IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Atty. Dkt. No. 080618-0716
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`First Inventor Name:
`
`Horst OLSCHEWSKI
`
`Title:
`
`Appl. No.:
`
`Filing Date:
`
`Examiner:
`
`Art Unit:
`
`TREPROSTINIL ADMINISTRATION
`BY INHALATION (as amended)
`
`12/591,200
`
`11/12/2009
`
`Sara Elizabeth TOWNSLEY
`
`1629
`
`Confirmation Number:
`
`4093
`
`SUPPLEMENT AMENDMENT AND REPLY UNDER37CFR1.111
`
`Mail Stop AMENDMENT
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Commissioner:
`
`This communication is supplemental to the response filed on November 9, 2015, in
`
`response to the Advisory Action dated February 27, 2015, and final Office Action dated
`
`October 10, 2014, concerning the above-referenced patent application.
`
`Amendments to the Claims are reflected in the listing of claims which begins on page 2
`
`of this document.
`
`Remarks/Arguments begin on page 5 of this document.
`
`Please amend the application as follows:
`
`4853-1738-0397.1
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`This listing of claims will replace all prior versions, and listings, of claims in the application.
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`AMENDMENTS
`
`Atty. Dkt. No. 080618-0716
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`Listing of Claims:
`
`1-17.
`
`(Canceled)
`
`18.
`
`(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 a pulsed ultrasonic nebulizer, wherein said
`
`therapeutically effective single event dose comprises from 15 µg to 90 µg of treprostinil or a
`
`pharmaceutically acceptable salt thereof, said therapeutically effective single event dose is
`
`inhaled in 18 or less breaths by the human.
`
`19.-24. (Canceled)
`
`25.
`
`(Previously Presented) The method of claim 18, wherein the single event dose
`
`contains from 15 µg to 60 µg of treprostinil or a pharmaceutically acceptable salt thereof.
`
`26-27. (Canceled)
`
`28.
`
`(Previously Presented) The method of claim 18, wherein said administering does
`
`not significantly disrupt gas exchange in said human.
`
`29.
`
`(Previously Presented) The method of claim 18, wherein said administering does
`
`not significantly affect heart rate of said human.
`
`30.
`
`(Previously Presented) The method of claim 18, wherein said administering does
`
`not significantly affect systemic arterial pressure and systemic arterial resistance of said human.
`
`31.
`
`(Canceled)
`
`32.
`
`(Previously Presented) The method of claim 18, wherein said administering of
`
`said therapeutically effective single event dose is performed in 5 or less breaths.
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`Atty. Dkt. No. 080618-0716
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`33.
`
`(Previously Presented) The method of claim 18, wherein said human receives
`
`several therapeutically effective single event doses per day.
`
`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 600
`
`µg/ml.
`
`35.
`
`(Previously Presented) The method of claim 18, wherein the single event dose is
`
`administered in 5 minutes or less.
`
`36.
`
`(Previously Presented) The method of claim 27, wherein the single event dose is
`
`administered in 5 minutes or less.
`
`37.
`
`(Previously Presented) The method of claim 34, wherein the single event dose is
`
`administered in 5 minutes or less.
`
`38.
`
`(Previously Presented) The method of claim 18, wherein said therapeutically
`
`effective single event dose is inhaled in 12 or less breaths by the human.
`
`39.
`
`(Previously Presented) The method of claim 27, wherein said therapeutically
`
`effective single event dose is inhaled in 12 or less breaths by the human.
`
`40.
`
`(Previously Presented) The method of claim 34, wherein said therapeutically
`
`effective single event dose is inhaled in 12 or less breaths by the human.
`
`41.
`
`(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 a pulsed ultrasonic nebulizer having a concentration of
`
`said treprostinil or a pharmaceutically acceptable salt thereof from 500 µg/m 1 to 2000 µg/ml,
`
`wherein said therapeutically effective single event dose comprises from 15 µg to 90 µg of
`
`treprostinil, or its acid derivative, or a pharmaceutically acceptable salt thereof, said
`
`therapeutically effective single event dose being inhaled in 18 or less breaths by the human.
`
`42.
`
`(Previously Presented) A method of treating pulmonary hypertension comprising:
`
`administering by inhalation to a human in need thereof a therapeutically effective single event
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`4853-1738-0397.1
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`dose of an inhalable formulation with a pulsed ultrasonic nebulizer having a concentration of
`
`said treprostinil or a pharmaceutically acceptable salt thereof of 600 µg/ml, wherein said
`
`therapeutically effective single event dose comprises from 15 µg to 90 µg of treprostinil, or its
`
`acid derivative, or a pharmaceutically acceptable salt thereof, said therapeutically effective single
`
`event dose being inhaled in 18 or less breaths by the human.
`
`43.
`
`(Previously Presented) The method of claim 18, wherein the pulsed ultrasonic
`
`nebulizer comprises an opto-acoustical trigger for timing inspiration by the human to coincide
`
`with generation of an aerosol pulse produced by the pulsed ultrasonic nebulizer.
`
`44.
`
`(Previously Presented) The method of claim 41, wherein the pulsed ultrasonic
`
`nebulizer comprises an opto-acoustical trigger for timing inspiration by the human to coincide
`
`with generation of an aerosol pulse produced by the pulsed ultrasonic nebulizer.
`
`45.
`
`(Previously Presented) The method of claim 42, wherein the pulsed ultrasonic
`
`nebulizer comprises an opto-acoustical trigger for timing inspiration by the human to coincide
`
`with generation of an aerosol pulse produced by the pulsed ultrasonic nebulizer.
`
`46.
`
`(Previously Presented) The method of claim 18, wherein said administering
`
`results in pulmonary vasodilation in the human for longer than 3 hours.
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`4853-1738-0397.1
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`Atty. Dkt. No. 080618-0716
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`REMARKS
`
`This supplemental response and attached Declarations are filed to supplement the
`
`response filed with the RCE on November 9, 2015. To assist the Examiner in considering the
`
`original response and this supplemental response, this supplemental response includes the same
`
`substantive comments included in the original response and also additional comments based on
`
`two newly submitted Declarations. Applicants respectfully request reconsideration and
`
`allowance of the present application.
`
`CLAIMS STATUS
`
`Applicants added new claims 41-46 in the previous response filed on November 9, 2015.
`
`No further amendments are made in this supplemental response.
`
`Upon entry of the amendments submitted November 9, 2015, claims 18, 25, 28-30, and
`
`32-46 will be pending and subject to examination.
`
`CLAIM REJECTIONS UNDER 35 U.S.C. § 103(a)
`
`Claims 18, 25, 27-30, and 32-40 stand rejected as obvious over U.S. Published Patent
`
`Application No. 2004/0265238 to Chaudry in view of U.S. Patent No. 6,357,671 to Cewers.
`
`Applicants respectfully traverse.
`
`To support an obviousness rejection, MPEP § 2143.03 requires "all words of a claim to
`
`be considered," and MPEP § 2141.02 requires consideration of the "[claimed] invention and
`
`prior art as a whole." Further, the Board of Patent Appeals and Interferences recently confirmed
`
`that a proper, post-KSR obviousness determination still requires the Office make "a searching
`
`comparison of the claimed invention - including all its limitations - with the teaching of the
`
`prior art." In re Wada and Murphy, Appeal 2007-3733 (BPAI Jan. 14, 2008) (citing In re Ochiai,
`
`71F.3d1565, 1572 (Fed. Cir. 1995)). In sum, it remains well-settled law that an obviousness
`
`rejection requires at least a suggestion of all of the claim elements.
`
`The obviousness rejection is improper because the cited references do not teach or
`
`suggest all features of the pending claims, including the "single event dose," "18 or less breaths,"
`
`or a "pulsed ultrasonic nebulizer," as discussed in greater detail below.
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`1.
`
`The cited references do not teach or suggest the "single event dose" recited in
`
`the pending claims
`
`According to the Office Action, the guidance allegedly provided by Chaudry regarding
`
`single event dose is found in prophetic example 4, reproduced here in its entirety:
`
`Example 4
`
`[0097]
`
`5 Treprostinil sodium 0.1-10.0 mg/ml Sodium Chloride 2.0-10.0 mg/ml Sodium
`Hydroxide q.s. Citric Acid q.s. Water q.s.
`
`[0098] Example 4 is a prophetic example of a formulation comprising the vasodilator
`epoprostenol [sic: treprostinil]. Sodium chloride may be added to the solution to adjust
`tonicity, and sodium hydroxide and citric acid are added to adjust the pH of the solution.
`The solution of Example 4 may be made by methods known to those of ordinary skill in
`the art.
`
`At best, this prophetic example gives a range of treprostinil concentration that varies 100-fold
`
`with the lowest concentration set at 0.1 mg/mL, i.e. 100 µg/mL. Such a wide dosing range is
`
`consistent with the prophetic nature of the example and does little to provide guidance to one of
`
`skill in the art.
`
`But more importantly, and as explained in the declaration under 37 C.F.R. § 1.132 by Dr.
`
`Edmund J. Elder, Jr. ("Elder Declaration"), the "single event dose" comprising "from 15 µg to
`
`90 µg of treprostinil or a pharmaceutically acceptable salt thereof' featured in the pending claims
`
`depends on at least two parameters: (1) the concentration of the treprostinil inhalation
`
`formulation; and (2) the volume of the formulation delivered through the single event ("delivered
`volume"). See Elder Declaration at iJ 8. In other words, Example 4, which only describes a
`broad range of treprostinil concentrations, lacks the information needed for one of ordinary skill
`
`in the art to determine how to develop a single event inhalation dose for this example.
`
`Specifically, Example 4 describes only broad ranges or concentration and provides no disclosure
`
`regarding the delivered volume. Consequently, one of ordinary skill in the art would need to
`
`look into Chaudry' s disclosure to obtain information, if any, regarding the "delivered volume"
`
`during a single inhalation event. Quite simply, prophetic Example 4 alone does not describe the
`
`recited "single event dose" or provide sufficient information to render obvious to one of ordinary
`
`skill in the art such a "single event dose."
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`4853-1738-0397.1
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`Furthermore, as explained in the Elder Declaration, the "delivered volume" of an
`
`inhalable formulation delivered through a single inhalation event by a nebulizer system is based
`
`on a number of factors. Those factors, in the case of Chaudry, include the initial volume of the
`
`formulation, i.e., the "fill volume," and the residual volume of the formulation that cannot be
`
`further delivered through the nebulizer, i.e., the "dead volume." The "delivered volume" can be
`calculated by subtracting the "dead volume" from the "fill volume". See Elder Declaration at ilil
`11-12. In other words, one of ordinary skill in the art would need to know both the "dead
`
`volume" and the "fill volume" in order to assess the volume of the formulation delivered through
`
`a single even inhalation.
`
`Turning to Chaudry's specification, one of ordinary skill in the art would note that
`
`Chaudry' s paragraph [0060] describes "fill volume" in the form of a laundry list containing
`
`many alternative ranges. Nothing in Chaudry's paragraph [0060] describes the corresponding
`
`"dead volume." Later, Chaudry's paragraph [0065] describes "dead volume" also in the form of
`
`a laundry list of many alternative ranges. Nothing in Chaudry' s paragraph [0065] describes the
`
`corresponding "fill volume." Thus, as explained in the Elder Declaration, Chaudry's vague
`
`disclosure in paragraphs [0060] and [0065] does not allow one of ordinary skill in the art to
`
`reasonably assess the "delivered volume" of the formulation in a single event inhalation,
`
`especially in light of the many alternative ranges provided in multiple disconnected paragraphs.
`See Elder Declaration at ilil 14-17. Indeed, some of the disclosed alternatives would be
`inoperative. Id. at iJ 17 ("[T]he combination of certain values selected from the "fill volume" and
`"dead volume" paragraphs results in a negative volume, which would be undeliverable.").
`
`On the other hand, one of ordinary skill in the art would identify paragraph [0064] as
`
`specifically disclosing both "dead volume" and "fill volume" of the nebulizing device used in
`
`Chaudry:
`
`For example, when nebulizing an inhalation solution comprising 2.5 rnl or rnore,
`about 0.7 ml of the solution remains in the nebulizer system after treatment,
`though the amount may vary depending on the model of the nebulizer used. In
`these instances. the individual is not receiving the prescribed dosage or optimum
`dosage of inhalation medication.
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`Chaudry at ii [0064] (emphasis added); see also Elder Declaration at ii 18. Thus, Chaudry's
`
`paragraph [0064] describes a problem of nebulizing devices in general --- insufficient delivery of
`
`formulation per inhalation event because of the dead volume. See Elder Declaration at ii 19.
`
`Moreover, one of ordinary skill in the art \.vould understand from paragraph [0064] that a
`
`delivery volume of 1.8 mL (2.5 mL fill volume --- 0.7 ml dead volume) would lead to the
`
`individual "not receiving the prescribed dosage or optirnurn dosage of inhalation medication,"
`
`including its exemplary formulations (e.g., prophetic example 4) containing at least 0.1 mg/mL,
`
`i.e. 100 µg/mL, of treprostinil. Moreover, as noted by Dr. Elder, the insufficiency or inadequacy
`
`of 1.8 ml delivery volume is later reconfirmed by Chaudry toward the end of paragraph [0064],
`
`stating that:
`
`For example, in one day, due to the residual medication remaining in the
`nehulizer system after each treatment, an individual fails to receive approximately
`2.1 rnl, or more of the prescribed daily amount of medication.
`
`Finally, as explained by Dr. Elder, Chaudry purportedly solves the problem by adjusting filling
`
`volume to reduce the dead volume with the ultimate effect of delivering more drug than
`
`conventional nebulizers:
`
`It is believed that the fill volumes of the one or more pulmonary hypertension
`reducing agents inhalation solutions of the present invention will result in lesser
`amounts of solution remaining in the nebulizer svstem after treatment, when
`compared to conventional inhalation solutions (e.g. 2.5 ml or 3 ml fill volume).
`Ls~Q'~-'~9.l.t1:tt.Qn_.rf:m_~'tining.l_rr..thf:_n_~!?_u.1h~~_r_,~_Q.tf:m __ rnf:11rr~ __ m_Q.rn_.r.r1f:dl_~_<:l.tl_9.n..l~-"K'--Q.Ef:
`or more pulmonary hvpertension reducing agents) administered to the individual
`during each treatment.
`
`Chaudry ii [0065]. Taken together, Chaudry specifically teaches the amount of medication
`
`delivered per nebulizing event as being greater than a conventional nebulizer, e.g. at least greater
`
`than the 1.8 ml delivery volume described in paragraph [0064]. Elder Declaration at iiii20-22.
`
`With the lower limit of treprostinil concentration in Chaudry being 100 µg/ml, the single event
`
`dose in Chaudry would be at least 180 µg of treprostinil, which is at least two times the upper
`
`limit of the single event dose featured in the pending claims, e.g., "from 15 µg to 90 µg" in claim
`
`18. See Elder Declaration at ii 22. Thus, Chaudry teaches away from the dosage required by the
`
`present claims and, specifically, teaches away from reducing the dosage such that one of skill in
`
`the art would arrive at the dosage recited in the present claims.
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`2.
`
`The cited references do not teach or suggest the "18 or less breaths" featured
`
`in the pending claims
`
`According to the latest Office Action, the guidance allegedly provided by Chaudry
`
`regarding the single event inhalation time is found in paragraph [0063]:
`
`... In another alternative embodiment, the fill volumes of the present invention may
`reduce each nehulization treatment to about 12, l 0, 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 frorn the
`medication prescribed.
`
`As explained by Dr. Elder, one of ordinary in the art would interpret the description of times
`
`recited in paragraph [0063] as referring to the following two alternative embodiments: (1) reduce
`
`each nebulization treatment to about 12, 10, 9, 8, 6, 5, 4, 3 minutes; or (2) reduce each
`
`nebulization treatment to less time over conventional nebulizer treatments. See Elder
`Declaration at ii 27. This interpretation is consistent with the rest of Chaudry's disclosure of
`regarding treatment time. For example, paragraph [0067] states:
`
`... The individual continues breathing into the mouthpiece or facemask until the
`nebulization treatment is finished. This may take about 12, 11, 10, 9, 8, 7, 6, 5, 4 or 3
`minutes. In an alternative embodiment, the nebulization treatment is finished when at
`least substantially all the mist is removed from the nebulizer chamber. This may take
`about 12, 11, 10, 9, 8, 7, 6, 5, 4, or 3 minutes ...
`
`The Office, however, inte11Jreted the "or less" in paragraph [0063] as a continuation of "3
`
`minutes", i.e., referring to "less than 3 minutes" of each nebulizing treatment tirne. As clarified
`
`by Dr. Elder, this interpretation would make the" l 2, 10, 9, 8, 6, 5, 4, 3 minutes, or less"
`
`referring not to the reduced inhalation tirne itself~ but to the difference between the reduced
`
`inhalation time and the conventional inhalation time - i.e. to reduce each nebulization treatment
`to about 'x' minutes over conventional nebulizer treatments. See Elder Declaration at ii 28.
`Without knowing the value of the conventional inhalation time or which of the various
`
`concentrations, fill volumes, dead volumes are to be used, one of ordinary skill in the art would
`
`not be able to assess what the reduced inhalation time is under the Office's interpretation of
`paragraph [0063]. See Elder Declaration at ii 26.
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`Moreover, as explained by Dr. Elder, one of ordinary skill in the art would understand
`
`that (l) the description of reduced inhalation time is general in nature (further generic/non(cid:173)
`
`helpful prophetic teachings), and (2) the purported benefit for the reduced inhalation time is to
`
`improve patient compliance as a general result of requiring less time for each inhalation event
`See Elder Declaration at ii 29.
`
`Of course, one of ordinary skill in the art would only consider adopting a reduced single
`
`event inhalation time if the reduced inhalation time does not lead to significant side effects. See
`Elder Declaration at ii 30. In other words, one of ordinary skill in the art would not adopt the
`reduced inhalation time taught in Chaudry to improve patient compliance if the reduced
`
`inhalation time of a specific active agent would likely lead to adverse side effects.
`
`This desire to avoid adverse events is important in the context of Chaudry. As explained
`
`in Applicants' response filed on January 16, 2013, it is known in the art that significant side
`
`effects are likely to occur when iloprost, one of the vasodilators specifically listed in Chaudry
`(paragraph [0026]), is inhaled too quickly. For example, page 17 of Gessler1 states that:
`
`"the inhalation time fbr delivery nf an equivalent ilop·rost dose at tht~
`.
`'
`mouthpk>ce 0-8 pg) \Vas reduced. frorn i 2 rnin 1.vith the jet nehuhzer system to 2 min
`
`with tht~ ultrasonic ne.bulizer, >vhcn retaining the sarnc concentration of the i!oprost
`
`solution { 10 J..tg·mL'i), ln prdirninat)' cathercr investigations, ho\vever, some increase
`
`in systemic side effects \.Vas nbservcd •.vhen administering the total iloprost dose of
`
`2.8 ~ig via the inhalation route for such a short time period:'
`
`Likewise, page 54 of Voswinckel 2 also states that:
`
`1 Gessler et al., European Respiratory Journal; 17: 14-19 (2001); Exhibit 5 (Elder
`
`Declaration).
`
`2 Vonswinckel et al., Pulmonary Pharmacology & Therapeutics; 22:50-56 (2009); Exhibit 6
`
`(Elder Declaration).
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`''A dose of mon:~ than 5 pg i!nprost pt~r inhalmkm or a reduttion of mhalatirm time tu
`
`kss than 3 rnin induces in most patients C(>nsidcrnbk systemic prnstunoid side effects
`like hypntcnsinn, dizziness, hcwJa:chc, jaw pain. nausea or !diarrhea]."
`
`One of ordinary skill in the art reading Chaudry at the time the present application was
`
`filed would be aware of the "considerable" systemic side effects of at least one of the specifically
`
`disclosed vasodilators (iloprost) if inhaled too quickly, e.g. "2 min" described in Gessler or "less
`than 3 min" described in Voswinckel. See Elder Declaration at ii 33. Moreover, one of ordinary
`skill in the art would recognize that "iloprost" is listed side-by-side as interchangeable with
`"treprostinil" under the specifically recognized class of "prostacyclin analogs." See Chaudry ii
`[0026] ("Vasodilators for use herein also include prostaglandins (Eicosanoids), including
`
`prostacyclin (Epoprostenol) and prostacyclin analogs, including Iloprost and Treprostinil, and
`
`prodrugs, salts and isomers thereof."). As such, one of ordinary skill in the art would not
`
`consider Chaudry's description of its single event inhalation time in paragraph [0063] as
`
`referring to "less than 3 minutes," at least not when the inhalable formulation contains iloprost or
`
`treprostinil. The specific teachings of Gessler and Voswinckel would cause one of ordinary skill
`
`in the art to avoid the shorter inhalation times disclosed by Chaudry assuming the correctness of
`the Office's interpretation of Chaudry. ,5ee Elder Declaration at ii 34.
`In sum, and as supported by the Elder Declaration, the PTO failed to establish a prima
`
`facie case of obviousness because the cited references do not teach or suggest at least two
`
`independent elements of the claimed invention. The cited references do not teach or suggest the
`
`"single event dose" and" 18 or less breaths" limitations of the pending claims. Accordingly,
`
`Applicants request withdrawal of the rejection.
`
`3.
`
`The cited references do not teach or suggest a pulsed ultrasonic nebulizer
`
`recited in the pending claims.
`
`The Office acknowledges on page 10, lines 5-6, of the Final Office Action that Chaudry
`
`does not teach a pulsed ultrasonic nebulizer recited in claim 18. To remedy these deficiencies of
`
`Chaudry, the Office relies on Cewers. Cewers, however, is far removed from the pulsed
`
`ultrasonic nebulizer of the present claims that controls the amount of drug administered per
`
`inhalation event, and it does not suggest the use of an "opto-acoustical trigger" as recited in
`
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`dependent claims 43-45. The Office appears to have misapprehended certain aspects of Cewers,
`
`so the following remarks provide a more detailed explanation of Cewers.
`
`The present specification defines the pulsed ultrasonic nebulizer in paragraph [0070] as
`
`"mimicking a metered dose inhaler." A metered dose inhaler is defined in paragraph [0040] as
`
`an inhaler "capable of delivering a metered or bolus dose of a respiratory drug to the lungs."
`
`This is achieved by the pulsed ultrasonic nebulizer through a "pulse" of aerosol production
`
`followed by a pause, as described in paragraph [0078] with the exemplary Optineb nebulizer,
`
`which allows the human to breathe in each pulse and exhale during a pause before the next
`
`breath is taken. The present claims recite a number of breaths that correspond to the number of
`
`pulses of aerosol, which, taken together with the recited concentration range, makes it possible to
`
`control the dosage delivered to the human (15 µg to 90 µg of treprostinil or a pharmaceutically
`
`acceptable salt thereof as recited in claim 18). In addition, the opto-acoustical trigger of claims
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`43-45 further improves accuracy by facilitating "inspiration by the human to coincide with
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`generation of an aerosol pulse produced by the pulsed ultrasonic nebulizer."
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`Although Cewers does have intermittent nebulization periods, there is no suggestion that
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`any of these nebulization periods would correspond to a timed "pulse" of aerosol that is inhaled
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`in one breath by the patient as presently claimed. To the contrary, Cewers expressly states that
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`the time periods during which nebulization is stopped are simply to allow measurement of liquid
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`volume inside the nebulizing chamber:
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`The variation is such that nebulization periods, during which high amplitude
`ultrasound are emitted which are sufficient to cause nebulization, alternate with
`measurement periods, during which only ultrasound sonar pulses are emitted having an
`amplitude, insufficient to affect i.e. disturb, the location of the upper boundary 6 to a
`measurable extent.
`During a measurement period a trigger signal is sent to the sonar detection stage
`11, corresponding to the oscillator 2 being driven, to generate an ultrasonic sonar pulse.
`The trigger signal, which may conveniently be provided either by the controller unit 12 or
`the driver 10, initiates the start of timing by the timer circuitry. The time measurement is
`stopped when the receipt of a reflected component of the generated ultrasonic pulse is
`detected at the oscillator 2.
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`Cewers, col. 3, 11. 21-33 (emphasis supplied). A trigger signal is used when nebulization stops in
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`order to start the measurement period with an ultrasonic sonar pulse. Thus, Cewers discloses
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`that the liquid level information obtained during a first and a second measurement period may be
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`compared to determine the amount of liquid nebulized during the intervening nebulization period
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`4853-1738-0397.1
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`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1163, p. 12 of 28
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`Atty. Dkt. No. 080618-0716
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`to provide dose information. Cewers at col. 3, 11. 51-63. The dose information is determined by
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`an emitted acoustic pulse reflected into the chamber that is used in a manner similar to sonar
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`detection to determine the amount of drug remaining in the chamber. Cewers at col. 3 11.1-9
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`and claim 1. Such a pulse is a "feedback" pulse, meaning that a reflected sound wave is used to
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`give the depth of fluid that remains in the nebulization chamber and has no impact on the dose
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`delivered, nor does it guide the human subject to coordinate inhalation of each breath so that it
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`coincides with the generation of a pulse of aerosol. Cewers at col. 2 11. 56-61.
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`Unlike the device disclosed in Cewers, a pulsed ultrasonic nebulizer offers a distinct
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`advantage of reducing waste of the nebulized drug. A pulsed ultrasonic nebulizer generates
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`pulses of aerosol spaced apart in time that correspond to each breath inhaled by a human. The
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`pulses allow inspiration of each pulse, and the pauses in between prevent drug being wasted
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`when inspiration is not occurring while a human exhales. The pauses also reduce the risk that
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`persons will be unintentionally exposed to drug that is not inhaled, "thereby providing exact
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`dosage." See Specification at paragraph 74.
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`The presently claimed methods use a pulsed ultrasonic nebulizer with a starting solution
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`of treprostinil having a certain drug concentration range. The pauses between pulses of aerosol
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`allow the human to inhale a precise amount of drug that varies between 15 to 90 micrograms in
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`18 or less breaths. By contrast, Cewers uses acoustical pulses to determine the depth of liquid
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`inside the nebulizer chamber for calculating how much drug remains. Measuring how much
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`drug was given or how much remains is not a teaching of a "pulsed ultrasonic nebulizer" capable
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`of delivering the dose range recited in the present claims using a certain number of breaths in one
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`event.
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`4.
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`The cited references are non-enabling as to the presently claimed methods
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`Prior art that is non-enabling cannot anticipate or render obvious a claimed invention.
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`Specifically, in Impax Laboratories v. Aventis Pharmaceuticals, 545 F.3d 1312 (Fed. Cir. 2008),
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`the Court held that a "[a] method for treating a mammal with amyotrophic lateral sclerosis,
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`comprising the step of administering to said mammal in recognized need of said treatment an
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`effective amount of 2-amino-6-(trifluoromethoxy)benzothiazole or a pharmaceutically
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`acceptable salt thereof' was not anticipated by a non-enabling generic reference. The brand
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`4853-1738-0397.1
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`-13-
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`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1163, p. 13 of 28
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`name of the claimed compound is "riluzole." Impax, 545 F.3d at 1312. Thus, the patent claims
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`at issue in Impax, like those currently pending in the present application, are directed to a method
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`of treating a specific disease with a specific compound.
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`Impax argued at trial that the claims at issue are invalid because they are anticipated by the
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`'940 patent, describing a generic "formula I compound," which "includes riluzole as a formula I
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`compound, suggests that formula I compounds may be used to treat ALS, and provides some
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`dosage information." Impax Labs., Inc. v. Aventis Pharms., Inc., 496 F.Supp. 2d 428 (D. Del.
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`2007). The trial court disagreed, finding that the '940 patent actually names riluzole "so to
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`exclude it from the claimed invention or to identify it as a 'raw' or starting material for the
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`synthesis of other compounds." Impax, 496 F.Supp 2d at 432. However, the trial court also
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`pointed to a number of additional factors that led away from enablement, stating that
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`"[ m ]oreover, the dosage guidelines are broad and not specific to any of the hundreds of formula I
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`compounds of the claimed invention or to any of the listed disease." Id The Court further notes
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`that "there are no working examples in the patent for the treatment of ALS with riluzole." Id
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`Finally, the Court concludes that"' [b ]ecause the link between riluzole and the treatment of ALS
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`is speculative and undue experimentation would be required to establish such a link, the Court
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`cannot conclude that the '940 patent is enabled." Id
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`On appeal, the Federal Circuit affirmed the district court's decision, stating that "the
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`district court applied the proper enablement standard and correctly determined that the '940
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`patent is not an enabling prior art reference and that it does not anticipate claims 1-5 of the '814
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`patent." Impax, 545 F.3d at 1315. Specifically, the Court noted that the district court relied on
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`the following factors: (1) "excessive experimentation would have been necessary to practice the
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`invention;" (2) "formula I of the alleged prior art discloses hundreds or thousands of compounds
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`and several diseases;" (3) "the trial court did not find the dosage information in the disclosure to
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`teach a proper treatment" and (4) "the noted the absence of working examples." Id The Federal
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`Circuit itself concluded that "the '940 patent's dosage guidelines are broad and general without
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`sufficient direction or guidance to prescribe a treatment regimen" and that "[t]he alleged prior art
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`also contains no working examples." Id Thus, the Court held that "each component of the
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`claimed invention - identifying riluzole as a treatment for ALS and devising dosage parameters -
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`would require undue experimentation ba