`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`
`WATSON LABORATORIES, INC.
`Petitioner
`
`v.
`
`UNITED THERAPEUTICS CORP.
`Patent Owner
`
`
`
`Patent No. 9,358,240
`Issue Date: June 7, 2016
`Title: TREPROSTINIL ADMINISTRATION BY INHALATION
`_______________
`
`Inter Partes Review No. 2017-01621
`____________________________________________________________
`
`PATENT OWNER RESPONSE
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`IPR2017-01621
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`Patent Owner Response
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`TABLE OF CONTENTS
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`
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 1
`
`SUMMARY OF ARGUMENT ....................................................................... 1
`
`III. BACKGROUND ............................................................................................. 2
`
`IV. CLAIM CONSTRUCTION ............................................................................ 5
`
`A.
`
`B.
`
`Person of Ordinary Skill in the Art (“POSA”) ...................................... 6
`
`Claim Terms .......................................................................................... 8
`
`1.
`
`2.
`
`3.
`
`“pulsed” and “pulse” ................................................................... 8
`
`“opto-acoustical trigger which allows said human to
`synchronize each breath to each pulse” .................................... 11
`
`“single event dose”.................................................................... 14
`
`V.
`
`PETITIONER HAS NOT MET ITS BURDEN TO ESTABLISH
`THAT VOSWINCKEL AND GHOFRANI ARE PRIOR ART ................... 15
`
`A.
`
`B.
`
`C.
`
`Petitioner has not demonstrated that Voswinckel was publicly
`accessible. ............................................................................................ 16
`
`Ghofrani is not prior art “by another.” ................................................ 21
`
`The Inventors Reduced To Practice At Least As Much Of The
`Claimed Invention As Is Taught By Ghofrani Before The Date
`of Public Accessibility ........................................................................ 27
`
`VI. PETITIONER HAS NOT ESTABLISHED OBVIOUSNESS OVER
`VOSWINCKEL, PATTON, AND GHOFRANI BY A
`PREPONDERANCE OF THE EVIDENCE. ................................................ 29
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`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`Voswinckel does not provide a POSA with a reasonable
`expectation of success for a method of treating
`pulmonary hypertension. ........................................................... 31
`
`Voswinckel does not teach a pulsed ultrasonic nebulizer
`“that aerosolizes a fixed amount of treprostinil or a
`pharmaceutically acceptable salt thereof per pulse”
`([B1]) or that comprises “an opto-acoustical trigger
`which allows said human to synchronize each breath to
`each pulse” ([C]). ...................................................................... 33
`
`Patton does not teach a pulsed ultrasonic nebulizer “that
`aerosolizes a fixed amount of treprostinil or a
`pharmaceutically acceptable salt thereof per pulse”
`([B1]) and that comprises “an opto-acoustical trigger
`which allows said human to synchronize each breath to
`each pulse” ([C]). ...................................................................... 36
`
`A POSA would not be motivated to combine
`Voswinckel, Patton, and Ghofrani to produce a pulsed
`ultrasonic nebulizer “that aerosolizes a fixed amount of
`treprostinil or a pharmaceutically acceptable salt thereof
`per pulse” ([B1]) or that comprises “an opto-acoustical
`trigger which allows said human to synchronize each
`breath to each pulse” ([C]). ....................................................... 38
`
`Ghofrani does not teach a “therapeutically effective
`single event dose” ([D]). ........................................................... 41
`
`A POSA would not be motivated to combine Ghofrani
`and Voswinckel to deliver a “therapeutically effective
`single event dose” ([D]). ........................................................... 42
`
`Claims 2, 5, and 6 are non-obvious for at least the same
`reasons as claim 1. .................................................................... 43
`
`Claims 3 and 9 are non-obvious and separately patentable
`over the combination of Voswinckel, Patton, and
`Ghofrani. ................................................................................... 43
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`9.
`
`Claim 4 is non-obvious and separately patentable over
`the combination of Voswinckel, Patton, and Ghofrani. ............ 44
`
`10. Claims 7-9 are non-obvious and separately patentable
`over the combination of Voswinckel, Patton, and
`Ghofrani. ................................................................................... 45
`
`B.
`
`Dr. Donovan’s testimony lacks credibility and relies on
`references outside the scope of the “prior art.” ................................... 46
`
`1.
`
`2.
`
`3.
`
`4.
`
`Dr. Donovan’s conclusion that a pulsed nebulizer
`requires breath synchronization is unsupported and
`contradicts her deposition testimony. ....................................... 48
`
`Dr. Donovan’s conclusion that including an opto-
`acoustical trigger with the pulsed nebulizer disclosed in
`Voswinckel would have been obvious based on a
`POSA’s appreciation and “necessity” is unsupported. ............. 50
`
`Dr. Donovan relies on the Optineb Manual (Ex. 1006),
`which is not cited under Ground 1 nor evidence of the
`“state of the art” since it is not publicly accessible. ................. 51
`
`Dr. Donovan incorrectly identified how many patients
`were treated four times a day in Voswinckel ............................ 54
`
`C.
`
`The objective indicia of non-obviousness weigh in favor of
`patentability. ........................................................................................ 55
`
`1.
`
`2.
`
`Unexpected Results ................................................................... 55
`
`Commercial Success ................................................................. 56
`
`D.
`
`Conclusion ........................................................................................... 62
`
`VII. THE PETITION SHOULD HAVE BEEN DENIED BECAUSE IT
`WAS NOT TIMELY FILED ......................................................................... 62
`
`VIII. THE INSTITUTION DECISION IS TAINTED BY THE BOARD’S
`CONSIDERATION OF PETITIONER’S REPLY TO THE
`PRELIMINARY RESPONSE ....................................................................... 63
`
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`IX. THE SUPREME COURT’S SAS DECISION DOES NOT APPLY ............ 63
`
`X.
`
`CONCLUSION .............................................................................................. 64
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`TABLE OF AUTHORITIES
`
`CASES
`
`Actavis, Inc. v. Research Corp. Techs., Inc., IPR2014-01126 (PTAB Jan. 9, 2015)
` ............................................................................................................................. 54
`
`Arendi S.A.R.L. v. Apple Inc., 832 F.3d 1355 (Fed. Cir. 2016) ............................... 48
`
`Blue Calypso, LLC v. Groupon, Inc., 815 F.3d 1331 (Fed. Cir. 2016) ............ 16, 53
`
`Canon Computer Systems, Inc. v. Nu-Kote International, Inc., 134 F.3d 1085 (Fed.
`Cir. 1998) ............................................................................................................ 22
`
`Dynamic Drinkware, LLC v. Nat’l Graphics, Inc., 800 F.3d 1375 (Fed. Cir. 2015)
` ............................................................................................................................. 15
`
`Emerachem Holdings, LLC v. Volkswagen Grp. of Am., 859 F.3d 1341 (Fed. Cir.
`2017) ................................................................................................................... 21
`
`Helifix, Ltd. v. Blok-Lok, Ltd., 208 F.3d 1339 (Fed. Cir. 2000) ................................ 7
`
`In re Antonie, 559 F.2d 618 (CCPA 1977) .............................................................. 47
`
`In re Cronyn, 890 F.2d 1158 (Fed. Cir. 1989) ......................................................... 53
`
`In re Hall, 781 F.2d 897 (Fed. Cir. 1986) ................................................................ 16
`
`In re Katz, 687 F.2d 450 (CCPA 1982) ................................................................... 22
`
`In re Lister, 583 F.3d 1307 (Fed. Cir. 2009) .................................................... 16, 28
`
`In re Smith International Inc., 871 F.3d 1375 (Fed. Cir. 2017) .............................. 13
`
`Kyocera Wireless Corp. v. ITC, 545 F.3d 1340, (2008) .......................................... 17
`
`Lacks Industries, Inc. v. McKechnie Vehicle Components USA, Inc., 322 F.3d 1335
`(Fed. Cir. 2003) ................................................................................................... 22
`
`Merck Sharp & Dohme Corp. v. Hospira, Inc., 874 F.3d 724 (Fed. Cir. 2017) ..... 62
`
`Merial Ltd. v. Virbac, IPR2014-01279 (PTAB 2015) ............................................. 29
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`Par Pharmaceutical Inc. v. TWI Pharmaceuticals, Inc. 773 F. 3d 1186 (Fed. Cir.
`2014) ................................................................................................................... 44
`
`Perfect Surgical Techniques, Inc. v. Olympus America, Inc. 841 F. 3d 1004 (Fed.
`Cir. 2016) ............................................................................................................ 27
`
`Phillips v. AWH Corp., 415 F.3d 1303 (Fed. Cir. 2005) ............................ 5, 8, 9, 11
`
`Riverwood Int’l Corp. v. R.A. Jones &Co., Inc., 324 F.3d 1346 (Fed. Cir. 2003) .. 22
`
`SAS Institute Inc. v. Iancu, ___ U.S. ___, No. 16-969 (April 24, 2018) ................ 63
`
`Synopsys, Inc. v. Mentor Graphics Corp., 814 F.3d 1309 (Fed. Cir. 2016) ............ 46
`
`Trs. of Columbia Univ. v. Illumina, Inc., 620 F. App'x 916 (Fed. Cir. 2015) ......... 46
`
`STATUTES
`
`35 U.S.C. § 314(a) .................................................................................................. 63
`
`35 U.S.C. § 102(a) ................................................................................................... 27
`
`35 U.S.C. § 313 .......................................................................................................... 1
`
`35 U.S.C. § 315(b) ................................................................................................... 62
`
`35 U.S.C. § 318(a) ................................................................................................... 63
`
`RULES
`
`37 C.F.R. § 42.100(b) ................................................................................................ 5
`
`37 C.F.R. § 42.107 .............................................................................................. 1, 63
`
`37 C.F.R. § 42.108 ................................................................................................... 29
`
`37 C.F.R. § 42.120(a) ............................................................................................... 64
`
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`Exhibit No.
`2001
`2002
`
`2003
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`2004
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`2005
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`2006
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`2007
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`2008
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`2009
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`2010
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`2011
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`2012
`2013
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`2014
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`2015
`2016
`2017
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`EXHIBIT LIST
`
`Description
`Declaration of Dr. Richard Dalby
`Oxford Dictionary of English. 2nd ed. Revised. Oxford University
`Press, 2005 (excerpt).
`Newman, Stephen P. Respiratory drug delivery: essential theory and
`practice. Respiratory Drug Delivery Online, 2009 (excerpt).
`Hill, N., Therapeutic Options for the Treatment of Pulmonary
`Hypertension, Medscape Pulmonary Medicine 9(2) (2005).
`Exhibits Accompanying First Declaration of Dr. Roham Zamanian
`and Amendment and Reply filed in 12/591,200 (Nov. 9, 2015) (Ex.
`1162)
`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 (excerpt).
`“Mechanical Ventilation.” American Journal of Respiratory and
`Critical Care Medicine 196(2):P3-4 (2017).
`Motion for Leave to File An Amended Complaint and Exhibits Filed
`in Civil Action No: 3:15-cv-05723 PGS-LHG
`Email Correspondence to Watson’s Counsel Serving Motion for
`Leave to File An Amended Complaint and attached Exhibits (Ex.
`2009).
`Consent Order Entering Motion for Leave to File An Amended
`Complaint in Civil Action No: 3:15-cv-05723 PGS-LHG
`Orange Book Listing for Tyvaso® (Accessed October 3, 2017)
`First Notice Letter Sent June 12, 2015 by Watson Regarding Orange
`Book Listed Tyvaso® Patents
`Issue Notifications for US Patent No. 9,399,507 and US Patent No.
`9,358,240
`FDA Form 3542, Listing US Patent No. 9,399,507 in Orange Book
`FDA Form 3542, Listing US Patent No. 9,358,240 in Orange Book
`Email Correspondence between United Therapeutics and Watson
`Regarding Proposed Schedule for Civil Action No: 3:15-cv-05723
`PGS-LHG in view of US Patent No. 9,399,507 and US Patent No.
`9,358,240
`
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`2018
`
`2019
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`2020
`2021
`2022
`2023
`2024
`
`2025
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`2026
`2027
`2028
`2029
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`2030
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`2031
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`2032
`2033
`2034
`2035
`2036
`
`2037
`
`2038
`2039
`2040
`2041
`2042
`2043
`
`2044
`
`Second Notice Letter Sent June 29, 2016 by Watson Regarding
`Orange Book Listed Tyvaso® Patents
`Docket Navigator Summary Statistics on Unopposed Motions for
`Magistrate Judge Lois H. Goodman
`Declaration of Dr. Werner Seeger
`Bourge et al., Cardiovascular Therapeutics 31:38-44 (2013)
`Curriculum vitae of Dr. Richard Dalby
`Curriculum vitae of Dr. Lewis Rubin
`2002 Press Release Regarding Promotion of Robert Roscingo
`(accessed October 10, 2017)
`Shield Therapeutics Biography for Carl Sterritt (accessed October
`10, 2017)
`Declaration of Dr. Hossein A. Ghofrani
`Declaration of Dr. Frank Reichenberger
`Declaration of Dr. Freidrich Grimminger
`Excerpts from Deposition of Dr. Maureen Donovan in Civil Action
`No: 3:15-cv-05723 PGS-LHG
`Email Correspondence with Orange Book Staff Confirming Date of
`Listing for US Patent No. 9,399,507 and US Patent No. 9,358,240
`Email Correspondence with USTPO regarding Petitioner’s Request
`to File a Reply
`Feb. 23, 2018 Conference Call Transcript
`Transcript from March 28, 2018 Deposition of Dr. Scott Bennett
`Transcript from April 4, 2018 Deposition of Dr. Maureen Donovan
`Transcript from April 6, 2018 Deposition of Dr. DeForest McDuff
`Email Correspondence with Petitioner regarding Deposition of
`Christopher Butler
`Listing of Issues and Supplements of Circulation Accessible on
`Circulation Website (accessed April 17, 2018)
`Second Declaration of Dr. Richard Dalby
`US 4,319,155 (“Nakai”)
`Declaration of Dr. Aaron Waxman
`Cirriculum vitae of Dr. Aaron Waxman
`Mosby’s Medical Dictionary. 7th ed. Mosby Elsevier, 2006 (excerpt).
`Leung, K, Louca E., & Coates, A. “Comparison of Breath-Enhanced
`to Breath-Actuated Nebulizers for Rate, Consistency, and
`Efficiency,” Chest, 126(5):1619-1627 (2004)
`Rau, J.L., “Design Principles of Liquid Nebulization Devices
`viii
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`2045
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`2046
`2047
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`2048
`2049
`2050
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`2051
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`2052
`2053
`2054
`2055
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`2056
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`2057
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`2058
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`2059
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`2060
`2061
`
`2062
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`2063
`2064
`2065
`2066
`2067
`
`Currently in Use,” Respir. Care, 47(11):1257-1275 (2002)
`Atkins, P.J. & T.M. Crowder. “The Design and Development of
`Inhalation Drug Delivery Systems,” Pharmaceutical Inhalation
`Aerosol Technology, 2nd Ed. (A.J. Hichey ed., CRC Press), Ch. 9
`(2003)
`Ventavis® Patient Brochure
`Rau, J.L. Respiratory Care Pharmacology. 6th Ed. Mosby, 2002
`(excerpt)
`Declaration of Dr. Robert Roscigno
`Excerpts from Tyvaso® NDA Integrated Summary of Efficacy (ISE)
`Clinical Investigation Report Synopsis for LungRx Study No: LRX-
`TRE-INH-0004
`Clinical Investigation Report Synopsis for LungRx Study No: LRX-
`TRE-INH-0007
`Letter from FDA confirming IND filing
`Declaration of Dr. Jeffrey Stec
`Curriculum vitae and Record of Prior Testimony of Dr. Jeffrey Stec
`Tyvaso® (treprostinil) An Inhaled Prostacyclin Analogue, Internal
`Presentation
`Classes of Heart Failure, American Heart Association (accessed
`April 19, 2017)
`FDA Approves TYVASO (Treprostinil) Inhalation Solution for the
`Treatment of Pulmonary Arterial Hypertension, July 30, 2009
`2014 Fourth-Quarter and Annual Financial Results, Investor
`Conference Call Q&A
`Voswinckel, R., et al., “Favorable Effects of Inhaled Treprostinil in
`Severe Pulmonary Hypertension: Results from Randomized
`Controlled Pilot Studies,” JACC, 48(6): 1672-1681(2006)
`Tyvaso®: Just Prescribed (accessed April 5, 2018)
`The World's Biggest Public Companies – United Therapeutics,
`Forbes (accessed April 26, 2018)
`America’s Best Small Public Companies, Forbes (accessed April 26,
`2018)
`Fastest-Growing Companies, Fortune (accessed April 26, 2018)
`United Therapeutics Corp., Morningstar (accessed March 29, 2017)
`Tyvaso 2014 Brand Plan, Internal
`2013 Marketing Plan, Internal
`Tyvaso Marketing Overview, August 19, 2015, Internal
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`2068
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`2069
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`2070
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`2071
`2072
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`2073
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`2074
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`2075
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`2076
`2077
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`2078
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`2079
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`2080
`
`2081
`2082
`2083
`
`2084
`
`2085
`2086
`
`Pulmonary Arterial Hypertension (PAH) Therapeutics – Global Drug
`Forecasts and Treatment Analysis to 2020, Internal
`Frumkin L.R., “The Pharmacological Treatment of Pulmonary
`Arterial Hypertension” Pharmacol. Rev. 64:583-620 (2012)
`Khaybullina D., et al., “Riociguat (Adempas): a Novel Agent For the
`Treatment of Pulmonary Arterial Hypertension and Chronic
`Thromboembolic Pulmonary Hypertension,” Pharmacy and
`Therapeutics. 39(11):749-758.
`Project Clock Discussion Materials, February 3, 2016, Internal
`Actelion Delivers Outstanding 2014 Results, Actelion website
`(accessed April 26, 2018)
`Bloomberg L.P. WACC Report for UTHR (accessed March 14,
`2017)
`Pulmonary Arterial Hypertension Market Surveillance ATU: Wave 5
`(Q2 ’15) – Final Report, Fielded July 2015, Internal
`2014 Fourth-Quarter and Annual Financial Results, Investor
`Conference Call Q&A, Internal
`RESERVED
`Gagnon, M-A & Lexchin, J. “The Cost of Pushing Pills: A New
`Estimate of Pharmaceutical Promotion Expenditures in the United
`States,” PLoS Medicine. 5(1):epub (2008).
`McDuff R.D. et al., “Thinking Economically about Commercial
`Success.” Landslide Magazine 9(4) (2017)
`David, J. & Stewart M.B. “Commercial Success: Economic
`Principles Applied to Patent Litigation.” Leonard G.K. & Stiroh
`L.J.(Ed.) Economic Approaches to Intellectual Property: Policy,
`Litigation, and Management. New York: National Economic
`Research Associates Inc. 196-207 (2005)
`Grabowski H. & Vernon J. “The Distribution of Sales Revenue from
`Pharmaceutical Innovation,” Pharmacoeconomics, 18 Suppl.1 (2000)
`US 8,410,121 (“the ’121 patent”)
`US 9,550, 716 (“the ’716 patent”)
`TRIUMPH I Phase II Clinical Trial Protocol, created by January 11,
`2005
`ClinicalTrials.gov entry for TRIUMPH trial, NCT00147199
`(accessed April 20, 2018)
`Declaration of Dean Bunce
`February 17, 2010 Withdrawal Letter
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`2088
`2089
`2090
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`2091
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`2092
`2093
`2094
`2095
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`2096
`2097
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`2098
`2099
`2100
`2101
`
`2102
`
`2103
`
`United Therapeutics Corporation 2017 10-K
`2012 Tyvaso Brand Plan, Internal
`Tyvaso Marketing Plan, December 2010, Internal
`GlobalData Advanced Export - Pulmonary Arterial Hypertension,
`April 2017
`St. Louis Federal Reserve, Consumer Price Index,
`https://fred.stlouisfed.org/series/CPIAUCSL (accessed April 5, 2017)
`Email from British Library regarding Voswinckel
`Declaration of Ms. Pilar Wyman
`Curriculum vitae of Pilar Wyman
`McLaughlin V.V. et al., “Addition of Inhaled Treprostinil to Oral
`Therapy for Pulmonary Arterial Hypertension: A Randomized
`Controlled Clinical Trial,” JACC, 18:1915-1922 (2010) (with
`appendix)
`Author & Subject Index for Circulation Supplement 17 (2004)
`Declaration of Dr. Werner Seeger Accompanying Amendment and
`Reply filed in 13/469,854 dated August 20, 2015
`Second Declaration of Dr. Werner Seeger
`Second Declaration of Dr. Hossein A. Ghofrani
`U.S. Application No. 60/800,016
`Services Agreement between Dr. Werner Seeger and LungRx dated
`Sept.23, 2003
`LungRx TRIUMPH Executive Committee Meeting Agenda dated
`October 22, 2003
`German language version of Ex. 1005 (also provided as Attachment
`2d to Ex. 1013)
`Bloomberg L.P. WACC Report for UTHR, 2003
`2104
`2105-2200 RESERVED
`2201
`Claims of Abandoned U.S. Application No. 11/748,205
`Inventor Oaths filed in U.S. Application No. 12/591,200 (granted as
`the ’240 patent) and U.S. Application No. 13/469,854 (granted as the
`’507 patent)
`Dismissal of Complaint of Dr. Lewis Rubin and Motion for
`Attorney’s Fees
`Excerpts from Deposition of Dr. Lewis Rubin
`
`2202
`
`2203
`2204
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`Patent Owner Response
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`I.
`
`INTRODUCTION
`
`
`
`Pursuant to 35 U.S.C. § 313 and 37 C.F.R. § 42.107, Patent Owner United
`
`Therapeutics Corporation (“Patent Owner” or “UTC”) files this Response to the
`
`Petition of Watson Laboratories, Inc. (“Petitioner” or “Watson”) challenging
`
`claims 1-9 of U.S. Patent No. 9,358,240 (“the ’240 patent”), in view of the Board’s
`
`decision to institute trial on Ground 1 – obviousness over Voswinckel1, Patton2,
`
`and Ghofrani3 (Paper 10, “Institution Decision”). This response is timely filed
`
`based on the agreement between Petitioner and Patent Owner; the agreed upon due
`
`date falls on April 27, 2018.
`
`II.
`
`SUMMARY OF ARGUMENT
`
`Patent Owner urges the Board to find claims 1-9 patentable over Ground 1
`
`because: (i) two of the three references relied upon for Ground 1 do not qualify as
`
`1 Robert Voswinckel, et al. “Inhaled treprostinil sodium for the treatment of
`
`pulmonary hypertension” Abstract #1414, Circulation, 110, 17, Supplement (Oct.
`
`2004): III-295 (Ex. 1003).
`
`2 WO 93/00951 (Ex. 1012).
`
`3 Hossein Ardeschir Ghofrani et al. “Neue Therapieoptionen in der Behandlung der
`
`pulmonalarteriellen Hypertonie,” Herz, 30, 4 (June 2005): 296-302 (the English
`
`translation of which is provided as Ex. 1005).
`
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`prior art; and (ii) Petitioner has failed to meet its burden of proving obviousness
`
`over Voswinckel, Patton, and Ghofrani by a preponderance of the evidence where
`
`critical elements of the claims are not found in the prior art, Petitioner fails to
`
`identify sufficient motivation to arrive at the invention, and objective indicia
`
`demonstrate nonobviousness.4
`
`III. BACKGROUND
`The ’240 patent relates to the treatment of pulmonary hypertension and is
`
`listed in the Orange Book for the product Tyvaso® (treprostinil) Inhalation
`
`Solution, a drug-device combination for delivery of treprostinil by inhalation. Ex.
`
`1001, col. 18:2-3; Ex. 2012. The first approved treatment for pulmonary
`
`hypertension—and sole approved treatment for over five years—was epoprostenol,
`
`which has significant burdens and challenges to patients associated with its
`
`instability, short half-life, and intravenous administration requiring a permanent
`
`intravenous catheter. Ex. 2040, ¶7-8. Later-approved intravenous and
`
`subcutaneous administration of treprostinil also had limitations, such as intolerable
`
`
`4 Regardless of the merits of Ground 1, and as previously argued, the Petition was
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`not timely filed and the Board improperly relied on Petitioner’s Reply in its
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`institution decision.
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`site pain in some patients. Ex. 1136, 1. Inhaled delivery of treprostinil, i.e.
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`Tyvaso®, has several benefits over epoprostenol and over subcutaneous or
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`intravenous administration of treprostinil. Ex. 2040, ¶8-9. Inhaled treprostinil is
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`less intrusive and complicated, and avoids the various problems posed by
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`subcutaneous and intravenous drug administration. Id.
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`As of May 15, 2006, the priority date of the ’240 patent, the only FDA-
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`approved prostacyclin-type drug that could be given in an inhalable form was
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`iloprost, marketed as Ventavis®. Ex. 2040, ¶10. At that time, the results of then
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`Aerosolized Iloprost Randomized (AIR) study documenting the effects of inhaled
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`iloprost had been public about three and a half years, and Ventavis® had been on
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`the market for about one and a half years. Ex. 1162, 21; Ex. 2005, 1-28; Ex. 2040,
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`¶10. Clinicians were largely still of the opinion, however, that intravenous
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`administration of a prostacyclin analog was preferable to inhaled delivery. Ex.
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`1162, 21; Ex. 2040, ¶10. Thus, there was concern that the adoption of Ventavis®
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`could be happening too rapidly without a full understanding of the side effects. Id.
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`Further, adoption of Ventavis® posed a number of issues. For instance,
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`Ventavis® needs to be used 6-9 times a day, as frequently as every 2 hours, which
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`was challenging for patients to implement. Id. Moreover, iloprost has a short
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`biological half-life when inhaled, so patients may be off-medication while asleep
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`unless they wake up to take a dose of the drug, which is risky and threatens
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`rebound hypertension. Id. There were also concerns about how to address the
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`interaction between the patient and the nebulizer. Id.
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`In contrast, because of the pharmacodynamic differences between iloprost
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`and treprostinil, Tyvaso® (inhaled treprostinil) does not need to be administered as
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`frequently as Ventavis®, leading to higher patient compliance and less risk of
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`rebound hypertension. Ex. 2040, ¶80. Due to favorable pharmacodynamics when
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`inhaled according to the claimed methods, Tyvaso® can be administered less
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`frequently — about 1 to 4 times a day. Ex. 1162, 23-24. Patients are more likely
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`to comply with a regimen that requires less frequent administrations. Furthermore,
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`because Tyvaso® has a longer duration per dose than Ventavis®, there is less risk
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`when the patient is asleep or otherwise unable to take the medication.
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`In the context of a pulmonary hypertension patient’s life, 2-5 fewer
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`administrations per day can have a substantial impact on the patient’s life. Studies
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`have shown a statistically significant improvement in quality of life reported by
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`pulmonary hypertension patients who switched from inhaled iloprost to inhaled
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`treprostinil, using FDA approved levels of iloprost and treprostinil. Ex. 1058, 17.
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`Another study reported that “the transition from inhaled iloprost to inhaled
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`treprostinil resulted in a time saving of approximately 1.4 h per day.” Ex. 2021, 5.
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`Patients transferring from inhaled iloprost to inhaled treprostinil also had improved
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`six-minute walk distances (a common metric to assess pulmonary hypertension),
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`improved patient satisfaction, and improved quality of life. Id. at 5-6.
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`Once Tyvaso® entered the market, it was clinically preferred to Ventavis®,
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`and Tyvaso® rapidly increased its market share, while the share held by Ventavis®
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`rapidly decreased. See, e.g., Ex. 1059, 9; Ex. 1162, 9; Ex. 1163, 16; Ex. 2040, ¶79;
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`Ex. 2053, ¶34-37, Fig. 4. Despite Ventavis’® long presence in the U.S. market
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`before the launch of Tyvaso®, Tyvaso® took away the majority of the U.S. market
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`for inhaled prostacyclins from Ventavis® in a single year. Id. As discussed below
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`and reflected in the Declaration of Dr. Jeffery Stec, Tyvaso® enjoyed tremendous
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`commercial success. Ex. 2053, ¶25-46.
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`IV. CLAIM CONSTRUCTION
`The claims are given their broadest reasonable interpretation consistent with
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`the specification as it would be interpreted by one of ordinary skill in the art
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`(“POSA”). 37 C.F.R. § 42.100(b). Patent claims are construed in the context of
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`the claim language, specification, prosecution history, and understanding in the art.
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`Phillips v. AWH Corp., 415 F.3d 1303, 1316 (Fed. Cir. 2005).
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`Independent claim 1 recites:
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`A method of treating pulmonary hypertension comprising:
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`administering by inhalation to a human suffering from
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`pulmonary hypertension a therapeutically effective single event dose
`of a formulation comprising from 200 to 1000 μg/ml of treprostinil or
`a pharmaceutically acceptable salt thereof
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`with a pulsed ultrasonic nebulizer that aerosolizes a fixed
`amount of treprostinil or a pharmaceutically acceptable salt thereof
`per pulse,
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`said pulsed ultrasonic nebulizer comprising an opto-acoustical
`trigger which allows said human to synchronize each breath to each
`pulse,
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`said therapeutically effective single event dose comprising from
`15 μg to 90 μg of treprostinil or a pharmaceutically acceptable salt
`thereof delivered in 1 to 18 breaths.
`Ex. 1001, col.18:2-17.
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`Person of Ordinary Skill in the Art (“POSA”)
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`A.
`The Board preliminarily found the limited pre-institution record supported
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`Petitioner’s POSA definition. Institution Decision, 9-10. The record, as developed
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`by this response, supports Patent Owner’s definition.
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`The ’240 patent claims are directed to medical treatment—methods for
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`“treating pulmonary hypertension” with a specific “pulsed ultrasonic nebulizer.” A
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`POSA at the time of invention would have had a post-graduate degree in medicine
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`or drug development (such as the pharmaceutical sciences) with at least two years
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`of experience investigating or treating pulmonary hypertension. Ex. 2040, ¶15.
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`Indeed, all but one of the named ’240 patent inventors have post-graduate degrees
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`in medicine or drug development, and all had years of research or clinical
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`experience in developing pharmaceutical products for the treatment of pulmonary
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`hypertension. Ex. 2020, ¶1, 7; Ex. 1028, 1; Ex. 1029, 1; Ex. 2023; Ex. 2024; Ex.
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`2025. See, e.g., Helifix, Ltd. v. Blok-Lok, Ltd., 208 F.3d 1339, 1347 (Fed. Cir.
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`2000). A POSA may also have had experience studying, developing, or using
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`dosage forms to treat pulmonary hypertension. Ex. 2040, ¶15. A POSA may have
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`had a lower level of formal education but more years of experience in the
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`investigation or treatment of pulmonary hypertension. Id.
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`Petitioner’s expert, Dr. Maureen Donovan, agreed that “[t]he POSA that I
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`have defined is a drug development expert, and so they are wishing to develop a
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`therapy to treat pulmonary hypertension.” Ex. 2034, 32:11-14. This focus on
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`pulmonary hypertension is consistent with Petitioner’s other expert, Dr. DeForest
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`McDuff, who consistently noted the importance of clinical experience in analysis
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`of the pending claims. Ex. 2035, 50:6-13, 102:4-25, 138:12-18.
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`Patent Owner’s expert Dr. Waxmanapplied both Petitioner’s and Patent
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`Owner’s proposed POSA definitions. Ex. 2040, ¶16. Dr. Dalby also considers
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`obviousness under Petitioner’s definition. Ex. 2001, ¶10; Ex. 2038, ¶3. Thus, their
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`testimony holds true should the Board adopt Petitioner’s definition. Dr. Donovan,
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`on the other hand, offers no testimony based on Patent Owner’s proposed
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`definition, and in fact, does not qualify as a POSA under Patent Owner’s
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`definition. Ex. 1002, ¶5-11. She lacks any experience in the treatment of
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`pulmonary hypertension and has not researched or worked with pulmonary
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`hypertension, treprostinil, or prostacyclins. Ex. 2034, 17:22-20:18.
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`B. Claim Terms
`In the Preliminary Response, Patent Owner offered claim construction for
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`the terms “pulsed,” “opto-acoustical trigger,” and “single event dose.” The Board
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`found claim construction was not required to determine whether to institute trial in
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`this case. Institution Decision, 11. At the post-institution stage, Patent Owner
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`urges the Board to construe each of the terms “pulsed,” “opto-acoustical trigger,”
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`and “single event dose,” as a clear discrepancy exists between the parties’
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`understanding of the claim terms that directly impacts the determination of
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`nonobviousness discussed below.
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`1.
`“pulsed” and “pulse”
`Analysis of the claims begins with the plain meaning. Phillips, 415 F.3d at
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`1312. Both terms “pulse” and “pulsed” appear in the ’240 patent claims. Ex.
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`1001, col.18:1-38. The term “pulsed” is an adjective form of the noun “pulse,”