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 Parfait Review No. 2017-01621
`
`
`DECLARATION OF DR. RICHARD DALBY
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`4838—2361—94092
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`UNITED THERAPEUTICS, EX. 2001
`WATSON LABORATORIES V. UNITED THERAPEUTICS, IPR201T-01621
`Page 1 of 26
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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 Parfait Review No. 2017-01621
`
`
`DECLARATION OF DR. RICHARD DALBY
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`4838—2361—94092
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`UNITED THERAPEUTICS, EX. 2001
`WATSON LABORATORIES V. UNITED THERAPEUTICS, IPR201T-01621
`Page 1 of 26
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`lPR2017-0162 1
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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
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`University of Maryland School of Pharmacy.
`
`1 received my Bachelor’s degree in
`
`Pharmacy with honors from the Nottingham University School of Pharmacy and
`
`my PhD. in Pharmaceutical Sciences from the University of Kentucky College of
`
`Pharmacy.
`
`1 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. 9,358,240 (“the ’240 patent”), in connection with lPR2017—01621. My
`
`compensation does not depend on the content of my opinions or the disposition of
`
`this proceeding.
`
`1 have been retained by United Therapeutics to provide technical
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`expertise and my expert opinion on the ’240 patent.
`
`3.
`
`While I am neither a patent lawyer nor an expert in patent law, 1 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.
`
`4.
`
`For reference, below is a list of the Exhibits that are cited herein:
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`Declaration of Dr. Richard Dalby
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`Exhibit No.
`Description
`
`1001
`US. Patent No- 9,358,240
`
`1002
`Declaration of Dr. Maureen Donovan
`
`Robert Voswinckel, et al. “Inhaled treprostinil sodium for the
`1003
`treatment of pulmonary hypertension” Abstract #1414, Circulation,
`
`110, 17, Supplement (Oct. 2004): 111-295
`Hossein Ardeschir Ghofrani, Robert Voswinckel, et aI., “Neue
`
`1005
`
`Therapieoptionen in der Behandlung der pulmonalarteriellen
`H pertonie,” Herz, 30,4 (June 2005): 296-302
`
`1006
`Opti—Neb—ir® Operating Instructions, Model ON—100/2 (2005)
`
`1008
`Venta—Neb—ir® A—I-C-I Operating Instructions, Model VN-100/4
`1009
`Annexes to Commission Decision O(2005)3436 0f 05 September
`2005: Annex III —Ventav1s® Labelhn; and Packa e Leaflet
`
`1010
`
`1012
`
`US. Patent No. 6,606,989
`
`WO 93/0095]
`
`
`
`
`
`1014
`Affidavit of Christo her Butler, June 15, 2017
`
`1031
`US. Patent No- 5,544,646
`1163
`Amendment and Reply filed in 12/591,200 (Feb. 2, 2016) (with
`
`accompanying Second Declaration of Dr. Roham T. Zamanian)
`Oxford Dictionary ofEnglish. 2nd ed. Revised. Oxford University
`2002
`
`Press, 2005 (excerpt)-
`Newman, Stephen P. Respiratory drug delivery: essential theory and
`ractice. Resirato Dru_ Delive OnIine, 2009 (exce t).
`Declaration of Dr. Edmund Elder and Exhibits Accompanying
`Second Declaration of Dr. Roham Zamanian Amendment and Reply
`filed in 12/591,200 (Feb. 2, 2016) (Ex. 1163)
`Finlay, Warren H. The Mechanics of Inhaled Pharmaceutical
`Aerosols: an Introduction. Academic Press, 2002 exce t .
`"Mechanical Ventilation." American Journal ofRespiratoiy and
`Critical Care Medicine 196(2):P3-4 (2017).
`Curriculum vitae of Dr. Richard Dalb
`
`2003
`
`2006
`
`2007
`
`2008
`
`2022
`
`I.
`
`BACKGROUND
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`5.
`
`Many drugs are inhaled through the mouth. Ex. 2003, 5. Inhaled
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`drug delivery for certain conditions minimizes the amount of drug to which the
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`body is exposed and results in a fast onset of drug action. Id. at 7- To realize these
`
`benefits a drug (or drugs) is usually incorporated into small paiticles or droplets to
`
`form an aerosol which is inhaled by the patient. Aerosolized drug is wasted and/or
`
`poses a secondary exposure hazard if aerosol is released into the environment
`
`(which typically occurs during exhalation).
`
`6.
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`Drug—containing aerosols can be created using several approaches,
`
`including the use of nebulizers. Id. at 11-13, 18—37. Nebulizers typically generate
`
`aerosol using the energy contained in a compressed gas (jet nebulizers) or
`
`electricity (in ultrasonic piezoelectric nebulizers) acting on a water-based
`
`(aqueous) drug solution. Id. The particle or droplet size and concentration of the
`
`aerosol generated is highly dependent on the design of the nebulizer. Id. If two
`
`solutions for inhalation are functionally identical but are aerosolized by nebulizers
`
`of different design, the quantity and quality of drug delivered to the patient is
`
`unlikely to be the same. Id. Conversely, if the same nebulizer is used to deliver
`
`two solutions for inhalation that are functionally identical, the quantity and quality
`
`of the drug delivered to the patient would be the same, assuming the patient inhales
`
`in an equivalent manner and there are no other variables. Id.
`
`7.
`
`One variable to consider during aerosol generation and administration
`
`(including by nebulization) is sedimentation. Ex. 2007, 4—7; Ex- 2003, 16—17.
`
`Aerosols consist of small particles or droplets suspended in air. Suspended
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`particles or droplets fall under the influence of gravity; therefore, the concentration
`
`of small particles or droplets suspended in air is time-dependent. Ex. 2007, 4-7.
`
`In
`
`order to achieve a constant (stable) concentration of suspended particles or droplets
`
`in air, either the rate at which particles or droplets are aerosolized (for example in a
`
`nebulizer) must equal the rate at which they fall out of suspension or the particle or
`
`droplet losses due to sedimentation must be negligible. Id. When aerosolization
`
`terminates, sedimentation 0f the particles or droplets continues, causing the
`
`concentration of the suspended particles or droplets in air to fall. Id. Therefore,
`
`the elapsed time following the end of aerosol generation can influence the amount
`
`of aerosol available for inhalation by a patient.
`
`Id.
`
`11.
`
`CLAIMS OF THE ”240 PATENT
`
`8-
`
`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 fi'om 200 to 1000 ug/ml 0f treprostinil or
`
`a pharmaceutically acceptable salt thereof
`
`with a pulsed ultrasonic nebulizer that aerosolizes a fixed
`
`amount of treprostinil or a pharmaceutically acceptable salt thereof
`
`per pulse,
`
`said pulsed ultrasonic nebulizer comprising an opto-acoustical
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`trigger which allows said human to synchronize each breath to each
`
`pulse,
`
`said therapeutically effective single event dose comprising from
`
`15 pg to 90 pg of treprostinil or a pharmaceutically acceptable salt
`
`thereof delivered in l to 18 breaths.
`
`I understand that this claim is an “independent claim” and that all subsequent
`
`claims, Le. 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.
`
`9.
`
`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 alt. 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
`
`10. My opinions herein are based on the definition of a POSA provided
`
`by Watson and Dr. Donovan’s declaration (Ex. 1002):
`
`As of the May 2006 filing date of the provisional application that the
`
`’240 patent claims as its effective filing date, a person having ordinary
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`skill in the art (“POSA”) had a PhD. degree in pharmaceutical
`
`science or a related discipline like chemistry or medicinal chemistry,
`
`as well as at least two years of practical experience in the
`
`development of potential drug candidates, specifically in the delivery
`
`of drugs by inhalation. The POSA could have had a lower level of
`
`formal education than a PhD. degree if such a person had more years
`
`of experience in the development of inhalable drugs. The POSA
`
`would regularly review literature about pharmaceutical sciences and
`
`drug delivery and would know how to carry out library research using
`
`library resources to find out more information about areas being
`
`researched.
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`In addition, the POSA would have known how to
`
`evaluate potential drugs for their in vitro and in viva activity and
`
`toxicity using tests disclosed in the relevant literature. Furthermore,
`
`because drug development involves a multidisciplinary approach, a
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`POSA may interface or consult with individuals having specialized
`
`expertise, for example, a pharrnacologist and/or physician with
`
`experience in the administration, dosing and efficacy of drugs for the
`
`treatment of a particular disease state.
`
`In this Petition, reference to a
`
`POSA refers to a person with these qualifications.
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`Pet- 8—9; Ex. 1002, 1W4.
`
`B.
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`“pulsed” and “pulse”
`
`11.
`
`Both the terms “pulse” and “pulsed” are found in claim 1. The term
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`“pulsed” is used as the adjective form of the word “pulse.”
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`12. 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.”
`
`13.
`
`In the specification of the ’240 patent, the term “pulse” is used to refer
`
`to the intermittent delivery of aerosol for a fixed duration, followed by pauses of a
`
`fixed duration. Ex. 1001, CO]. 13:59—60. Each “pulse” is meant to correspond with
`
`each breath. 1d,, claim 1. A similar interpretation of the term is found in Exhibit
`
`1163, which I understand to be documents and a declaration submitted during the
`
`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
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`generated pulses are “spaced apart in time that correspond to each breath inhaled
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`bya human.” Ex. 1163, 12—13.
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`14.
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`Based on the specification and prosecution history, it is apparent that
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`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.
`
`15.
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`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.
`
`C. “opto-acoustical trigger”
`
`16.
`
`l 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.
`
`17.
`
`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
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`“trigger” as “an event that is the cause of a particular action, process, or situation.”
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`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.
`
`18.
`
`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.l3:60—62. Therefore, in view of
`
`the plain meaning of the word and the specification, a POSA would understand the
`
`optical element (cg, light) and the acoustical element (eg, sound) are designed to
`
`“cause the particular action, process, or situation” of the synchronization of the
`
`patient’s inhalation with each pulse.
`
`19.
`
`The specification further teaches that synchronization between breath
`
`and pulse with the opto—acoustical trigger is used to provide exact dosage. Ex.
`
`1001, col. 13:60—62- In order to provide an exact dosage, the timing of inhalation
`
`must be synchronized with the pulse to avoid sedimentation. See supra Section 1.
`
`Thus, if an inhalation is not synchronized with the pulse, it would be impossible to
`
`deliver an exact dosage due to the sedimentary loss during the time elapsed
`
`between pulse and inhalation. Accordingly, a POSA would understand the term
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`“opto—acoustical trigger” to refer to an optical element (tag, light) and an
`
`acoustical element (eg, sound) that is designed to cause a human to immediately
`
`inhale each aerosol pulse from the pulsed ultrasonic nebulizer.
`
`20.
`
`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. 1 3:61-62. A combination of an optical element and an acoustical
`
`element that simply provides infbrmation, 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”
`
`2].
`
`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
`
`pulmonary hypertension patient in a “single event dose.” 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. . ..
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`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.
`
`Ex. 1001, col. 7 :54-62. The patent specification also presents results showing that
`
`an inhaled dose of 15 micrograms “induced pulmonary vasodilation for longer than
`
`3 hours compared to placebo inhalation.” Ex. 1001, col. 17:14-19. Claims 3 and 9
`
`further indicate that the patient is instructed “not to repeat the single event dose for
`
`a period of at least 3 hours.” Based on how “single event dose” is used in the
`
`patent, a POSA would understand it to mean the total time during which the
`
`pulmonary hypertension patient inhales a necessary dose of treprostinil in one
`
`sitting, which may be spaced apart from the next single event dose by several
`
`hours, and there may be more than one pulse and more than one breath
`
`corresponding to each pulse within a single event dose.
`
`111. GROUNDS 1-3 OF THE PETITION
`
`22.
`
`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
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`demonstrate the reason for and reasonable expectation of success in combining
`
`selected teachings, but, regardless of the rationale used, it must be supported by
`
`evidence.
`
`23.
`
`I understand that Watson has alleged that claims 1-9 are obvious in
`
`view of three different combinations of references or “Grounds,” listed below:
`
`Robert Voswinckel, et al. “Inhaled treprostinil
`
`sodium for the treatment of pulmonary
`
`hypertension” Abstract #1414, Circulation, 1 10, 17,
`
`Supplement (Oct. 2004): 111-295 (“‘Voswinckel,”
`
`Ex. 1003)
`
`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)
`
`Voswinckel
`
`
`
`0pti-Neb-ir® Operating Instructions, Model
`
`ON—100/2 (2005) (“the Opti—Neb Manual,”
`
`Ex. 1006)
`
`Voswinckel
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`Annexes to Commission Decision C(2005)3436 of
`
`(“the EU Community Register, ” Ex. 1009)
`
`05 September 2005: Annex III —
`
`Ventavis® Labelling and Package Leaflet
`
`I further understand that Watson has relied on Dr. Donovan’s declaration to
`
`support these grounds. In this section, I provide my opinions on specific
`
`references in relation to Watson’s arguments and the supporting testimony
`
`provided in Dr. Donovan’s declaration-
`
`24.
`
`To begin, Dr. Donovan’s declaration includes a background section
`
`that suggests inhalable pulmonary hypertension treatment is a simple matter of
`
`combining drugs and devices which have been known in the art for decades. See,
`
`e.g., Ex. 1002,1122-63. This characterization belies the complexities of designing a
`
`drug-device combination that can successfully deliver a drug in a therapeutically
`
`effective amount for a target indication. See supra Section I. Inhaled therapeutics
`
`present challenges in terms of the device used and the breathing pattern of a
`
`patient. 1d. These and other variables can result in a lack of consistent dosing and
`
`other issues, such that the design of a drug—device combination is anything but
`
`simple or predictable. 1d.
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`A. The claimed “opto-acoustical trigger” is distinct from the
`information signals or alerts provided in other references.
`
`25.
`
`The method claimed in the ’240 patent employs a pulsed ultrasonic
`
`nebulizer with an “opto—acoustical trigger” that is designed to cause a human to
`
`immediately inhale each aerosol pulse from the pulsed ultrasonic nebulizer. See
`
`supra Section ILB. This approach achieves consistent dosing and is different from
`
`the approaches taken by the references cited by Watson and Dr- Donovan. Id.
`
`Thus, not a single reference cited by Watson teaches this limitation.
`
`1.
`
`Patton
`
`26.
`
`Patton indicates that one problem with metered dose inhalers is that
`
`they require coordination between activation and inhalation to deliver a precise
`
`amount of medication, and proposes a way to deliver consistent doses without the
`
`need for coordination. Ex. 1012, 3:32-34, 6:28-7:25. To achieve this, Patton
`
`proposes maintaining a stable aerosol concentration, 6.3. assuring “that at least
`
`40% by weight of the aerosolized material entering the chamber will remain
`
`aerosolized and suspended within the chamber, thus being available for subsequent
`
`inhalation through the mouthpiece” and including structures to “block aerosol
`
`outflow.” Id. at 7:5—8, 8:28—32.
`
`In addition, Patton proposes delivering an
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`aerosolized bolus of medication into a holding chamber, where the total volume of
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`the bolus is substantially less than a patient’s inspiratory capacity. Ex. 1012, 7 :13-
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`18. As a result, the patient can inhale the entire dose and additional ambient air in
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`a single breath. Id. at 7:18-22. The additional ambient air avoids drug wastage in
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`the larger airways. Id. Thus, an inhalation event would consist of only one breath.
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`Patton teaches if a larger dose is to be delivered to a patient that the inhalation
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`event should be repeated multiple times. Id. at 7:23—25.
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`27-
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`Patton’s inhalation strategy does not employ pulsed (Le. periodic)
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`delivery within a single event dose. Rather, Patton proposes a single dose
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`delivered in a single breath. Id. If finther doses are required to achieve a larger
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`total dose, further single doses may be inhaled in subsequent single breaths. Id.
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`Thus, using more than one breath does not employ pulsing, or any degree of
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`periodicity or fixed intervals, but the uncoordinated repetition of a larger
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`procedure.
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`28.
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`Patton does not require synchronizing inhalation with aerosolization
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`to deliver a precise amount of medication- Instead, Patton’s ability to deliver a
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`consistent dose comes from the stability of the aerosol concentration in the holding
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`chamber and the patient’s ability to empty the holding chamber in a single
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`inhalation. Ex. 1012, 6:28-7:25. As a result, timing and duration of the single
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`breath are not critical in Patton. 1d.
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`29-
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`Patton recites a “light 50 and/or an audible signal 52” that “will alert
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`the user that a puff is ready to be withdrawn from chamber 42 when compressor 22
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`shuts down.” EX. 1012, 14:3—20. This light and/or audible signal is just that — a
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`signal informing the user that at some time after aerosolization is completed the
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`bolus dose may be withdrawn from the device; the signal does not necessitate
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`immediate inhalation. For at least the aforementioned reasons, there is no
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`indication or need in Patton to synchronize the user’s breath to start and end at a
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`particular time or to deliver and synchronize to periodic pulses.
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`2.
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`Breath-Actuated Nebulizers
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`30.
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`Some of the other devices mentioned in Dr. Donovan’s declaration
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`feature informational signals or alerts, but, as with the device in Patton, the lights
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`and/or sounds do not serve as an opto-acoustical trigger. U.S. Patent No.
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`6,606,989 (“Brand,” Ex. 1010), U.S. Patent No. 5,544,646 (“L10yd,” Ex. 1031),
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`and HaloLite are all examples of breath-actuated devices. See Ex. 1010, col. 1:62-
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`col. 2:2, 3:1—9; Ex. 1031, col. 24:7—11;Ex. 1002, 1138. A breath actuated device
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`does not require conscious inhalation synchronized with aerosol generation; rather,
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`the device is programmed to sense when a user inhales and to generate the aerosol
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`in response. Id. ; see also Ex. 2003, 24. This is the opposite of the pending claims
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`where the opto-acoustical trigger is designed to cause a human to immediately
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`inhale each generated aerosol pulse from the pulsed ultrasonic nebulizer. These
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`breath-actuated devices do not require an opto-acoustical trigger because drug
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`delivery is adapted to the user’s breathing pattern by the device. Id. The EU
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`Community Register also discusses breath-actuated devices, noting that the
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`“inhalation time depends on the patient’s breathing pattern” for the disclosed
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`models of HaloLite and ProDose- Ex. 1009, 2. While the breath—actuated devices
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`discussed in Dr- Donovan’s declaration sometimes feature optical and acoustical
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`elements, the sounds and/or lights they produce serve only as signals and/or alerts.
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`See, e.g., Ex. 1031, col. 18:4-16, 57-65. These signals and/or alerts provide
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`information but are not designed to cause inhalation synchronized with an aerosol
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`pulse.
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`3.
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`The Opti-Neb Manual
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`31.
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`The Opti—Neb Manual describes a series of devices including one
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`referenced as an “Opti-Neb-ir” device, which features a multifunction light that
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`changes color to show changes in status, such as whether the nebulizer is on and
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`whether aerosol production is in progress. EX. 1006, 16.
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`It also features an
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`acoustic signal that sounds when the device is turned off. 1d. Neither of these
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`signals are designed to cause a user to inhale a particular pulse of aerosol and
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`synchronize each breath to each pulse. A POSA would understand that these
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`signals only provide information on device status. Id. Further, based on the
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`diagrams and photographs in the Opti-Neb Manual, the multi-function light is not
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`within a user’s field of View when the mouthpiece is in the user’s mouth. 1d. at 1,
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`8. Therefore, a user could not see the multi-function light during an inhalation
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`event or rely on the information it conveys to synchronize his/her inhalation. Id.
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`B. Dr. Donovan’s declaration selectively interprets the references to
`arrive at the limitations of the ’240 claims.
`
`1.
`
`The Opti—Neb Manual
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`32.
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`The Opti-Neb Manual does not indicate that a user should coordinate
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`inhalation with a sound or a light, and, furthermore, it also lacks any discussion of
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`suitable doses for drug delivery. Nevertheless, Dr. Donovan uses this reference as
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`the basis for calculations to determine possible dosing using this device.
`
`33.
`
`In her calculations, Dr. Donovan picks an average breathing rate for a
`
`normal human of 12 to 15 breaths per minute based on Ganong’s Review of
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`Medical Physiology. Ex. 1002, 11174 (citing EX. 1060, 3)- However, this average
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`for a “normal human” is not necessarily indicative of the breathing rate for a
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`patient suffering from a particular disease, cg. pulmonary hypertension.
`
`I
`
`understand that a later edition of Ganong’s Review of Medical Physiology, closer
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`to the filing date of the patent, was submitted during prosecution of the ’240 patent
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`and recites a range of 10 to 30 breaths per minute in humans. Ex. 2006, 31-34- Dr.
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`Donovan’s declaration does not explain why she chose the narrower 12 to 15 range
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`over the wider 10 to 30 range.
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`34.
`
`Dr- Donovan calculates that 12 to 15 breaths per minute means that a
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`breath consisting of an inhalation and an exhalation occurs within the span of 4 to
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`5 seconds. Ex. 1002,11174. Without providing any further basis, Dr. Donovan
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`then concludes that the inhalation portion takes between 2 to 3 seconds. 10’.
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`However, inhalation may occupy significantly less than half of the duration of the
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`breath in patients with lung diseases. EX. 2003, 4. Thus, even if a human suffering
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`from pulmonaiy hypertension takes 12 to 15 breathes per minute, Dr. Donovan’s
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`estimate of a 2 to 3 second inhalation is inconsistent with the breathing pattern of
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`patients with lung diseases. Further, Dr. Donovan’s line of reasoning that the
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`dosing delivered by the device would be calculated based on the patient’s
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`breathing rate highlights the difference in configuration and how the prior devices
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`operated compared to the present patent, which uses a device that synchronizes a
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`patient’s breathing rate to inhale individual pulses of aerosol through use of an
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`opto—acoustical trigger.
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`2.
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`The EU Community Register
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`35. Next, Dr. Donovan discusses two programs described in the EU
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`Community Register: “P1, which delivers 5 ug of iloprost in 25 inhalation cycles;
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`and P2, which delivers 2.5 pg in 10 inhalation cycles.” Ex- 1002,11196; Ex. 1009,
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`3, 30. She equates the phrase “inhalation cycles” used in the EU Community
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`Register to “breaths.” Ex. 1002, 11197. The EU Community Register also provides
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`an estimated inhalation time for each dose using a different device from Opti-Neb
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`called the “Venta—Neb” device: 2.5 pg in 4 minutes and 5 pg in 8 minutes. Ex.
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`1009, 3, 30. If, as Dr- Donovan assumes, “inhalation cycle” is the same as a
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`breath, it would seem that the EU Community Register discloses an estimated total
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`of 10 breaths in 4 minutes (2.5 breaths per minute) and 25 breaths in 8 minutes
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`(3.125 breaths per minute) to deliver the respective doses. Ex. 1002,11197. This
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`would be an unrealistically low breathing rate for a healthy person, let alone one
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`suffering from pulmonary hypertension. Based on the reasoning provided by Dr.
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`Donovan, a POSA would not know how the dose is delivered in both the disclosed
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`number of breaths (10-25) and the disclosed inhalation time (4-8 min), 8. g. whether
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`the user takes non-drug-containing breaths in the 4 to 8 minutes between the 10 to
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`25 breaths in which the iloprost is delivered, and which, if any, of these breaths
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`would be coordinated with aerosol generation. Furthermore, Dr. Donovan’s
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`assertions of 10-25 breaths taken in 4-8 minutes is inconsistent with Dr. Donovan’s
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`previous assertion of a breathing rate of 12 to 15 breaths per minute (which
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`corresponds to 48-60 breaths in 4 minutes and 96-120 breaths in 8 minutes). Id. at
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`$74. Dr. Donovan provides no way to reconcile these various teachings.
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`36. Adding to this lack of clarity is the EU Community Register’s
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`disclosure concerning the fiinction of the “optical and acoustical signal” of Venta-
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`Neb. The signal “prompts a patient to inhale” and “stops after the pre—set dose has
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`been delivered.” Ex. 1009, 3, 30. The only pre-set doses taught in the EU
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`Cormnunity Register for use with Venta-Neb are 5 ug and 2.5 ug in P1 and P2,
`
`respectively. Id. Therefore, a POSA could reasonably understand that the signal
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