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
`WATSON LABORATORIES v. UNITED THERAPEUTICS, IPR2017-01622
`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
`WATSON LABORATORIES v. UNITED THERAPEUTICS, IPR2017-01622
`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:
`
`L,
`
`I am a Professor in the Department of Pharmaceutical Sciencesat the
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`University of Maryland School of Pharmacy.
`
`I received my Bachelor’s degree in
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`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 U.S. Patent
`
`No. 9, 339,507 (Ex. 1001, “the ’507 patent”), in connection with IPR2017-
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`01622. My compensation does not depend on the content of my opinionsor the
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`disposition of this proceeding.
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`I have been retained by United Therapeutics to
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`provide technical expertise and my expert opinion on the *507 patent.
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`Be
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`While I am neither a patent lawyer nor an expert in patent law, I have
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`been informed of the applicable legal standards for obviousness ofpatent claims.
`
`I
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`understand that the Petition brought forward by Watson Laboratories, Inc.
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`(“Petitioner” or “Watson’”) challenges claims 1-9 of the *507 patent and that the
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`Patent Trial and Appeal Board(“the Board’’) is now considering whether these
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`claims are obvious over the combination of Voswinckel (Ex. 1003), Chaudry (Ex.
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`WATSON LABORATORIES v. UNITED THERAPEUTICS, IPR2017-01622
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`IPR2017-01622
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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
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`supplements myprior declaration (Ex. 2001).
`
`4,
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`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
`Robert Voswinckel, et al. “Inhaled treprostinil sodium for the
`treatment of pulmonary hypertension” Abstract #1414, Circulation,
`110, 17, Supplement
`(Oct. 2004): HI-295
`U.S. Patent Application Publication No. 2004/0265238
`Hossein Ardeschir Ghofrani, Robert Voswinckel,et al., “Neue
`Therapieoptionen in der Behandlung der pulmonalarteriellen
`Hypertonie,” Herz, 30,4 (June 2005): 296-302
`WO 93/0095 1
`1012
`
`2001
`Declaration of Dr. Richard Dalby
`2003
`Newman,Stephen P. Respiratory drug delivery: essential theory and
`practice. Respiratory Drug Delivery Online, 2009 (excerpt).
`Curriculum vitae of Dr. Richard Dalb
`US 4,319,155 (“Nakai”)
`
`1003
`
`1004
`
`1005
`
`2022
`2039
`
`3.
`
`I have been informedthat in order for a patent claim to be considered
`
`obvious, each and every limitation of the claim must be present within the priorart
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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,andthat such a person would havea reason for
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`and reasonable expectation of success in combining these teachings to achieve the
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`claimed invention.
`
`I understand there may bea variety of rationales that can
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`demonstrate the reason for and reasonable expectation of success in combining
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`UNITED THERAPEUTICS, EX. 2038
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`IPR2017-01622
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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
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`evidence.
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`6.
`
`I understand that Board is reviewing whether claims 1-9 are obvious
`
`over the references provided in “Ground 1”noted below.
`
`
`Ground
`References
`
`
`
`Ground |
`
`
`
`Robert Voswinckel, et al. “Inhaled treprostinil
`
`sodium for the treatment of pulmonary
`
`hypertension” Abstract #1414, Circulation, 110, 17,
`
`Supplement(Oct. 2004): III-295 (“Voswinckel,”
`
`Ex. 1003)
`
`U.S. Patent Application Publication No.
`
`2004/0265238 (“Chaudry,” 1004)
`
`WO93/00951 (“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 that Board hasrelied on both the references cited under
`
`“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 about Voswinckel(Ex.
`
`1003), Chaudry (Ex. 1004), Ghofrani (Ex. 1005), and Patton (Ex. 1012) in relation
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`IPR2017-01622
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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 summarizedthe critical question with
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`regard to the combination of Voswinckel, Chaudry, Ghofrani, and Patton as
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`follows (emphasis added):
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`The relevant question is not whether Patton employs a nebulizer that
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`requires breath synchronization — i.e. a pulsed nebulizer.
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`Voswinckel expressly discloses a pulsed nebulizer. Ex. 1003. Rather,
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`the relevant question is whether it would have been obviousto use a
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`light and soundsignal, like that taught in Patton, in Voswinckel’s
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`pulsed nebulizer.
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`Paper 10, 29. But the Board’s framing of the question is based on Watson’s
`
`incorrect assumption that a “pulsed nebulizer” requires (or is synonymouswith, as
`
`indicated by the “‘1.e.””) synchronization of individual breaths by the patient to
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`individual pulses of aerosol. This assumption appears to be based on parts of
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`paragraphs 126 to 127 of Dr. Donovan’s declaration, whichstate:
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`The primary purpose of using a pulsed nebulizeris to avoid
`
`wasting the drug that gets aerosolized while the patientis
`
`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 whenthe drug is ready to be inhaled, otherwisethe efficiency
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`IPR2017-01622
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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
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`POSA would implement somesort 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
`
`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, Chaudry, Ghofrani,
`
`or Patton for Dr. Donovan’s conclusion and she doesnot cite any evidencefor 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 require synchronization.
`
`8.
`
`Of the four references Voswinckel, Chaudry, Ghofrani, and Patton,
`
`only Voswinckel uses the word “pulsed.” The word appears only oncein
`
`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 “pulsed 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
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`“Ultrasonic Nebulizers”). Voswinckel does not explain the word “pulsed” nor
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`Declaration of Dr. Richard Dalby
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`does it mention if the pulsed feature wasin use andit certainly does notidentify
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`the length of a pulse or that one pulse is to be synchronized to one breath.
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`Voswinckel does not describe any features or advantages associated with a pulsed
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`nebulizer.
`
`9.
`
`The term “pulsed” refers to the generation of pulses of aerosol with a
`
`specified periodicity. Ex. 2001, 11-15. 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
`
`aimedat 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 twostates— one in whichthefluid 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 outputis 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. 3
`
`NEBULIZATION LEVEL
`
`HIGH
`
`Low
`
`OFF
`
`Therefore, the nebulizer in Nakai is pulsed and achievesits 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 “require breath synchronization.”
`
`11.
`
`The word “pulsed” does not inherently describe how or whenthe
`
`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
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`the timeframe 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,
`
`438; Ex. 2001, 430. Such breath-actuated devices do not require conscious
`
`inhalation synchronized with aerosol generation; rather, the device is programmed
`
`to sense whena userinhales and to generate the aerosol in response. Jd.
`
`In other
`
`words, with this type of device, the aerosol pulse adapts to the patient’s breathing,
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`Declaration of Dr. Richard Dalby
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`whichis in contrast to the presently claimed nebulizer device where the reverse
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`occurs — namely, the nebulizer has an opto- acoustical trigger that tells the patient
`
`whento inhale.
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`12.
`
`The requirement for conscious synchronization is actually considered
`
`a drawbackfor inhalation devices. See, e.g., Ex. 1012, 3:1-27. Thus, alternative
`
`approacheshavebeen proposed: for example, breath-actuated devices and the
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`device in Patton. Ex. 2001, 426-30. Patton itself negates the need for
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`synchronization by generating a stable aerosol, whichis stored in the holding
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`chamberandcan be inhaledlater by a patient. Ex. 1012, 6:28-7:25. Thus, should
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`the method of Patton be used in conjunction with an ultrasonic nebulizer, the
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`resulting device would function as intended yet not require synchronization
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`between aerosol generation and patient inhalation. Ex. 2001, 426-28.
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`13.|Voswinckel provides no guidanceas to how or whythe
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`“pulsed...ultrasound nebulizer” is utilized. Chaudry does not teach a pulsed
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`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
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`synchronization. Thus, none of the references discloses “a pulsed ultrasonic
`
`nebulizer that aerosolizes a fixed amountoftreprostinil...per pulse” and “allows
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`[a] human to synchronize each breath to each pulse”as required bythe claims.
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`Declaration of Dr. Richard Dalby
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`14.
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`Therefore, in view of Voswinckel, Chaudry, Ghofrani, and Patton, a
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`POSAwould not necessarily conclude that synchronization of each breath with
`
`each pulse of aerosol is required for a pulsed ultrasonic nebulizer to function as
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`intended. While Watson and Dr. Donovanread this synchronization into the
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`phrase “pulsed nebulizer,” a POSA reading these three references would not
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`understand such a “pulsed nebulizer” to require synchronization between the
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`pulsing and the patient’s breathing. Instead, a POSA would read a “pulsed
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`nebulizer” merely to mean that the nebulization occurs in pulses, and could
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`conclude the nebulizer of Voswinckeldescribes any of the situations exemplified
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`in paragraphs 10 to 12. If the phrase “pulsed ultrasonic nebulizer” simply
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`necessarily meantthat it aerosolizes a fixed amountper pulse and requires a human
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`to synchronize each breath to each pulse, then muchofthe claim language in the
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`patents would be redundant.
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`I do not believe that a POSA would read “pulsed
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`ultrasonic nebulizer” as necessarily having these additional features without an
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`explicit statement that they are included.
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`[The remainderof this pageis intentionally left blank]
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`Declaration of Dr. Richard Dalby
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`15.
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`Ihereby declare that all statements made herein of my knowledgeare
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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 knowledgethat willful false
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`statements andthe 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
`
`Richard Dalk
`
`
`
`Dr. Richard Dalby
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`4818-9518-0386
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