IN THE UNITED STATES PATENTAND TRADEMARK OFFICE
`
`Atty. Dkt. No. 080618-0716
`Appl. No. 12/591,200
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`Applicant:
`
`Horst OLSCHEWSKI et al.
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`Title:
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`TREPROSTINIL
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`ADMINISTRATION BY
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`INHALATION (AMENDED)
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`Appl. No.:
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`12/591,200
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`Filing Date:
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`11/12/2009
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`Examiner:
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`Sara Elizabeth Townsley
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`Art Unit:
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`1629
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`Confirmation
`Number:
`
`4093
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`‘REPLY UNDER 37 CFR_§ 1.116
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`Mail Stop AF
`Commissioner for Patents
`PO. Box 1450
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`Alexandria, VA 22313-1450
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`Commissioner:
`
`This paper responds to the Final Office Action dated October 17, 2012.
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`The listing of claims begins on page 2 of this document.
`
`Remarks begin on page 4 ofthis document.
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`Atty. Dkt. No. 080618-0716
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`Appl. No. 12/591,200
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`Listing of Claims:
`
`1-17. (Canceled)
`
`18.
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`(Previously Presented) A method 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
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`therapeutically effective single event dose comprises from 15 ug to 90 ug of treprostinil or a
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`pharmaceutically acceptable salt thereof and said therapeutically effective single event dose
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`is inhaled in 10 or less breaths by the human.
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`19.-24. (Canceled)
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`25.
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`(Previously Presented) The method of claim 18, wherein the single event dose
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`contains from 15 ug to 60 ug oftreprostinil or a pharmaceutically acceptable salt thereof.
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`26.
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`(Canceled)
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`27.
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`(Previously Presented) The method of claim 18, wherein the ultrasonic
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`nebulizer comprises an aerosolable solution having a concentration of said treprostinil or a
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`pharmaceutically acceptable salt thereof from 500 ug/ml to 2500 ug/ml.
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`28.
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`(Previously Presented) The method of claim 18, wherein said administering
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`does not significantly disrupt gas exchange in said human.
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`29.
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`(Previously Presented) The method ofclaim 18, wherein said administering
`
`does not significantly affect heart rate of said human.
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`30.
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`(Previously Presented) The method of claim 18, wherein said administering
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`does not significantly affect systemic arterial pressure and systemic arterial resistance of said
`
`human.
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`31.
`
`(Canceled)
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`32.
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`(Previously Presented) The method of claim 18, wherein said administering of
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`said therapeutically effective single event dose is performed in 5 or less breaths.
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`33.
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`(Previously Presented) The method of claim 18, wherein said human receives
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`several therapeutically effective single event doses per day.
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`34.
`
`(Previously Presented) The method of claim 27, wherein the concentration of
`
`said treprostinil or a pharmaceutically acceptable salt thereof in the aerosolable solution is
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`600 ug/ml.
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`Atty. Dkt. No. 080618-0716
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`Appl. No. 12/591,200
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`REMARKS
`
`Applicants respectfully request reconsideration and allowance of the present
`
`application.
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`CLAIMS STATUS
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`Claims 18, 25, 27-30 and 32—34 are pending.
`
`CLAIM REJECTIONS UNDER 35 U.S.C. § 103(a)
`
`Claims 1-8, 10—23 and 25-31 stand rejected as obvious over Chaudry (US
`
`2004/0265238) in view of Sandifier et al. (J. Appl. Physiol. 99:2363-68 (2005)) and Cloutier
`
`(US patent no. 6,521,212). Applicants respectfully traverse.
`
`Before addressing the rejection in greater detail, Applicants note that Sandifier may
`
`be disqualified as prior art under 37 C.F.R. 1.131. Applicants reserve the right to submit a
`Declaration under Rule 131 to disqualify Sandifier.
`
`Even if Sandifier is applied to the instant claims, the PTO has not established a prima
`
`facie case of obviousness for the reasons discussed below.
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`In addition, the evidence of
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`secondary considerations provided in prior responses and submitted herewith would rebut
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`any possible case ofprima facie obviousness by establishing that the presently claimed
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`method constitutes an improvement over the results reported in Sandifier.
`
`Chaudry relates to inhalable formulations for treating pulmonary hypertension and
`
`methods of using same, see e.g. title. Chaudry teaches that “his formulation comprises at
`
`least one hypertension reducing agent, including but not limited to an angiotensin converting
`
`enzyme inhibitor, angiotensin receptor blocker, beta-blocker, calcium-channel blocker or
`
`vasodilator, or any combination thereof,” see abstract. Chaudry further discloses his
`
`hypertension reducing agents in an extensive list in paragraphs 0022-0027. Applicants
`
`acknowledge that in paragraph 0026, Chaudry mentions treprostinil among a multitude of
`
`examples of vasodilators that can be used in his formulations. Applicants further
`
`acknowledge that Chaudry’s prophetic example 4 discloses a formulation comprising
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`treprostinil sodium. However, each active agent is unique, with different potency and side
`
`effect profiles, so that they exhibit different treatment results in humans depending on (a) the
`
`type of inhalation device and (b) the dosing regimen applied to that type of inhalation device.
`
`. Chaudry discloses a large number inhalation devices, which may be used for
`
`administering his formulations in paragraphs 0052-0057. Applicants acknowledge that
`
`Chaudry mentions ultrasonic nebulizers in paragraph 0057 as a part of this disclosure. As
`
`noted above, however, each active agent is unique, with different potency and side effect
`
`profiles, so that they exhibit different treatment results in humans depending on (a) the type
`
`of inhalation device and (b) the dosing regimen applied to that type of inhalation device.
`
`Chaudry does not teach at least the following elements ofclaim 18:
`
`1) Chaudry does not disclose a combination of treprostinil and an ultrasonic
`
`nebulizer, i.e., does not disclose treprostinil and a ultrasonic nebulizer in a single
`
`embodiment, despite mentioning a) treprostinil in paragraph 0026 and in example 4 and b) an
`
`ultrasonic nebulizer in paragraph 0057.
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`2) Chaudry does not teach administering by inhalation to a human in need thereofa
`
`therapeutically effective single event dose of an inhalable formulation with an ultrasonic
`
`nebulizer, wherein the therapeutically effective single event dose that comprises from 15
`
`[g to 90 ug of treprostinil or a pharmaceutically acceptable salt thereofbeing inhaled in 10
`
`or less breaths by the human,
`
`Applicants respectfully submit that one of ordinary skill in the art would not have
`
`arrived at any of these missing elements based on the cited references.
`
`
`ELEMENT 1 — Ultrasonic Nebulizer
`
`With respect to element 1, not only does Chaudry fail to disclose the combination of
`
`treprostinil and an ultrasonic nebulizer, but Chaudry also fails to provide any reason for one
`
`of ordinary skill to arrive at the combination of treprostinil and an ultrasonic nebulizer by
`
`selecting treprostinil from the list ofhis hypertension reducing agents in paragraphs 0022-
`
`0027, while selecting an ultrasonic nebulizer from Chaudry’s inhalation devices mentioned in
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`paragraphs 0052-0057. Thus, one of ordinary skill would have arrived at the combination of
`
`treprostinil and an ultrasonic nebulizer only through judicious picking and choosing through
`
`myriad possible combinations of hypertension reducing agent/inhalation device encompassed
`
`by Chaudry.
`
`Applicants respectfully submit that, in the Office Action, the PTO failed to explain
`
`why one of ordinary skill in the art would have been motivated to select treprostinil from the
`
`list of his hypertension reducing agents in paragraphs 0022-0027, while selecting an
`
`ultrasonic nebulizer from Chaudry’s inhalation devices mentioned in paragraphs 0052-0057.
`
`In this regard, Applicants point out the following legal standard for obviousness analysis
`
`from MPEP § 2143, which wasestablished in the Supreme Court decision in KSR v. Teleflex:
`
`“The Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. _, _, 82
`USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a
`conclusion of obviousness which are consistent with the proper “functional approach”
`to the determination of obviousness as laid down in Graham. The key to supporting
`any rejection under 35 U.S.C. 103 is the clear articulation of the reasongs) why
`_ the claimed invention would have been obvious. The Supreme Court in KSR noted
`that the analysis supporting a reiection under 35 U.S.C. 103 should be made
`explicit. > In BallAerosol v. Limited Brands, 555 F.3d 984 (Fed. Cir. 2009), the
`Federal Circuit offered additional instruction as to the need for an explicit analysis.
`The Federal Circuit explained that the Supreme Court’s requirement for an explicit
`analysis does not require record evidence of an explicit teaching of a motivation to
`combine in the prior art.
`
`|T|he analysis that “should be made explicit” refers not to the teachings in the
`prior art ofa motivation to combine, but to the court’s analysis. .
`.
`. Under the
`flexible inquiry set forth by the Supreme Court, the district court therefore erred by
`failing to take account of “the inferences and creative steps,” or even routine steps,
`that an inventor would employ and by failing to find a motivation to combine related
`pieces from the prior art.
`
`Bat/Aerosol, 555 F.3d at 993. The Federal Circuit’s directive in BallAerosol was
`addressed to a lower court, but it applies to Office personnel as well. When setting
`forth a rejection, Office personnel are to continue to make appropriate findings of
`fact as explained in MPEP § 2141 and § 2143, and must provide a reasoned
`explanation as to why the invention as claimed would have been obvious to a
`person of ordinary skill in the art at the time of the invention. This requirement
`for explanation remains even in situations in which Office personnel may properly
`rely on intangible realities such as common sense and ordinary ingenuity.” (Bold
`underlining added)
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`Since neither Chaudry nor the Office Action provide any reason for selecting treprostinil
`
`from the list of Chaudry’s hypertension reducing agents in paragraphs 0022-0027, while
`
`selecting an ultrasonic nebulizer from Chaudry’s inhalation devices in paragraphs 0052—0057,
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`Applicants’ understanding is that the PTO assumes that each and every hypertension
`
`reducing agent can be administered using each and every inhalation device mentioned in
`
`Chaudry’s paragraphs 0052-0057.
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`In other words, the rejection has implicitly relied on an
`
`assumption ofinterchangeability of drug choice and inhalation device choice. Ifthis is the
`
`case, then Applicants submit that the PTO’s assumptions are not correct.
`
`In this regard, Applicants bring the PTO’s attention to the enclosed references:
`
`Gessler et al. (Eur. Respir. J. 2001; 17; 14-19) and Voswinckel et al. (Pulmonary
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`Pharmacology & Therapeutics 22 (2009) 50-56) as well as to example 2 of the specification
`
`as filed, which provide evidence that iloprost (mentioned by Chaudry twice in paragraph
`
`0026), cannot be administered using a metered dose inhaler, a device among the list of
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`possible inhalation devices in paragraphs 0052-0057 of Chaudry. To the best of Applicants’
`
`knowledge, iloprost is the only prostacyclin analog, other than treprostinil, which is approved
`
`by the FDA for treatment pulmonary hypertension when administered by inhalation. See,
`
`e.g, Gessler and also Voswinckel (2009) page 54:
`
`“Iloprost leads to potent and selective pulmonary vasodilatation after a single
`
`inhalation of the approved doses of2.5w5 ug. The acute effect of inhaled iloprost may
`
`last up to 90 min. . .Long term treatment with repetitive inhalations ofIloprost was
`
`shown also to reduce pulmonary vascular resistance at
`
`trough levels and to improve
`
`patient exercise capacity and survival.”
`
`A metered dose inhaler usually delivers an inhaled drug in a short period of time (less
`
`than several minutes). Furthermore, for a metered dose inhaler, it may be preferred to
`
`administer a high dose of an inhaled drug in order to minimize a time of administration.
`
`Iloprost cannot be administered by a metered dose inhaler because iloprost’s delivery
`
`in high doses and/or short periods oftimes (less than 2 or 3 minutes) increases systemic side
`
`effects in patients. See e.g. Gessler, page 17, right column, 2nd full paragraph:
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`“the inhalation time for delivery of an equivalent iloprost dose at the
`
`mouthpiece (2.8 ug) was reduced from 12 min with thejet nebulizer system to 2 min
`
`with the ultrasonic nebulizer, when retaining the same concentration of the iloprost
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`solution (10 ug-mL'l).
`
`In preliminary catherer investigations, however, some increase
`
`in systemic side effects was observed when administering the total iloprost dose of
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`2.8 ug via the inhalation route for such a short time period.”
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`See Voswinckel (2009), page 54, sentence bridging left and right columns:
`
`“A dose of more than 5 ug iloprost per inhalation or a reduction of inhalation time to
`
`less than 3 min induces in most patients considerable systemic prostanoid side effects
`
`like hypotension, dizziness, headache, jaw pain, nausea or [diarrhea].”
`
`See also Example 2 of the application as filed presenting data that demonstrate that
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`administration of 7.5 ug ofiloprost via Optineb ultrasonic nebulizer caused systemic side
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`effects, see paragraphs 0082 and 0091.
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`Applicants further submit that not every formulation in Chaudry’s prophetic examples
`
`1-4 can be administered with every inhalation device mentioned in Chaudry’s paragraph
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`0052—0057. For example, in example 3, Chaudry provides “a prophetic example of
`
`formulation comprising the vasodilator epoprostenol in suspension form." One of ordinary
`skillin the art would not have concluded that Chaudry’s epoprostenol formulation in
`
`suspension form disclosed in his prophetic example 3 can be administered using an ultrasonic
`
`nebulizer disclosed in Chaudry’s paragraph 0057 because it is known that “[u]ltrasonic
`
`nebulizers do not nebulize suspensions well,” see the abstract of the enclosed reference, Rau,
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`Respiratory Care, 2002, 47, 1257-1278.
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`Besides failing to explain why one of ordinary skill in the art would select treprostinil
`
`from the list of his hypertension reducing agents in paragraphs 0022-0027, while selecting an
`
`ultrasonic nebulizer from Chaudry’s inhalation devices mentioned in paragraphs 0052-0057,
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`the PTO also failed to provide a required finding on why selection ofthe combination of
`
`treprostinil/ultrasonic nebulizer would be predictable.
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`In this regard, Applicants bring the
`
`PTO’s attention to MPEP § 2143, which provides a number of exemplary rationales which
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`may support a conclusion of obviousness. Although it is not clear which particular rationale
`
`the PTO utilizes in the present rejection, each of the exemplary rationales from MPEP § 2143
`
`requires articulating a finding regarding predictability/reasonable expectation of success of
`
`the proposed modification of the prior art. At least one deficiency of the PTO’s obviousness
`
`analysis is that the PTO failed to articulate the required finding regarding
`
`predictability/reasonable expectation of success. Thus, at least for this reason, the PTO failed
`
`to establish a primafacie case of obviousness. The PTO would not be able to provide the
`
`required finding regarding predictability/reasonable expectation of success in the view of the
`
`above evidence of unpredictability established by the iloprost/metered dose inhaler
`
`combination and the epoprostenol suspension formulatiorflnebulizer combination.
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`Sandifier and Cloutier cannot remedy the deficiencies of Chaudry with respect to
`
`element 1. Although they do teach that treprostinil can be used to treat pulmonary
`
`hypertension by inhalation, they do not suggest the specific improvement of utilizing an
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`ultrasonic nebulizer together with the presently claimed dosage regimen.
`
`In sum, the PTO failed to establish aprimafacie case of obviousness at least because
`
`ofthe reasons discussed above in this section.
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`ELEMENT 2 — Dosing Regimen
`
`With respect to element 2, namely administering by inhalation to a human in need
`
`thereof a therapeutically effective single event dose of an inhalable formulation with an
`
`ultrasonic nebulizer, wherein the therapeutically effective single event dose that
`
`comprises from 15 lg to 90 gg of treprostinil or a pharmaceutically acceptable salt thereof
`
`being inhaled in 10 or less breaths by the human, Applicants respectfully submit that one
`
`of ordinary skill in the art would not have arrived at this element based on Chaudry per 56 at
`
`least because, according to Chaudry, the smallest time for an individual inhalation event or
`
`session is 3 minutes, see e.g. paragraph 0067, which corresponds to 30—42 breaths taking into
`
`account that a normal respiratory rate for an adult human at rest is 10—14 breaths per minute.
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`Administering a therapeutically effective single event dose in 10 or less breaths
`
`cannot be achieved for every compound known to be administered by inhalation.
`
`In this
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`regard, Applicants refer the PTO to the above discussed example ofiloprost, which, on one
`
`hand, is known to be effective for treating pulmonary hypertension when administered by
`
`inhalation, but, on the other, cannot be administered by inhalation in high doses in short
`
`periods oftimes (less than 2 or 3 minutes) based on the above discussed evidence provided
`
`by Gessler and Voswinckel, as well as example 2 of the specification as filed because such
`
`concentrated doses of ilopost cause unacceptable systemic side effects. Applicants
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`respectfully submit that Example 2 of the application as filed demonstrates that l)
`
`Treprostinil, unlike iloprost, can be administered by inhalation in high doses (up to 90 ug)
`
`without causing systemic side effects and 2) Treprostinil, unlike iloprost, can be administered
`
`by inhalation in a very short time down literally to a single breath without causing systemic
`
`side effects. These data of Example 2 represent surprising results that one of ordinary skill in
`
`the art would not have expected based on Chaudry.
`
`Sandifier and Cloutier cannot remedy the deficiencies of Chaudry with respect to
`
`element 2. Although they do teach that treprostinil can be used to treat pulmonary
`
`hypertension by inhalation, they do not suggest the improvement of administering by
`
`inhalation a therapeutically effective single event dose of an inhalable formulation with a
`
`ultrasonic nebulizer, wherein the therapeutically effective single event dose that
`
`comprises from 15 gg to 90 ug of treprostinil or a pharmaceutically acceptable salt thereof
`
`being inhaled in 10 or less breaths by the human. Applicants further submit that
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`Sandifier’s and Cloutier’s disclosure of treprostinil’s use for treating pulmonary hypertension
`
`by inhalation is not sufficient for arriving at claimed invention, which involves administering
`
`a therapeutically effective single event dose inhaled in 10 or less breaths by the human
`
`because the above example of iloprost provides the evidence that not every compound known
`
`to be administered by inhalation can be administered by inhalation in very short periods of
`
`time, such as 10 breaths or less.
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`Applicants further submit that Sandifier’s term “large doses” (first filll paragraph, left
`
`column of page 2367), which the PTO cites on page 7 ofthe Office Action, is a relative term.
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`One of ordinary skill in the art would interpret Sandifier’s term “large doses” in view of the
`
`rest of Sandifier’s disclosure. As such, one of ordinary skill in the art would recognize that
`
`the highest dose of treprostinil in Sandifier is 1000 ng-kg'l-min'l administered over a 30
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`minute period (see page 2364). One of ordinary skill in the art would not extrapolate
`
`Sandifier’s teaching regarding his “large doses” to the presently claimed invention, in which
`
`administering a therapeutically effective single event dose occurs in 10 or less breaths by the
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`pulmonary hypertension patient.
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`
`Unexpected Results Rebut Any Possible Case of Prima Facie Obviousness And Are
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`Not Taught By Sandifier’s Administration of Treprostinil Over A 30 Minute Period
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`Applicants emphasize that the combination of(a) the claimed dosing regimen of
`
`treprostinil and (b) administration with an ultrasonic nebulizer resulted in a method that could
`
`be used to deliver a dosage oftreprostinil by inhalation that was substantially more
`
`convenient to pulmonary hypertension patients than the only other available inhaled
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`prostacyclin on the market (i.e., iloprost) at the time of filing. This was shown previously in
`
`the Rule 132 Declarations of Drs. Rubin and Gotzkowsky filed on May 23, 2012 and Aug.
`
`10, 2012, respectively. Accordingly, the presently claimed method represents an
`
`improvement over the dosing regimen taught by Sandifier.
`
`The PTO suggested that Sandifier discloses “large” doses of'inhaled treprostinil and
`
`relatively few side effects, so that the results ofthe Declarations reported by Drs. Rubin and
`
`Gotzkowsky would have been predictable. Applicants respectfully disagree. As noted
`
`above, Sandifier relates to larger doses that were administered over a 30 minute time period.
`
`One of ordinary skill in the art would not have expected that, by selecting an ultrasonic
`
`nebulizer and further concentrating the dosing regimen to a single event dose comprising
`
`from 15 ug to 90 ug oftreprostinil or a pharmaceutically acceptable salt thereof in 10 breaths
`
`m, it would have been possible to avoid significant side effects observed with iloprost
`
`(believed to be the only other commercially available inhaled prostacyclin at that time) and
`
`significantly improve patient satisfaction scores in several dimensions as reported in the Rule
`
`132 Declarations previously submitted.
`
`It was not known at the time ofthe invention whether more concentrated doses of
`
`inhaled treprostinil or a salt thereof administered in 10 or fewer breaths with an ultrasonic
`
`nebulizer would be effectively delivered and sufficien_tly longflcting in_pulmonagy
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` hypertension patients to result in fewer doses and better_patient satisfaction, even assuming
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`that the side effect profile was acceptable and that such concentrated dosage levels could be
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`administered with an ultrasonic nebulizer. For example, Labiris et a1. (“Pulmonary drug
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`delivery. Part II: The role of inhalant delivery devices and drug formulations in therapeutic
`
`effectiveness of aerosolized medications”, Br. J. Clin. Pharmacol, 56(6): 2003, pp. 600-612)
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`(copy enclosed) reports that:
`
`“high drug concentrations may_decrease the dmgputmit with some nebulizers;
`colomycin at concentrations >75 mg ml*1 foams in all nebulizers, especially
`ultrasonic ones, making aerosolization ofthe drug vergy inefficient if not impossible,”‘
`see page 601, right column, first full paragraph, last sentence.
`
`Thus, contrary to the rejection’s suggestion that all ofthe results ofthe presently claimed
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`method presented in the Rule 132 Declarations of Drs. Rubin and Gotzkowsky would have
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`been predicted based on Sandifier’s results with a 30 minute inhalation regimen, one of
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`ordinary skill in the art would not have reached such a conclusion.
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`Accordingly, Applicants request withdrawal of the rejection.
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`DOUBLE PATENTING REJECTION
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`Claims 18, 25, 27-30 and 32-34 stand provisionally rejected on the ground of non-
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`statutory obviousness-type double patenting over claims 1, 4-17 and 52-59 of co-pending
`Application No. 11/748,205 in view of Chaudry et al. (US Pub. No. 2004/0265328), Byron
`(Proc. Am. Thor. Soc. (1), pp. 321-328, 2004) and Cloutier et al. (USPN 6,521,212).
`
`Applicants will address this rejection at such time (if ever) that it becomes non-provisional.
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1168, p. 12 of 13
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`4822-2834-17782
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`-12-
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1168, p. 12 of 13
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`

`

`Atty. Dkt. No. 080618—07l6
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`Appl. No. 12/591,200
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`CONCLUSION
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`Applicants believe that the present application is in condition for allowance.
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`Favorable reconsideration of the application is respectfully requested. The Examiner is
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`invited to contact the undersigned by telephone if it is felt that a telephone interview would
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`advance the prosecution of the present application.
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`The Commissioner is hereby authorized to charge any additional fees which may be
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`required regarding this application under 37 C.F.R. §§ 1.16—1.17, or credit any overpayment,
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`to Deposit Account No. 19—0741. Should no proper payment be enclosed herewith, as by a
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`check being in the wrong amount, unsigned, post—dated, otherwise improper or informal or
`
`even entirely missing or a credit card payment form being unsigned, providing incorrect
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`information resulting in a rejected credit card transaction, or even entirely missing, the
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`Commissioner is authorized to charge the unpaid amount to Deposit Account No. 19—0741.
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`If any extensions of time are needed for timely acceptance of papers submitted herewith,
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`Applicants hereby petition for such extension under 37 C.F.R. §1i136 and authorizes
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`payment of any such extensions fees to Deposit Account No. 19—0741.
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` Date January $2013
`FOLEY & LARDNER LLP
`Telephone:
`(202) 672—5569
`
`Customer Number: 22428
`
`Facsimile:
`
`(202) 672—5399
`
`Respectfully submitted,
`
`. //
`A
`Q
`By ,
`//ex/ fi/fi”)
`f'éfié’Stephen B. Maebius
`Registration No. 35,264 / #5393}
`
`Attorney for Applicants
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1168, p. 13 of 13
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`482228344 7782
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`-13-
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1168, p. 13 of 13
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`