UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`WATSON LABORATORIES, INC.
`Petitioner
`
`V.
`
`UNITED THERAPEUTICS CORP.
`
`Patent Owner
`
`Patent No. 9,358,240
`
`Issue Date: June 7,2016
`Title: TREPROSTINIL ADMINISTRATION BY INHALATION
`
`Inter Partes Review No. 2017—01621
`
`
`SECOND DECLARATION OF DR. AARON WAXMAN
`
`4841-1310-0898
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`UNITED THERAPEUTICS, EX. 2105
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`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017-01621
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`IPR2017—01621
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`Declaration of Dr. Aaron Waxman
`
`I, Dr. Aaron Waxman, hereby declare as follows:
`
`1.
`
`I am a pulmonary critical physician in Boston, Massachusetts.
`
`I am
`
`the Executive Director of the Center for Pulmonary and Heart Disease in the Heart
`
`and Vascular Center at Brigham and Women’s Hospital in Boston, Massachusetts.
`
`I am board certified in Internal Medicine, Pulmonary Disease, and Critical Care
`
`Medicine.
`
`I have been practicing as a pulmonary and critical care doctor for over
`
`20 years.
`
`I am a member of the American College of Chest Physicians, the
`
`American Thoracic Society, the Pulmonary Hypertension Association, and the
`
`Pulmonary Vascular Research Institute.
`
`2.
`
`I am an Associate Professor of Medicine at Harvard Medical School
`
`and have dual appointments in the Pulmonary Critical Care and Cardiovascular
`
`Medicine divisions at the Brigham and Women’s Hospital. I have previously
`
`served as assistant professor in Medicine at the Yale University School of
`
`Medicine and Tufts University School of Medicine. I have authored or co-
`
`authored more than 100 peer—reviewed journal articles, book chapters and reviews.
`
`3.
`
`I received my Bachelor’s degree from George Washington University.
`
`I received a Ph.D. in Anatomy and Neuroscience at the Albany Medical College,
`
`and an MD. from Yale University School of Medicine.
`
`I completed my internship
`
`and residency in Internal Medicine at Yale New Haven Hospital. I also completed
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`Declaration of Dr. Aaron Waxman
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`a Fellowship in Pulmonary and Critical Care at the Yale School of Medicine. My
`
`curriculum vitae is provided as Exhibit 2041.
`
`4.
`
`I am a paid consultant for United Therapeutics, the assignee of US
`
`Patent No. 9,358,240 (“the ’240 patent”), in connection with IPR2017-01621. My
`
`compensation does not depend on the content of my opinions or the disposition of
`
`this proceeding. I have been retained by United Therapeutics to provide technical
`
`expertise and my expert opinion on the ’240 patent.
`
`5.
`
`I understand that the Petition brought forward by Watson
`
`Laboratories, Inc. (“Watson”) challenges claims 1-9 of the ”240 patent. In my
`
`previous declaration (Ex. 2040), I addressed “Ground 1” of the Petition — tie.
`
`whether these claims are obvious over the combination of Voswinckel (Ex. 1003),
`
`Ghofrani (Ex. 1005), and Patton (EX. 1012). I understand the Patent Trial and
`
`Appeal Board (“the Board”) has now changed the scope of the proceeding to also
`
`consider whether the claims are obvious over two additional combinations —
`
`“Ground 2” and “Ground 3” — summarized below. The testimony provided below
`
`supplements my previous declaration (Ex. 2040) and specifically relates to Ground
`
`2 and Ground 3.
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`IPR2017—01621
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`Declaration of Dr. Aaron Waxman
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`6.
`
`For reference, below is a list of the Exhibits that are cited herein:
`
`
`
`
`Exhibit No.
`Description
`
`1001
`U.S. Patent No. 9,358,240
`
`1002
`Declaration of Dr. Maureen Donovan
`
`1003
`
`1006
`
`1005
`
`Robert Voswinckel, et a1. “Inhaled treprostinil sodium for the
`treatment of pulmonary hypertension” Abstract #1414, Circulation,
`110, 17, Su lement Oct. 2004 : 111—295
`
`Hossein Ardeschir Ghofrani, Robert Voswinckel, et al., “Neue
`Therapieoptionen in der Behandlung der pulmonalarteriellen
`H nertonie,” Herz, 30,4 June 2005 : 296-302
`
`Annexes to Commission Decision C(2005)3436 of 05 September
`1009 2005: Annex III — Ventavis® Labelling and Package Leaflet
`
`
`
`
`
`1012
`
`1014
`
`WO 93/00951
`
`William F. Ganong, Review ofMedical Physiology 591-92 (17th ed.
`1060
`1995)
`FDA Drug Details Website, Ventavis,
`https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=Ba
`1099
`
`sicSearch.process (accessed 5/17/2017)
`Newman, Stephen P. Respiratory drug delivery: esseniial iheory and
`2003
`:raciice. Respiratory Drug Delivery Online, 2009 (excerpt).
`"Mechanical Ventilation." American Journal ofRespiratory
`and Critical Care Medicine 196 2 :P3-4 2017 .
`
`2008
`
`Declaration of Dr. Aaron Waxman
`2040
`
`2041
`Curricu/um vitae of Dr. Aaron Waxman
`
`2113
`2114
`
`Merck Manual — Professional Version — Evaluation of the Pulmonary
`Patient (accessed July 6, 2018)
`FDA Ventavis Label under Action Date 12/29/2004 (accessed July 2,
`
`FDA Ventavis Label under Action Date 8/24/2005 (accessed July 2,
`2
`115
`
`2018)
`
`7.
`
`I have been informed that in order for a patent claim to be considered
`
`obvious, each and every limitation of the claim must be present within the prior art
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`or within the prior art in combination with the general knowledge held by a POSA
`
`at the time an invention was made, and that such a person would have a reason for
`
`and reasonable expectation of success in combining these teachings to achieve the
`
`claimed invention.
`
`I understand there may be a variety of rationales that can
`
`demonstrate the reason for and reasonable expectation of success in combining
`
`selected teachings, but, regardless of the rationale used, it must be supported by
`
`evidence.
`
`8.
`
`I understand that the Board was previously only considering whether
`
`claims 1~9 are obvious over the references provided in “Ground 1,” but is now also
`
`considering whether claims 1~9 are obvious over the references provided in
`
`“Ground 2” and “Ground 3” noted below.
`
`References
`Ground
`
`
`
`
`Robert Voswinckel, et a1. “Inhaled
`
`treprostinil sodium for the treatment of
`
`pulmonary hypertension” Abstract #1414,
`
`Circulation, 110, 17, Supplement (Oct.
`
`Ground 2
`
`2004): III-295 (“Voswinckel,” Ex. 1003)
`
`WO 93/0095] (“‘Patton,” EX. 1012)
`
`Opti—Neb—ir® Operating Instructions, Model
`
`ON—100/2 (2005) (“the 0ptiNeb~ir Manual,”
`
`
`
`Ex. 1006)
`
`
`Voswinckel
`Ground 3
`
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`Declaration of Dr. Aaron Waxman
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`
`
`Annexes to Commission Decision C(2005)3436 of
`
`05 September 2005: Annex III —
`
`Ventavis® Labelling and Package Leaflet
`
`(“the EU Community Register, ” Ex. 1009)
`
`Hossein Ardeschir Ghofrani, Robert
`
`
`
`Voswinckel, et al., “Neue Therapieoptionen
`
`in der Behandlung der pulmonalarteriellen
`
`Hypertonie,” Herz, 30,4 (June 2005): 296—
`
`302 (“Ghofrani,” Ex. 1005)
`
`In this section, I provide my opinions on the OptiNeb—ir Manual (Ex. 1006), the
`
`EU Community Register (Ex. 1009), and their use in combination with the other
`
`references in Ground 2 and Ground 3, respectively.
`
`A. The OptiNeb-ir Manual
`
`9.
`
`I was instructed to assume that the OptiNeb-ir Manual provided as
`
`Exhibit 1006 is an English translation of a document originally in German. Ex.
`
`1006, 33.
`
`I fiirther understand that Watson submitted a declaration from
`
`Christopher Butler (Ex. 1014) in which there is a German language manual
`
`(Exhibit 84), which appears to report a different nebulization output than the
`
`translated OptiNeb—ir Manual. As shown below, Exhibit B4 of Mr. Butler’s
`
`declaration reports a “Verneblerleistung” of “< 0,6 ml/min” whereas the OptiNeb-
`
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`ir Manual reports a “Nebuliser output” of “0.6 ml/min” in the same numbered
`
`section.
`
`
`
`
`
`Excerpt from Ex. 1006, 23 Excerpt from Ex. 1014, 198
`
`".0 Technical data at me OPTIMEB-SJ-ir ultrasonic nebulizer
`
`.
`
`GEWICHE ClES Grundgeral
`Stromversorgungsanen
`
`14.0 Technisclle Damn ties Ultrascllallvernehlers ()I"I'I.VICII'—k
`(3,559“
`93 x 5.5 11 105 mm
`
`”93 K66 ’-joists";
`...
`...
`...
`ailigm'hiffiaisticlaim-CHE;
`”2309
`.Power supply 1.11111 1101230 VAC.
`.
`Power supmv type
`etzgerat 1103230 VAC
`
`. 12 V motor vemcle charette IlghtEI adapter
`.
`.
`.
`'
`12 V Klz'Adapt” z'gamnenanmnder
`.
`..12 1:00. 1.5 A manmum
`Esectncal supply...
`.
`Elektrlsche Versoruung.
`..
`12V0015A Maximum
`
`13 watt mammum
`Power consumntlon dunno operauon
`Stromverblauch bel Belnob.....
`.18 Wall Mammum
`.24 MHZ {nominal}
`Uttrasonlc frequency.
`Ultraschalflremenz .......
`.2.4 MHz[nom'nalJ
`
`.... 0.6 milmln
`Nemltser OUlput
`.
`.
`.
`.....
`.
`.
`Vemeblerleistung _______________
`___<o_5m|fmjn
`
`MMAD
`. 2 3’3 333 El" 5 Hm taepencllng on battle N319} MMAD....2.31"3..3.’3.814 5 Um”flue nach Prallolatte]
`Fassungsvermogen des Medlkamenlenbechers ........................... P’ 5 m1 Maximum
`(:3ch oi [he medlcauon cup
`'
`' "
`..i’g ml maxlmum
`Eifirfglgrgieec‘iibwigjgd resenrmr "
`'
`”11”1:39":
`Fassungsvermogen des KontaktfIussigkejtsbehalters
`..45 ml
`Elektrlsche Schutzklasse|| Typ B
`
`
`.
`
`..
`
`'
`
`
`
`10.
`
`The OptiNeb-ir Manual describes a device known as an “OptiNeb-ir”
`
`and its use with a mechanical ventilator. Ex. 1006, 6-14, 17, 20, 21. The device
`
`features a multifimction light that changes color to show changes in status, such as
`
`whether the nebulizer is on and whether aerosol production is in progress. Ex.
`
`1006, 16. It also features an acoustic signal that sounds when the device is turned
`
`ofi‘. Id. Neither of these signals are designed to cause a user to inhale a particular
`
`pulse of aerosol and synchronize each breath to each pulse. A POSA would
`
`understand that these signals only provide information on device status. Id.
`
`1 1.
`
`As noted above, a patient using a ventilator is not in control of his/her
`
`inhalation; rather, a ventilator, when triggered to deliver a breath, uses positive
`
`pressure to cause gas to flow into the lungs constituting a breath — i.e., mechanical
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`Declaration of Dr. Aaron Waxman
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`ventilation. Ex. 2008. While the OptiNeb-ir Manual features programs that
`
`provide intermittent delivery (P 1, P2, P6, and P3 (in part)) and programs that
`
`provide continuous delivery (P4, P5, and P3 (in part)) of aerosol, the only program
`
`that refers to coordination of any kind (P6) is designed to coordinate aerosolization
`
`with such mechanical ventilation. Since patients using a ventilator are unable to
`
`breathe without assistance, the OptiNeb model described in the OptiNeb-ir Manual
`
`would not and could not synchronize inhalation with a pulse of aerosol.
`
`12. When used with a mechanical ventilator, the device is connected into
`
`the ventilator airflow circuit. Ex. 1006, 1, 11-13. In this regard, the multi-function
`
`light would not be within the user’s field of View such that a user would be able to
`
`coordinate any sort of breathing. Indeed, when used with a ventilator, there would
`
`be no use for such an acoustic or visual signal for any sort of coordination, since
`
`airflow would be under the control of the mechanical ventilator which would be
`
`directly triggered by the patient’s breathing effort or time cycled. Ex. 2008.
`
`13.
`
`Further, based on the diagrams and photographs in the OptiNeb-ir
`
`Manual, the multi-function light is not within a user’s field of view when used with
`
`a mouthpiece. EX. 1006, l, 8. Therefore, even if a mouthpiece was used with the
`
`device, a user could not see the multi-function light during an inhalation event or
`
`rely on the information it conveys to synchronize his/her inhalation. Id.
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`Declaration of Dr. Aaron Waxman
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`B. Ground 2 — Obviousness over Voswinckel, Patton, and the OptiNeb-
`ir Manual
`
`14.
`
`I disagree with Dr. Donovan that the claims of the ’240 patent are
`
`invalid as obvious over Voswinckel in view of Patton and the OptiNeb—ir Manual.
`
`I understand that the proper question is whether the claim as a whole, not just some
`
`portion of it, would be obvious. However,
`
`limitation [D] (“said single event dose
`
`comprising from 15 ug to 90 ug of treprostinil or a pharmaceutically acceptable
`
`salt thereof delivered in 1 to 18 breaths”) is the only limitation of claim 1 that Dr.
`
`Donovan states “would have been obvious over Voswinckel, in view of Patton,
`
`and the OptiNeb®~ir User Manual.” Ex. 1002, 11170—171. Dr. Donovan does not
`
`suggest that limitation [D] is disclosed explicitly, and she does not analyze claim 1
`
`as a whole. Id. at 11172—179. Dr. Donovan also does not discuss an expectation of
`
`success in connection with her opinion. Id. at 1172-185.
`
`15.
`
`The OptiNeb-ir Manual does not indicate that a user should coordinate
`
`inhalation with a sound or a light, and, indeed, a patient on a ventilator would not
`
`require or be capable of such coordination. Furthermore, the OptiNeb—ir Manual
`
`lacks any discussion of suitable doses for drug delivery. Nevertheless, Dr.
`
`Donovan uses this reference as the basis for calculations to determine possible
`
`dosing using this device in combination with Voswinckel and Patton. EX. 1002,
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`1172-178. The proposed calculations are based on a series of inaccurate
`
`assumptions and would not be undertaken by a POSA to calculate dose.
`
`16.
`
`In her calculations, Dr. Donovan picks an average breathing rate for a
`
`normal human of 12 to 15 breaths per minute based on Ganong’s Review of
`
`Medical Physiology. Ex. 1002, 1]]74 (citing Ex. 1060, 3). However, this average
`
`for a “normal human” is not indicative of the breathing rate for a patient suffering
`
`from a particular disease, ag. pulmonary hypertension. Rather, in my clinical
`
`experience, patients with cardiopulmonary disease, such as pulmonary
`
`hypertension, have a much higher breathing rate — closer to 18 to 22 breaths per
`
`minute.
`
`17.
`
`Dr. Donovan calculates that 12 to 15 breaths per minute means that a
`
`breath consisting of an inhalation and an exhalation occurs within the span of 4 to
`
`5 seconds. Ex. 1002, 11174. Without providing any fiirther basis, Dr. Donovan
`
`then concludes that the inhalation portion takes between 2 to 3 seconds. Id.
`
`However, inhalation may occupy significantly less than half of the duration of the
`
`breath in patients with lung diseases. Ex. 2003, 4. Thus, even if a human suffering
`
`from pulmonary hypertension takes 12 to 15 breaths per minute, Dr. Donovan’s
`
`estimate of a 2 to 3 second inhalation is inconsistent with the breathing pattern of
`
`patients with lung diseases. Rather, in my clinical experience, patients have a
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`much shorter inhalation than exhalation, and those patients with cardiopulmonary
`
`disease, such as pulmonary hypertension, have significantly shorter inhalation
`
`times — usually less than 1 second and at most 1.5 second per inhalation. See Ex.
`
`2113, 4, 6.
`
`18.
`
`Further, Dr. Donovan relies on the OptiNeb-ir Manual for a
`
`nebulization output rate of 0.6 mllmin and assumes that a POSA would adopt this
`
`rate for delivering the 600 11le of treprostinil in Voswinckel. As an initial
`
`matter, although the OptiNeb-ir Manual states a nebulization rate of 0.6ml/min, the
`
`German document provided in Exhibit 1014 shows that the nebulization rate must
`
`be less than 0.6 ml/min, making the reliance on this rate even more improper. And
`
`even Dr. Donovan admits that there is a range of possible nebulization output rates
`
`that a POSA would be aware of, specifically that “[a] POSA would have
`
`understood that the Nebu—Tec device could be programmed to achieve different
`
`rates of nebulization that were at least somewhere between 0.173 — 0.6 mL/min.”
`
`Ex. 1002, 11176. However, a POSA would neither have motivation nor a
`
`reasonable expectation of success to select the highest nebulization output rate
`
`disclosed in the OptiNeb-ir Manual to deliver the drug of Voswinckel for at least
`
`two reasons. First, the OptiNeb—ir Manual relates to a configuration for ventilator
`
`use, whereas the patients in Voswinckel are not described as requiring mechanical
`
`ventilation. Ex. 1003, 7. Second, as explained in my previous declaration,
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`Voswinckel is a preliminary study which addresses efficacy only in the context of
`
`a single acute dosing. Ex. 2040, 1130—35. In my clinical experience, such studies
`
`are conducted cautiously, involving dose escalation; therefore, without filrther
`
`information a POSA would start at a low nebulization rate not a high one.
`
`19.
`
`It is also outside the purview of a POSA’s expertise to reconfigure or
`
`reprogram a device such as the OptiNeb model described in the OptiNeb-ir
`
`Manual, let alone to do so based on teachings related to a structurally different
`
`device. For example, as explained in my prior declaration, Patton relates to a gas
`
`jet device using a “compressor” to generate a continuous flow of air, which in turn
`
`aerosolizes an active agent. Ex. 2040, 1148; Ex. 1012, 12:13-25. The light and/or
`
`audible signal in Patton is keyed to the “operation of the compressor.” Ex. 2040,
`
`148; Ex. 1012, 14:11-14. The OptiNeb-ir Manual, on the other hand, describes an
`
`ultrasonic nebulizer for use with a ventilator. Ex. 1006. As explained in my prior
`
`declaration, such ultrasonic nebulizers differ structurally from a gas jet based
`
`device, using a piezoelectric element rather than a compressor to aerosolize an
`
`active agent. Ex. 2040, 1148; Ex. 2003, 26, 28. A POSA would have no indication
`
`on how to adapt the compressor keyed signal to function in an ultrasonic device.
`
`Ex. 2040,1148.
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`20.
`
`For at least the reasons stated above, limitation [D] is neither
`
`disclosed nor “obvious.” In addition, the OptiNeb—ir Manual does not disclose any
`
`other limitation of claim 1 including a nebulizer that aerosolizes a fixed amount of
`
`treprostinil per pulse [B 1] or an opto-acoustical trigger which allows a human to
`
`synchronize each breath to each pulse [C].
`
`C. The EU Community Register
`
`21.
`
`The EU Community Register provided as Exhibit 1009 appears to
`
`relate to devices that can be used in combination with iloprost in the product
`
`Ventavis® in Europe. However, there is no identifying information such as a date
`
`or URL indicating from Where the document was obtained.
`
`22.
`
`The EU Community Register describes the use of three different
`
`devices with iloprost — HaloLite, ProDose, and Venta-Neb. Ex. 1009, 2-3, 29-30.
`
`The HaloLite and ProDose devices are dosimetric — delivering a fixed dose of
`
`either 2.5 ug or 5 ug in a fixed amount of time. The Venta—Neb also delivers the
`
`same two doses; however, the method of dosing is given in “inhalation cycles” and
`
`in relation to an estimated time. Ex. 1009, 3, 30. The 2.5 ug dose is estimated to
`
`require 10 inhalation cycles and 4 minutes for delivery; the 5 ug dose is estimated
`
`to require 25 inhalation cycles and 8 minutes for delivery. Id. There is no
`
`indication that this Venta—Neb is “pulsed.”
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`23. While Dr. Donovan concludes that the term “inhalation cycle” is
`
`synonymous with breath, this conclusion is not readily apparent from the EU
`
`Community Register. Ex. 1002, 11196499. Indeed, earlier in the EU Community
`
`Register, it uses “inhalation cycle” in relation to Venta-Neb for delivering a 5 ug
`
`dose, recommending “to complete two inhalation cycles with 2.5 pg pre-set dose
`
`program.” Ex. 1009, 3, 30. Nevertheless, if Dr. Donovan is correct and the term
`
`“inhalation cycle” intends breath, the EU Community Register teaches breathing in
`
`iloprost in 3.125 breaths per minute (25 breaths / 8 minutes) and a time from one
`
`breath to the next of 19.2 seconds (480 seconds / 25 breaths) for a dose of 5 ug.
`
`This is inconsistent with any possible breathing rate and with the breathing rate
`
`selected by Dr. Donovan in her analysis for Ground 2: 12 to 15 breaths per minute
`
`with a cycle of inhaling and exhaling lasting between 4 to 5 seconds. Ex. 1002,
`
`11174. Based on these breathing rates, a patient would take between 48 and 60
`
`breaths in 4 minutes and between 96 and 120 breaths in 8 minutes.
`
`24. Accepting Dr. Donovan’s interpretation, a POSA would not know
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`how the dose is delivered in both the disclosed number of breaths (10-25) and the
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`disclosed inhalation time (4-8 min). Specifically, a POSA would not know whether
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`the user takes non—drug-containing breaths in the 4 to 8 minutes between the 10 to
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`25 breaths in which the iloprost is delivered.
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`25.
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`To further complicate a POSA’s understanding of the Venta-Neb
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`device — the relationship between dose and “inhalation cycle” is non—linear. While
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`a 2.5 ug dose is delivered in 10 inhalation cycles, it takes more than twice this
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`number of inhalation cycles (25 inhalation cycles) to deliver twice the dose (5 ug).
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`EX. 1009, 3, 30. Hence, a POSA would have further uncertainty on how to adapt
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`the Venta—Neb to delivering an entirely different dose and determining the number
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`of “inhalation cycles” in which it could be delivered.
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`26.
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`The Venta-Neb also features a signal that which begins when a dose is
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`ready and “stops after the pre-set dose has been delivered.” Ex. 1009, 3, 30.
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`Regardless of how the term “inhalation cycle” is interpreted, in View of the
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`estimated time of inhalation, the dose described would necessarily occur over
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`several breaths. Ex. 1009, 3, 30. Therefore, the signal occurs at the start of dose
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`delivery and ends once the total dose is delivered, regardless of the number of
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`breaths — informing the patient medication is ready to be inhaled without causing
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`the patient to synchronize each breath with each pulse, as required by the claims.
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`Ex. 1009, 3, 30.
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`D. Ground 3 — Obviousness over Voswinckel, the EU Community
`Register, and Ghofrani
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`27.
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`I disagree with Dr. Donovan that the claims of the ’240 patent are
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`invalid as obvious over Voswinckel in view of Ghofrani and the EU Community
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`Register. Specifically, for the reasons discussed above, I disagree with Dr.
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`Donovan that the EU Community Register discloses a pulsed ultrasonic nebulizer
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`that aerosolizes a fixed amount of treprostinil per pulse (limitations [B] and [B 1])
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`or an opto-acoustical trigger which allows a human to synchronize each breath to
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`each pulse (limitation [C]). And though Dr. Donovan does not address limitation
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`[D] (requiring certain high doses), this limitation is also not disclosed but, in fact,
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`is taught away from in the EU Community Register.
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`28.
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`The only “motivations to combine” and “expectations of success” Dr.
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`Donovan suggests are that Ventavis is the closest competitor (Ex. 1002 11187), that
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`the Venta-Neb nebulizer is manufactured by Nebu-Tec (id. at 11204), and that it was
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`a “known technique to coordinate inhalation with the delivery of medication” (id.
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`at 11202.) For the reasons discussed above, a POSA would not be able to use the
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`Venta-Neb device with a different drug or close with a reasonable expectation of
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`success. Indeed, looking at the EU Community Register, the only clear teaching
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`offered to a POSA is with respect to the use of the dosimetric devices, which —
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`unlike Venta-Neb i were FDA approved.
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`29.
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`As explained above, the Venta—Neb is not suited for use with doses
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`outside those prescribed in the EU Community Register because there is a non-
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`linear relationship between the dosing and the number of “inhalation cycles” in
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`which it is delivered. Further, the lack of clarity in the term “inhalation cycles”
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`and how they correspond to breath and dose delivery mean a POSA would not
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`have a reasonable expectation of success in utilizing the Venta-Neb with a
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`different drug or dose, even if the relationship between dose and “inhalation cycle”
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`had been linear. This uncertainty, coupled with the lack of FDA approval of the
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`Venta-Neb, would lead a POSA away from using such a device, particularly for the
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`high theoretical doses described in Ghofrani. Ex. 2040, 1145, 72.
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`30.
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`Indeed, guided by the EU Community Register, a POSA would be
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`more likely to look at its clear teachings relating to ProDose and HaloLite — the
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`ProDose being FDA approved (EX. 2114, 1; Ex. 2115, 11) and both being
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`dosimetric, non-pulsed, non-ultrasonic, and precluding synchronization— and
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`attempting to use these devices as an alternative to the OptiNeb mentioned in
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`Voswinckel (Ex. 1003, 7).
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`[This section of the page is intentionally left blank]
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`1 These labels were obtained from the FDA website by navigating to the page
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`provided as Exhibit 1099 and clicking on the “Label (PDF)” link under “Action
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`Date” 12/29/2004 (Ex. 2114) and “Action Date” 8/24/2005 (Ex. 2115).
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`Declaration of Dr. Aaron Waxman
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`31.
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`I hereby declare that all statements made herein of my knowledge are
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`true and that all statements made on information and belief are believed to be true;
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`and further that these statements were made with the knowledge that willful false
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`statements and the like so made are punishable by fine or imprisonment, or both
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`under Section 1001 of Title 18 of the United States Code.
`
`Date:
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`July 9
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`, 2018
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`
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`Dr. Aa on Waxman
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