UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`WATSON LABORATORIES, INC.
`Petitioner
`
`V.
`
`UNITED THERAPEUTICS, INC.
`Patent Owner
`
`Patent NO. 9,339,507
`
`Issue Date: May 17,2016
`Title: TREPROSTINIL ADMINISTRATION BY INHALATION
`
`Inter Partes Review NO. 2017—01622
`
`
`DECLARATION OF DR. AARON WAXMAN
`
`43330937691“
`
`UNITED TH ERAPEUTICS, EX. 2040
`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017-01622
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`IPR2017-01622
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`Declaration of Dr. Aaron Waxman
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`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 PhD. 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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`4832-0937-8914.1
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`IPR2017-01622
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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 IPR2017-01622. 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 ’507 patent.
`
`5.
`
`While I am neither a patent lawyer nor an expert in patent law, I have
`
`been informed of the applicable legal standards for obviousness of patent claims.
`
`I
`
`understand that the Petition brought forward by Watson Laboratories, Inc.
`
`(“Petitioner” or “Watson”) challenges claims 1—9 of the ’507 patent.
`
`6.
`
`For reference, below is a list of the Exhibits that are cited herein:
`
`Exhibit No.
`
`1001
`U.S. Patent No. 9,339,507
`
`1002
`
`Declaration of Dr. Maureen Donovan
`
`1003
`
`1004
`
`Robert Voswinckel, et a1. “Inhaled treprostinil sodium for the
`treatment of pulmonary hypertension” Abstract #1414, Circulation,
`110, 17, Su lement Oct. 2004 : III—295
`U.S. Patent A ulication Publication No. 2004/0265238
`
`Hossein Ardeschir Ghofrani, Robert Voswinckel, et al., “Neue
`
`WO 93/00951 1013
`
`Therapieoptionen in der Behandlung der pulmonalarteriellen
`1005
`
`Hypertonie,” Herz, 30,4 (June 2005): 296-302
`
`1012
`
`Declaration of Dr. Scott Bennett
`
`1028
`Olschewski H., et al., Aerosolized Prostacyclin and Ilaprost in
`
`4832-0937-8914.1
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`3
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`Declaration of Dr. Aaron Waxman
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`
`1046
`
`Severe Pulmonary Hypertension, 1996 Ann. Intern. Med. 124(9),
`
`820-824 (1996)
`Olschewski, et al., Pharmacodynamics and Pharmacokinetics of
`1029
`Inhaled Iloprost, Aerosolized by Three Different Devices, in Severe
`
`Pulmonary Hypertension, Chest J., 124(4), l294~1304 (Oct. 2003)
`Voswinckel, R., et a1., “Inhaled treprostinil is a potent pulmonary
`vasodilator in severe pulmonary hypertension,” 25 European Heart
`Journal 22, 218 2004
`Substantive Submission filed in 12/591,200 (Nov. 9, 2015) (with
`1162
`
`accompanying Declaration of Dr. Roham T. Zamanian)
`Amendment and Reply filed in 12/591,200 (Feb. 2, 2016) (with
`’
`Second Declaration of Dr. Roham T. Zamanian
`
`1163
`
`
`
`Newman, Stephen P. Respiratory drug delivery: essential theory and
`
`tractice. Respiratory Drug Delivery Online, 2009 (excerpt).
`Hill, N., Therapeutic Optionsfor the Treatment ofPulmonary
`Hypertension, Medscape Pulmonary Medicine 9(2) (2005).
`Exhibits Accompanying First Declaration of Dr. Roham Zamanian
`and Amendment and Reply filed in 12/591,200 (Nov. 9, 2015) (Ex.
`
`2002
`
`2003
`
`2004
`
`2005
`
`2012
`
`2020
`
`
`
`2025
`
`2037
`
`2021
`
`2023
`Curriculum vitae of Dr. Lewis Rubin
`2024
`2002 Press Release Regarding Promotion of Robert Roscingo
`(accessed October 10, 2017)
`Shield Therapeutics Biography for Carl Sterritt (accessed October
`10, 2017)
`Listing of Issues and Supplements of Circulation Accessible on
`Circulation Website accessed A Ii] 17, 2018
`
`2041
`Curriculum vitae of Dr. Aaron Waxman
`2042
`Mosby ’s Medical Dictionary. 7‘"h ed. Mosby Elsevier, 2006 (excerpt).
`Leung, K, Louca E ,& Coates, A. “Comparison of BreathEnhanced
`to BreathActuated Nebulizers for Rate, Consistency, and
`Rau, J.L.,“Design Principles of Liquid Nebulization Devices
`
`2043
`2044
`
`
`
`
`Currentl
`
`in Use,” Res ir. Care, 47 11:1257—1275 2002
`
`2045
`
`Atkins, P.J. & T.M. Crowder. “The Desi_n and Develo-ment of
`
`4832-0937-89141
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`4
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`Declaration of Dr. Aaron Waxman
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`Inhalation Drug Delivery Systems,” Pharmaceutical Inhalation
`Aerosol Technology, 2nd Ed. (AJ. Hichey ed., CRC Press), Ch. 9
`2003
`
`2046
`2047
`
`
`
`Ventavis® Patient Brochure
`Rau, J.L. Respiratory Care Pharmacology. 6‘11 Ed. Mosby, 2002
`exce t
`
`I.
`
`BACKGROUND
`
`7.
`
`At the time of the invention, as today, pulmonary hypertension was a
`
`poorly understood, ofien fatal, disease with limited treatment options. Prior
`
`treatments of pulmonary hypertension with a prostacyclin analog included
`
`epoprostenol, which had significant burdens and challenges to patients.
`
`Epoprostenol can only be administered intravenously. Ex. 2004. The need for a
`
`permanent transcutaneous intravenous catheter to administer epoprostenol posed
`
`risks of infection and sepsis. Id. Epoprostenol patients also risk sudden occlusion
`
`of the catheter which can precipitate hemodynamic collapse because of the several
`
`minute half-life of the drug. Id. Moreover, epoprostenol requires daily mixing and
`
`refrigeration, thus, requiring the patient to carry a cold pack to avoid degradation at
`
`room temperature and an infiision pump to safely administer the drug.
`
`8.
`
`Because of these drawbacks, epoprostenol is not suitable for treating
`
`all patients. Indeed, there are a number of patients for whom intravenous therapy
`
`is not suitable. For example, for pulmonary hypertension patients with lung
`
`disease, it is critical to maintain matched ventilation and perfusion to optimize
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`4832-0937-8914.1
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`oxygenation and the excretion of carbon dioxide from the lung. When a patient
`
`suffers from lung disease (6. g. pneumonia, emphysema, or interstitial lung
`
`diseases), the lung automatically diverts blood flow away from diseased areas of
`
`the lung and toward the non-diseased portions — Optimizing lung function. Since
`
`intravenous delivery of a vasodilator results in indiscriminate vasodilation, this
`
`optimization is disrupted by intravenous delivery. Similar drawbacks exist with
`
`intravenous and subcutaneous treprostinil.
`
`9.
`
`In addition, in my clinical experience, I have found that patients prefer
`
`inhaled treatment because it is less intrusive (tie. doesn’t require constant infusions
`
`or a Hickman catheter) and also has less systemic side effects. The preference for
`
`inhaled treatment over intravenous administration is about 2 or 3 to 1. Thus, as a
`
`clinician considering what drug to administer a pulmonary hypertension patient, I
`
`would not compare intravenous therapeutics to inhaled therapeutics. Rather, the
`
`relevant comparison for a patient who either cannot support intravenous
`
`administration or has requested inhaled administration would be which of the two
`
`inhaled pulmonary hypertension products — Tyvaso ® or Ventavis ® - would be
`
`suitable for treatment.
`
`10.
`
`Prior to May 15, 2006, the only FDA-approved prostacyelin-type drug
`
`that could be given in an inhalable form was iloprost, marketed as Ventavis ®. At
`
`that time, the results of an Aerosol Iloprost Randomized (AIR) Study documenting
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`4832-0937-8914.1
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`the effects of inhaled iloprost had been public for about three-and-a-half years, and
`
`Ventavis ® had been on the market for about one—and—a—half years. Ex. 1 162, 21;
`
`Ex. 2005, l-28. As Dr. Zamanian noted in his Declaration of May 15, 2016,
`
`clinicians were concerned that the adoption of Ventavis® was happening too
`
`rapidly and were still largely of the opinion that intravenous administration of a
`
`prostacyclin analog was preferable to inhaled delivery. Ex. 1162, 21.
`
`Surprisingly, even in view of these concerns, when Tyvaso ® entered the market in
`
`2009, there was a rapid shift from Ventavis ® to Tyvaso ®. See Ex. 1162, 19—39;
`
`Ex. 1163, 23-28.
`
`II.
`
`CLAIMS OF THE ’507 PATENT
`
`l l.
`
`I have reviewed the claims of the ’507 patent. Provided below for
`
`reference is the language of claim 1 of the ’507 patent:
`
`A kit for treating pulmonary hypertension comprising:
`
`a formulation comprising 200 to 1000 11ng of treprostinil or a
`
`pharmaceutically acceptable salt thereof;
`
`a pulsed ultrasonic nebulizer comprising an opto—acoustical
`
`trigger configured to (a) aerosolize a fixed amount of treprostinil per
`
`pulse, and (b) deliver by inhalation a therapeutically effective single
`
`event dose of said formulation,
`
`said single event dose comprising from 15 pg to 90 pg of
`
`treprostinil or a pharmaceutically acceptable salt thereof delivered in 1
`
`to 18 breaths; and
`
`instructions for using the pulsed ultrasonic nebulizer with the
`
`4832-0937-8914.1
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`formulation to treat a patient with pulmonary hypertension by
`
`delivering 15 ug to 90 ug treprostinil or a pharmaceutically acceptable
`
`salt thereof in 1 to 18 breaths to the patient in the single event dose.
`
`Ex. 1001, col. 18:12-28.
`
`I understand that this claim is an “independent claim” and
`
`that all subsequent claims, tie. claims 2—9, depend from this claim — meaning that
`
`claims 2-9 require the same features or “limitations” as claim 1 but also include
`
`additional limitations. Ex. 1001, col. 18:29-52.
`
`12.
`
`I have been informed that the terms found in the claims of a patent
`
`must be given their broadest reasonable interpretation consistent with the body
`
`text, or “specification,” of the patent at issue and the statements made during
`
`prosecution of the patent, or “prosecution history,” as it would be interpreted by
`
`one of ordinary skill in the art. Therefore, in this section, I provide my opinions on
`
`how a person of ordinary skill in the art (“POSA”) would understand certain claim
`
`terms .
`
`A.
`
`Person of Ordinary Skill in the Art
`
`13.
`
`I am informed by counsel that a patent is to be interpreted from the
`
`perspective of a hypothetical person referred to as the person of ordinary skill in
`
`the art (which I will often refer to as a “POSA”) to which the patent pertains.
`
`I am
`
`further informed that a determination of the level of ordinary skill is based on,
`
`among other things, the type of problems encountered in the art, prior art solutions
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`4832-0937-8914.1
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`to those problems, rapidity with which innovations are made, sophistication of the
`
`art, and the educational level of active workers in the field.
`
`14.
`
`The claims of the ’507 patent are directed to a kit for “treating
`
`pulmonary hypertension” with a specific “pulsed ultrasonic nebulizer.” Ex. 1001,
`
`col. 18: 12-52.
`
`I understand that several of the inventors listed on the ’507 patent
`
`have post-graduate degrees in the field of medicine or drug development and all
`
`had at least several years of research, executive, and/or clinical experience in the
`
`investigation and treatment of pulmonary hypertension and in developing
`
`pharmaceutical products for the treatment of pulmonary hypertension. Ex. 2020,
`
`111, 7; Ex. 1028, 1; Ex. 1029, 1; Ex. 2023; Ex. 2024; Ex. 2025.
`
`15.
`
`Consistent with the experience of the named inventors, it is my
`
`opinion that a POSA at the time of invention would have been a person with a
`
`post-graduate degree in medicine or drug development (such as the pharmaceutical
`
`sciences) with at least two years of experience in the investigation or treatment of
`
`pulmonary hypertension. A POSA may also have had additional experience in the
`
`study, development, or use of dosage forms that had been used to treat pulmonary
`
`hypertension, such as solid oral dosage forms (e.g., tablets and capsules),
`
`injectables, and inhaled therapies. A POSA may have had a lower level of formal
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`4832-0937-8914.1
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`education if such a person had more years of experience in the investigation or
`
`treatment of pulmonary hypertension.
`
`16.
`
`I understand the Petitioner and its expert Dr. Donovan have offered a
`
`different interpretation of a POSA. Ex. 1002, 1174. Even if this definition is
`
`applied, it would not affect my ultimate conclusions regarding the ’507 patent
`
`discussed herein.
`
`B.
`
`“pulsed” and “pulse”
`
`17.
`
`Both the terms “pulse” and “pulsed” are found in claim 1. Ex. 1001,
`
`col. 18:12-28. The term “pulsed” is used as the adjective form of the word
`
`G‘pulse-SS
`
`18.
`
`A POSA would understand the plain meaning of the term “pulse.”
`
`For example, the Oxford Dictionary of English provides the following definition of
`
`the word “pulse”: “[a] single vibration or short burst of sound, electric current,
`
`light, or other wave.” Ex. 2002, 3. The same dictionary defines the word “wave”
`
`in the physics context as “a periodic disturbance of the particles of a substance
`
`which may be propagated without net movement of the particles, such as in the
`
`passage of undulating motion, heat, or sound.” Ex. 2002, 5. A POSA would
`
`accept both dictionary definitions as providing the plain meaning of the terms
`
`“pulse” and “wave.” In the scientific and medical context “pulse” is also
`
`4832-0937-8914.1
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`understood to refer to rhythmic and periodic waves. See, e.g., Ex. 2042, 4
`
`(defining “pulse” as “a brief electromagnetic wave” and “a rhythmic beating or
`
`vibrating movement”; defining “pulsed Doppler” as “a type of Doppler device
`
`involving the transmission of a short-duration burst of sound into the region to be
`
`examined”; and defining “pulsed laser” as “a laser that emits short bursts of energy
`
`at fixed intervals rather than a continuous stream of energy”). In the same way, in
`
`the context of “pulsed nebulizers,” pulsed has long come to be understood as
`
`meaning short periods of nebulization at fixed intervals, rather than continuous
`
`nebulization. Ex. 2043 (distinguishing pulsed nebulization versus continuous
`
`nebulization).
`
`19.
`
`In the specification of the ’507 patent, the term “pulse” is used to refer
`
`to the intermittent and periodic delivery of aerosol for a fixed duration, followed
`
`by pauses of a fixed duration in cycles. Ex. 1001, col. 14:36—39. For example, the
`
`specification identifies that “[a] pulse of aerosol was generated every 6 seconds”
`
`and that the pulsed ultrasonic nebulizer generated aerosol “in cycles consisting of 2
`
`seconds aerosol production (pulse) and 4 seconds pause.” Ex. 1001, col. 4:41-42;
`
`col. 14:36-39.
`
`20.
`
`In the claims, each “pulse” is meant to correspond with each breath.
`
`Ex. 1001, col. 18:12-28. A similar interpretation of the term is found in Exhibit
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`4832-0937-8914.1
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`1163, which I understand to be documents and a declaration submitted during the
`
`prosecution of US. Patent No. 9,358,240 (“the ’240 patent”), where it says a
`
`“pulsed” ultrasonic nebulizer produces “a ‘pulse’ of aerosol production followed
`
`by a pause” and that the generated pulses are “spaced apart in time that correspond
`
`to each breath inhaled by a human.” Ex. 1163, 12-13.
`
`I understand that “the ’240
`
`patent has the same specification as the ’507 patent and also uses the term “pulsed”
`
`in the claims.
`
`I have also been informed that, since the ’240 patent is “related” to
`
`the ’507 patent, statements submitted in prosecution of the “240 patent are relevant
`
`to the interpretation of the claims of the ’507 patent. BX. 1001, 1(60).
`
`21.
`
`Based on the specification and the ’240 prosecution history, it is
`
`apparent that the term pulse in the claims refers to a short burst of aerosol
`
`production. Further, the specification and prosecution are consistent with the
`
`meaning of both pulse and wave in that the pulse of aerosol must occur with a
`
`specified periodicity: in other words, a wave form with consistent time intervals
`
`between each pulse.
`
`22.
`
`In view of the plain meaning, specification, and prosecution history, a
`
`POSA would understand the term “pulse” to refer to a period of aerosol generation
`
`and the term “pulsed” to refer to the generation of such pulses with a specified
`
`periodicity, or fixed interval.
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`4832-0937-8914.1
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`C. “Opto-acoustical trigger which allows said patient to synchronize
`
`each breath to each pulse”
`
`23.
`
`I have been informed that United Therapeutics and Watson reached an
`
`agreement in a related litigation that the phrase “an opto-acoustical trigger” in
`
`claim 1 means “a trigger with an optical element (e.g., light) and an acoustical
`
`element (e. g., sound)” I also understand that this agreement applies to this
`
`proceeding as well.
`
`24.
`
`The definition above provides examples of both the optical and
`
`acoustical elements of the “opto-acoustical trigger” but no definition for the word
`
`“trigger” is provided. Therefore, a POSA would understand the word “trigger” in
`
`this phrase according its plain meaning. The Oxford Dictionary of English defines
`
`“trigger” as “an event that is the cause of a particular action, process, or situation.”
`
`Ex. 2002, 4. Thus, an “opto—acoustical trigger” would be understood to require an
`
`optical element (e.g., light) and an acoustical element (e.g., sound) that is designed
`
`to cause a particular action, process, or situation.
`
`25.
`
`The specification of the ’507 patent describes the “opto-acoustical
`
`trigger” as synchronizing inhalation to pulses. Ex. 1001, col. 14:39-41. Therefore,
`
`in view of the plain meaning of the word and the specification, a POSA would
`
`understand the optical element (e.g, light) and the acoustical element (e.g., sound)
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`4832-0937-8914.1
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`are designed to “cause the particular action, process, or situation” of the
`
`synchronization of the patient’s inhalation with each pulse. This synchronization
`
`of the patient’s breathing to the device contrasts the claimed pulsed ultrasonic
`
`nebulizer from other kinds of pulsed ultrasonic nebulizers, such as a breath-
`
`actuated pulsed ultrasonic nebulizer where the device adapts the pulse to the
`
`patient’s individual breathing pattern, allowing the patient to control length of
`
`pulse and spacing between pulses.
`
`26.
`
`The claimed “opto-acoustical trigger” is different from the
`
`combination of an optical element and an acoustical element. The “opto-acoustical
`
`trigger” is designed to cause a human to immediately inhale each aerosol pulse
`
`from the pulsed ultrasonic nebulizer as it is generated and to “synchronize the
`
`inspiration to the end of the aerosol pulse, thereby providing exact dosage.” EX.
`
`1001, col. 14:40—41. A combination of an optical element and an acoustical
`
`element that simply provides information, such as a signal or an alert, cannot be
`
`considered an “opto~acoustical trigger” without evidence that it is designed to
`
`cause immediate inhalation of individual aerosol pulses, as is used in this patent.
`
`D. “single event dose”
`
`27.
`
`Claim 1 also refers to a “single event dose” and requires that 15 to 90
`
`micrograms of treprostinil or its salt be delivered in 1 to 18 breaths to the
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`pulmonary hypertension patient in a “single event dose.” Ex. 1001, 001.18zl9-23.
`
`I further note that the patent specification gives the following supporting
`
`explanation of this term:
`
`Administering of treprostinil in a single event can be carried out in a
`
`limited number of breaths by a patient. . ..
`
`The total time of a single administering event can be less than 5
`
`minutes, or less than 1 minute, or less than 30 seconds.
`
`Treprostinil can be administered a single time per day or several times
`
`per day.
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`Ex. 1001, col. 7:54-62. The patent specification also presents results showing that
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`an inhaled dose of 15 micrograms “induced pulmonary vasodilation for longer than
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`3 hours compared to placebo inhalation.” Ex. 1001, col. 17:39-44. Claims 3 and 9
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`fiirther indicate that the patient is instructed “not to repeat the single event dose for
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`a period of at least 3 hours.” Ex. 1001, col. 18:32-34, 50-52. Based on how
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`“single event dose” is used in the patent, a POSA would understand it to mean the
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`total time during which the pulmonary hypertension patient inhales a necessary
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`dose of treprostinil in one sitting, which may be spaced apart from the next single
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`event dose by several hours, and there may be more than one pulse and more than
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`one breath corresponding to each pulse within a single event dose.
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`III.
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`INSTITUTED GROUND l
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`28.
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`I have been informed that in order for a patent claim to be considered
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`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
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`at the time an invention was made, and that such a person would have a reason for
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`and reasonable expectation of success in combining these teachings to achieve the
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`claimed invention.
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`I understand there may be a variety of rationales that can
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`demonstrate the reason for and reasonable expectation of success in combining
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`selected teachings, but, regardless of the rationale used, it must be supported by
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`evidence.
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`29.
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`I understand the Board is reviewing Whether claims 1—9 are obvious
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`over the references provided in “Ground 1” noted below.
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`
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`Ground References
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`Robert Voswinckel, et a1. “Inhaled treprostinil
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`sodium for the treatment of pulmonary
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`hypertension” Abstract #1414, Circulation, 110, 17,
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`Supplement (Oct. 2004): 111-295 (“Voswinckel,”
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`Ground 1
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`EX. 1003)
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`
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`
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`US. Patent Application Publication No.
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`2004/0265238 (“Chaudry,” Ex. 1004)
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`WO 93/00951 (“Patton,” Ex. 1012)
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`Hossein Ardeschir Ghofrani, Robert Voswinckel, et
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`al., “Neue Therapieoptionen in der Behandlung der
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`pulmonalarteriellen Hypertonie,” Herz, 30,4 (June
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`2005): 296-302 (“Ghofrani,” Ex. 1005)
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`I finther understand the Board has relied on both the references cited under
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`“Ground 1” and Dr. Donovan’s declaration (Ex. 1002) in its decision to “institute
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`trial” on this ground. In this section, I provide my opinions on Voswinckel (Ex.
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`1003), Chaudry (Ex. 1004), Ghofrani (Ex. 1005), and Patton (Ex. 1012) in relation
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`to the Board’s decision, Watson’s arguments, and the supporting testimony
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`provided in Dr. Donovan’s declaration.
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`A. Voswinckel
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`30.
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`Dr. Donovan’s reliance on Voswinckel for showing the “safety,
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`tolerability, and clinical efficacy” of inhaled treprostinil (Ex. 1002, 1l78) is
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`inconsistent with how a POSA would interpret Voswinckel’s findings and is
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`premised on a fundamental misunderstanding of Voswinckel.
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`.
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`31. While the authors do state they are interested in evaluating the safety,
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`tolerability and clinical efficacy in patients, they fail to disclose any information
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`about the amount of drug per breath or spacing of breaths within an inhalation
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`event, and the conclusions actually reflected a far more cautious conclusion. The
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`conclusion expressly addresses efficacy only in the context of single acute dosing
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`and only of a single measure of pulmonary hemodynamics—this cannot lead to a
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`conclusion of clinical efficacy. Ex. 1003, 7. At best, the authors suggest long term
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`treatment (based on 2 compassionate use patients) is “promising” and agree the
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`results “warrant controlled studies investigating this approach in a larger series of
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`patients.” Id. This invitation to investigate further is hardly the demonstration of
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`effective and safe treatment Dr. Donovan claims.
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`32. Voswinekel is a single-paragraph conference abstract, meaning that
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`(1) it is not edited by a peer review panel of editors but published as-submitted
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`following a less-stringent grading and acceptance criteria than scientific
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`manuscripts and (2) it is not meant to be a definitive work. Ex. 1003, 1-7. Rather,
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`such abstracts are generally submitted by researchers looking to provide their
`
`administration with a reason they should attend the meeting. To POSAs, these
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`abstracts are not considered publications per 36. In fact, at Harvard, my colleagues
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`and I are required to remove an abstract from our CV5 if it has not resulted in a
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`publication within three years. This happens quite often since conference abstracts
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`reflect preliminary data and hypotheses which often end up being contradicted by
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`full studies. A POSA would not rely on such preliminary data to conclude that a
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`drug of any kind was safe, tolerable, or clinically efficacious.
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`33.
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`To the extent that Voswinckel reports “promising” results with
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`inhaled treprostinil, a POSA would view this with a degree of skepticism. A
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`reader would review the abstract results for what they actually show.
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`It is a huge
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`leap for Dr. Donovan to conclude safety and efficacy from such a conference
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`abstract that only purports to be “promising” for long-term potential — a leap a
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`POSA would not take.
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`34. At best, Voswinckel sets out a study to assess “the effects of inhaled
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`TRE [treprostinil] on pulmonary hemodynamics and gas exchange in severe
`
`pulmonary hypertension.” EX. 1003, 7. No criticality is attributed to the type of
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`device used nor is any clarification given on how the device is used or what actual
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`dose (in ug ) is delivered. Id The dose and device in Voswinckel are incidental.
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`Id.
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`It is also unclear from Voswinckel what inhalation regimen was used for the
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`two “compassionate treatment” patients and whether they are a subset of or a
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`separate population from the 17 patients treated with 3 single breaths of the 600
`
`ug/mL solution, with no information on how much drug was delivered within each
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`breath or how the breaths were spaced apart. Id. The only clear teaching is that
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`the two “compassionate treatment” patients were given four inhalations of
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`treprostinil per day. Id. A POSA would not know what dose, concentration, or
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`device was used to deliver the “compassionate treatment” based on the scant
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`information provided. A POSA would also be cautious of results gleaned from a
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`two—patient, uncontrolled sample size, particularly where those patients are
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`“compassionate use” treatment.
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`35.
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`I have been informed that in order for Voswinckel to be considered
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`“prior art,” for the purposes of this proceeding, it must have been “publicly
`
`accessible” and that the legal standard for accessibility was whether Voswinckel
`
`was disseminated or otherwise made available to the extent that a POSA exercising
`
`reasonable diligence can locate it. Based on this legal standard, it is my opinion
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`that Voswinckel was not publicly accessible.
`
`36.
`
`A POSA looking for information on treatment of pulmonary
`
`hypertension with treprostinil on or before May 15, 2006 would typically do most
`
`of his or her research online. The primary resource for online searching in the field
`
`is PubMed. A POSA typically searches PubMed using a string of search terms,
`
`which could include the disease (8.g. “pulmonary hypertension” or “pulmonary
`
`arterial hypertension”) and/or the active agent of interest (e.g., “prostacyclin-
`
`analog” or “treprostinil”). In circumstances where a POSA is already aware of the
`
`work of a set of authors or institution, a search of PubMed of those terms might
`
`also be employed.
`
`37.
`
`There is no PubMed entry for Voswinckel at all, much less one keyed
`
`to the authors, their institution, pulmonary hypertension, or treprostinil.
`
`Conference abstracts, like Voswinckel, are not usually indexed on PubMed
`
`because, as noted above, they are not considered peer-reviewed to the same extent
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`as a journal publication. Therefore, a POSA exercising reasonable diligence would
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`not have been able to locate it in the most typical and helpful way employed by a
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`POSA.
`
`38.
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`In the unlikely event that no relevant resources were pulled up on
`
`PubMed, a POSA might turn to a library to locate books and peer-reviewed
`
`journals (in print) that are relevant to pulmonary hypertension. Typically, peer-
`
`reviewed journals are about 100 pages and contain an index or table of contents.
`
`39.
`
`For a POSA to find Voswinckel through either of these methods is
`
`akin to finding a needle in a haystack. Voswinckel is one of over 1,000 abstracts
`
`in a supplement to Circulation providing all the abstracts for the American Heart
`
`Association’s 2004 Scientific Sessions in advance of the conference; the
`
`supplement is over 1,000 pages (an order of magnitude longer than a peer-
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`reviewed j ournal). Ex. 1003, 4, 7. The version provided by Watson does not even
`
`contain a table of contents showing how the supplement is organized and/or if it
`
`could be searched. Ex. 1003.
`
`40.
`
`I understand that Watson has relied on Dr. Bennett for the evidence
`
`that Voswinckel was publicly available. I have reviewed Dr. Bennett’s declaration
`
`(Ex. 1013) and disagree with him that Voswinckel was publicly accessible.
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`Importantly, he concludes only that “in [his] opinion, Circulation and its abstract
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`supplements were suffic