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. 9,358,240
`
`Issue Date: June 7, 2016
`Title: TREPROSTINIL ADMINISTRATION BY INHALATION
`
`Inter Partes Review NO. 2017—01621
`
`
`DECLARATION OF DR. AARON WAXMAN
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`4345436642425
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`UNITED TH ERAPEUTIOS, EX. 2040
`WATSON LABORATORIES v. UNITED THERAPEUTICS, IPR2017-01621
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`Page 1 of 48
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`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`WATSON LABORATORIES, INC.
`Petitioner
`
`V.
`
`UNITED THERAPEUTICS, INC.
`Patent Owner
`
`Patent NO. 9,358,240
`
`Issue Date: June 7, 2016
`Title: TREPROSTINIL ADMINISTRATION BY INHALATION
`
`Inter Partes Review NO. 2017—01621
`
`
`DECLARATION OF DR. AARON WAXMAN
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`4345436642425
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`UNITED TH ERAPEUTIOS, EX. 2040
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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 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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`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.
`
`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 ’240 patent.
`
`6.
`
`For reference, below is a list of the Exhibits that are cited herein:
`
`Exhibit No.
`
`
`
`Hossein Ardeschir Ghofrani, Robert Voswinckel, et al., “Neue
`Therapieoptionen in der Behandlung der pulmonalarteriellen
`1005
`
`Hypertonie,” Herz, 30,4 (June 2005): 296-302
`
`W0 93/0095]
`1012
`
`1013
`
`1028
`
`Declaration of Dr. Scott Bennett
`
`Olschewski H., et al., Aerosolized Prostacyclin and Iloprost in
`Severe Pulmonary Hypertension, 1996 Ann. Intern. Med. 124(9),
`
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`1002
`
`Declaration of Dr. Maureen Donovan
`
`1003
`
`Robert Voswinckel, et a1. “Inhaled treprostinil sodium for the
`treatment of pulmonary hypertension” Abstract #1414, Circulation,
`110, 17, Su lement Oct. 2004 : III—295
`
`
`
`IPR2017-0162l
`
`Declaration of Dr. Aaron Waxman
`
`
`
`
`820-824 (1996)
`Olschewski, et al., Pharmacodynamics and Pharmacokinetics of
`Inhaled Iloprosi, Aerosolized by Three Different Devices, in Severe
`Pulmona H ertension, Chest J., 124 4 , 1294—1304 Oct. 2003
`
`1029
`
`1046
`
`Voswinckel, R., et al., “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
`accompanying Declaration of Dr. Roham T. Zamanian)
`1162
`
`Amendment and Reply filed in 12/591,200 (Feb. 2, 2016) (with
`1163
`
`accompanying Second Declaration of Dr. Roham T. Zamanian)
`Oxford Dictionary ofEnglish. 2nld ed. Revised. Oxford University
`Press, 2005 (exce t).
`Newman, Stephen P. Respiratory drug delivery: essential theory and
`ractice. Resirato Dru_
`'
`Online, 2009 exce t .
`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 12/59l,200 (Nov. 9, 2015) (Ex.
`
`2002
`
`2003
`
`2004
`
`
`
` 2044
`
`2005
`
`2012
`
`2020
`
`2021
`
`2023
`
`
`
`2024
`
`2025
`
`2002 Press Release Regarding Promotion of Robert Roscingo
`(accessed October 10, 2017)
`Shield Therapeutics Biography for Carl Sterritt (accessed October
`10,2017
`
`Circulation Website accessed Airil 17, 2018
`
`2041
`
`2042
`Mosby ’s Medical Dictionary. ’7th ed. Mosby Elsevier, 2006 (excerpt).
`Leung, K, Louca E., & Coates, A. “Comparison of Breath-Enhanced
`to Breath—Actuated Nebulizers for Rate, Consistency, and
`Efficienc ,” Chest, 126 5 :1619—1627 2004
`
`2043
`
`Rau, J.L., “Design Principles of Liquid Nebulization Devices
`Currently in Use,” Respir. Care, 47(11):1257-1275 (2002)
`Atkins, P.J. & T.M. Crowder. “The Design and Development of
`Inhalation Dru_ Delive
`S stems,” Pharmaceutical Inhalation
`
`2045
`
`4345435522425
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`Aerosol Technology, 2nd Ed. (AJ. Hichey ed., CRC Press), Ch. 9
`
`(2003)
`
`Ventavis® Patient Brochure
`2046
`
`
`
`2047
`
`Rau, J.L. Respiratory Care Pharmacology. 6‘11 Ed. Mosby, 2002
`(excerpt)
`
`I.
`
`BACKGROUND
`
`7.
`
`At the time of the invention, as today, pulmonary hypertension was a
`
`poorly understood, often 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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`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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`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, 1-28. 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 ’240 PATENT
`
`l l.
`
`I have reviewed the claims of the ’240 patent. Provided below for
`
`reference is the language of claim 1 of the ’240 patent:
`
`A method of treating pulmonary hypertension comprising:
`
`administering by inhalation to a human suffering from
`
`pulmonary hypertension a therapeutically effective single event dose
`
`of a formulation comprising from 200 to 1000 ug/ml of treprostinil or
`
`a pharmaceutically acceptable salt thereof
`
`with a pulsed ultrasonic nebulizer that aerosolizes a fixed
`
`amount of treprostinil or a phannaceutically acceptable salt thereof
`
`per pulse,
`
`said pulsed ultrasonic nebulizer comprising an opto-acoustical
`
`trigger which allows said human to synchronize each breath to each
`
`pulse,
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`said therapeutically effective single event dose comprising from
`
`15 pg to 90 pg of treprostinil or a pharmaceutically acceptable salt
`
`thereof delivered in 1 to 18 breaths.
`
`Ex. 1001, col. 18:2—16.
`
`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. 18:17—37.
`
`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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`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 ’240 patent are directed to methods for “treating
`
`pulmonary hypertension” with a specific “pulsed ultrasonic nebulizer.” Ex. 1001,
`
`col. 18:2-37. I understand that several of the inventors listed on the ’240 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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`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, 1W4. Even if this definition is
`
`applied, it would not affect my ultimate conclusions regarding the ’240 patent
`
`discussed herein.
`
`B.
`
`“pulsed” and “pulse”
`
`17.
`
`Both the terms “pulse” and “pulsed” are found in claim 1. BX. 100],
`
`col. 1812-16. The term “pulsed” is used as the adjective form of the word “pulse.”
`
`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
`
`understood to refer to rhythmic and periodic waves. See, e.g., Ex. 2042, 4
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`(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 ’240 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. 13:59-60. 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. 4:45—46;
`
`col. 13:58-60.
`
`20.
`
`In the claims, each “pulse” is meant to correspond with each breath.
`
`Ex. 1001, col. 18:2-16. A similar interpretation of the term is found in Exhibit
`
`1163, which I understand to be documents and a declaration submitted during the
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`prosecution of the ’240 patent. Exhibit 1163 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
`
`byahuman.” Ex. 1163, 12-13.
`
`21.
`
`Based on the specification and 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.
`
`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
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`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 “opto-acoustical trigger” is required by the language of claim 1 to
`
`“allow[] said human to synchronize each breath to each pulse.” The specification
`
`of the ’240 patent is consistent with its description of the opto-acoustical trigger
`
`synchronizing inhalation to pulses. Ex. 1001, col.lS:60—62. 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) 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
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`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-acoustieal trigger” is different from the mere
`
`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. 13:61-62. 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 l to 18 breaths to the
`
`pulmonary hypertension patient in a “single event dose.” Ex. 1001, col. 18: 14—16.
`
`I fiirther note that the patent specification gives the following supporting
`
`explanation of this term:
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`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
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`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. 17:14~19. Claims 3 and 9
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`further 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. 18:20-21, 36-37. 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.
`
`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
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`Declaration of Dr. Aaron Waxrnan
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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.
`
`29.
`
`I understand the Board is reviewing whether claims 1-9 are obvious
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`over the references provided in “Ground I” noted below.
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`
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`References
`Ground
`
`
`
`
`Robert Voswinekel, et a1. “Inhaled treprostinil
`
`sodium for the treatment of pulmonary
`
`hypertension” Abstract #1414, Circulation, 110, 17,
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`Supplement (Oct. 2004): III—295 (“Voswinckel,”
`
`Ground 1
`
`Ex. 1003)
`
`
`WO 93/00951 (“Patton,” Ex. 1012)
`
`
`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)
`
`
`I further understand the Board has relied on both the references cited under
`
`“Ground 1” and Dr. Donovan’s declaration (Ex. 1002) in its decision to “institute
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`Declaration of Dr. Aaron Waxman
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`trial” on this ground. In this section, I provide my opinions on Voswinckel (Ex.
`
`1003), Ghofrani (Ex. 1005), and Patton (Ex. 1012) in relation to the Board’s
`
`decision, Watson’s arguments, and the supporting testimony provided in Dr.
`
`Donovan’s declaration.
`
`A. Voswinckel
`
`30.
`
`Dr. Donovan’s reliance on Voswinckel for showing the “safety,
`
`tolerability, and clinical efficacy” of inhaled treprostinil (EX. 1002, 1178) is
`
`inconsistent with how a POSA would interpret Voswinckel’s findings and is
`
`premised on a fundamental misunderstanding of Voswinckel.
`
`31. While the authors do state they are interested in evaluating the safety,
`
`tolerability and clinical efficacy in patients, they fail to disclose any information
`
`about the amount of drug per breath or spacing of breaths within an inhalation
`
`event, and the conclusions actually reflected a far more cautious conclusion. The
`
`conclusion expressly addresses efficacy only in the context of single acute dosing
`
`and only of a single measure of pulmonary hemodynamics—this cannot lead to a
`
`conclusion of clinical efficacy. Ex. 1003, 7. At best, the authors suggest long term
`
`treatment (based on 2 compassionate use patients) is “promising” and agree the
`
`results “warrant controlled studies investigating this approach in a larger series of
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`Declaration of Dr. Aaron Waxrnan
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`patients.” Id. This invitation to investigate further is hardly the demonstration of
`
`effective and safe treatment Dr. Donovan claims.
`
`32. More importantly, Dr. Donovan’s conclusions about Voswinckel are
`
`premised on an apparent misreading of the document. Dr. Donovan’s assertion
`
`that “[t]hese 17 patients [in Voswinckel] received a three—breath inhalation
`
`treatment four times per day” is flatly incorrect. Ex. 1002, 11109. This teaching is
`
`nowhere to be found in Voswinckel. Ex. 1003. The 17 patients very clearly
`
`received a single acute administration of treprostinil. Ex. 1003, 7. A single acute
`
`dose while the patient is catheterized is not the “treatment of pulmonary
`
`hypertension,” much less the safe and therapeutically effective treatment of such.
`
`Dr. Donovan’s clear misunderstanding is further highlighted where she talks about
`
`“four times per day” and “long term” treatment in the context of “single acute
`
`dosing.” Ex. 1002,11104.
`
`33. Voswinckel is a single-paragraph conference abstract, meaning that
`
`(1) it is not edited by a peer review panel of editors but published as-submitted
`
`following a less-stringent grading and acceptance criteria than scientific
`
`manuscripts and (2) it is not meant to be a definitive work. Ex. 1003, 1-7. Rather,
`
`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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`Declaration of Dr. Aaron Waxrnan
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`abstracts are not considered publications per se. In fact, at Harvard, my colleagues
`
`and I are required to remove an abstract from our CVs if it has not resulted in a
`
`publication within three years. This happens quite often since conference abstracts
`
`reflect preliminary data and hypotheses which often end up being contradicted by
`
`full studies. A POSA would not rely on such preliminary data to conclude that a
`
`drug of any kind was safe, tolerable, or clinically efficacious.
`
`34.
`
`To the extent that Voswinckel reports “promising” results with
`
`inhaled treprostinil, a POSA would View this with a degree of skepticism. A
`
`reader would review the abstract results for what they actually show. It is a huge
`
`leap for Dr. Donovan to conclude safety and efficacy from such a conference
`
`abstract that only purports to be “promising” for long-term potential — a leap a
`
`POSA would not take.
`
`35. At best, Voswinckel sets out a study to assess “the effects of inhaled
`
`TRE [treprostinil] on pulmonary hemodynamics and gas exchange in severe
`
`pulmonary hypertension.” Ex. 1003, 7. No criticality is attributed to the type of
`
`device used nor is any clarification given on how the device is used or what actual
`
`dose (in ug) is delivered. Id. The dose and device in Voswinckel are incidental.
`
`Id.
`
`It is also unclear from Voswinckel what inhalation regimen was used for the
`
`two “compassionate treatment” patients and whether they are a subset of or a
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`Declaration of Dr. Aaron Waxrnan
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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
`
`breath or how the breaths were spaced apart. Id. The only clear teaching is that
`
`the two “compassionate treatment” patients were given four inhalations of
`
`treprostinil per day. Id. A POSA would not know what dose, concentration, or
`
`device was used to deliver the “compassionate treatment” based on the scant
`
`information provided. A POSA would also be cautious of results gleaned from a
`
`two—patient, uncontrolled sample size, particularly where those patients are
`
`“compassionate use” treatment.
`
`36.
`
`I have been informed that in order for Voswinckel to be considered
`
`“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
`
`that Voswinckel was not publicly accessible.
`
`37.
`
`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,
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`Declaration of Dr. Aaron Waxrnan
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`which could include the disease (eg. “pulmonary hypertension” or “pulmonary
`
`arterial hypertension”) and/or the active agent of interest (cg, “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.
`
`38.
`
`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
`
`as a journal publication. Therefore, a POSA exercising reasonable diligence would
`
`not have been able to locate it in the most typical and helpful way employed by a
`
`POSA.
`
`39.
`
`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.
`
`40.
`
`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 2,000 abstracts
`
`in a supplement to Circulation providing all the abstracts for the American Heart
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`Declaration of Dr. Aaron Waxman
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`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—
`
`reviewed journal). 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.
`
`41.
`
`I understand that Watson has relied on Dr. Bennett for t
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