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. 9,339,507
`Issue Date: May 17, 2016
`Title: TREPROSTINIL ADMINISTRATION BY INHALATION
`
`Inter Partes Review No. 2017-01622
`
`
`SECOND DECLARATIONOF DR. AARON WAXMAN
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`IPR2017-01622
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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 boardcertified in Internal Medicine, Pulmonary Disease, and Critical Care
`
`Medicine.
`
`I have been practicing as a pulmonary andcritical care doctor for over
`
`20 years.
`
`I am a memberof the American College of Chest Physicians, the
`
`American Thoracic Society, the Pulmonary Hypertension Association, and the
`
`Pulmonary Vascular Research Institute.
`
`De
`
`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 journalarticles, 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 M.D. 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 U.S.
`
`Patent No. 9,339,507 (“the ’507 patent”), in connection with IPR2017-01621. My
`
`compensation does not depend on the content of my opinionsorthe disposition of
`
`this proceeding. I have been retained by United Therapeutics to provide technical
`
`expertise and my expert opinion on the °507 patent.
`
`a.
`
`I understand that the Petition brought forward by Watson
`
`Laboratories, Inc. (“Watson”) challenges claims 1-9 of the *507 patent. In my
`
`previous declaration (Ex. 2040), I addressed “Ground 1”of the Petition — i.e.
`
`whether these claims are obvious over the combination of Voswinckel (Ex. 1003),
`
`Chaudry (Ex. 1004), Ghofrani (Ex. 1005), and Patton (Ex. 1012).
`
`I understand the
`
`Patent Trial and Appeal Board (“the Board’’) has now changed the scope ofthe
`
`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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`Declaration of Dr. Aaron Waxman
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`6.
`
`For reference, below is a list of the Exhibits that are cited herein:
`
`
`
`1003
`
`1004
`1006
`
`
`Exhibit No.
`Description
`
`1001
`U.S. Patent No. 9,339,507
`
`1002 Declaration of Dr. Maureen Donovan
`Robert Voswinckel, et al. “Inhaled treprostinil sodium for the
`treatment of pulmonary hypertension” Abstract #1414, Circulation,
`110, 17, Supplement
`(Oct. 2004): III-295
`US 2004/0265238
`Opti-Neb-ir® Operating Instructions, Model ON-100/2 (2005
`Hossein Ardeschir Ghofrani, Robert Voswinckel, et al., “Neue
`Therapieoptionen in der Behandlung der pulmonalarteriellen
`1005
`
`Hypertonie,” Herz, 30,4 (June 2005): 296-302
`Annexes to Commission Decision C(2005)3436 of 05 September
`2005: Annex III — Ventavis® Labelling and Package Leaflet
`WO 93/00951
`
`
`
`1009
`
`1012
`1014
`
`2003
`008
`
`William F. Ganong, Review ofMedical Physiology 591-92 (17th ed.
`1060
`
`1995).
`FDADrug 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: essential theory and
`Online, 2009 (excerpt).
`"Mechanical Ventilation." American Journal ofRespiratory
`and Critical Care Medicine 196(2):P3-4 (2017).
`
`2040
`Declaration of Dr. Aaron Waxman
`
`2041
`Curriculum vitae of Dr. Aaron Waxman
`113
`Merck Manual— Professional Version — Evaluation of the Pulmonary
`Patient (accessed July 6, 2018
`FDAVentavis Label under Action Date 12/29/2004 (accessed July 2,
`2018
`FDAVentavis Label under Action Date 8/24/2005 (accessed July 2,
`2018)
`
`2114
`
`2115
`
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`7.
`
`[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 priorart
`
`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 havea reason for
`
`and reasonable expectation of success in combining these teachings to achieve the
`
`claimed invention.
`
`I understand there may bea 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.
`
`
`
`Ground
`
`References
`
`
`
`Robert Voswinckel,et al. “Inhaled
`
`treprostinil sodium for the treatment of
`
`pulmonary hypertension” Abstract #1414,
`
`Ground 2
`
`Circulation, 110, 17, Supplement (Oct.
`
`2004): HI-295 (“Voswinckel,” Ex. 1003)
`
`US 2004/0265238 (“Chaudry,” Ex. 1004)
`
`WO 93/00951 (“Patton,” Ex. 1012)
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`
`
`Opti-Neb-ir® Operating Instructions, Model
`
`ON-100/2 (2005) (“the OptiNeb-ir Manual,”
`
`Ex. 1006)
`
`Chaudry
`
`
`Annexes to Commission Decision C(2005)3436 of
`
`05 September 2005: Annex III —
`
`Ventavis® Labelling and Package Leaflet
`
`
`
`Ground 3
`
`(“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 Ground3, respectively.
`
`A. The OptiNeb-ir Manual
`
`2.
`
`I was instructed to assumethat the OptiNeb-ir Manual provided as
`
`Exhibit 1006 is an English translation of a documentoriginally in German. Ex.
`
`1006, 33.
`
`I further understand that Watson submitted a declaration from
`
`Christopher Butler (Ex. 1014) in which there is a German language manual
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`(Exhibit B-4), which appears to report a different nebulization output than the
`
`translated OptiNeb-ir Manual. As shown below, Exhibit B-4 of Mr. Butler’s
`
`declaration reports a “Verneblerleistung” of “< 0,6 ml/min” whereas the OptiNeb-
`
`ir Manualreports a “Nebuliser output” of “0.6 ml/min”in the same numbered
`
`section.
`
` Excerpt from Ex. 1006, 28
`Excerpt from Ex. 1014, 198
`
`14.0 Technische Daten des Ultraschallverneblers OPTINER’-ir
`14.0 Technical data of the OPTINEB®-ir ultrasonic nebulizer
`Grobe ..
`deitittsittivittsttisitistiviuwunu0.8 X% 66% 105 mm
`
`Size ofbaseSecs ee ee oO GewichtdesGrundgerates...
`uttusaseseveseeevaseesses280g
`
`
`
`ener
`Stromversorgungsarten.
`etzgerat 110/230 VAC
`DOWIC8
`eid
`IE
`
`
`~--+-------- Power supply unit 110/230 VAC
`en
`A
`lapter Zi arettenanziinder
`Power supply type.
`“12 Vv motor vehicle cigarette lighter adapter
`P
`io
`
`ssa
`ns
`salience
`ancodaneaccces
`12 V battery
`12V Akku
`Elektrische Versorgung..
`"12VDC.15r Maximum
`as
`sis
`Electrical supply
`42 VDC, 1 5 Amaximum
`
`Stromverbrauch bei Betrieb.....
`seeeeee 18 Watt Maximum
`Power consumption during operation
`ag ee 18 watt maximum
`
`Ultrasonic eeeoo ccseee
`uuuuususaauanenenensee
`.. 2.4 MHz (nominal)
`Ultraschallfrequenz.......
`nA MHa2(nominal)
`cose
`
`-
`‘
`veces 0,6 ml/min
`Nebuliser output..
`nae
`- 0.6 mi/min
`Verneblerleistung.....
`
`pease.oewii =e
`7.5m bear
`FassungsvermdgendesMadikamentenbechers...cscsco..us......7,5ml Maximum
`MMABD............
`.
`2.33.373.8/4.5umm(dependingoon1baffle plate)
`MMAD...
`215
`“2‘ay3,3/3,a/4,Bipmm(a nach Prallplatte)
`—
`
`nore of
`the contact
`reservoir...
`:
`:
`Fassungsvermégen des Kontaktfldssigkeitsbehalters.... :
`vesteenteereeeeeeeesS ml
`fluid
`ctrical protection Class oo...
`isicabatccoasattaen
`woes
`elditeche Schutskiasse
`Typ B
`
`HH type 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 multifunction light that changes color to show changesin 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 deviceis turned
`
`off. Id. Neither of these signals are designedto causea userto 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.
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`11.
`
`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 lungsconstituting a breath — i.e., mechanical
`
`ventilation. Ex. 2008. While the OptiNeb-ir Manualfeatures programsthat
`
`provide intermittent delivery (P1, P2, P6, and P3 (in part)) and programsthat
`
`provide continuousdelivery (P4, PS, and P3 (in part)) of aerosol, the only program
`
`that refers to coordination of any kind (P6) is designed to coordinate aerosolization
`
`with such mechanicalventilation. 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 underthe 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 photographsin the OptiNeb-ir
`
`Manual, the multi-function light is not within a user’s field of view when used with
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`a mouthpiece. Ex. 1006, 1, 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. Jd.
`
`B. Ground 2 — Obviousness over Voswinckel, Chaudry, Patton, and the
`OptiNeb-ir Manual
`
`14.
`
`I disagree with Dr. Donovanthat the claims of the ’507 patent are
`
`invalid as obvious over Voswinckel in view of Chaudry, 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, limitations [B] and [C]
`
`are the only limitations of claim 1 that Dr. Donovanstates “would have been
`
`obvious over Voswinckel in view of Chaudry, Patton, and the OptiNeb®-ir User
`
`Manual.” Ex. 1002, 9183. Dr. Donovan does not suggest that limitation [C] is
`
`disclosed explicitly, and she does not analyze claim 1 as a whole. Jd. at 4182-204.
`
`Dr. Donovan also does not discuss an expectation of success in connection with
`
`her opinion. Jd.
`
`15.
`
`The OptiNeb-ir Manual doesnot indicate that a user should coordinate
`
`inhalation with a soundoralight, 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 usesthis reference as the basis for calculations to determine possible
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`dosing using this device in combination with Voswinckel, Chaudry, and Patton.
`
`Ex. 1002, 4196-204. The proposed calculations are based on a series of inaccurate
`
`assumptions and would not be undertaken by a POSAto calculate dose.
`
`16.
`
`Inher 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, 9200 (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, e.g. pulmonary hypertension. Rather, in myclinical
`
`experience, patients with cardiopulmonary disease, such as pulmonary
`
`hypertension, have a much higherbreathing rate — closer to 18 to 22 breaths per
`
`minute.
`
`17.
`
`Dr. Donovan calculates that 12 to 15 breaths per minute meansthat a
`
`breath consisting of an inhalation and an exhalation occurs within the span of4 to
`
`5 seconds. Ex. 1002, 4200. Without providing any further basis, Dr. Donovan
`
`then concludesthat the inhalation portion takes between 2 to 3 seconds. Jd.
`
`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 humansuffering
`
`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
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`patients with lung diseases. Rather, in my clinical experience, patients have a
`
`muchshorter 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 Manualfor a
`
`nebulization output rate of 0.6 ml/min and assumes that a POSA would adoptthis
`
`rate for delivering the 600 pg/ml oftreprostinil in Voswinckel. Asaninitial
`
`matter, although the OptiNeb-ir Manualstates a nebulization rate of 0.6ml/min, the
`
`German documentprovided in Exhibit 1014 showsthat 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 awareof, specifically that “[a] POSA would have
`
`understood that the Nebu-Tec device could be programmedto achievedifferent
`
`rates of nebulization that were at least somewhere between 0.173 — 0.6 mL/min.”
`
`Ex. 1002, 9202. However, a POSA would neither have motivation nor a
`
`reasonable expectation of successto select the highest nebulization outputrate
`
`disclosed in the OptiNeb-ir Manualto deliver the drug of Voswinckelforat least
`
`two reasons. First, the OptiNeb-ir Manualrelates to a configuration for ventilator
`
`use, whereasthe patients in Voswinckel are not described as requiring mechanical
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`ventilation. Ex. 1003, 7. Second, as explained in my previous declaration,
`
`Voswinckelis a preliminary study which addressesefficacy only in the context of
`
`a single acute dosing. Ex. 2040, 430-35. In my clinical experience, such studies
`
`are conducted cautiously, involving dose escalation; therefore, without further
`
`information a POSA wouldstart 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 teachingsrelated 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 ofair, which in turn
`
`aerosolizes an active agent. Ex. 2040, 948; Ex. 1012, 12:13-25. The light and/or
`
`audible signal in Patton is keyed to the “operation of the compressor.” Ex. 2040,
`
`948; 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 myprior
`
`declaration, such ultrasonic nebulizers differ structurally from a gas jet based
`
`device, using a piezoelectric element rather than a compressorto aerosolize an
`
`active agent. Ex. 2040, 948; Ex. 2003, 26, 28. A POSA would have noindication
`
`on how to adapt the compressor keyed signal to function in an ultrasonic device.
`
`Ex. 2040, 948.
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`20.
`
`For the reasons stated above,limitations [B] and [C] are neither
`
`disclosed nor “‘obvious.”
`
`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 suchas a date
`
`or URL indicating from where the document wasobtained.
`
`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 pg in a fixed amountof time. The Venta-Nebalso 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 tg dose is estimated
`
`to require 25 inhalation cycles and 8 minutes for delivery. Jd. There is no
`
`indication that this Venta-Nebis “pulsed.”
`
`23. While Dr. Donovan concludesthat the term “inhalation cycles”is
`
`synonymouswith breath, this conclusion is not readily apparent from the EU
`
`Community Register. Ex. 1002, 9221-223. Indeed, earlier in the EU Community
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`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 ug pre-set dose
`
`program.” Ex. 1009, 3, 30. Nevertheless, if Dr. Donovanis 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 pg.
`
`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,
`
`4/200. Based on these breathingrates, 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
`
`howthe doseis delivered in both the disclosed numberof breaths (10-25) and the
`
`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 betweenthe 10 to
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`25 breaths in whichthe iloprostis 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 doseis delivered in 10 inhalation cycles, it takes more than twicethis
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`numberof inhalation cycles (25 inhalation cycles) to deliver twice the dose (5 Wg).
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`Ex. 1009, 3, 30. Hence, a POSA would havefurther uncertainty on how to adapt
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`the Venta-Nebto 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-Nebalso features a signal that which begins when a doseis
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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 endsoncethetotal 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, Chaudry, the EU
`Community Register, and Ghofrani
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`27.
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`I disagree with Dr. Donovanthat the claims of the ’507 patentare
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`invalid as obvious over Voswinckelin view of Chaudry, Ghofrani, and the EU
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`Community Register. Specifically, for the reasons discussed above,I disagree
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`with Dr. Donovan that the EU Community Register discloses a pulsed ultrasonic
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`nebulizer that aerosolizes a fixed amountoftreprostinil per pulse (limitation [B1])
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`or an opto-acoustical trigger (limitation [B]). And though Dr. Donovan does not
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`identify a disclosure of limitation [D] (requiring instructions for certain high
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`doses), this limitation is also not disclosed but, in fact, is taught away from in the
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`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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`Donovansuggests are that Ventavis is the closest competitor (Ex. 1002 4214), that
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`the Venta-Neb nebulizer is manufactured by Nebu-Tec(id. at 9225), 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 9223.) For the reasons discussed above, a POSA would notbe able to use the
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`Venta-Neb device with a different drug or dose 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 POSAis with respectto the use of the dosimetric devices, which —
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`unlike Venta-Neb — 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 numberof“inhalation cycles” in
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`whichit 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 approvalof 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, 945, 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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`morelikely 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, 1') 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 pageis intentionally left blank]
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`
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`' 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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`31.
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`Thereby declare that all statements made herein of my knowledge are
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`true andthat 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 knowledgethat 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.
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`Date:
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`duly 9
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`, 2018
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`
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`Dr. Aaron Waxman
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