UNITED STA IBS p A IBNT AND TRADEMARK OFFICE
`
`UNITED STA TES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`Address: COMMISSIONER FOR PATENTS
`P.O. Box 1450
`Alexandria, Virginia 22313-1450
`www.uspto.gov
`
`APPLICATION NO.
`
`FILING DATE
`
`FIRST NAMED INVENTOR
`
`ATTORNEY DOCKET NO.
`
`CONFIRMATION NO.
`
`12/591,200
`
`11112/2009
`
`Horst Olschewski
`
`080618-0716
`
`4093
`
`10/10/2014
`7590
`22428
`FOLEY AND LARDNER LLP
`SUIIB 500
`3000 K STREET NW
`WASHINGTON, DC 20007
`
`EXAMINER
`
`TOWNSLEY, SARA ELIZABETH
`
`ART UNIT
`
`PAPER NUMBER
`
`1629
`
`MAILDATE
`
`DELIVERY MODE
`
`10/10/2014
`
`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)
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1164 , p. 1 of 24
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`

`

`Application No.
`12/591,200
`
`Applicant(s)
`OLSCHEWSKI ET AL.
`
`Examiner
`SARA E. TOWNSLEY
`
`Art Unit
`1629
`
`Office Action Summary
`
`AIA (First Inventor to File)
`Status
`No
`-- The MAILING DA TE of this communication appears on the cover sheet with the correspondence address -(cid:173)
`Period for Reply
`A SHORTENED STATUTORY PERIOD FOR REPLY IS SET TO EXPIRE .J. MONTHS 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 )~ Responsive to communication(s) filed on 412812014.
`0 A declaration(s)/affidavit(s) under 37 CFR 1.130(b) was/were filed on __ .
`2a)~ This action is FINAL.
`2b)0 This action is non-final.
`3)0 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)0 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 G.D. 11, 453 O.G. 213.
`
`Disposition of Claims*
`5)~ Claim(s) 18,25,27-30 and 32-40 is/are pending in the application.
`5a) Of the above claim(s) __ is/are withdrawn from consideration.
`6)0 Claim(s) __ is/are allowed.
`7)~ Claim(s) 18, 25, 27-30, and 32-40 is/are rejected.
`8)0 Claim(s) __ is/are objected to.
`9)0 Claim(s) __ are subject to restriction and/or election requirement.
`* If any claims have been determined allowable, you may be eligible to benefit from the Patent Prosecution Highway program at a
`participating intellectual property office for the corresponding application. For more information, please see
`http://www.uspto.gov/patents/init events/pph/index.jsp or send an inquiry to PF'Hfeedback(wuspto.aov.
`
`Application Papers
`10)0 The specification is objected to by the Examiner.
`11 )0 The drawing(s) filed on __ is/are: a)O accepted or b)O 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).
`
`Priority under 35 U.S.C. § 119
`12)0 Acknowledgment is made of a claim for foreign priority under 35 U.S.C. § 119(a)-(d) or (f).
`Certified copies:
`a)O All b)O Some** c)O None of the:
`Certified copies of the priority documents have been received.
`1.0
`Certified copies of the priority documents have been received in Application No. __ .
`2.0
`Copies of the certified copies of the priority documents have been received in this National Stage
`3.0
`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) 0 Notice of References Cited (PT0-892)
`
`2) ~ Information Disclosure Statement(s) (PTO/SB/08a and/or PTO/SB/08b)
`Paper No(s)/Mail Date 611312014.
`
`3) 0 Interview Summary (PT0-413)
`Paper No(s)/Mail Date. __ .
`4) 0 Other: __ .
`
`U.S. Patent and Trademark Office
`PTOL-326 (Rev. 11-13)
`
`Office Action Summary
`
`Part of Paper No./Mail Date 20140922
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1164 , p. 2 of 24
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`Application/Control Number: 12/591,200
`Art Unit: 1629
`
`Page 2
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`FINAL REJECTION
`
`Receipt is acknowledged of Applicants' Amendments and Remarks, filed Apr. 28,
`
`2014.
`
`Rejections and/or objections not reiterated from previous Office Actions are
`
`hereby withdrawn. The rejections and/or objections set forth below are either
`
`maintained or newly applied, and constitute the complete set presently applied to the
`
`instant claims.
`
`STATUS OF THE CLAIMS
`
`Claims 1-17, 19-24, 26, and 31 have been canceled.
`
`No claims have been amended, and no new claims have been added.
`
`Thus, claims 18, 25, 27-30, and 32-40 now represent all claims currently pending
`
`and under consideration.
`
`INFORMATION DISCLOSURE STATEMENT
`
`The information disclosure statement (I OS) submitted on Jun. 13, 2014 was filed
`
`after the mailing date of the non-final action on Mar. 19, 2014. The submission is in
`
`compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure
`
`statement has been considered.
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1164 , p. 3 of 24
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`Application/Control Number: 12/591,200
`Art Unit: 1629
`
`Page 3
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`MAINTAINED REJECTIONS
`
`The following rejections are maintained from the previous Office Action dated
`
`Mar. 19, 2014, on the ground that the references cited therein continue to read on the
`
`limitations of the amended claims.
`
`Claim Rejections - 35 USC § 103
`
`Claims 18, 25, 27-30, and 32-40 stand rejected under pre-AIA 35 U.S.C. 103(a)
`
`as being unpatentable over Chaudry (US Pub. 2004/0265238) in view of Cewers (USPN
`
`6,357,671 ).
`
`Chaudry discloses methods for treating pulmonary hypertension in humans by
`
`administering an inhalable formulation comprising at least one hypertension reducing
`
`agent, e.g., a vasodilator, in the form of a solution or suspension (abstract). In particular,
`
`Chaudry exemplifies an inhalable formulation comprising a pharmaceutically acceptable
`
`salt of treprostinil, treprostinil sodium, in a concentration of 0.1-10.0 mg/ml (Example 4;
`
`claim 44), which is preferably administered via nebulization (paras. [0040], para. [0057];
`
`claims 27-29).
`
`Chaudry teaches that a nebulized solution is a particular form of an aerosol
`
`(para. [0055]), and that administration of a nebulized aerosol is preferred (para. [0053]);
`
`thus, it is implicit that the disclosed inhalable formulations are aerosolizable solutions.
`
`Further, Chaudry discloses that prophetic examples 1-4 (including treprostinil,
`
`Example 4) are believed to "be suitable for administration via nebulization to an
`
`individual suffering from pulmonary hypertension ... The objective of these formulations
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1164 , p. 4 of 24
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`Application/Control Number: 12/591,200
`Art Unit: 1629
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`Page 4
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`is to provide localized delivery of a pulmonary hypertension reducing agent to a
`
`mammal (e.g. humans) in need thereof." Thus, the disclosed compounds, and in
`
`particular the exemplified compounds, are administrable by inhalation via a nebulizer.
`
`Thus, Chaudry discloses a method of treating pulmonary hypertension
`
`comprising administering by inhalation to a human in need thereof a therapeutically
`
`effective dose of an inhalable formulation with an ultrasonic nebulizer, as recited by
`
`claim 18.
`
`The inhalable formulation of Chaudry Example 4 comprises treprostinil sodium in
`
`a concentration of 0.1-10.0 mg/ml (Example 4; claim 44), which encompasses the range
`
`of 500-2500 mcg/ml (= 0.5-2.5 mg/ml) as recited by claim 27.
`
`Chaudry further discloses that a therapeutically effective amount of the
`
`hypertension-reducing agent (e.g., treprostinil) may include from about, e.g.,
`
`• 0.51 mg/ml to about 1.00 mg/ml (510 - 1000 mcg/ml);
`
`• 1.01 mg/ml to about 1.50 mg/ml (1010 - 1500 mcg/ml); and
`
`• 1.51 mg/ml to about 2.00 mg/ml (1510 - 2000 mcg/ml)
`
`(para. [0037]). These concentration ranges fall squarely within the claimed range of 500
`
`- 2500 mcg/ml, as recited by claim 27.
`
`Chaudry also teaches that "[t]he solution of Example 4 may be made by methods
`
`known to those of ordinary skill in the art" (para. [0098]). In other words, the reference
`
`itself teaches that any concentration within the exemplified range can be arrived at by
`
`routine experimentation.
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1164 , p. 5 of 24
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`

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`Application/Control Number: 12/591,200
`Art Unit: 1629
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`Page 5
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`Therefore, a skilled artisan would have had a reasonable expectation of success
`
`of treating pulmonary hypertension by administering by inhalation an aerosol solution of
`
`treprostinil at a concentration of 600 mcg/ml (0.6 mg/ml), as recited by claim 34.
`
`Chaudry teaches other embodiments in which the dose of the inhalation solution
`
`may be administered 1, 2, 3, 4, 5, 6, 7, or 8 times per day by nebulization, i.e., several
`
`times per day, as recited by claim 33. Chaudry also teaches that nebulizer fill volumes
`
`may be adjusted to reduce each nebulization treatment to about, e.g., 5, 4, 3 minutes,
`
`or less (para. [0063]), as recited by claims 35-37.
`
`Chaudry does not specifically teach inhalation administration of a therapeutically
`
`effective single event dose of treprostinil
`
`•
`
`•
`
`•
`
`•
`
`•
`
`in an amount of 15 to 90 mcg, as recited by claim 18,
`
`in an amount of 15 to 60 mcg, as recited by claim 25;
`
`in 18 or less breaths, as recited by claim 18;
`
`in 12 or less breaths, as recited by claims 38-40; or
`
`in 5 or less breaths, as recited by claim 32.
`
`However, Chaudry discloses inhalation administration by ultrasonic nebulizer of
`
`therapeutically effective doses of treprostinil, in the concentration ranges noted above.
`
`The dose administered during a "single event," i.e., a single breath, depends on factors
`
`such as, e.g., the concentration of the solution used, the volume of solution the device is
`
`calibrated to dispense with each "puff," the patient's condition and capabilities, and the
`
`judgment of the treating physician. These factors also influence the number of breaths
`
`administered in a given treatment interval, and the number of intervals per day.
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1164 , p. 6 of 24
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`Application/Control Number: 12/591,200
`Art Unit: 1629
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`Page 6
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`Chaudry teaches embodiments in which the disclosed fill volumes "may reduce
`
`each nebulization treatment to about 12, 10, 9, 8, 6, 5, 4, 3 minutes, or less over
`
`conventional nebulizer treatments (e.g. 2.5 ml or 3.0 ml fill volume). Reducing the
`
`amount of time to complete the treatment means individuals will be more likely to
`
`comply with the prescribed dosing regimen and achieve optimal benefit from the
`
`medication prescribed" (para. [0063]). Reducing the amount of time to complete the
`
`treatment implies a higher drug concentration, so that a given amount of drug is
`
`delivered in a shorter time interval and/or fewer breaths
`
`Chaudry teach that other features of the disclosed invention include "improved
`
`user compliance and quality of life as compared to conventional treatments for
`
`pulmonary hypertension. While the level of compliance of any pulmonary hypertension
`
`treatment depends in part on the motivation of the user and the skill of the individual
`
`dispensing the treatment, compliance nevertheless may be improved by controlling
`
`factors such as the ease with which the treatment may be administered, as well as the
`
`desirability of receiving the treatment" (para. [0082]).
`
`Thus, a skilled artisan would have had a reasonable expectation of success of
`
`optimizing the drug concentration and increasing the dose in order to reduce the
`
`amount of time, and hence, the number of breaths to complete the treatment, such as
`
`18 or 12 or 5 breaths, because Chaudry teaches that treatment can be completed in 3
`
`minutes or less, and that reducing the duration of the treatment enhances patient
`
`compliance.
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1164 , p. 7 of 24
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`Application/Control Number: 12/591,200
`Art Unit: 1629
`
`Page 7
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`Further, it would have been within the judgment of an ordinarily skilled clinician to
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`optimize the treprostinil concentration and dose, the frequency and duration of
`
`administration, and/or the number of breaths of the formulation inhaled, because these
`
`are result-effective variables which can be modified and adjusted by routine
`
`experimentation, as taught by Chaudry. As recognized by MPEP § 2144.05,
`
`Generally, differences in concentration or temperature will not support the patentability of
`subject matter encompassed by the prior art unless there is evidence indicating such
`concentration or temperature is critical. '1W]here the general conditions of a claim are
`disclosed in the prior art, it is not inventive to discover the optimum or workable ranges
`by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA
`1955).
`
`Therefore, it would have been prima facie obvious to one of ordinary skill in the
`
`art at the time the invention was made to optimize the concentration, single-event
`
`dosage, frequency, and duration of inhaled treprostinil administration to treat pulmonary
`
`hypertension with a reasonable expectation of success, because Chaudry discloses
`
`drug concentration ranges overlapping those claimed, which may be modified by
`
`methods known to those of ordinary skill in the art; and Chaudry discloses treatment
`
`intervals which read on or encompass those claimed, and teaches the advantage that
`
`reducing the amount of time, and hence, the number of breaths, to complete treatment
`
`enhances patient compliance.
`
`Thus, Chaudry discloses, teaches, and suggests methods of treating pulmonary
`
`hypertension comprising administering by inhalation to a human in need thereof a
`
`therapeutically effective single event dose of an inhalable formulation with an ultrasonic
`
`nebulizer, wherein said therapeutically effective single event dose comprises from 15
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1164 , p. 8 of 24
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`Application/Control Number: 12/591,200
`Art Unit: 1629
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`Page 8
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`mcg to 60 mcg or 90 mcg of treprostinil and is inhaled in 18, 12, or 5 or less breaths, as
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`recited by claims 18, 32, and 38-40;
`
`wherein the treprostinil is inhaled in 5 minutes or less, as recited by claims 35-37;
`
`wherein the ultrasonic nebulizer comprises an aerosolable solution having a
`
`concentration of treprostinil from 500 mcg/ml to 2500 mcg/ml, specifically 600 mcg/ml,
`
`as recited by claims 27 and 34, respectively; and
`
`wherein the human receives several therapeutically effective single event doses
`
`per day, as recited by claim 33.
`
`Regarding claims 28-30, as evidenced by, e.g., the instant specification, it is
`
`intrinsic in the methods disclosed by Chaudry that treprostinil administered by inhalation
`
`does not significantly disrupt gas exchange, as recited by claim 28 (para. [0015]; Fig. 2);
`
`does not significantly affect heart rate, as recited by claim 29 (para. [0015]; Fig. 2); and
`
`does not significantly affect systemic arterial pressure and systemic arterial resistance
`
`(para. [0014]; Fig. 1 ), as recited by claim 30.
`
`By disclosing inhalation administration of a therapeutically effective amount of
`
`treprostinil to a patient in need of such treatment to treat pulmonary hypertension, the
`
`resulting physiological responses, as recited by claims 28-30, are intrinsic in the
`
`methods of Chaudry, even if those effects or responses were not known or appreciated.
`
`As evidenced by, e.g., the data presented in Figures 1 and 2 of the instant specification,
`
`carrying out the methods taught by Chaudry produces the claimed results.
`
`All the molecular and cellular mechanisms by which a compound exerts its
`
`therapeutic effects are intrinsic in the methods of Chaudry, and occur each time
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1164 , p. 9 of 24
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`Application/Control Number: 12/591,200
`Art Unit: 1629
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`Page 9
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`treprostinil in the claimed amounts is administered by inhalation to the patient
`
`population in need of treatment for pulmonary hypertension, regardless of whether
`
`anyone was aware of those molecular and cellular mechanisms.
`
`A novel use of a known compound can be patentable. However, the instant
`
`claims do not recite a novel use of a known compound, but rather a previously unknown
`
`property of known compounds known to treat the same conditions in the same patient
`
`population.
`
`The discovery of a new use for an old structure based on unknown properties of
`
`the structure might be patentable to the discoverer as a process of using. In re Hack,
`
`245 F.2d 246, 248, 114 USPQ 161, 163 (CCPA 1957). However, when the claim recites
`
`the use of a known compound in a known method and the "use" is directed to a result or
`
`property of that compound, then the claim is anticipated. In re May, 574 F.2d 1082,
`
`1090, 197 USPQ 601 (CCPA 1978) affirmed the rejection of claims 1 and 6, directed to
`
`methods of effecting nonaddictive analgesia, which were anticipated by the applied prior
`
`art which disclosed the same compounds for effecting analgesia, but which was silent
`
`as to addiction. The court affirmed the rejection on the grounds that the applicants had
`
`merely found a new property of the compound and such a discovery did not constitute a
`
`new use. 197 USPQ 601, 607.
`
`Claims 28-30 recite intrinsic results that naturally flow from administering inhaled
`
`treprostinil to a human in the claimed amounts to treat pulmonary hypertension. While
`
`the references do not show a specific recognition of those results, their discovery is
`
`tantamount only to finding a new property intrinsic in carrying out an old method.
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1164 , p. 10 of 24
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`Application/Control Number: 12/591,200
`Art Unit: 1629
`
`Page 1 O
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`Because reference teaches methods of administering the same compound in the same
`
`amounts to treat the same condition in the same patient population, the physiological
`
`effects of such administration are intrinsic in the methods of Chaudry.
`
`While Chaudry discloses ultrasonic nebulizers and breath-actuated nebulizers
`
`(claim 29), the reference does not explicitly disclose pulsed ultrasonic nebulizers, as
`
`recited by claim 18.
`
`Cewers discloses ultrasonic nebulizers for the delivery of controlled doses of
`
`medication to a patient (col. 1, lines 5-26), wherein the aerosol is delivered in pulses
`
`separated by intervals during which no nebulization occurs (claim 1 ), i.e., a "pulsed
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`ultrasonic nebulizer," as recited by claim 18.
`
`A skilled artisan would have been motivated to treat pulmonary hypertension by
`
`administering treprostinil with a pulsed ultrasonic nebulizer, as disclosed by Cewers,
`
`with a reasonable expectation of success, because Chaudry teaches that any ultrasonic
`
`nebulizer is contemplated for use (para. [0054]).
`
`As recognized by MPEP §2143, combining prior art elements according to known
`
`methods to yield predictable results would motivate the skilled artisan to modify the
`
`references with a reasonable expectation of success. The rationale to support a
`
`conclusion of prima facie obviousness is that all the claimed elements were known in
`
`the prior art, and a skilled artisan could have combined the elements as claimed by
`
`known methods with no change in their respective functions, and the combination
`
`yielded nothing more than predictable results to one of ordinary skill in the art. See KSR
`
`Int'/ Co. v. Teleflex Inc. (550 U.S. 398, 409).
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1164 , p. 11 of 24
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`Application/Control Number: 12/591,200
`Art Unit: 1629
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`Page 11
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`Double Patenting
`
`Claims 18, 25, 27-30, and 32-40 stand provisionally rejected on the ground of
`
`nonstatutory obviousness-type double patenting as being unpatentable over claims 1, 4-
`
`13, 15-18, and 52-59 of copending Application No. 11/748,205 in view of Chaudry
`
`(US Pub. 2004/0265238), Byron (Proc. Am. Thorac. Soc. (1 ), pp. 321-328, 2004) and
`
`Cloutier et al (USPN 6,521,212).
`
`Reference claims 1, 4-13, 15-18, and 52-59 are drawn to methods for treating
`
`pulmonary hypertension, comprising administering to a subject in need thereof
`
`treprostinil or treprostinil derivative, or a pharmaceutically acceptable salt thereof by a
`
`metered dose inhaler, wherein said treprostinil derivative is selected from C1-4 alkyl
`
`esters of treprostinil and C1-4 alkyl amides of treprostinil,
`
`wherein the metered dose inhaler is a soft mist inhaler,
`
`wherein said treprostinil is formulated as a solution, wherein a solvent of the
`
`solution comprises water, ethanol or a mixture thereof,
`
`wherein a concentration of the treprostinil ranges from about 500 µg/ml to about
`
`2500 µg/ml, or from about 1000 µg/ml to about 2000 µg/ml,
`
`wherein a dose of the treprostinil administered during a single event ranges from
`
`about 15 µg to about 100 µg, or from about 30 µg to about 90 µg, or from about 30 µg to
`
`about 60 µg,
`
`wherein said administering does not have a systemic side effect on said subject,
`
`wherein the systemic side effect is selected from the group consisting of headache,
`
`flush, nausea, and dizziness,
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`Application/Control Number: 12/591,200
`Art Unit: 1629
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`Page 12
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`wherein said administering does not disrupt gas exchange in said subject,
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`wherein said administering does not change heart rate of said subject,
`
`wherein said administering does not affect systemic arterial pressure and
`
`systemic arterial resistance,
`
`wherein said administering is carried out in 20 breaths or less breaths in a single
`
`event, or 10 or less breaths in a single event, or in 5 or less breaths in a single event,
`
`wherein said administering lasts less than 5 minutes, or less than 1 minute,
`
`wherein said subject is a human being,
`
`wherein said administering comprises administering aerosol particles containing
`
`the treprostinil and said particles have a diameter of less than 10 microns, or a diameter
`
`of less than 5 microns.
`
`The reference claims do not recite administration with an ultrasonic nebulizer, as
`
`recited by examined claims 18 and 27.
`
`Chaudry discloses methods of treating pulmonary hypertension by
`
`administering inhalable formulations of treprostinil by way of a metered dose inhaler, a
`
`dry powder inhaler, a pressurized aerosol (para. 0052), i.e., a pressurized metered dose
`
`inhaler, or via nebulization (para. 0040). Chaudry teaches that any nebulizer is suitable,
`
`including ultrasonic nebulizers (para. 0057).
`
`Byron discloses drug delivery devices for inhalation such as metered dose
`
`inhalers (MD ls), specifically soft mist MDls, as recited by the reference claims, as well
`
`as ultrasonic nebulizers, as recited by the examined claims, e.g., computer-controlled
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1164 , p. 13 of 24
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`Application/Control Number: 12/591,200
`Art Unit: 1629
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`Page 13
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`ultrasonic (piezoelectric) nebulizers that monitor each patient's breathing pattern and
`
`administer nebulizer output phased with inspiration (p. 323, left col.).
`
`Because Chaudry teaches that any conventionally known method of
`
`administering inhalable medicaments may be used in methods of administering
`
`inhalable treprostinil to treat pulmonary hypertension (para. 0052), it would have been
`
`predictable to a skilled artisan to administer inhalable treprostinil formulations with either
`
`a soft-mist inhaler, as recited by the reference claims, or with an ultrasonic nebulizer, as
`
`recited by the examined claims, with a reasonable expectation of success.
`
`In addition, as recognized by MPEP §2144.06, it is prima facie obvious to
`
`substitute art-recognized equivalents, and an express suggestion to substitute one
`
`equivalent component or process for another is not necessary to render such
`
`substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982).
`
`This is a provisional obviousness-type double patenting rejection.
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`RESPONSE TO ARGUMENTS
`
`Applicant's arguments filed Apr. 28, 2014 have been fully considered but they are
`
`not persuasive.
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`With respect to the rejection under 35 U.S.C. § 103, Applicant contends that a
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`prima facie case of obviousness has not been established, because, using the same
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`references, a similar or identical rejection could be made with respect to iloprost; yet a
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`single event dose of iloprost cannot be administered with a pulsed ultrasonic nebulizer
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`in 18 or less breaths, which indicates that the PTO's logic is deficient (Remarks, pp. 4-
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1164 , p. 14 of 24
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`Application/Control Number: 12/591,200
`Art Unit: 1629
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`Page 14
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`5). In other words, Applicant's traversal of the rejection is based on the thesis that
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`Chaudry and Cewers are equally applicable to iloprost and treprostinil (Remarks, p. 6).
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`However, this is insufficient to rebut the rejection. To clarify, the instant claims
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`are drawn to methods of treating pulmonary hypertension by administering treprostinil
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`with a pulsed ultrasonic nebulizer in 18 or less breaths. Search and examination is
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`directed to the claimed invention, which does not encompass iloprost. Thus, the
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`relevance of whether the same combination of references also teaches other distinct,
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`unrecited embodiments is unclear.
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`Alternatively, Applicant contends that the fact that a single event dose of
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`treprostinil can be administered with a pulsed ultrasonic nebulizer in 18 breaths or less,
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`while iloprost cannot, represents surprising results that could not be expected based on
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`the cited references (Remarks, pp. 6-7), citing the Gessler reference (of record) and
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`Example 2 of the instant specification.
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`First, Gessler et al. compared administration of iloprost by jet nebulizer versus
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`ultrasonic nebulizer. "Based on the data of the physical characterization, the inhalation
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`time for delivery of an equivalent iloprost dose at the mouthpiece (2.8 µg) was reduced
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`from 12 min with the jet nebulizer system to 2 min with the ultrasonic nebulizer, when
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`retaining the same concentration of the iloprost solution (10 µg/ml). In preliminary
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`catheter investigations, however, some increase in systemic side effects was observed
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`when administering the total iloprost dose of 2.8 µg via the inhalation route for such a
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`short time period. Therefore we reduced the iloprost concentration from 10 µg/ml to 5
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`µg/ml when employing the ultrasonic nebulizer, and consequently doubled the inhalation
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1164 , p. 15 of 24
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`Application/Control Number: 12/591,200
`Art Unit: 1629
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`Page 15
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`time to 4 min with this device. This inhalation protocol was generally well tolerated.
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`Furthermore, by diluting the solution, drug waste in the dead space of the nebulizer was
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`reduced" (p. 17, col. 2).
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`Thus, Gessler et al. report that 2.8 µg iloprost can be administered via ultrasonic
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`nebulizer in 2 min, at a concentration of 10 µg/ml (with some increase in side effects), or
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`in 4 min, at a concentration of 5 µg/ml (without an increase in side effects).
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`Gessler et al. conclude that, due to the markedly higher efficiency and output of
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`the ultrasonic device, wastage of drug is largely avoided and duration of inhalation can
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`be shortened to one-third (from 12 minutes to 4 minutes), with comparable
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`haemodynamic effects and without enforcing side effects (abstract; p. 19, col. 1 ).
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`Therefore, Gessler et al. provides a reason to select an ultrasonic nebulizer over
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`other devices, such as a jet nebulizer, and thus supports the teaching of Chaudry, which
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`discloses that administration of a nebulized aerosol is preferred (para. [0053]) and
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`discloses exemplary ultrasonic nebulizers (para. [0057]; claim 29).
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`Next, Example 2 of the instant specification, study (i), compared administration of
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`iloprost and treprostinil with a pulsed ultrasonic nebulizer at an inhaled dose of 7.5 µg
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`(paras. [0068]-[0071 ]). "In study (i) it was shown that the inhalation of treprostinil and
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`iloprost in similar doses resulted in a comparable maximum pulmonary vasodilatory
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`effect. However, marked differences in the response profile were noted. The onset of
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`the pulmonary vasodilatory effect of inhaled treprostinil was delayed compared to
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`iloprost, but lasted considerably longer, with the PVR decrease continuing beyond the
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`one-hour observation period. Although the average dose of treprostinil was higher than
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1164 , p. 16 of 24
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`Application/Control Number: 12/591,200
`Art Unit: 1629
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`the iloprost dose, no systemic effects were noted after treprostinil inhalation, whereas
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`flush and transient SAP decrease, accompanied by more prominent cardiac output
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`increase, occurred after iloprost inhalation" (para. [0087]).
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`The occasionally observed mild side effects of iloprost inhalation at the given
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`dose (transient flush, headache) were not observed with inhaled treprostinil (para.
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`[0078]). Inhaled treprostinil is advantageous to inhaled iloprost in terms of duration of
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`effect and systemic side effects (para. [0069]).
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`Thus, the results presented in the instant specification demonstrate that it is
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`possible to administer both iloprost and treprostinil via pulsed ultrasonic nebulizer -
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`which would have been expected in view of Gessler et al. - but that treprostinil has
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`certain advantages over iloprost, such as reduced or no side effects at higher doses.
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`The question is whether these results are truly unexpected, or simply the natural
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`outcome of following the guidance and direction provided in the prior art.
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`As recognized by MPEP §716.02(c)(ll), "[e]xpected beneficial results are
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`evidence of obviousness of a claimed invention, just as unexpected results are
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`evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602,
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`604 (CCPA 1967). Analogously, in Pfizer v. Apotex, 82 USPQ2d 1321 (Fed. Cir. 2007),
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`the Court held that
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`the prior art provided not only the means of creating acid addition salts but also
`predicted the results, which Pfizer merely had to verify through routine testing.
`Merck, 874 F.2d at 809 .... [O]ur conclusion here relies on the fact that one skilled in
`the art would have had a reasonable expectation of success at the time the invention
`was made, and merely had to verify that expectation [emphasis added].
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`We find this case analogous to the optimization of a range or other variable within the
`claims that flows from the "normal desire of scientists or artisans to improve upon what is
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1164 , p. 17 of 24
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`Application/Control Number: 12/591,200
`Art Unit: 1629
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`Page 17
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`already generally known." In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003)
`(determining where in a disclosed set of percentage ranges the optimum combination of
`percentages lies is prima facie obvious). In In re Aller, 220 F.2d 454, 456 (C.C.P.A.
`1955), our predecessor court set forth the rule that the discovery of an optimum value of
`a variable in a known process is usually obvious. 82 USPQ2d at 1335.
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`As noted in the previous action, the rationale to administer treprostinil with an
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`ultrasonic nebulizer is that Chaudry exemplifies only four formulations for inhalation
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`(which do not include iloprost), one of which is treprostinil (Example 4), and specifically
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`identifies ultrasonic nebulizers as a suitable delivery device (para. [0057]). Notably,
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`Chaudry claims both of these features:
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`27. A method of treating pulmonary hypertension in a mammal, said method
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`comprising the step of administering to said mammal a formulation comprising a
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`therapeutically effective amount of a hypertension reducing agent, wherein said
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`hypertension reducing agent is at least one of a