IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`
`
`
`
`
`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
`
`
`PATENT OWNER RESPONSE
`
`
`
`
`
`
`
`

`

`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`TABLE OF CONTENTS
`
`I. 
`II. 
`
`A. 
`B. 
`
`III. 
`IV. 
`
`INTRODUCTION ..................................................................................... 1 
`BACKGROUND ....................................................................................... 2 
`Pulmonary Hypertension ....................................................................... 2 
`The Inventors Developed a Novel Method of Treating
`PAH That Overcame Limitations of Existing Treatments .................... 4 
`Claim Construction and Person of Ordinary Skill in the Art .................... 7 
`PETITIONER HAS NOT MET ITS BURDEN TO ESTABLISH THAT
`CLAIMS 1-8 OF THE ’793 PATENT ARE ANTICIPATED OR
`OBVIOUS ................................................................................................. 8 
`A.  Ground 1: the ’212 Patent, Voswinckel JESC, and
`Voswinckel JAHA Fail to Render Claims 1-8 Obvious ..................... 10 
`1. 
`Petitioner Has Not Established That Voswinckel
`JAHA And Voswinckel JESC Were Publicly
`Accessible Prior Art Before The Priority Date ......................... 11 
`None of the identified references teaches a single
`event dose of 15 micrograms to 90 micrograms in 1
`to 3 breaths ................................................................................ 18 
`A POSA would not have a reasonable expectation
`of success
`in combining
`the
`’212 patent,
`Voswinckel JESC and JAHA or have been
`motivated to combine them ....................................................... 23 
`Ground 2: the ’212 Patent and Voswinckel JESC Fail to
`Render Claims 1-8 Obvious ................................................................ 38 
`Grounds 3-6 Fail Because Each Ground Relies On
`Publications That Petitioner Has Failed to Establish Are
`Prior Art ............................................................................................... 44 
`1. 
`Ghofrani .................................................................................... 46 
`2. 
`Voswinckel 2006 ....................................................................... 51 
`OBJECTIVE INDICIA OF NONOBVIOUSNESS ................................ 55 
`A.  Unexpected Results ............................................................................. 55 
`B. 
`Copying ............................................................................................... 57 
`C. 
`Long-Felt Unmet Need ........................................................................ 61 
`VI. 
`CONCLUSION ....................................................................................... 63 
`
`
`2. 
`
`3. 
`
`B. 
`
`C. 
`
`V. 
`
`
`
`
`
`
`
`
`
`i
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`

`

`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Federal Cases
`Acceleration Bay, LLC v. Activision Blizzard Inc.,
`908 F.3d 765 (Fed. Cir. 2018) ....................................................12, 13, 14, 15, 18
`In re Aller,
`220 F.2d 240 (CCPA 1955) ................................................................................ 55
`Allergan, Inc. v. Apotex Inc.,
`754 F.3d 952 (Fed. Cir. 2014) ................................................................ 45, 50, 54
`Blue Calypso, LLC v. Groupon, Inc.,
`815 F.3d 1331 (Fed. Cir. 2016) ........................................................ 11, 12, 18, 27
`Cellco Partnership v. Bridge and Post, Inc.,
`IPR2018-00054, paper 40, 20 (PTAB Apr. 15, 2019) .................................. 45, 50
`In re Cronyn,
`890 F.2d 1158 (Fed. Cir. 1989) .......................................................................... 27
`CSL Behring LLC v. Bioverative Therapeutics Inc.,
`IPR2018-01313, paper 10, 11 (PTAB Jan. 9, 2019) ........................................... 52
`E.I. DuPont de Nemours & Company v. Synvina C.V.,
`904 F.3d 996 (Fed. Cir. 2018) ............................................................................ 55
`In re Geisler,
`116 F.3d 1465 (Fed. Cir. 1997) .......................................................................... 55
`In re Katz,
`687 F.2d 450 (CCPA 1982) .............................................................. 45, 48, 49, 52
`In re Klopfenstein,
`380 F.3d 1345 (Fed. Cir. 2004) .......................................................................... 12
`Kyocera Wireless Corp. v. Int’l Trade Comm’n,
`545 F.3d 1340 (Fed. Cir. 2008) .......................................................................... 12
`Lacks Industries, Inc. v. McKechnie Vehicle Components USA, Inc.
`322 F.3d 1335 (Fed. Cir. 2003) .......................................................................... 44
`ii
`
`
`
`

`

`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`
`Liqwd, Inc. v. L’Oreal USA, Inc.,
`941 F.3d 1133 (Fed. Cir. 2019) .................................................................... 57, 58
`In re Lister,
`583 F.3d 1307 (Fed. Cir. 2009) .......................................................................... 15
`Ormco Corp. v. Align Technology, Inc,
`463 F.3d 1299 (Fed. Cir. 2006) .......................................................................... 55
`Proctor & Gamble Co. v. Teva Pharmaceuticals USA, Inc.,
`566 F.3d 989 (Fed. Cir. 2009) ............................................................................ 61
`Trans Ova Genetics, LC v. XY, LLC,
`IPR2018-00250, paper 35 (PTAB Jun. 26, 2019) ........................................ 45, 50
`Federal Statutes
`35 U.S.C. § 102(a) ................................................................................. 10, 44, 45, 50
`35 U.S.C. § 316I ......................................................................................................... 8
`Regulations
`37 C.F.R. § 42.108 ..................................................................................................... 8
`Other Authorities
`IPR2017-01621 and -01622 ............................................................................... 47, 48
`IPR2017-01622, Paper 9 .................................................................................... 49, 50
`MPEP § 2132.01 ...................................................................................................... 45
`PubMed, available at https://pubmed.ncbi.nlm.nih.gov/ (last visited Nov. 1,
`2021) ................................................................................................................... 16
`
`
`
`
`
`
`
`
`iii
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`

`

`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`
`EXHIBIT LIST
`
`Description
`Declaration of Dr. Aaron Waxman
`Dr. Waxman’s curriculum vitae
`Declaration of Dr. Werner Seeger
`Declaration of Dr. Hossein A. Ghofrani
`Declaration of Dr. Frank Reichenberger
`Declaration of Dr. Friedrich Grimminger
`Tyvaso Orange Book listing
`Hill, N., 2005, Therapeutic Options for the Treatment of
`Pulmonary Hypertension, Medscape Pulmonary Medicine 9(2).
`Substantive Submission filed in 12/591,200 (Mar. 9, 2015)
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-1 (public
`docket).
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-11 (public
`docket).
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-16 (public
`docket).
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), unnumbered
`docket entry dated 7/30/2020
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-20 (public
`docket)(excerpted).
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-29 (public
`docket).
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-45 (public
`docket).
`
`Exhibit
`EX2001
`EX2002
`EX2003
`EX2004
`EX2005
`EX2006
`EX2007
`EX2008
`
`EX2009
`EX2010
`
`EX2011
`
`EX2012
`
`EX2013
`
`EX2014
`
`EX2015
`
`EX2016
`
`
`
`iv
`
`

`

`Exhibit
`EX2017
`
`EX2018
`
`EX2019
`
`EX2020
`
`EX2021
`
`EX2022
`
`EX2023
`
`EX2024
`
`EX2025
`
`EX2026
`
`EX2027
`
`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`
`Description
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-21 (public
`docket).
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-41 (public
`docket).
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-49 (public
`docket).
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-68 (public
`docket).
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-71 (public
`docket).
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-40 (public
`docket).
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-47 (public
`docket).
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-75 (public
`docket).
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-80 (public
`docket).
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-81 (public
`docket).
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-92 (public
`docket).
`
`
`
`v
`
`

`

`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`
`Description
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-74 (public
`docket).
`Hess 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. Care. 47(12):1455-1458
`Hess 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),
`available
`at
`https://www.sciencedirect.com/topics/medicine-anddentistry/
`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., Cardiovascular Therapeutics, 31:38-44 (2013)
`McLaughlin et al., Efficacy and safety of treprostinil: an
`epoprostenol analog for primary pulmonary hypertension, J.
`Cardiovascular Pharmacology, 41:293-299 (2003)
`Springer website (from fn 13 of Hall-Ellis Decl)
`(Intentionally Left Blank)
`Springer website (from fn 14 of Hall-Ellis Decl)
`University of Wisconsin–Madison Library Catalog Search for
`holdings of Circulation: the journal of the American Heart
`Association
`Declaration of Ms. Pilar Wyman
`Ms. Pilar Wyman’s curriculum vitae
`Deposition Transcript of Sylvia Hall-Ellis, Ph. D.
`American Heart Association Listing of Circulation Supplements
`
`Exhibit
`EX2028
`
`EX2029
`
`EX2030
`
`EX2031
`
`EX2032
`
`EX2033
`
`EX2034
`EX2035
`EX2036
`
`EX2037
`EX2038
`EX2039
`EX2040
`
`EX2041
`EX2042
`EX2043
`EX2044
`
`
`
`vi
`
`

`

`Exhibit
`EX2045
`EX2046
`EX2047
`EX2048
`EX2049
`
`EX2050
`
`EX2051
`
`EX2052
`EX2053
`EX2054
`EX2055
`EX2056
`EX2057
`
`EX2058
`
`EX2059
`EX2060
`
`EX2061
`
`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`
`Description
`Chemical Abstracts Plus Search Results Transcript
`Ovid Search Results for “Voswinckel”
`PubMed Search Results for “Voswinckel”
`Compilation Showing Search Results for Descriptor Terms
`Oxford Academic Listing of European Heart Journal
`Supplements
`Simonneau et al., Updated Clinical Classification of Pulmonary
`Hypertension., J Am. College of Cardiol, 62(25)D34-D42 at
`D34-D35 (2013)
`Sitbon and Noordegraaf, Epoprostenol and pulmonary arterial
`hypertension: 20 years of clinical experience, Eur. Respir Rev.
`26:160055 (2017)
`Second Declaration of Dr. Aaron Waxman
`Declaration of Dr. Jason McConville
`Dr. McConville’s curriculum vitae
`Deposition of Dr. Nicholas Hill
`Deposition of Igor Gonda, Ph. D.
`Vital Signs (Body Temperature, Pulse Rate, Respiration Rate,
`Blood Pressure), Johns Hopkins Medicine, available at
`https://www.hopkinsmedicine.org/health/conditions-and-
`diseases/vital-signs-body-temperature-pulse-rate-respiration-
`rate-blood-pressure
`Pharmacokinetics of Inhaled Drugs, available at
`https://media.lanecc.edu/users/
`driscolln/RT127/Softchalk/Pharmcology_SFTCHLK_Lesson/
`Pharmacology_lesson10.html
`(Intentionally Left Blank)
`Waxman et al., Inhaled Treprostinil in Pulmonary Hypertension
`Due to Interstitial Lung Disease, N. Eng. J. Med. 384:325-334
`(2021)
`Watson Labs., Inc. v. United Therapeutics Inc., IPR2017-01622,
`Declaration of Dr. Robert Roscigno (EX2048)
`
`
`
`vii
`
`

`

`Exhibit
`EX2062
`
`EX2063
`
`EX2064
`
`EX2065
`
`EX2066
`
`EX2067
`
`EX2068
`
`EX2069
`
`EX2070
`
`EX2071
`
`EX2072
`
`EX2073
`
`EX2074
`
`EX2075
`
`EX2076
`
`EX2077
`
`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`
`Description
`Watson Labs., Inc. v. United Therapeutics Inc., IPR2017-01622,
`(EX2049)
`Watson Labs., Inc. v. United Therapeutics Inc., IPR2017-01622,
`(EX2050)
`Watson Labs., Inc. v. United Therapeutics Inc., IPR2017-01622,
`(EX2051)
`Declaration of Dr. Werner Seeger regarding Application No.
`11/748,205
`Watson Labs., Inc. v. United Therapeutics Inc., IPR2017-01621
`Declaration of Dr. Werner Seeger (EX2020)
`Watson Labs., Inc. v. United Therapeutics Inc., IPR2017-01621/-
`01622 Declaration of Dr. Hossein A. Ghofrani (EX2026)
`Watson Labs., Inc. v. United Therapeutics Inc., IPR2017-01621/-
`01622 Declaration of Dr. Frank Reichenberger (EX2027)
`Watson Labs., Inc. v. United Therapeutics Inc., IPR2017-01621/-
`01622 Declaration of Dr. Friedich Grimminger (EX2028)
`Watson Labs., Inc. v. United Therapeutics Inc., IPR2017-01621
`Declaration of Dr. Werner Seeger (EX2097)
`Watson Labs., Inc. v. United Therapeutics Inc., IPR2017-01621
`Second Declaration of Dr. Werner Seeger (EX2098)
`Watson Labs., Inc. v. United Therapeutics Inc., IPR2017-01621
`(EX2101)
`Watson Labs., Inc. v. United Therapeutics Inc., IPR2017-01621
`(EX2102)
`Watson Labs., Inc. v. United Therapeutics Inc., IPR2017-01621/-
`01622 Second Declaration of Dr. Hossein A. Ghofrani (EX2099)
`Le Brun et al., A review of the technical aspects of drug
`nebulization, Pharmacy World & Science, 22(3):75-81 (2000)
`Kendrick, et al., Selecting and Using Nebuliser Equipment,
`Thorax, 52(Suppl 2):S92-S101 (1997)
`Rau et al., Performance Comparison of Nebulizer Designs:
`Constant-Output, Breath-Enhanced, and Dosimetric,
`Respiratory Care, 49(2):174-179 (2004)
`
`
`
`viii
`
`

`

`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`
`Description
`Rau, The Inhalation of Drugs: Advantages and Problems,
`Respiratory Care, 50(3):367-382 (2005)
`Hess et al., Medication Nebulizer Performance, Laboratory and
`Animal Investigations, 110(2):498-505 (1996)
`FDA Guidance 2002
`Newman et al., Efficient Delivery to the Lungs of Flunisolide
`Aerosol from a New Portable Hand-Held Multidose Nebulizer,
`1996 85(9) J. Pharm Sciences 960 (1996)
`Dubus et al., Aerosol Deposition in Neonatal Ventilation,
`PEDIATRIC RESEARCH, 58(1):10-15 (2005)
`Treprostinil, PubChem, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/Treprostinil
`Roscigno et al., 2020 Pharmacokinetics and tolerability of
`treprostinil.
`LIQ861, a novel dry-powder
`formulation of
`Pulmonary Circulation, 10(4):1-9 (2020)
`Roscigno et al., Comparative bioavailability of inhaled
`treprostinil administered as LIQ861 and Tyvaso® in healthy
`subjects, Vascular Pharmacology 138:106840 (2021)
`Declaration of Dr. Roham T. Zamanian regarding Application
`No. 12/591,200
`Sandifer et al., Potent Effects of aerosol compared with
`intravenous Treprostinil on the pulmonary circulation, J. Appl.
`Physiol. 99:2363-2368 (2005)
`U.S. Patent Publication No. 2012/0177693 (Cipolla et al.)
`Liquidia SEC Form 10-K (2020)
`Preston et al., Safety and efficacy of transition from inhaled
`treprostinil to parenteral treprostinil in selected patients with
`pulmonary arterial hypertension. Pulm Cir. 4(3):456-461 (2014)
`Expert Report of Dr. Igor Gonda (D. Del) (excerpts)
`
`
`
`ix
`
`Exhibit
`EX2078
`
`EX2079
`
`EX2080
`EX2081
`
`EX2082
`
`EX2083
`
`EX2084
`
`EX2085
`
`EX2086
`
`EX2087
`
`EX2088
`EX2089
`EX2090
`
`EX2091
`
`
`
`
`
`

`

`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`
`I.
`
`INTRODUCTION
`Liquidia Technologies, Inc. (“Petitioner”) has failed to meet its burden of
`
`proving claims 1-8 of U.S. Patent No. 10,716,793 (“the ’793 patent”) are
`
`unpatentable because it relies on references that are not, in fact, prior art and bases
`
`its arguments on impermissible hindsight rather than teachings in the prior art.
`
`First, each of Petitioner’s six unpatentabily grounds rely upon references that
`
`Petitioner has failed to establish constitute prior art. Grounds 1, 2, and 4 expressly
`
`rely on Voswinckel JESC and/or Voswinckel JAHA, but Petitioner has not set forth
`
`sufficient evidence to show that either abstract was publicly accessible as of the
`
`priority date of the claimed inventions. Grounds 3-6 expressly rely on Ghofrani
`
`and/or Voswinckel 2006, but Petitioner has not set forth sufficient evidence to show
`
`that either of these references are antedating or “by others.” This fundamental failure
`
`of proof is fatal to Petitioner’s case-in-chief.
`
`Second, Petitioner’s unpatentability grounds based on the combination of the
`
`’212 patent, Voswinckel JESC, and/or Voswinckel JAHA cobble together bits of
`
`disclosure guided by impermissible hindsight and expert declarations that rely on
`
`unsupported assumptions and unreliable calculations. None of these references
`
`disclose administration of a single event dose from 15-90 μg to a human, let alone
`
`delivery of that dose in 1-3 breaths. The ’212 patent discloses sheep data delivered
`
`over 30 or more minutes. Voswinckel JESC and JAHA disclose concentrations, but
`
`
`
`1
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`

`

`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`not single event doses. Petitioner therefore cites an undated device manual that
`
`Petitioner has not proven was publicly available and relies on assumptions of its
`
`experts in an attempt to calculate a single event dose. The POSA, however, would
`
`not perform these calculations and the calculations are flawed. Without disclosure
`
`of the claimed single event dose, Petitioner’s grounds fail.
`
`Accordingly, Petitioner has not carried its burden to prove unpatentability and
`
`the claims are patentable over all of the cited grounds.
`
`II. BACKGROUND
`The ’793 patent relates to the treatment of pulmonary hypertension and is
`
`listed in the Orange Book for Tyvaso® (treprostinil) Inhalation Solution, a drug-
`
`device combination for delivery of treprostinil by inhalation marketed by Patent
`
`Owner, United Therapeutics Corporation (“UTC”). EX1001, 18:22-23; EX2007.
`
`A.
`Pulmonary Hypertension
`Pulmonary hypertension is a disease associated with high blood pressure in
`
`the pulmonary vasculature. See generally EX2050. At the time of the invention, as
`
`is the case even today, pulmonary hypertension is a poorly understood, often fatal,
`
`disease with limited treatment options.
`
`Epoprostenol is a prostacyclin and was the first and only FDA-approved drug
`
`for the treatment of pulmonary arterial hypertension (“PAH”) from 1995 to 2001.
`
`EX2051. The use of epoprostenol had substantial shortcomings. The half-life of
`
`
`
`2
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`

`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`epoprostenol is only a few minutes, meaning that it is cleared from the body very
`
`quickly has a short duration of action. EX2008, 7-10. Thus, epoprostenol required
`
`administration by continuous intravenous infusion to maintain adequate levels in the
`
`body. Unfortunately, the need for a permanent transcutaneous intravenous catheter
`
`posed risks of infection, occlusion, and sepsis. Moreover, even a short interruption
`
`in infusion could increase the risk of hemodynamic collapse and even death because
`
`the half-life of epoprostenol is so short. Epoprostenol also requires daily mixing and
`
`refrigeration, which meant the patient must carry a cold pack to avoid degradation
`
`at room temperature and an infusion pump to administer the drug, which adversely
`
`affect patient compliance.
`
`In 2004, a synthetic prostacyclin analog, iloprost (Ventavis®), was approved
`
`as an inhaled treatment for PAH. Id. at 10. Although inhaled iloprost had a slightly
`
`longer duration of action than epoprostenol, doctors still preferred intravenous
`
`administration of a prostacyclin analog over inhaled delivery of iloprost for a number
`
`of reasons. Id. For instance, iloprost has a half-life between 20-25 minutes and
`
`needs to be used 6-9 times a day, as frequently as every 2 hours, which is considered
`
`challenging for patients. Id. at 21, 23-24. Moreover, the fact that iloprost has a short
`
`half-life results in periods of patients being under-medicated while asleep unless
`
`they wake at regular intervals to take another dose. Id.
`
`
`
`3
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`

`

`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`Treprostinil, the compound described in the ’793 patent, was approved to treat
`
`PAH as a subcutaneous formulation (Remodulin®) by 2002 and for intravenous use
`
`in 2004. Id. Treprostinil offered benefits over both epoprostenol and iloprost such
`
`as room temperature stability and a half-life of several hours versus several minutes.
`
`Patients no longer needed to carry ice packs to ensure the stability, safety, and
`
`efficacy of the drug. Id. However, there were still significant limitations to
`
`subcutaneous and intravenous delivery of treprostinil, such as severe site pain for
`
`some patients, and systemic side effects. EX1018, 1.
`
`B.
`The Inventors Developed a Novel Method of Treating PAH That
`Overcame Limitations of Existing Treatments
`At the time of the invention, the inventors recognized a need for improving
`
`existing pulmonary hypertension treatments. The ’793 patent relates to a
`
`breakthrough method of treating pulmonary hypertension using high dose
`
`administration of inhaled treprostinil that addressed many of the substantial
`
`shortcomings of other existing treatments. The ’793 patent claims methods of
`
`treating pulmonary hypertension using a single event dose of 15-90 micrograms of
`
`treprostinil, or a salt thereof, delivered by inhalation in only 1 to 3 breaths. By using
`
`the inhalation route of administration, the claimed methods overcame limitations to
`
`subcutaneous and intravenous administration, such as site pain injection, systemic
`
`side effects, and the need for patients to lug around bulky pumps. The inventors also
`
`improved the safety and efficacy of treatment with the surprising discovery that
`
`
`
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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`treprostinil could be delivered at higher drug concentrations and shorter inhalation
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`times (3 breaths) with fewer side effects.
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`The ’793 patent issued from an application filed on January 31, 2020 and
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`claims priority to a provisional application, 60/800,016, filed on May 15, 2006.
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`Petitioner does not contest this priority date.
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`The ’793 patent has 1 independent claim and 7 dependent claims. Independent
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`claim 1 recites:
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`treating pulmonary hypertension comprising
`A method of
`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 15 micrograms to 90 micrograms
`of treprostinil or a pharmaceutically acceptable salt thereof delivered in
`1 to 3 breaths.
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`EX. 1001, claim 1. Dependent claims 2 through 5 require specific types of
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`inhalation devices, namely a soft mist inhaler (claim 2), a pulsed ultrasonic nebulizer
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`(claim 3), a dry powder inhaler (claim 4) or a pressurized metered dose inhaler (claim
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`5). Dependent claim 6 requires the formulation to be a dry powder, and dependent
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`claim 7 requires the powder to comprise particles less than 5 micrometers in
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`diameter. Dependent claim 8 requires the formulation to contain no metacresol.
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`The ’793 patent teaches that administration of treprostinil using the claimed
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`methods resulted in a significant reduction in pulmonary vascular resistance (PVR)
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`and pulmonary artery pressure (PAP) and an increase in cardiac output. EX1001,
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`5
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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`FIG. 10; 16:32-42. The specification describes the surprising result of clinical
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`studies showing that the time of inhalation could be reduced by increasing the
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`concentration of treprostinil aerosol. Id. at 16:61-63, 17:44-46. This single-breath
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`drug administration induced pulmonary vasodilation for longer than 3 hours with
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`minimal side effects. Id. at 18:1-6. Surprisingly, very high concentrations of
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`treprostinil were well tolerated (id.), even though initial clinical trials showed that
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`increasing concentration from 16 mcg/ml to 64 mcg/ml led to significant side effects
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`without increasing pulmonary vasodilation. EX1007 (at 16 mcg/ml, “near maximal
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`pulmonary vasodilation is achieved without adverse effects”).
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`The commercial embodiment of the ’793 patent, Tyvaso® (treprostinil)
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`Inhalation Solution, has shown distinct advantages over the other available
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`treatments for pulmonary hypertension. Tyvaso® has a much longer half-life than
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`Ventavis®. Thus, there is less risk of undermedication when the patient is asleep or
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`otherwise unable to take the medication. Additionally, Tyvaso® does not need to
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`be administered as frequently as Ventavis® (only 4 times a day, down from 6-9
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`times/day). Less frequent dosing leads to higher patient compliance, time savings
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`of 1.4 hours per day (EX2052, ¶43) and lower risk of rebound hypertension. Patients
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`transferring from inhaled iloprost to inhaled treprostinil also had improved six-
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`minute walk distances (a common metric to assess pulmonary hypertension),
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`improved patient satisfaction, and improved quality of life. Id. at 8-9. Notably, once
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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`Tyvaso® entered the market, it was clinically preferred to Ventavis®. As illustrated
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`below, Tyvaso® rapidly increased its market share after launch at Ventavis®’s
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`expense, indicating the clinical advantages that Tyvaso® has over Ventavis®:
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`EX2086, ¶18.
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`III. CLAIM CONSTRUCTION AND PERSON OF ORDINARY SKILL
`The parties agree that all claim limitations of the ’793 patent should be given
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`their plain and ordinary meaning in the art by a person of ordinary skill in the art
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`(POSA) as of May 15, 2006.
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`A POSA, with respect to the ’793 patent, would have an M.D. or a graduate
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`degree (Masters or Ph.D.) in a field relating to drug development and at least two
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`years practical experience in either (i) the investigation or treatment of pulmonary
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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`hypertension; or (ii) in the development of potential drug candidates, specifically in
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`the delivery of drugs by inhalation. EX2052, ¶¶13-16; EX2053, ¶¶28-31.
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`IV. PETITIONER HAS NOT MET ITS BURDEN TO ESTABLISH THAT
`CLAIMS 1-8 OF THE ’793 PATENT ARE ANTICIPATED OR
`OBVIOUS
`Petitioner has “the burden of proving a proposition of unpatentability by a
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`preponderance of the evidence.” 35 U.S.C. § 316I; see also 37 C.F.R. § 42.108.
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`Petitioner has failed to carry that burden for any of its six Grounds:
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`Ground 1 (Claims 1-8): Obvious over ’212 Patent, Voswinckel JESC, and
`Voswinckel JAHA
`Ground 2 (Claims 1-8): Obvious over ’212 Patent and Voswinckel JESC
`Ground 3 (Claim 1): Anticipated by Ghofrani
`Ground 4 (Claims 1, 3, and 8): Obvious over Voswinckel JAHA and Ghofrani
`Ground 5 (Claims 1 and 3): Anticipated by Voswinckel 2006
`Ground 6 (Claims 2 and 4-8): Obvious over Voswinckel 2006 and the ’212
`Patent
`Grounds 1 and 2 rely upon a combination of the ’212 patent and Voswinckel
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`JESC (Ground 2) and in further view of Voswinckel JAHA (Ground 1). Petitioner
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`has failed to show that Voswinckel JAHA and Voswinckel JESC were publicly
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`accessible prior art. Even setting aside this fatal flaw, none of the references
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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`expressly teach a “single event dose”1 of “15 micrograms to 90 micrograms of
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`treprostinil or a pharmaceutically acceptable salt thereof delivered in 1 to 3 breaths.”
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`In an effort to fill this gap, Petitioner relies on flawed calculations and assumptions
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`and an undated Operating Instruction Manual (EX1037) for a device referred to by
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`Petitioner as “Optineb 2005.” Pet., 23; see also, e.g., EX1004, ¶¶74, 108; EX1002,
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`¶47.2 In addition to improperly relying on the undated OptiNeb Manual, the POSA
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`would not be able to calculate a delivered dose based on the scant information in
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`Voswinckel JAHA or JESC, let alone with any reasonable accuracy. Accordingly,
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`Petitioner cannot meet its burden of establishing that the ’212 patent, Voswinckel
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`JESC and/or Voswinckel JAHA teaches or suggests the claimed dose or that a POSA
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`would have been motivated to combine the teachings of these prior art references to
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`achieve the claimed invention with a reasonable expectation of success.
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`
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`1 A POSA would understand “single event dose” to mean the dose administered in
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`one sitting, which could be one or multiple breaths. EX2053, ¶50 n.5; EX2052, ¶48
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`n.4.
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`2 Both Drs. Gonda (EX1004, ¶108) and Hill (EX1002, ¶47) rely on the specification
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`of the ’793 patent as disclosing that a “pulsed” feature of the Optineb device was
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`known, but the modifications that gave rise to this “pulsed” feature in the Optineb
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`device are not prior art. EX2003, ¶26.
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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`Further, Grounds 3 through 6 explicitly rely on Ghofrani and/or Voswinckel
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`2006. Ghofrani and Voswinckel 2006 do not qualify as prior art under § 102(a)
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`because they are not “by another” as Drs. Seeger, Ghofrani, Reichenberger, and
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`Grimminger explain, the information relied upon by Petitioner for these two
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`references was solely the work of the inventors of the ’793 patent. As discussed
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`below, these references are also antedated because the claimed invention was
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`invented prior to the publication date of Ghofrani and Voswinckel 2006 and are thus,
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`not qualifying prior art.
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`A. Ground 1: the ’212 Patent, Voswinckel JESC, and Voswinckel
`JAHA Fail to Render Claims 1-8 Obvious
`The Petition fails to establish by a preponderance of the evidence that any of
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`the challenged claims are invalid as obvious over the combination in Ground 1 for
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`several reasons. First, Petitioner has not set forth sufficient evidence to show that
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`Voswinckel JAHA and Voswinckel JESC were publicly accessible prior art.
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`Specifically, Petitioner failed to establish that either of these abstracts were received
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`by a library before the priority date. Furthermore, Petitioner failed to identify how
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`a POSA could allegedly locate these abstracts through the exercise of reasonable
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`diligence before the priority date. To the contrary, the evidence shows that the
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`Voswinckel JAHA and Voswinckel JESC abstracts are not indexed and difficult to
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`find even today.
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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`Second, none of the cited prior art references teaches or suggests a “single
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`event dose” of “15 micrograms
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`to 90 micrograms of
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`treprostinil or a
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`pharmaceutically acceptable salt thereof delivered in 1 to 3 breaths.” The ’212
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`patent specified a broad range of delivered doses, but on a per kilogram and a per
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`minute basis – not a total dose delivered. Voswinckel JESC and Voswinckel JAHA
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`only provide the initial concentration of a pre-aerosolized drug solution and the
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`length of time that the drug is inhaled. As explained in more detail below, the single
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`event dose delivered for any given patient using an inhalation device depends upon
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`numerous factors relating to the type of inhalation device u