UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`WATSON LABORATORIES, INC.
`
`Petitioner
`
`V.
`
`UNITED THERAPEUTICS CORP.
`
`Patent Owner
`
`Patent No. 9,358,240
`
`Issue Date: June 7, 2016
`Title: TREPROSTINIL ADMINISTRATION BY INHALATION
`
`Inter Parfes Review No. 20 1 7—0 1 621
`
`
`SECOND DECLARATION OF DR. RICHARD DALBY
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`4830-4129-5967
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`UNITED THERAPEUTICS, EX. 2038
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`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR201T-01621
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`Page 1 of 11
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`
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`WATSON LABORATORIES, INC.
`
`Petitioner
`
`V.
`
`UNITED THERAPEUTICS CORP.
`
`Patent Owner
`
`Patent No. 9,358,240
`
`Issue Date: June 7, 2016
`Title: TREPROSTINIL ADMINISTRATION BY INHALATION
`
`Inter Parfes Review No. 20 1 7—0 1 621
`
`
`SECOND DECLARATION OF DR. RICHARD DALBY
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`4830-4129-5967
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`UNITED THERAPEUTICS, EX. 2038
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`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR201T-01621
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`Page 1 of 11
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`IPR2017-01621
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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
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`Pharmacy.
`
`I have over 25 years of experience working and consulting in the field
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`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. 9,358,240 (EX. 1001, “the ’240 patent”), in connection with IPR2017-
`
`01621. My compensation does not depend on the content of my opinions or the
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`disposition of this proceeding.
`
`1 have been retained by United Therapeutics to
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`provide technical expertise and my expert opinion on the ’240 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.
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`(“Petitioner” or “Watson”) challenges claims 1-9 of the ’240 patent and that the
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`Patent Trial and Appeal Board (“the Boar ”) is now considering whether these
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`claims are obvious over the combination of Voswinckel (Ex. 1003), Ghofrani (Ex.
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`[PR2017-01621
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`Declaration of Dr. Richard Dalby
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`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
`
`Robert Voswinckel, et a1. “Inhaled treprostinil sodium for the
`treatment of pulmonary hypertension” Abstract #1414, Circulation,
`110, 17, Su lement Oct. 2004 : III—295
`
`1005
`
`Hossein Ardeschir Ghofrani, Robert Voswinckel, et a1., “Neue
`Therapieoptionen in der Behandlung der pulmonalarteriellen
`H ertonie,” Herz, 30,4 June 2005 : 296—302
`WO 93/00951
`1012
`
`2001
`Declaration of Dr. Richard Dalby
`2003
`Newman, Stephen P. Respiratory drug delivery: essential theory and
`ractice. Respiratory Drug Delivery Online, 2009 (excerpt).
`Curriculum vitae of Dr. Richard Dalb
`
`
`
`
`
`2022
`
`2039
`
`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
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`or within the prior art in combination with the general knowledge held by a POSA
`
`at the time an invention was made, and that such a person would have a reason for
`
`and reasonable expectation of success in combining these teachings to achieve the
`
`claimed invention.
`
`I understand there may be a variety of rationales that can
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`demonstrate the reason for and reasonable expectation of success in combining
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`[PR2017-01621
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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
`
`Robert Voswinckel, et a1. “Inhaled treprostinil
`
`sodium for the treatment of pulmonary
`
`hypertension” Abstract #1414, Circulation, 110, 17,
`
`Supplement (Oct. 2004): III-295 (“Voswinckel,”
`
`Ex. 1003)
`
`
`WO 93/00951 (“Patton,” Ex. 1012)
`
`
`
`
`Ground 1
`
`
`
`Hossein Ardeschir Ghofrani, Robert Voswinckel, et
`
`a1., “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), 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.
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`Declaration of Dr. Richard Dalby
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`7.
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`I understand that the Board summarized the critical question with
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`regard to the combination of Voswinckel, 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
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`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 127 to 128 of Dr. Donovan’s declaration, which state:
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`The primary puppose 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
`
`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 patient would be unable
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`Declaration of Dr. Richard Dalby
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`to synchronize their breathing to the distribution of drug, and the
`
`pulsed nebulizer would not function as intended.
`
`No basis for this conclusion is provided in any of Voswinckel, 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 three references Voswinckel, 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/m1).” Ex.
`
`1003, 7.
`
`I have read the phrase “m 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 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.
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`Declaration of Dr. Richard Dalby
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`9.
`
`The term “pulsed” refers to the generation of pulses of aerosol with a
`
`specified periodicity. Ex. 2001, 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. 1:65-00]. 2:6. As stated in Nakai, the “primary object” of
`
`the described invention is “constant and accurate particle size control.” Ex. 2039,
`
`col. 1:65-00]. 2:6; col. 421-15. 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:
`
`FIG?)
`
`NEBULI ZATION 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
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`Declaration of Dr. Richard Dalby
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`breaths is not synonymous with the word “pulsed” and a “pulsed nebulizer” does
`
`not “require 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, 1130. 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,
`
`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
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`Declaration of Dr. Richard Dalby
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`synchronization by generating a stable aerosol, which is stored in the holding
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`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 fiinction as intended yet notw synchronization
`
`between aerosol generation and patient inhalation. Ex. 2001, 1126—28.
`
`13. Voswinckel provides no guidance as to how or why the
`
`“pulsed. . .ultrasound nebulizer” is utilized. 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.
`
`14.
`
`Therefore, in View of Voswinckel, 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
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`“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
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`Declaration of Dr. Richard Dalby
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`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
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`amount per pulse and requires a human to synchronize each breath to each pulse,
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`then much of the claim language in the patents would be redundant.
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`I do not
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`believe that a POSA would read “pulsed ultrasonic nebulizer” as necessarily
`
`having these additional features without an explicit statement that they are
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`included.
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`[The remainder of this page is intentionally left blank]
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`Declaration of Dr. Richard Dalby
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`15.
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`I hereby declare that all statements made herein of my knowledge are
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`true and that all statements made on information and belief are believed to be true;
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`and further that these statements were made with the knowledge that willful false
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`statements and the like so made are punishable by fine or imprisonment, or both
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`under Section 1001 of Title 18 of the United States Code.
`
`Date: April 18, 2018
`
`1?) Clara 3)
`
`
`
`Dr. Richard Dalby
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`4830—4129—5967
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