IPR2021-00406
`Declaration of Dr. Aaron Waxman
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`LIQUIDIA TECHNOLOGIES, Inc.,
`Petitioner,
`
`v.
`
`UNITED THERAPEUTICS CORPORATION,
`Patent Owner.
`
`IPR2021-00406
`U.S. Patent No. 10,716,793
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`DECLARATION OF DR. AARON WAXMAN
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`IPR2021-00406
`United Therapeutics EX2001
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`
`Declaration of Dr. Aaron Waxman
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`LIQUIDIA TECHNOLOGIES, Inc.,
`Petitioner,
`
`v.
`
`UNITED THERAPEUTICS CORPORATION,
`Patent Owner.
`
`IPR2021-00406
`U.S. Patent No. 10,716,793
`
`DECLARATION OF DR. AARON WAXMAN
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`IPR2021-00406
`United Therapeutics EX2001
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`
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`IPR2021-00406
`Declaration of Dr. Aaron Waxman
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`I, Aaron Waxman, Ph.D., M.D., declare as follows:
`
`1.
`
`I am a pulmonary critical physician in Boston, Massachusetts. I am
`
`Executive Director of the Center for Pulmonary and Heart Disease in the Heart and
`
`Vascular and Lung Centers, and Director of the Pulmonary Vascular Disease
`
`Program at Brigham and Women’s Hospital in Boston, Massachusetts. I am board
`
`certified in Internal Medicine, Pulmonary Disease and Critical Care Medicine. I
`
`have been practicing as a pulmonary and critical care doctor for over 20 years. I am
`
`a member of the American College of Chest Physicians, The American Thoracic
`
`Society, the Pulmonary Hypertension Association, and the Pulmonary Vascular
`
`Research Institute.
`
`2.
`
`I am an Associate Professor of Medicine at Harvard Medical School
`
`and have dual appointments in the Pulmonary Critical Care and Cardiovascular
`
`Medicine divisions at Brigham and Women’s Hospital. I have previously served as
`
`an assistant professor in Medicine at the Yale University School of Medicine and
`
`Tufts University School of Medicine. I have authored or co-authored more than 150
`
`peer-reviewed journal articles, book chapters and reviews.
`
`3.
`
`I received my Bachelor’s degree from George Washington University.
`
`I received a Ph.D. in Anatomy and Neuroscience at the Albany Medical College,
`
`and an M.D. from Yale University School of Medicine. I completed my internship
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`and residency in Internal Medicine at Yale New Haven Hospital. I also completed
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`a Fellowship in Pulmonary and Critical Care at the Yale School of Medicine. My
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`curriculum vitae is provided as Exhibit 2002.
`
`4.
`
`I am a paid consultant for United Therapeutics Corporation, the
`
`assignee of U.S. Patent No. 10,716,793 (“the ’793 patent”), in connection with
`
`IPR2021-00406. My compensation does not depend on the content of my opinions
`
`or the disposition of this proceeding. I have been retained by United Therapeutics
`
`Corporation to provide technical expertise and my expert opinion on the ’793 patent.
`
`5. While I am neither a patent lawyer nor an expert in patent law, I have
`
`been informed of the applicable legal standards for obviousness of patent claims. I
`
`understand that the Petition brought forward by Liquidia Technologies, Inc.
`
`(“Petitioner” or “Liquidia”) challenges claims 1-8 of the ’793 patent.
`
`6.
`
`For reference, below is a list of the Exhibits that are cited herein:
`
`Exhibit No.
`EX1001
`EX1002
`EX1004
`EX1006
`EX1007
`
`EX1008
`
`Description
`U.S. Patent No. 10,716,793 (“’793 Patent”)
`Declaration of Dr. Nicholas Hill (“Hill Decl.”)
`Declaration of Dr. Igor Gonda (“Gonda Decl.”)
`U.S. Patent No. 6,521,212 B1 to Cloutier, et al. (“’212 patent”)
`Voswinckel, R., et al., Abstract 218: “Inhaled treprostinil is a
`potent pulmonary vasodilator in severe pulmonary
`hypertension, Journal of the European Society of Cardiology,
`Volume 25, Abstract Supplement (August/September 2004)
`Voswinckel, R. et al., Abstract 1414: “Inhaled Treprostinil
`Sodium (TRE) For the Treatment of Pulmonary
`Hypertension,” Abstracts from the 2004 Scientific Sessions of
`the American Heart Association, Circulation, 110(17
`Suppl.):III-295 (October 26, 2004) (“Voswinckel JAHA”)
`
`2
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`
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`EX1009
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`EX1010
`
`EX1018
`EX2008
`
`EX2009
`EX2029
`
`EX2030
`
`EX2031
`
`EX2032
`
`EX2033
`
`EX2034
`EX2035
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`Voswinckel R. et al., “Clinical Observations” on “Inhaled
`Treprostinil for Treatment of Chronic Pulmonary Arterial
`Hypertension,” “Letters” Section of the Annals of Internal
`Medicine, 144(2):149-50 (January 2006) (“Voswinckel 2006”)
`Ghofrani, H.A. et al., Neue Therapieoptionen in der
`Behandlung der pulmonalarteriellen Hypertonie, 30(4) HERZ,
`30(4):296–302 (June 2005) (“Ghofrani”) (Foreign article and
`English translation attached)
`Remoludin® 2004 Label
`Hill, N., “Therapeutic Options for the Treatment of Pulmonary
`Hypertension,” Medscape Pulmonary Medicine 9(2) (2005)
`Substantive Submission filed in 12/591,200 (Mar. 9, 2015)
`Hess D., et al., 2007, “A guide to aerosol delivery devices for
`respiratory therapists.” American Association for Respiratory
`Care
`Dennis JH, 2002. “Standardization issues: in vitro assessment
`of nebulizer performance.” Respir Car, 47(12):1455-1458
`Hess D., et al., 1996, “Medication nebulizer performance.
`Effects of diluent volume, nebulizer flow, and nebulizer
`brand.” Chest, 110(2):498-505
`Rubin BK et al., 2008 Treatment Delivery Systems (in
`Clinical Asthma)
`https://www.sciencedirect.com/topics/medicine-and-
`dentistry/nebulizer
`Gardenhire, D.S., et al., 2017, A Guide to Aerosol Delivery
`Devices for Respiratory Therapists (4th Ed.) American
`Association for Respiratory Care.
`Tyvaso® Label 2021
`Bourge et al., “Rapid Transition from Inhaled Iloprost to
`Inhaled Treprostinil in Patients with Pulmonary Arterial
`Hypertension”, Cardiovascular Therapeutics, 31:38-44 (2013)
`
`I.
`
`BACKGROUND
`7.
`I have reviewed the ’793 patent, and understand it to relate to the
`
`treatment of pulmonary hypertension. At the priority date of the ’793 patent, as
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`today, pulmonary hypertension was a poorly understood, often fatal, disease with
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`limited
`
`treatment options.
`
` The first approved
`
`treatment for pulmonary
`
`hypertension—and the sole approved treatment for over five years—was
`
`epoprostenol, which has significant burdens and challenges to patients.
`
`8.
`
`Epoprostenol can only be administered intravenously. Ex. 2008.
`
`Further, the half-life of this drug is just a few minutes, which means that even a short
`
`interruption in infusion could increase the risk of hemodynamic collapse and even
`
`death because of delivery complications. Id. Moreover, epoprostenol requires daily
`
`mixing and refrigeration, thus requiring the patient to carry a cold pack to avoid
`
`degradation at room temperature and an infusion pump in order to safely administer
`
`the drug. Id.
`
`9.
`
`Later-approved intravenous and subcutaneous administration of
`
`treprostinil had some benefits over epoprostenol—for example, it is stable at room
`
`temperature and has a half-life of several hours rather than several minutes. This
`
`freed patients of having to carry ice packs to ensure the safety and efficacy of the
`
`drug. Id. There were still limitations to intravenous and subcutaneous delivery of
`
`treprostinil, such as intolerable site pain in some instances. EX1018, 1.
`
`10. By the priority date of the ’793 patent, clinicians had begun to explore
`
`inhalation therapies for the treatment of pulmonary hypertension. See, e.g., EX1007.
`
`At that time, the only FDA-approved prostacyclin-type drug that could be given in
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`an inhalable form was iloprost, marketed as Ventavis®. At that time, the results of
`
`an Aerosolized Iloprost Randomized (AIR) Study documenting the effects of inhaled
`
`iloprost had been public about three and a half years, and Ventavis® had been on
`
`the market for about one and a half years. EX2009, 21. Clinicians were largely still
`
`of the opinion, however, that intravenous administration of a prostacyclin analog
`
`was preferable to inhaled delivery. Id.
`
`11.
`
`Further, adoption of Ventavis® posed a number of issues. For instance,
`
`Ventavis® has a half-life between 20-25 min. Id. at 21, 23-24. As a result,
`
`Ventavis® needs to be used 6-9 times a day, as frequently as every 2 hours, which
`
`was considered challenging for patients to implement. Id. Moreover, the fact that
`
`Ventavis® has a short half-life results in periods where patients may be off-
`
`medication while asleep unless they wake up to take a dose of the drug. Id.
`
`12.
`
`There were several known methods for delivering a drug using
`
`inhalation. One class of inhalation devices are known as “continuous nebulizers”.
`
`Continuous nebulizers deliver small amounts of drug by converting drug solutions
`
`or suspensions into aerosols, which the patient inhales over a specified period of
`
`time (frequently between 5 and 30 minutes). EX2032 (“only 10% of the total dose
`
`loaded in a [continuous] nebulizer is in reality deposited in the lungs”). The patient
`
`wears a mask and breathes in unmeasured portions of the entire nebulized output
`
`delivered through the mask:
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`EX. 2033
`13. Continuous nebulizers are designed to be used with a broad range of
`
`liquid formulations, but have several drawbacks. They require delivery over a longer
`
`period of time, and the dosage is difficult to control. Various types of continuous
`
`nebulizers were available at the priority date of the ’793 patent, and several studies
`
`have indicated that performance varies between manufacturers and also between
`
`nebulizers from the same manufacturer. EX2029-EX2030. Various factors that
`
`would affect the dose of drug received by a patient through a continuous nebulizer
`
`include: gas flow and pressure, fill and dead volumes, gas density, and humidity and
`
`temperature conditions, breathing pattern and device interface.
`
`14. Other types of inhalation devices are are capable of delivering a precise
`
`amount of a medication in a specific number of breaths over a single inhalation
`
`event. They can provide a fixed dose of medication per breath. For example, in a
`
`pulsed ultrasonic nebulizer—as described in the ’793 patent and employed with
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`Tyvaso®—the patient completely inhales the nebulized output in one “pulse” of the
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`device by enclosing the device’s mouthpiece within their mouth and inhaling at the
`
`time indicated after the fixed amount of aerosol per breath is generated:
`
`EX2034.
`
`15.
`
`Examples of these types of inhalers include: pressurized metered-dose
`
`inhalers, soft-mist
`
`inhalers, pulsed ultrasonic nebulizers, breath-actualized
`
`nebulizers, and dry powder inhalers. While some early studies with treprostinil
`
`employed continuous nebulization methods, the studies first described in the ’793
`
`patent, surprisingly demonstrated that a modified-pulsed ultrasonic nebulizer could
`
`be used to safely increase the concentration of tresprostinil, such that a
`
`therapeutically effective dose of 15 micrograms to 90 micrograms could be delivered
`
`to a patient in just a few breaths. Id. at 16:61-63; see also id. at 17:44-46 (“Study
`
`iii) successfully demonstrated that the inhalation time could be reduced to literally
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`one single breath of 2000 μg/ml treprostinil solution, thereby applying a dose of 15
`
`μg.”) This drug administration with a single breath induced pulmonary vasodilation
`
`for longer than 3 hours with minimal side effects. Id. at 18:1-6. Surprisingly, high
`
`concentrations of treprostinil were well tolerated. Id.
`
`16.
`
`The commercial embodiment of the ’793 patent, Tyvaso® (inhaled
`
`treprostinil) has shown distinct advantages over the other available treatments for
`
`pulmonary hypertension. For example, Tyvaso® (inhaled treprostinil) does not need
`
`to be administered as frequently as Ventavis®, leading to higher patient compliance
`
`and less risk of rebound pulmonary hypertension. Tyvaso® (inhaled treprostinil) has
`
`a much longer half-life than Ventavis® when inhaled by human subjects suffering
`
`from pulmonary hypertension. This allows Tyvaso® to be administered markedly
`
`less frequently — about 4 times a day. Patients are more likely to comply with a
`
`regimen that requires less frequent administrations. Furthermore, because Tyvaso®
`
`has a longer half-life than Ventavis®, there is less risk when the patient is asleep or
`
`otherwise unable to take the medication.
`
`17. Another study reported that “the transition from inhaled iloprost to
`
`inhaled treprostinil resulted in a time saving of approximately 1.4 h per day.”
`
`EX2035, 5. Patients transferring from inhaled iloprost to inhaled treprostinil also
`
`had improved six-minute walk distances (a common metric to assess pulmonary
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`8
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`
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`hypertension), improved patient satisfaction, and improved quality of life. Id. at 5-
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`6.
`
`II.
`
`CLAIMS OF THE ’793 PATENT
`18.
`I have reviewed the claims and specification of the ’793 patent. The
`
`’793 patent relates to a break-through therapy permitting treatment of pulmonary
`
`hypertension using inhaled treprostinil—a treatment addressing a variety of
`
`limitations burdening Ventavis® treatment. Specifically, the ’793 patent relates to a
`
`method of treating pulmonary hypertension by administering by inhalation a
`
`therapeutically effective single event dose that comprises from 15 micrograms to 90
`
`micrograms of treprostinil or a pharmaceutically acceptable salt thereof delivered in
`
`1 to 3 breaths.
`
`19.
`
`Provided below for reference is the language of claim 1 of the ’793
`
`patent:
`
`1. 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 treprostinil or a pharmaceutically acceptable
`salt thereof with an inhalation device, wherein the therapeutically
`effective single event dose comprises from 15 micrograms to 90
`micrograms of treprostinil or a pharmaceutically acceptable salt thereof
`delivered in 1 to 3 breaths.
`20. Dependent claims 2 through 5 require specific types of inhalation
`
`devices, namely a soft mist inhaler (claim 2), a pulsed ultrasonic nebulizer (claim 3),
`
`a dry powder inhaler (claim 4) or a pressurized metered dose inhaler (claim 5).
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`Dependent claim 6 requires the formulation to be a dry powder, and dependent claim
`
`7 requires the powder to comprise particles less than 5 micrometers in diameter.
`
`Dependent claim 8 requires the formulation to contain no metacresol.
`
`III. THE PRIOR ART IDENTIFIED BY LIQUIDIA FAILS TO TEACH A
`“THERAPEUTICALLY SINGLE EVENT DOSE OF 15
`MICROGRAMS TO 90 MICROGRAMS”
`21.
`I have been informed that in order for a patent claim to be considered
`
`anticipated or obvious, each and every limitation of the claim must be present within
`
`the prior art or within the prior art 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 have also been informed that Liquidia has asserted
`
`six grounds of invalidity, relying upon various combinations of the following
`
`references:
`
`• United States Patent no. 6,521,212 (the “’212 patent”) (EX1006)
`
`• Voswinckel, R., et al., Abstract 218: “Inhaled treprostinil is a potent
`pulmonary vasodilator in severe pulmonary hypertension,” European
`Heart Journal 25:22 (2004) (“Voswinckel JESC”)(EX1007)
`
`• Voswinckel, R., et al., Abstract 1414: “Inhaled Treprostinil Sodium (TRE)
`for the Treatment of Pulmonayr Hypertension,” Abstracts from the 2004
`Scientific Sessions of the American Heart Association, Circulation,
`(“Voswinckel
`110(17
`Suppl.):III-295
`(October
`26,
`2004)
`JAHA”)(EX1008)
`
`• Voswinckel, R., et al., “Clinical Observations” on “Inhaled Treprostinil for
`Treatment of Chronic Pulmonary Arterial Hypertension,” “Letters”
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`Section of the Annals of Internal Medicine, 144(2)149-50 (January
`2006)(“Voswinckel 2006”) (EX1009)
`
`• Ghofrani, H.A., et al., Neue Therapieoptionen in der Behandlung der
`pulmonarlarteriellen
`Hypertonie,
`30(4):296-302
`(Junen
`2005)(“Ghofrani”)(translated)(EX1010)
`I understand that Voswinckel 2006 and Ghofrani are not properly
`
`22.
`
`considered prior art, and thus, the analysis in my declaration focuses on the ’212
`
`patent, Voswinckel JESC and Voswinckel JAHA. As a person of ordinary skill in
`
`the art, I do not read these references to teach or suggest each and every limitation
`
`of the claimed inventions of the ’793 patent. Among other reasons, for example,
`
`none of the references listed above, alone or in combination, teach a “therapeutically
`
`effective single event dose of 15 micrograms to 90 micrograms”.
`
`23. Rather than disclosing the single event dose, these three references only
`
`provide the initial concentration of the pre-aerosolized drug and the length of time
`
`that the drug is inhaled. As explained in more detail below, the actual dose achieved
`
`for any given patient using an inhalation device depends upon the type of inhalation
`
`device used, gas flow and pressure, fill and dead volumes, gas density, and humidity
`
`and temperature conditions, breathing pattern and device interface. EX2029-
`
`EX2031. But for the ’212 patent, Voswinckel JESC, Voswinckel JAHA, many of
`
`these critical details are missing:
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`Reference
`’212 Patent
`(EX1006)
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`Disclosure
`Device: “AM-601 Medicator Aerosol Delivery SystemTM” (Healthline
`Medical) (5:30-36)
`Pre-aerosolized conc.: 31.25 mcg/mL (9:3-8)
`Nebulization Rate: 0.28 mL/min(9:7-8; 10: 43-44; 11: 9-10)
`Duration: 30, 60 or 90 min (9:14; 10:43-44; 11:11-13)
`Single Event Dose: Unknown
`
`Voswinckel
`JESC
`(EX1007)
`
`Device: “OptiNeb ultrasound nebulizer, Nebu-tec, German”
`Pre-aerosolized conc.: 6, 32, 48, and 64 mcg/mL
`Duration: 6 min
`Single Event Dose: Unknown
`
`Voswinckel
`JAHA
`(EX1008)
`
`Device: “pulsed OptiNeb® ultrasound nebulizer”
`Pre-aerosolized conc.: 600 mcg/mL
`Duration: Three breaths
`Single Event Dose: Unknown
`
`24.
`
`For the reasons discussed below, a person of ordinary skill would not
`
`read any of these references, alone or in combination, to teach or suggest “a
`
`therapeutically effective single event dose of 15 μg to 90 μg” “delivered in 1 to 3
`
`breaths.”
`
`A.
`25.
`
`The ’212 Patent
`The’212 patent relates to continuous nebulization over a period of time,
`
`not nebulization in which the therapeutically effective single event dose is “delivered
`
`in 1 to 3 breaths.” (’793 Patent, claim 1). The examples of the ’212 patent teach a
`
`nebulization time period of at least 30 minutes, during which a patient would take
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`approximately 360 to 480 breaths, many orders of magnitude beyond the upper limit
`
`of “3 breaths” in claim 1.
`
`26.
`
`The arguments made in Liquidia’s Petition overlook the fundamental
`
`difference in operating principles of various inhalation devices (constant
`
`nebulization output versus metered-dose inhalers). Liquidia incorrectly suggests
`
`that the ’212 patent describes an “inhalation device” that would be capable of
`
`delivering the claimed dosage to a patient. In fact, the ‘212 patent describes an “AM-
`
`601 MEDICATOR AEROSOL DELIVERY SYSTEM” (a nebulizer manufactured
`
`by Healthline Medical in Baldwin Park, Calif.) (Ex. 1006, 5:34-36) as the preferred
`
`device, which is the only specific device mentioned anywhere in the patent.
`
`27. As can be seen in the supporting literature for this nebulizer, this is a
`
`continuous nebulizer with a face mask designed to deliver small amounts of
`
`medication in a dosing event spread over hundreds of breaths over long dosing
`
`intervals. It would be impossible to use such a device to deliver a measured amount
`
`of drug in the range of 15 micrograms to 90 micrograms of treprostinil or a
`
`pharmaceutically acceptable salt thereof delivered in only 1 to 3 breaths.
`
`28.
`
`Similarly, the working examples of the ’212 patent use continuous
`
`nebulization as the delivery method and describe nebulizing a treprostinil solution
`
`over a 90 minute interval, or for a 30 minute or 60 minute interval (EX1006, 10:44
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`and 11:11-13). Each of these dosing events would contain hundreds of breaths,
`
`which are far removed from the claimed limit of 3 breaths.
`
`29.
`
`The entire premise of the ’212 patent is to provide continuous
`
`nebulization, which seeks to establish pharmacokinetic equivalence with the daily
`
`infusion dose of a continuous intravenous infusion of treprostinil:
`
`the dosage for inhalation, taking into account that some of the
`active ingredient is breathed out and not taken into the
`bloodstream, should be sufficient to deliver an amount that is
`equivalent to a daily infusion dose in the range of 25 μg to 250
`mg; typically from 0.5 tg[sic] to 2.5 mg, preferably from 7 μg to
`285 μg, per day per kilogram bodyweight. For example, an
`intravenous dose in the range 0.5 μg to 1.5 mg per kilogram
`bodyweight per day may conveniently be administered as an
`infusion of from 0.5 [μg] to 1.0 μg per kilogram bodyweight per
`minute. A preferred dosage is 10 ng/kg/min.
`EX1006, 5:56-67.
`30.
`Likewise, the ’212 patent states that “aerosolized UT-15 has a greater
`
`potency as compared to intravascularly administered UT-15, since the actual amount
`
`of UT-15 delivered via aerosolization delivery is only a fraction (10-50%) of the
`
`dosage delivered intravascularly.” Id. at 8:9-13.
`
`31.
`
`Liquidia attempts but fails to address this fundamental recognition of
`
`these limitations on inhalation set out in the ’212 patent by resorting to hindsight.
`
`First, Liquidia looks to the specific dosages for Remodulin®, the FDA-approved
`
`intravascular treprostinil sodium solution. From the Remodulin® prescribing
`
`information, Liquidia then calculates the intravascular dosage as 108 to 117
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`micrograms, to which it applies “the ’212 Patent’s 10-50% adjustment between
`
`intravascular and inhaled dosing” to reach an inhaled dosage of 10.8 to 58.5
`
`micrograms. Pet., 39.
`
`32. However, such a calculation is overly simplistic, and ultimately
`
`meaningless because the pharmacokinetic effect of a given dose of a pulmonary drug
`
`administered by continuous nebulization over a 30-minute time interval (or 60 or 90
`
`minute interval) is completely different from the effect of the same pulmonary drug
`
`administered with a metered dose inhaler. In the case of claim 1 of the ’793 patent,
`
`15 to 90 micrograms of treprostinil are delivered in 1 to 3 breaths, which leads to
`
`more drug potentially entering systemic circulation than is the case when tiny
`
`amounts per breath are delivered to the lungs over 30 minutes.
`
`33.
`
`In fact, the ’212 patent describes matching the pharmacodynamics of
`
`continuous intravenous infusion of treprostinil by employing a continuous
`
`nebulization process with a low concentration solution. Such an approach would be
`
`expected to reduce peaks and troughs in the level of medication to avoid side effects.
`
`Remodulin® intravenous infusion is dosed continuously, and 108 to 117 micrograms
`
`would be the dosage over a continuous 24 hours. EX1018. The ’212 patent teaches,
`
`therefore, that 10.8 to 58.5 micrograms would be the expected daily inhaled dose,
`
`and not a single event dosage. Furthermore, the continuous nature of the drug
`
`delivery in the prior art confirms that one single event dose is insufficient to control
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`PAH for an entire day. For example, Voswinckel JAHA confirms that 4 individual
`
`dosing events were required throughout the day to treat pulmonary hypertension.
`
`EX1008. Even at the high end, the simple math demonstrates that a 58.5 microgram
`
`daily dose would amount to less than 15 micrograms of treprostinil sodium per single
`
`event dose when spread over four individual dosing events.
`
`34.
`
`For these reasons, the ’212 patent does not direct anyone to a single
`
`event dose that would fall within the 15 microgram to 90 microgram requirement
`
`delivered in 1 to 3 breaths of claim 1, and dissuades one from the idea of discrete,
`
`metered dose inhalation altogether.
`
`B.
`35.
`
`Voswinckel JESC
`Like the ’212 patent, Voswinckel JESC also teaches continuous
`
`nebulization, albeit at a shorter time interval, over 6 minutes, at very low
`
`concentrations (16, 32, 48, and 64 μg/mL). EX1007. Voswinckel JESC specifies
`
`the concentration of the drug in the pre-aerosolized solution, but does not specify the
`
`dose. Liquidia (through its experts—Drs. Hill and Ghonda) has attempted to impute
`
`a dosage to the teaching of Voswinckel JESC by applying multiplying a
`
`“nebulization rate” (in mL/min) by the stated concentrations (in μg/mL) by the
`
`deliver time (6 minutes). See, e.g., EX1002, ¶65. This analysis is flawed for the
`
`following reasons:
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`36.
`
`First, the actual dose delivered by a continuous nebulizer depends on
`
`more than just the nebulization rate, concentration and time. It also depends on gas
`
`flow and pressure, fill and dead volumes, gas density, and humidity and temperature
`
`conditions, breathing pattern and device interface. EX2029-EX2031. None of these
`
`parameters were disclosed in Voswinckel JESC. Thus, a person of ordinary skill in
`
`the art would be unable to determine from the disclosure in Voswinckel JESC what
`
`the single event dose administered in the described study was.
`
`37.
`
`Second,
`
`the relevant parameters for determining dosage vary
`
`significantly not only between manufacturers, but also between nebulizers from the
`
`same manufacturer. Id. Voswinckel JESC simply states that an “OptiNeb,
`
`ultrasound nebulizer (Nebu-tec, Germany)” was used, but does not provide a
`
`catalogue number, or any identifying information that would allow a person of
`
`ordinary skill in the art to determine precisely which OptiNeb ultrasound nebulizer
`
`was used.
`
`38.
`
`Third, even if a person of ordinary skill could determine the dosage
`
`based on the simplified formula used by Dr. Hill in his declaration, Dr. Gonda’s
`
`assertion that “[a] POSA would have known that nebulizers conventionally deliver
`
`between 1 and 5 mL dose” (para 56 and n. 4) and Dr. Hill’s assertion that he had in
`
`his own practice “prescribed volumes of at[sic] least 1 mL for inhalation therapy
`
`using nebulizers” (paragraph 65) is flatly irrelevant, because neither declarants’
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`statement takes into account the particular drug to be administered or the
`
`concentration of that drug solution. The fact that Ventavis®--a drug with a different
`
`potency and a different half-life—is prescribed at a total volume of 2.5-5 mLs is
`
`completely irrelevant to understanding amount of treprostinil delivered in the dosing
`
`regimen of Voswinckel 2006.
`
`39.
`
`Finally, the pharmacokinetic effects of inhaling a low concentration of
`
`a medication over a long period of time (several minutes) is different than the
`
`pharmacokinetic effects of receiving that same dose over a shorter period of time
`
`(such as 1-3 breaths). For example, during a 6-minute dosing event, the expected
`
`number of breaths would be in the range of 72 to 96 (a patient breathes
`
`approximately 12-16 times per minute, which equates to 72 to 96 breaths during a
`
`continuous nebulization session of 6 minutes). This is orders of magnitude beyond
`
`the upper limit of 3 breaths in claim 1 and results in completely different
`
`pharmacokinetic effects (e.g., the amount of spillover treprostinil that enters
`
`systemic circulation is far lower with continuous nebulization).
`
`Voswinckel JAHA
`C.
`40. Voswinckel JAHA also does not teach a therapeutically effective single
`
`event dose of 15 micrograms to 90 micrograms. Voswinckle JAHA is an abstract
`
`published in “Circulation-the Journal of the American Heart Association, which
`
`discloses “TRE inhalation by use of the pulsed OptiNeb® ultrasound nebulizer (3
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`single breaths, TRE solution 600 μg/ml.” While this reference does disclose a pre-
`
`aerosolized concentration for the treprostinil solution that is far higher than the
`
`continuous nebulizer concentration of Voswinckel JESC for inhalation over a
`
`specific number of breaths, it does not provide sufficient detail for a person of
`
`ordinary skill in the art to determine the precise dosage each patient received. A
`
`person of skill in the art would not be able to determine the “single event dose”
`
`delivered without knowing critical details of the pulsed Optineb device, including
`
`time between pulse generation and breath, volume of nebulized solution per breath,
`
`and features that allow the patient to inhale one pulse with each breath after it is
`
`generated, none of which are disclosed in this reference.
`
`41. As I understand it, the Petition relies on two additional references to
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`argue “a POSA would have expected to succeed in reducing the number of breaths
`
`when delivering 15-90 μg of inhaled treprostinil.” The first reference is Ghofrani
`
`(EX1010). I have been told that Ghofrani is not properly considered prior art, and
`
`have thus focused my analysis on the second reference. The second reference is a
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`publication by Geller et al. (EX1034), which disclose delivery by inhalation of
`
`rhDNase (also known as Pulmozyme®) for the treatment of cystic fibrosis. EX1034.
`
`rhDNase is a much larger molecule (a 260-amino acid glycoprotein) designed to
`
`treat a different disorder (cystic fibrosis). Id. The feasibility of delivering an
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`aerosolized large-molecule protein at a concentration of “0.45 mg loaded dose per
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`inhalation”1 is irrelevant to the feasibility of the claimed inhalation therapy for
`
`treprostinil.
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`IV. CONCLUSION
`42.
`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: May 17, 2021
`
`1 Petitioners erroneously assert that EX1034 teaches “delivery of 0.45 mg of drug
`in 3 breaths.” The references teaches that “[t]he daily dose of AERx rhDNase in
`this study consisted of three inhalations (1.35 mg total loaded dose, or 0.45 mg
`loaded dose per inhalation). This is the equivalent of 1,350 micrograms in a single
`event dose. Thus, even if the dosages of this biologic were considered relevant in
`considering the proper dosage of treprostinil, it is well outside the range of “15
`micrograms to 90 micrograms”.
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