at risk of one or more adverse events. Patients are intrinsically identified for nitric
`
`oxide inhalation treatment, diagnosed for congenital heart disease which intrinsically includes
`
`left ventricular dysfunction, and if the patient meets the criteria than treatment with NO is
`
`performed thereby reducing the risk of adverse events associated with the treatment. The neonate
`
`must breathe oxygen to survive.
`
`Loh et al. teach that inhaled nitric oxide in patients with left ventricular dysfunction may
`
`have adverse effects in patients with LV failure (Title and Abstract). Loh et al. clearly teaches
`
`that patients with pulmonary artery wedge pressure, which is synonymous with the instantly
`
`claimed pulmonary capillary wedge pressure, of greater than or equal to 18 mm Hg had a
`
`greater effect of inhaled NO due to the greater degree of reactive pulmonary hypertension
`
`present in such patients (page 2784, left column). Loh et al. state: "Since the degree of reactive
`
`pulmonary hypertension is generally related to the severity of hemodynamic compromise in
`
`patients with LV failure, it might he anticipated that patients with more severe heart failure will
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`Application/Control Number: 12/821,020 (cid:9)
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`Page 10
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`have a more marked hemodynamic response to inhaled NO." Loh et al. examined this prediction
`
`further and verified it (page 2784, left column). Loh et al. establishes that a pulmonary capillary
`
`wedge pressure (PCWP) of greater than 18 mg Hg serves as a guidepost for alerting the artisan to
`
`adverse events from inhaled NO. Thus, the art already teaches inhaled NO increases the wedge
`
`pressure as taught by Loh et al. (see entire document).
`
`Beghetti et al. teach:
`
`A structurally nonrial heart with severe LV dysfunction and a bi-
`directional shunt tlyough a patent <luaus arteriosus does not sug-
`gest that systemic: perfusion is duct dependent, inasmuch as the
`shunt is not exclusively unidirectional right to left. Bidirectional
`shunting usually is explained by a high, near systemic, total pulmo-
`nary vascular resistance resulting from maladaptation of the
`pulmonary circulation to the extrauterine life, and perhaps also by
`reflex pulmonary vasoconstriction induced by severe LV dysfunc-
`tion,
`In patients with inereasttl pulmonary venous pressure caused by
`LV dysfunction and elevated left atrial pressure, a decrease in pill-
`mona*i vascular resistance (induced by iNO) will lead to an
`increase in pulmonary %,enous return and hence to an nicrease in left
`atrial and LV filling pressure:1'1 This increase may not be assumed
`by a failing left ventricle that is working on the flat portion of the
`Frank-Starling curve, Accordingly, we believe that, in the patient
`described, massive vasodiiation induced by iNO resulted in further
`LV failure,
`inhaled nitric oxide should be administered with caution to ba-
`bie:s with LV dysfunction because pulmonary vasoconstriction may
`act as a protective rnedianism (cid:9)
`LV
`
`Let the Examiner reiterate: "Inhaled nitric oxide should be administered with caution
`
`to babies with LV dysfunction because pulmonary vasoconstriction may act as a protective
`
`mechanism of LV overfilling." (page 844).
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`Application/Control Number: 12/821,020 (cid:9)
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`Page 11
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`1chinose et al. teach inhalation of NO can increase left ventricle filling pressure in
`
`patients with severe left ventricle dysfunction and that it is important to be aware of the
`
`possibility that inhaled NO can produce pulmonary vasodilation and may overwhelm a failing
`
`left ventricle thereby producing pulmonary edema (page 3109 bottom left to top right columns).
`
`INOmax insert provides a source of compressed blend of nitrogen and nitric oxide gas for
`
`inhalation therapy (see entire insert).
`
`Summary of the art
`
`Babies, hence a neonate or child, are administered inhaled nitric oxide therapy as taught
`
`by Atz, Fraisse, Ichinose and Beghetti.
`
`Neonates can have left ventricle dysfunction which can be physically manifested in
`
`different forms as taught by Fraisse.
`
`The preponderance of art cited clearly indicates that inhaled NO can produce pulmonary
`
`vasodilation and can overwhelm a dysfunctional left ventricle resulting in pulmonary edema
`
`regardless of right to left shunting.
`
`The art teaches that iNO increases pulmonary wedge pressure as taught by Loh.
`
`The art cautions and warns of administering inhaled NO to babies with left ventricle
`
`dysfunction as taught by Atz, Beghetti and Ichinose because of adverse events which include
`
`pulmonary edema.
`
`Ascertainment of the difference between the prior art and the claims
`
`(MPEP 2141.02)
`
`1. The difference between the instant application and Fraisse et al. is that Fraisse et al. do
`
`not expressly teach the step of excluding a child with LVD from a plurality of children from iNO
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`Application/Control Number: 12/821,020 (cid:9)
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`Page 12
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`therapy such that the risk of occurrence of pulmonary edema is reduced or informing the medical
`
`provider that iNO may cause pulmonary edema in a child with pre-existing LVD or wherein the
`
`child has a pulmonary capillary wedge pressure that is greater than or equal to 20 mm Hg but
`
`administering iNO therapy to a child that does not have pre-existing LVD but has congenital
`
`heart disease. This deficiency in Fraisse et al. is cured by the teachings of Kinsella et al., Loh et
`
`al. Fraisse, Ichinose and Beghetti.
`
`2. The difference between the instant application and Fraisse et al. is that Fraisse et al. do
`
`not expressly teach the source of nitric oxide gas is a cylinder containing a compressed blend of
`
`nitric oxide and nitrogen. This deficiency in Fraisse et al. is cured by the teachings of the
`
`INOmax insert.
`
`Finding of prima facie obviousness
`
`Rational and Motivation (MPEP 2142-2143)
`
`1. It would have been obvious to one of ordinary skill in the art at the time the claimed
`
`invention was made to perform the method of Fraisse et al. and exclude a child with LVD from a
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`plurality of children from iNO therapy such that the risk of occurrence of pulmonary edema is
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`reduced or informing the medical provider that iNO may cause pulmonary edema in a child with
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`pre-existing LVD or wherein the child has a pulmonary capillary wedge pressure that is greater
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`than or equal to 20 mm Hg but administering iNO therapy to a child that does not have pre-
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`existing LVD but has congenital heart disease, as suggested by Atz et al., Kinsella et al., Loh et
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`al. Fraisse, Ichinose and Beghetti., and produce the instant invention.
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`Praxair v. INO Therapeutics
`IPR2015-00529
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`

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`Application/Control Number: 12/821,020 (cid:9)
`Art Unit: 1613
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`Page 13
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`One of ordinary skill in the art would have been motivated to do this because it is
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`overwhelmingly known in the art that inhaled nitric oxide can cause pulmonary edema especially
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`in those with a dysfunctional left ventricle. Consequently, it requires absolutely no inventive skill
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`to exclude those patients with pre-existing left ventricle dysfunction from inhalation of nitric
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`oxide gas in order to reduce the occurrence of pulmonary edema by informing the medical
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`provider because iNO is known not only to increase pulmonary wedge pressure but also cause
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`pulmonary edema. Indeed, Loh et al. provide the benchmark value for the wedge pressure as
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`discussed above. Furthermore, allowing those patients without left ventricle dysfunction but
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`having congenital heart disease to receive iNO therapy is part of the purpose of iNO therapy in
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`the first place and requires absolutely no inventive skill to perform as evidenced by the numerous
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`references cited by the Examiner in this rejection and the references made of record by the
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`Examiner.
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`For the record, to reduce the risk of occurrence of any adverse side effect of any medical
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`therapy the obvious choice is to exclude that patient from the medical therapy based on the sound
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`logic that if the medical therapy is not administered then the adverse side effect cannot occur
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`because of the medical therapy. In the instant case, the preponderance of art teaches and suggests
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`that children with left ventricle dysfunction regardless of directional blood shunting are prone to
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`adverse effects from iNO therapy. The artisan with that knowledge can then exclude or include
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`such a patient for iNO therapy at their discretion knowing and expecting that an adverse event
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`such as pulmonary edema can occur. As stated by Berghetti et al: "Inhaled nitric oxide should
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`be administered with caution to babies with LV dysfunction because pulmonary
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`vasoconstriction may act as a protective mechanism of LV overfillinz." (page 844). The
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`IKARIA EXHIBIT 2002
`Praxair v. INO Therapeutics
`IPR2015-00529
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`Application/Control Number: 12/821,020 (cid:9)
`Art Unit: 1613
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`Page 14
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`consequence of this is that the left ventricle overfills and the blood backs up to the lungs thereby
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`increasing the pressure which forces fluid into the tissue and causes pulmonary edema. In other
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`words, the art is already aware that patients with left ventricular dysfunction are at risk of
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`pulmonary edema from iNO therapy and consequently it obvious to the ordinary artisan that this
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`will occur regardless of the shunting of blood direction. As stated in paragraph 22 of Dr.
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`Greene's Declaration: "On analyzing the data from the study, the inventors concluded that a
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`correlation did, in fact, exist between the severe adverse events that had occurred during the
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`study and the left ventricular dysfunction of the patients that had suffered them." It is the
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`Examiner's position that all Applicant has done is confirmed what was already known in the art
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`and that the data is worthy of publication but is obvious to the ordinary artisan given the art as a
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`whole.
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`2. It would have been obvious to one of ordinary skill in the art at the time the claimed
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`invention was made to perform the method of Fraisse et al. with the nitric oxide source from
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`INOmax and produce the instant invention.
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`One of ordinary skill in the art would have been motivated to do this because Fraisse et
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`al. teach using inhaled nitric oxide but not the source and the INOmax insert provides a ready
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`source of nitric oxide blended with nitrogen in a cylinder for use in inhalation therapy. It is then
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`simply a matter of judicious selection of known sources of nitric oxide for inhalation therapy by
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`the ordinary artisan.
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`In light of the forgoing discussion, the Examiner concludes that the subject matter
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`defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
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`IPR2015-00529
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`Application/Control Number: 12/821,020 (cid:9)
`Art Unit: 1613
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`Page 15
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`From the teachings of the references, it is apparent that one of ordinary skill in the art
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`would have had a reasonable expectation of success in producing the claimed invention.
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`Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at
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`the time the invention was made, as evidenced by the references, especially in the absence of
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`evidence to the contrary.
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`Response to Arguments:
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`In light of the new ground of rejection and despite Applicant's 26 pages of argument, the
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`Declaration of Dr. Greene and the informative recent interview conducted with Applicant's
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`representative, Applicant's arguments are moot and the claims remain rejected as obvious.
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`Respectfully, the totality of the art informs the artisan that patients, be they neonates, children or
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`adults, with a failing left ventricle can be predisposed to pulmonary edema due to inhalation of
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`NO gas therapy. It appears that Applicant has confirmed the teachings in the art and it remains
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`obvious to exclude those patients with pre-existing left ventricular dysfunction from iNO therapy
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`because of the risk of adverse effects such as pulmonary edema. In other words, the risk of
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`pulmonary edema from iNO therapy is 0% if the patient does not receive iNO.
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`Double Patenting
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`The nonstatutory double patenting rejection is based on a judicially created doctrine
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`grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or
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`improper timewise extension of the "right to exclude" granted by a patent and to prevent possible
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`harassment by multiple assignees. A nonstatutory obviousness-type double patenting rejection
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`is appropriate where the conflicting claims are not identical, but at least one examined
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`Praxair v. INO Therapeutics
`IPR2015-00529
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`Application/Control Number: 12/821,020 (cid:9)
`Art Unit: 1613
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`Page 16
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`application claim is not patentably distinct from the reference claim(s) because the examined
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`application claim is either anticipated by, or would have been obvious over, the reference
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`claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re
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`Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225
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`USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re
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`Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163
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`USPQ 644 (CCPA 1969).
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`A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may
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`be used to overcome an actual or provisional rejection based on a nonstatutory double patenting
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`ground provided the conflicting application or patent either is shown to be commonly owned
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`with this application, or claims an invention made as a result of activities undertaken within the
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`scope of a joint research agreement.
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`Effective January 1, 1994, a registered attorney or agent of record may sign a terminal
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`disclaimer. A terminal