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 DECLARATION OF DR. RICHARD DALBY
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`4818-9518-0386
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`UNITED THERAPEUTICS, EX. 2038
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`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017-01622
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`Page 1 of 11
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`
`
`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 DECLARATION OF DR. RICHARD DALBY
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`4818-9518-0386
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`UNITED THERAPEUTICS, EX. 2038
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`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017-01622
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`Page 1 of 11
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`IPR2017-01622
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`Declaration of Dr. Richard Dalby
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`I, Dr. Richard Dalby, hereby declare as follows:
`
`1.
`
`I am a Professor in the Department of Pharmaceutical Sciences at the
`
`University of Maryland School of Pharmacy.
`
`I received my Bachelor’s degree in
`
`Pharmacy with honors from the Nottingham University School of Pharmacy and
`
`my Ph.D. in Pharmaceutical Sciences from the University of Kentucky College of
`
`Pharmacy.
`
`I have over 25 years of experience working and consulting in the field
`
`of inhaled and nasal medications and devices. My curriculum vitae is provided as
`
`Exhibit 2022.
`
`2.
`
`I am a paid consultant for United Therapeutics, the assignee of US Patent
`
`No. 9, 339,507 (Ex. 1001, “the ’507 patent”), in connection with IPR2017-
`
`01622. My compensation does not depend on the content of my opinions or the
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`disposition of this proceeding.
`
`I have been retained by United Therapeutics to
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`provide technical expertise and my expert opinion on the ’507 patent.
`
`3.
`
`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 and that the
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`Patent Trial and Appeal Board (“the Boar ”) is now considering whether these
`
`claims are obvious over the combination of Voswinckel (Ex. 1003), Chaudry (Ex.
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`[PR2017-01622
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`Declaration of Dr. Richard Dalby
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`1004), Ghofrani (Ex. 1005), and Patton (Ex. 1012). The testimony provided below
`
`supplements my prior declaration (Ex. 2001).
`
`4.
`
`For reference, below is a list of the Exhibits that are cited herein:
`
`
`Exhibit No.
`Description
`1001
`1002
`
`U.S. Patent No. 9,358,240
`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 : 111—295
`U.S. Patent A lication Publication No. 2004/0265238
`
`1005
`
`Hossein Ardeschir Ghofrani, Robert Voswinckel, et a1., “None
`Therapieoptionen in der Behandlung der pulmonalarteriellen
`H pertonie,” Herz, 30,4 June 2005 : 296—302
`
`WO 93/00951
`1012
`
`
`
`
`
`2001
`2003
`
`2022
`
`2039
`
`Declaration of Dr. Richard Dalby
`Newman, Stephen P. Respiratory drug delivery: essential theory and
`:ractice. Res irato Dru_ Delive Online, 2009 exce t .
`Curriculum vitae of Dr. Richard Dalb
`
`US 4,319,155 (“Nakai”)
`
`5.
`
`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
`
`or within the prior art in combination with the general knowledge held by a POSA
`
`at the time an invention was made, and that such a person would have a reason for
`
`and reasonable expectation of success in combining these teachings to achieve the
`
`claimed invention.
`
`I understand there may be a variety of rationales that can
`
`demonstrate the reason for and reasonable expectation of success in combining
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`[PR2017-01622
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`Declaration of Dr. Richard Dalby
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`selected teachings, but, regardless of the rationale used, it must be supported by
`
`evidence.
`
`6.
`
`I understand that Board is reviewing whether claims 1—9 are obvious
`
`over the references provided in “Ground I” noted below.
`
`
`
`Ground
`
`References
`
`
`
`Ground 1
`
`
`
`
`
`Robert Voswinckel, et al. “Inhaled treprostinil
`
`sodium for the treatment of pulmonary
`
`hypertension” Abstract #1414, Circulation, 110, 17,
`
`Supplement (Oct. 2004): III-295 (“Voswinckel,”
`
`U.S. Patent Application Publication No.
`
`Ex. 1003)
`
`
`2004/0265238 (“Chaudry,” 1004)
`
`
`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 fiirther understand that Board has relied on both the references cited under
`
`“Ground 1” and Dr. Donovan’s declaration (Ex. 1002) in its decision to “institute
`
`trial” on this ground. In this section, I provide my opinions about Voswinckel (Ex.
`
`1003), Chaudry (Ex. 1004), Ghofrani (Ex. 1005), and Patton (Ex. 1012) in relation
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`[PR2017-01622
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`Declaration of Dr. Richard Dalby
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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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`7.
`
`I understand that the Board summarized the critical question with
`
`regard to the combination of Voswinckel, Chaudry, Ghofrani, and Patton as
`
`follows (emphasis added):
`
`The relevant question is not whether Patton employs a nebulizer that
`
`reguires breath synchronization — i.e. a pulsed nebulizer.
`
`Voswinckel expressly discloses a pulsed nebulizer. EX. 1003. Rather,
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`the relevant question is whether it would have been obvious to use a
`
`light and sound signal, like that taught in Patton, in Voswinckel’s
`
`pulsed nebulizer.
`
`Paper 10, 29. But the Board’s framing of the question is based on Watson’s
`
`incorrect assumption that a “pulsed nebulizer” reguires (or is synonymous with, as
`
`indicated by the “i.e.”) synchronization of individual breaths by the patient to
`
`individual pulses of aerosol. This assumption appears to be based on parts of
`
`paragraphs 126 to 127 of Dr. Donovan’s declaration, which state:
`
`The primary purpose of using a pulsed nebulizer is to avoid
`
`wasting the drug that gets aerosolized while the patient is
`
`exhaling. Thus, the patient must synchronize their breath to the
`
`pulse of drug that is being delivered. [. . .] A POSA would therefore
`
`appreciate that when using a pulsed nebulizer, the patient needs to
`
`know when the drug is ready to be inhaled, otherwise the efficiency
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`Declaration of Dr. Richard Dalby
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`gains from the pulsed nebulizer would be lost. Thus, by necessity, a
`
`POSA would implement some sort of signal to demonstrate to the
`
`patient that the device is generating aerosol and is ready for the patient
`
`to inhale. Without this sort of trigger, the Qatient would be unable
`
`to synchronize their breathing to the distribution of drug, and the
`
`Qulsed nebulizer would not function as intended.
`
`No basis for this conclusion is provided in any of Voswinckel, Chaudry, Ghofrani,
`
`or Patton for Dr. Donovan’s conclusion and she does not cite any evidence for this
`
`supposed assumption of a POSA.
`
`I disagree that a POSA would necessarily equate
`
`a “pulsed nebulizer” with one requiring that “the patient must synchronize their
`
`breath to the pulse of drug that is being delivered.” Rather, based on these
`
`references, an ordinary skilled artisan would not necessarily understand a pulsed
`
`nebulizer to reguire synchronization.
`
`8.
`
`Of the four references Voswinckel, Chaudry, Ghofrani, and Patton,
`
`only Voswinckel uses the word “pulsed.” The word appears only once in
`
`Voswinckel, in the statement: “Patients received a TRE inhalation by use of the
`
`pulsed Optineb ultrasound nebulizer (3 single breaths, TRE solution 600
`
`micrograms/ml).” Ex. 1003, 7.
`
`I have read the phrase “PM Optineb
`
`ultrasound nebulizer” to refer to a nebulizer which uses ultrasonic vibration to
`
`nebulize an active agent in a periodic manner. Ex. 2003, 28 (discussing
`
`“Ultrasonic Nebulizers”). Voswinckel does not explain the word “pulsed” nor
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`IPR2017-01622
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`Declaration of Dr. Richard Dalby
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`does it mention if the pulsed feature was in use and it certainly does not identify
`
`the length of a pulse or that one pulse is to be synchronized to one breath.
`
`Voswinckel does not describe any features or advantages associated with a pulsed
`
`nebulizer.
`
`9.
`
`The term “pulsed” refers to the generation of pulses of aerosol with a
`
`specified periodicity. BX. 200], 111 1-15. Pulses with a specified periodicity can be
`
`implemented in ultrasonic nebulizers in different ways and for various reasons.
`
`10.
`
`For example, Nakai (Ex. 2039) describes an ultrasonic nebulizer
`
`aimed at accurately controlling the particle size generated through the use of
`
`pulses. Ex. 2039, col. 1:65-col. 2:6. As stated in Nakai, the “primary object” of
`
`the described invention is “constant and accurate particle size control.” Ex. 2039,
`
`col. 1:65-col. 2:6; col. 4: 1-15. This is achieved by alternating the ultrasonic
`
`vibrator between two states— one in which the fluid is nebulized and one in which
`
`the fluid is not nebulized. Ex. 2039, col. 4:4—5; col. 2:22-25; Figures 3—4. This
`
`pulsing of aerosol output is clearly depicted in Figure 3:
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`IPR2017-01622
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`Declaration of Dr. Richard Dalby
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`FIG?)
`
`NEBULIZATION LEVEL
`
`HIGH
`
`Lo w
`
`OFF
`
`Therefore, the nebulizer in Nakai is pulsed and achieves its primary purpose of
`
`controlling particle size. Synchronization of aerosol pulsing with individual
`
`breaths is not synonymous with the word “pulsed” and a “pulsed nebulizer” does
`
`not “reguire breath synchronization.”
`
`11.
`
`The word “pulsed” does not inherently describe how or when the
`
`pulse will be generated. For example, the pulse could be automatically generated
`
`at the onset of a patient’s inhalation or multiple pulses could be generated within
`
`the timefi‘ame of a single inhalation. Dr. Donovan’s declaration provides examples
`
`of such breath-actuated devices — including Halo-Lite — in which the nebulizer
`
`automatically generates a pulse of aerosol as a patient takes in a breath. Ex. 1002,
`
`1138; Ex. 2001, 1I30. Such breath-actuated devices do not require conscious
`
`inhalation synchronized with aerosol generation; rather, the device is programmed
`
`to sense when a user inhales and to generate the aerosol in response. Id.
`
`In other
`
`words, with this type of device, the aerosol pulse adapts to the patient’s breathing,
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`IPR2017-01622
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`Declaration of Dr. Richard Dalby
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`which is in contrast to the presently claimed nebulizer device where the reverse
`
`occurs — namely, the nebulizer has an opto- acoustical trigger that tells the patient
`
`when to inhale.
`
`12.
`
`The requirement for conscious synchronization is actually considered
`
`a drawback for inhalation devices. See, e.g., Ex. 1012, 3: 1-27. Thus, alternative
`
`approaches have been proposed: for example, breath-actuated devices and the
`
`device in Patton. Ex. 2001, 1126—30. Patton itself negates the need for
`
`synchronization by generating a stable aerosol, which is stored in the holding
`
`chamber and can be inhaled later by a patient. Ex. 1012, 6:28-7:25. Thus, should
`
`the method of Patton be used in conjunction with an ultrasonic nebulizer, the
`
`resulting device would function as intended yet not r_eLiire synchronization
`
`between aerosol generation and patient inhalation. BX. 200], 1126-28.
`
`13. Voswinckel provides no guidance as to how or why the
`
`“pulsed. . .ultrasound nebulizer” is utilized. Chaudry does not teach a pulsed
`
`nebulizer. Ghofrani offers no teaching on how to select an appropriate device for
`
`delivery of drug by inhalation. Patton’s method explicitly avoids the need for
`
`synchronization. Thus, none of the references discloses “a pulsed ultrasonic
`
`nebulizer that aerosolizes a fixed amount of treprostinil. . .per pulse” and “allows
`
`[a] human to synchronize each breath to each pulse” as required by the claims.
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`Declaration of Dr. Richard Dalby
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`14.
`
`Therefore, in View of Voswinckel, Chaudry, Ghofrani, and Patton, a
`
`POSA would not necessarily conclude that synchronization of each breath with
`
`each pulse of aerosol is reguired for a pulsed ultrasonic nebulizer to function as
`
`intended. While Watson and Dr. Donovan read this synchronization into the
`
`phrase “pulsed nebulizer,” a POSA reading these three references would not
`
`understand such a “pulsed nebulizer” to require synchronization between the
`
`pulsing and the patient’s breathing. Instead, a POSA would read a “pulsed
`
`nebulizer” merely to mean that the nebulization occurs in pulses, and could
`
`conclude the nebulizer of Voswinckel describes any of the situations exemplified
`
`in paragraphs 10 to 12. If the phrase “pulsed ultrasonic nebulizer” simply
`
`necessarily meant that it aerosolizes a fixed amount per pulse and requires a human
`
`to synchronize each breath to each pulse, then much of the claim language in the
`
`patents would be redundant.
`
`I do not believe that a POSA would read “pulsed
`
`ultrasonic nebulizer” as necessarily having these additional features without an
`
`explicit statement that they are included.
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`[The remainder of th is page is intentionalbz left blank]
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`[PR2017-01622
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`Declaration of Dr. Richard Dalby
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`15.
`
`I hereby declare that all statements made herein of my knowledge are
`
`true and that all statements made on information and belief are believed to be true;
`
`and further that these statements were made with the knowledge that willful false
`
`statements and the like so made are punishable by fine or imprisonment, or both
`
`under Section 1001 of Title 18 of the United States Code.
`
`Date: April 18, 2018
`
`IQICl/Iaml 300%
`
`
`
`Dr. Richard Dalby
`
`4818—9518—0386
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