Reply in Support of Petition for Inter Partes Review of
`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 B2
`Issue Date: July 21, 2020
`
`
`
`Title: Treprostinil Administration by Inhalation
`
`
`
`REPLY IN SUPPORT OF PETITION FOR INTER PARTES REVIEW
`OF U.S. Patent No. 10,716,793 B2
`
`
`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 B2
`Issue Date: July 21, 2020
`
`
`
`Title: Treprostinil Administration by Inhalation
`
`
`
`REPLY IN SUPPORT OF PETITION FOR INTER PARTES REVIEW
`OF U.S. Patent No. 10,716,793 B2
`
`
`
`I.
`
`II.
`
`B.
`
`TABLE OF CONTENTS
`GROUND 1: CLAIMS 1-8 ARE OBVIOUS OVER THE ’212
`PATENT, JESC, AND JAHA ........................................................................ 1
`A.
`JESC and JAHA Were Publicly Accessible Before 2006 .................... 1
`1.
`JESC was publicly accessible before 2006 ................................ 2
`2.
`JAHA was publicly accessible before 2006 .............................. 6
`Claim 1’s “Single Event Dose” of 15-90µg “delivered in 1 to 3
`breaths” is Obvious Over Combination of the ’212 Patent,
`JAHA, and JESC .................................................................................. 9
`1.
`JESC Renders Obvious 15-90µg Delivered Dosage ............... 10
`2.
`’212 Patent Renders Obvious 15-90µg Inhaled Dosing .......... 15
`3.
`A POSA Would Have Been Motivated to Combine the
`Dosage Disclosures in the Three References ........................... 19
`Claims 4, 6, and 7 are Obvious Over the Same Combination ........... 20
`C.
`GROUND 2: CLAIMS 1-8 ARE OBVIOUS OVER THE ’212
`PATENT AND JESC ................................................................................... 21
`III. NO SECONDARY CONSIDERATIONS OF NON-OBVIOUSNESS
`EXIST ........................................................................................................... 23
`A.
`PO is Not Entitled to a Presumption of Nexus ................................... 23
`B.
`PO Fails to Provide Any Evidence of Nexus Between
`Secondary Considerations and the Claimed Invention ...................... 24
`1.
`No Unexpected Results Due to Well-Tolerated Dosage ......... 24
`2.
`No Evidence of Copying .......................................................... 25
`3.
`No Long-Felt Unmet Need ...................................................... 26
`IV. CONCLUSION ............................................................................................. 27
`
`
`i
`
`
`
`EXHIBITS
`
`Description of Document
`
`Exhibit
`No.
`1001 U.S. Patent No. 10,716,793 B2 to Olschewski, et al. (“’793 patent”)
`1002 Declaration of Dr. Nicholas Hill (“Hill Decl.”)
`1003 Curriculum Vitae of Dr. Nicholas Hill
`1004 Declaration of Dr. Igor Gonda (“Gonda Decl.”)
`1005 Curriculum Vitae of Dr. Igor Gonda
`1006 U.S. Patent No. 6,521,212 B1 to Cloutier, et al. (“’212 patent”)
`1007 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”)
`1008 Robert Voswinckel, Beate Enke, Andre Kreckel, Frank
`Reichenberger, Stefanie Krick, Henning Gall, Tobias Gessier, Thomas
`Schmehl, Markus G. Kohstall, Friedrich Grimminger, Hossein A.
`Ghofrani, Werner Seeger, and Horst Olschewski, 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”)
`1009 Robert Voswinckel, Hossein A. Ghofrani, Friedrich Grimminger, and
`Werner Seeger, “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”)
`1010 Hossein Ardeschir Ghofrani, Robert Voswinckel, 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)
`First Amended Complaint filed in United Therapeutics Corporation
`v. Liquidia Technologies, Inc., Case No. 1:20-cv-00755-RGA (D.
`Del.)
`
`1011
`
`ii
`
`
`
`EXHIBITS
`
`Exhibit
`Description of Document
`No.
`1012 United Therapeutics Corporation’s Answer to Defendant Liquidia
`Technologies, Inc.’s Counterclaims filed in United Therapeutics
`Corporation v. Liquidia Technologies, Inc., Case No. 1:20-cv-00755-
`RGA (D. Del.)
`1013 United Therapeutics Corporation’s Opening Brief in Support of its
`Motion to Dismiss Defendant’s Counterclaim filed in United
`Therapeutics Corporation v. Liquidia Technologies, Inc., Case No.
`1:20-cv-00755-RGA (D. Del.)
`1014 Memorandum Order denying United Therapeutics Corporation’s
`Motion to Dismiss Defendants Counterclaim filed in United
`Therapeutics Corporation v. Liquidia Technologies, Inc., Case No.
`1:20-cv-00755-RGA (D. Del.)
`
`10,716,793 Patent Prosecution History
`
`10,376,525 Patent Prosecution History (excerpted)
`
`1015
`1016
`1017
`9,339,507 Patent Prosecution History (excerpted)
`1018 Remodulin® 2004 Label
`Stein, S.W., et al., “The History of Therapeutic Aerosols: A
`1019
`Chronological Review,” Journal of Aerosol Medicine and
`Pulmonary Drug Delivery, 30(1):20-41 (2017) (“Stein”)
`1020 Clark, A.R., “Medical Aerosol Inhalers: Past, Present, and Future,”
`Aerosol Science and Technology, 22:374-91 (1995) (“Clark”)
`1021 Ruan, C.-H., et al., “Prostacyclin Therapy for Pulmonary Arterial
`Hypertension,” Texas Heart Institute Journal, 37(4):391-99 (2010)
`(“Ruan”)
`1022 Walmrath, D., et al., “Direct Comparison of Inhaled Nitric Oxide and
`Aerosolized Prostacyclin in Acute Respiratory Distress Syndrome,”
`American Journal of Respiratory Critical Care Medicine, 153:991-
`96 (1996) (“Walmrath 1996”)
`1023 Olschewski, H., et al., “Inhaled Prostacyclin and Iloprost in Severe
`Pulmonary Hypertension Secondary to Lung Fibrosis,” American
`
`iii
`
`
`
`EXHIBITS
`
`Exhibit
`No.
`
`Description of Document
`Journal of Respiratory Critical Care Medicine, 160:600-07 (1999)
`(“Olschewski 1999”)
`1024 Haché, M., et al., “Inhaled epoprostenol (prostacyclin) and
`pulmonary hypertension before cardiac surgery,” Journal of
`Thoracic and Cardiovascular Surgery, 125:642-49 (2003) (“Hache”)
`1025 De Wet, C.J., et al., “Inhaled prostacyclin is safe, effective, and
`affordable in patients with pulmonary hypertension, right heart
`dysfunction, and refractory hypoxemia after cardiothoracic surgery,”
`Journal of Thoracic and Cardiovascular Surgery, 127:1058-67
`(2004) (“De Wet”)
`1026 Denver, J. and Dyche, T., “The Adaptive Aerosol Delivery (AAD)
`Technology: Past, Present, and Future,” Journal of Aerosol Medicine
`and Pulmonary Drug Delivery, 23(1 suppl):S-1-S10 (2010) (“Denver
`and Dyche”)
`1027 U.S. Patent No. 6,242,482 B1 to Shorr, et al. (“Shorr”)
`1028 U.S. Patent Application Publication No. US 2004/0265238 A1 to
`Chaudry (“Chaudry”)
`1029 Ventavis® Label 2004
`1030 Newman, S.P., “Aerosols”, Chapter from Encyclopedia of
`Respiratory Medicine pp. 58-64 (2006) (“Newman”)
`1031 Geller, D.E., “Comparing Clinical Features of the Nebulizer,
`Metered-Dose Inhaler, and Dry Powder Inhaler,” Respiratory Care,
`50(10):1313-21 (2005) (“Geller 2005”)
`1032 Bender, B., et al., “Nonadherence in asthmatic patients: is there a
`solution to the problem?” Annals of Allergy, Asthma & Immunology,
`79:177-86 (1997) (“Bender 1997”)
`1033 Rau, J.L., “Determinants of Patient Adherence to an Aerosol
`Regimen,” Respiratory Care 50(10):1346-56 (2005) (“Rau 2005”)
`1034 Geller, D., et al., “Bolus Inhalation of rhDNase with the AERx
`System in Subjects with Cystic Fibrosis,” Journal of Aerosol
`
`iv
`
`
`
`EXHIBITS
`
`Exhibit
`No.
`
`Description of Document
`Medicine, 16(2):175-82 (2003) (“Geller 2003”)
`1035 Chattaraj, S.C., “Treprostinil sodium Pharmacia,” Current Opinion
`in Investigational Drugs, 3(4):582-86 (Apr. 2002), available at
`https://pubmed.ncbi.nlm.nih.gov/12090728/ (“Chattaraj”)
`1036 Declaration of Sylvia Hall-Ellis, Ph.D. (“Hall-Ellis Decl.”)
`1037 English translation of OptiNeb® User Manual 2005
`1038 Atkins, P.J., “Dry Powder Inhalers: An Overview,” Respiratory
`Care, 50(10):1304-12 (2005) (“Atkins”)
`Frijlink, H.W. and De Boer, A.H., “Dry powder inhalers for
`pulmonary drug delivery,” Expert Opinion on Drug Delivery,
`1(1):67-86 (2004) (“Frijlink and De Boer”)
`1040 Chew N. and Chan H.-K., “Pharmaceutical Dry Powder Aerosol
`Delivery,” KONA, No. 19, pp. 46-56 (2001) (Chew and Chan)
`1041 Reserved
`January 27, 2020 Press Release, “Liquidia Submits New Drug
`1042
`Application for LIQ861 (Treprostinil) Inhalation Powder to U.S.
`Food And Drug Administration for the Treatment of Pulmonary
`Arterial Hypertension (PAH),” available at
`https://investors.liquidia.com/news-releases/news-release-
`details/liquidia-submits-new-drug-application-liq861-treprostinil
`2009 Tyvaso® Label, available at
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022387s
`015lbl.pdf
`
`1039
`
`1043
`
`1044
`9,358,240 Patent Prosecution History (excerpted)
`1045 Reserved
`1046 U.S. Patent No. 9,358,240 to Olschewski, et al. (“’240 Patent”)
`1047 Hoeper, M.M., et al., “Long-Term Treatment of Primary Pulmonary
`Hypertension with Aerosolized Iloprost, a Prostacyclin Analogue,” N
`
`v
`
`
`
`EXHIBITS
`
`Exhibit
`No.
`
`Description of Document
`Engl J Med, 342:1866-70 (2000) (“Hoeper”)
`1048 Walmrath, D., et al., “Aerosolised prostacyclin in adult respiratory
`distress syndrome,” Lancet, 342:961-62 (1993) (“Walmrath 1993”)
`1049 April 8, 2020 Press Release, “Liquidia Announces FDA Acceptance
`of New Drug Application for LIQ861 (Treprostinil) Inhalation
`Powder for the Treatment of Pulmonary Arterial Hypertension,”
`available at https://investors.liquidia.com/news-releases/news-
`release-details/liquidia-announces-fda-acceptance-new-drug-
`application-liq861
`
`1050
`1051
`
`Pulmozyme® Label
`Farber, H.W. and Loscalzo, J., “Pulmonary Arterial Hypertension,”
`N Engl J Med, 351:1655-65 (2004) (“Farber and Loscalzo”)
`1052 Rubin, L.J. and Badesch, D.B., “Evaluation and Management of the
`Patient with Pulmonary Arterial Hypertension,” Ann Intern Med.,
`143:282-92 (2005) (“Rubin and Badesch”)
`
`1053
`Flolan® Label
`1054 Gonda, I., “A semi-empirical model of aerosol deposition in the
`human respiratory tract for mouth inhalation,” J. Pharm.
`Pharmacol., 33:692-96 (1981) (“Gonda 1981”)
`1055 Gonda, I., “Study of the effects of polydispersity of aerosols on
`regional deposition in the respiratory tract,” J. Pharm. Pharmacol.,
`33 (Suppl.) 52P (1981) (“Gonda 1981b”)
`1056 Telko, M.J. and Hickey, A.J., “Dry Powder Inhaler Formulation,”
`Respiratory Care, 50(9):1209-27 (2005) (“Telko and Hickey”)
`1057 October 24, 2005 Press Release, “Aradigm Corporation And United
`Therapeutics Corporation Sign Development and Commercialization
`Agreement Targeting Pulmonary Hypertension,” available at
`https://www.biospace.com/article/releases/aradigm-corporation-and-
`united-therapeutics-corporation-sign-development-and-
`commercialization-agreement-targeting-pulmonary-hypertension-/
`
`vi
`
`
`
`EXHIBITS
`
`1060
`
`Exhibit
`Description of Document
`No.
`1058 Ziegler, J. and Wachtel, H., “Comparison of Cascade Impaction and
`Laser Diffraction for Particle Size Distribution Measurements,”
`Journal of Aerosol Medicine, 18(3):311-24 (2005) (“Ziegler and
`Wachtel”)
`1059 Nauser, T.D., “Pulmonary Hypertension: New Perspectives,” CHF,
`9:155-62 (2003) (“Nauser 2003”)
`Pitcairn, G., et al., “Deposition of Corticosteroid Aerosol in the
`Human Lung by Respimat® Soft Mist™ Inhaler Compared to
`Deposition by Metered Dose Inhaler or by Turbuhaler® Dry Powder
`Inhaler,” Journal of Aerosol Medicine, 18(3):264-72 (2005)
`(“Pitcairn”)
`1061 Dalby, R., et al., “A review of the development of Respimat® Soft
`MistTM Inhaler,” International Journal of Pharmaceutics, 283:1-9
`(2004) (“Dalby”)
`1062 Gessler, T., et al., “Ultrasonic versus jet nebulization of iloprost in
`severe pulmonary hypertension,” Eur Respir J, 17:14-19 (2001)
`(“Gessler”)
`1063 Reserved
`1064 Dolovich, M.B., et al., “Device Selection and Outcomes of Aerosol
`Therapy: Evidence-Based Guidelines,” CHEST, 127:335-71 (2005)
`(“Dolovich”)
`1065 Olschewski, H., et al., “Inhaled Iloprost for Several Pulmonary
`Hypertension,” N Engl J Med, 347(5):322-29 (2002) (“Olschewski
`2002”)
`1066 AccuNeb® Label
`1067 Anderson, P.J., “History of Aerosol Therapy: Liquid Nebulization to
`MDIs to DPIs,” Respiratory Care, 50(9):1139-49 (2005) (“Anderson
`2005”)
`1068 Vachiéry, J.-L., et al., “Transitioning From IV Epoprostenol to
`Subcutaneous Treprostinil in Pulmonary Arterial Hypertension,”
`CHEST, 121:1561-65 (2002) (“Vachiéry 2002”)
`
`vii
`
`
`
`EXHIBITS
`
`1071
`
`Exhibit
`Description of Document
`No.
`1069 Zierenberg, B. and Eicher, J., Chapter 78 “The Respimat, a New Soft
`Mist Inahler for Delivering Drugs to The Lungs,” MODIFIED-
`RELEASE DRUG DELIVERY TECHNOLOGY (2002) pp.925-933
`(“Zierenberg”)
`1070 Beasley, R., et al., “Preservatives in Nebulizer Solutions: Risks
`without Benefit,” Pharmacotherapy, 18(1):130-39 (1998)
`(“Beasley”)
`Prober, C.G., et al., “Technical Report: Precautions Regarding the
`Use of Aerosolized Antibiotics,” Pediatrics, 106(6):1-6 (2000)
`(“Prober”)
`1072 Reserved
`1073 Aradigm Corporation Form 10-Q for the quarterly period ended June
`30, 2009, available at
`https://www.sec.gov/Archives/edgar/data/1013238/00009501230903
`1361/f53244e10vq.htm
`1074 Orenitram® Label, available at
`https://www.orenitram.com/pdf/Orenitram-Prescribing-
`Information.pdf
`1075 November 17, 2008 Press Release, “Eli Lilly and Company Licenses
`U.S. Rights for Tadalafil PAH Indication to United Therapeutics
`Corporation,” available at
`https://www.fiercebiotech.com/biotech/eli-lilly-and-company-
`licenses-u-s-rights-for-tadalafil-pah-indication-to-united
`1076 October 23, 2017 Press Release, “United Therapeutics Announces
`FDA Approval Of Third Generation Nebulizer For The Tyvaso®
`Inhalation System,” available at https://www.prnewswire.com/news-
`releases/united-therapeutics-announces-fda-approval-of-third-
`generation-nebulizer-for-the-tyvaso-inhalation-system-
`300540953.html
`1077 Boyle, M.P., “So Many Drugs, So Little Time. The Future Challenge
`of Cystic Fibrosis Care,” CHEST, 123(1):3-5 (2003) (“Boyle 2003”)
`
`viii
`
`
`
`EXHIBITS
`
`Description of Document
`
`Exhibit
`No.
`1078 Azmacort® Label 2003
`1079 Hill, N.S., et al., “Inhaled Therapies for Pulmonary Hypertension,”
`Respiratory Care, 60(6):794-805 (2015) (“Hill 2015”)
`1080 Declaration of Deepa Kannappan in Support of Motion for Pro Hac
`Vice Admission
`1081 Biography of Deepa Kannappan
`1082 Biography of Jonathan Davies
`1083 Declaration of Jonathan Davies in Support of Motion for Pro Hac
`Vice Admission
`1084 Reserved
`1085 Reserved
`1086 Reserved
`1087 Butler Affidavit
`1088 Tyvaso® Label 2021 (Note: PO’s Ex. 2034, described as “Tyvaso®
`Label 2021,” is the 2009 label)
`1089 Voswinckel JESC, UWash
`1090 Voswinckel JESC, UWisc
`1091 Voswinckel JESC, British Library
`1092 Voswinckel JESC, Add’l Pages
`1093 Voswinckel JAHA, British Library
`1094 Voswinckel JAHA, Library of Congress
`1095 Voswinckel JAHA, Stanford
`1096 Voswinckel JAHA, UC Davis
`1097 Rhind, G.B. et al., “Effect of Spirometry of Distilled Water and
`Cromoglycate Solutions Nebulised by a Small Portable Ultrasonic
`Nebuliser,” Respiration, 51:86-90 (1987) (“Rhind 1987”)
`1098 Hager, J., et al., “Measurement of Particle and Mass Distribution of
`
`ix
`
`
`
`EXHIBITS
`
`Exhibit
`No.
`
`Description of Document
`Pentamidine Aerosol by Ultrasonic and Air Jet Nebulizers,” Journal
`of Aerosol Medicine, Vol. 5, No. 2 (1992) (“Hager 1992”)
`1099 Leigh, T.R., et al., “Performance characteristics of the DeVilbiss
`Ultraneb 99 ultrasonic nebuliser with reference to use in sputum
`induction,” International Journal of Pharmaceutics, 67 (1991) 275-
`282 (“Leigh 1991”)
`1100 Ventavis EU Summary of Product Characteristics
`1101 Denyer, J., et al., “Adaptive Aerosol Delivery (AAD®) technology,”
`Expert Opinion on Drug Delivery, 1:1, 165-176 (“Denyer 2004”)
`1102 Byrne, N.M., et al., “Comparison of lung deposition of colomycin
`using the HaloLite and the Pari LC Plus nebulisers in patients with
`cystic fibrosis,” Arch Dis Child 2003;88:715–718 (“Byrne 2003”)
`1103 Leung, K., et al., “Comparison of Breath-Enhanced to Breath-
`Actuated Nebulizers for Rate, Consistency, and Efficiency,” CHEST
`2004; 126:1619–1627 (“Leung 2004”)
`Sulica, R. and Poon, M., “Medical therapeutics for pulmonary
`arterial hypertension: from basic science and clinical trial design to
`evidence-based medicine,” Expert Rev. Cardiovasc. Ther. 3(2),
`(2005) (“Sulica 2005”)
`1105 European Society of Cardiology Annual Report 2005
`1106 Reply Declaration of Nicholas Hill, M.D.
`1107 Reply Declaration of Igor Gonda, Ph.D.
`1108 Transcript from the January 8, 2022 Deposition of Aaron Waxman,
`M.D., Ph.D., Liquida Technologies, Inc. v. United Therapeutics
`Corp., IPR2021-00406
`1109 Transcript from the January 11, 2022 Deposition of Jason
`McConville, Liquida Technologies, Inc. v. United Therapeutics
`Corp., IPR2021-00406
`1110 Transcript from the December 29, 2021 Deposition of Lyndsey Pilar
`Wyman, Liquida Technologies, Inc. v. United Therapeutics Corp.,
`IPR2021-00406
`
`1104
`
`x
`
`
`
`EXHIBITS
`
`Description of Document
`
`Exhibit
`No.
`1111 Reserved
`1112 Reply Declaration of Sylvia Hall-Ellis, Ph.D.
`1113
`JAHA Supplement Author Index
`1114 American Heart Association 2004 Online Archive, pages available
`at
`https://web.archive.org/web/20041130084648/http://circ.ahajournals.
`org:80/;
`https://web.archive.org/web/20041206215947/http://aha.agora.com/a
`bstractviewer/;
`https://web.archive.org/web/20041128050933/http://circ.ahajournals.
`org/contents-by-date.0.shtml; and
`https://web.archive.org/web/20041204145419/http://circ.ahajournals.
`org/content/vol110/issue17/
`1115 Affidavit of Duncan Hall, December 7, 2021
`1116 Voswinckel JAHA British Library Declaration
`1117 Voswinckel JAHA Supplement PubMed Search Results
`1118
`PubMed.gov search results for Sulica, R. and Poon, M., “Medical
`therapeutics for pulmonary arterial hypertension: from basic science
`and clinical trial design to evidence-based medicine,” Expert Rev.
`Cardiovasc. Ther. 3(2), (2005)
`1119 Voswinckel JESC British Library Declaration
`1120 Voswinckel JESC Web of Science Search Results
`1121 Ghofrani 2005, British Library
`1122 Ghofrani 2005 Search Results
`1123 Circulation MARC record, British Library
`1124 Circulation MARC record, Library of Congress
`1125 Circulation MARC record, Stanford
`1126 Circulation MARC record, UC Davis
`1127 European Heart Journal bibliographic record, UWash
`
`xi
`
`
`
`EXHIBITS
`
`Description of Document
`
`Exhibit
`No.
`1128 European Heart Journal MARC record, UWisc
`1129 European Heart Journal MARC record, British Library
`1130
`January 27, 2020 Press Release “Liquidia Submits New Drug
`Application for LIQ861 (treprostinil) inhalation powder to U.S. Food
`and Drug Administration for the Treatment of Pulmonary Arterial
`Hypertension (PAH),” available at https://www.liquidia.com/news-
`releases/news-release-details/liquidia-submits-new-drug-application-
`liq861-treprostinil
`1131 Michael Mellon et al., Comparable Efficacy of Administration with
`Face Mask or Mouthpiece of Nebulized Budesonide Inhalation
`Suspension for Infants and Young Children with Persistent Asthma,
`162 AM. J. RESPIR. CARE MED. 593 (2000) (“Mellon 2000”)
`1132 Transcript from the January 15, 2022 deposition of Aaron B.
`Waxman, M.D., Ph.D., United Therapeutics Corp. v. Liquidia
`Technologies, Inc., Case No. 1:20-cv-00755 (D. Del.)
`
`xii
`
`
`
`Reply in Support of Petition for Inter Partes Review of
`U.S. Patent No. 10,716,793 B2
`
`
`Voswinckel JESC (“JESC”) and Voswinckel JAHA (“JAHA”) were publicly
`
`accessible before 2006, and grounds 1 and 2 render obvious the ’793 Patent’s
`
`claimed dosage. Petitioner thus requests the Board find claims 1-8 unpatentable.
`
`I.
`
`GROUND 1: CLAIMS 1-8 ARE OBVIOUS OVER THE ’212 PATENT, JESC, AND
`JAHA
`
`A.
`
`JESC and JAHA Were Publicly Accessible Before 2006
`
`“A reference will be considered publicly accessible if it was ‘disseminated or
`
`otherwise made available to the extent that persons interested and ordinarily skilled
`
`in the subject matter or art exercising reasonable diligence, can locate it.’” Blue
`
`Calypso v. Groupon, 815 F.3d 1331, 1348 (Fed. Cir. 2016).
`
`PO’s evidence that the JESC and JAHA references were not publicly
`
`accessible comes from a single unqualified “expert” Pilar Wyman. (EX2041,
`
`EX2042.) Wyman lacks relevant library or research-related degrees, is not a “trained
`
`librarian,” has never assessed the public accessibility of a document outside of this
`
`IPR and an IPR on a related patent, never worked in a research library or library that
`
`generated MARC records, or done any indexing relevant to public availability. (See
`
`EX1112, ¶¶28-32; EX1110, 49:13-19, 27:15-20, 50:22-53:11.) Her lack of
`
`qualifications is apparent from her mistakes and disregard of contradictory evidence
`
`known to her, detailed below. Accordingly, her opinions should be accorded “little
`
`weight.” Elbit Sys. of Am. v. Thales Visionix, 881 F.3d 1354, 1358 (Fed. Cir. 2018).
`
`1
`
`
`
`Reply in Support of Petition for Inter Partes Review of
`U.S. Patent No. 10,716,793 B2
`
`
`1.
`
`JESC was publicly accessible before 2006
`
`JESC was published by Elsevier, an established publisher since 1880.1
`
`(EX1089, 4; 1112, ¶88.) “When there is an established publisher there is a
`
`presumption of public accessibility as of the publication date.” VidStream v. Twitter,
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`981 F.3d 1060, 1065 (Fed. Cir. 2020).
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`Additionally, a reference can qualify as a “printed publication” if publicly
`
`presented, independent of whether that presentation was further distributed, or
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`meaningfully indexed. See, e.g., In re Klopfenstein, 380 F.3d 1345, 1350-52 (Fed.
`
`Cir. 2004); Ecolochem v. S. Cal. Edison, 227 F.3d 1361, 1369 (Fed. Cir. 2000);
`
`Mass. Inst. of Tech. v. AB Fortia, 774 F.2d 1104, 1109 (Fed. Cir. 1985); MPEP
`
`§2128.01(IV). As the supplement cover shows, the JESC abstract was presented at
`
`the European Society of Cardiology (ESC) Congress. (Pet.22; EX1007, 1-2.) The
`
`page where the abstract appears states it was presented on August 29, 2004 as an
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`abstract on “Epidemiology and treatment of pulmonary arterial hypertension.”
`
`(EX1007, 2.) It is undisputed the conference was widely attended by POSAs.
`
`(EX1105, 19 (conference had 24,527 attendees, including 18,413 professionals);
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`EX1106, ¶28; EX1108, 117:4-13.) Both parties’ experts agree that a POSA would
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`
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`1 See https://www.elsevier.com/about.
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`2
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`Reply in Support of Petition for Inter Partes Review of
`U.S. Patent No. 10,716,793 B2
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`have received a copy of the abstract book prior to or at the meeting. (See EX1106,
`
`¶28; EX1108, 105:20-108:1.) Both experts agree that a POSA would have been
`
`interested in treatments for pulmonary hypertension, including pulmonary arterial
`
`hypertension (“PAH”), and would have been interested in the session in which JESC
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`was presented. (See EX1106, ¶29; EX1108, 104:10-20.)
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`Contrary to PO’s argument (POR15-16), PO’s expert testified that a POSA
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`would have been able to find the JESC abstract within the supplement in which it
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`appears. (EX1108, 104:22-105:15.) This is at least because the supplement (1) had
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`a short table of contents, in which JESC could be found as one of just five abstracts
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`under the subject “Epidemiology and treatment of pulmonary arterial hypertension”
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`(EX1007, 2, 7; Pet.22 (citing EX1036, ¶67)), and (2) was indexed by topic, with
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`JESC appearing as one of two lines of abstracts listed under the subject “Therapy
`
`(Pulmonary circulation)” (EX1092, 10). The table of contents was only five pages,
`
`with the relevant topic on the first page (EX1007, 2), and the topic index only nine
`
`pages. (EX1092, 2-10.) A POSA would have been interested in these topics (see,
`
`e.g., EX1110, 156:3-6), and looked for and easily found the abstract within the
`
`supplement. (EX1106, ¶¶29, 32; EX1112, ¶¶87, 90.) Accordingly, JESC was made
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`publicly available based on the conference. (EX1112, ¶92.)
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`Additionally, JESC was cited in the June 2005 Ghofrani article in the journal
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`Herz (EX1010, 298, 301), an article that was publicly accessible (a point PO does
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`3
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`
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`Reply in Support of Petition for Inter Partes Review of
`U.S. Patent No. 10,716,793 B2
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`not dispute). (EX1036, ¶¶47-55; EX1112, ¶89.) An interested POSA would have
`
`relied on Ghofrani’s disclosures to seek other references on the treatment of PAH
`
`(EX1106, ¶30) and would have been able to access the JESC abstract—by exercising
`
`no more than reasonable diligence—before May 15, 2006. See Bruckelmyer v.
`
`Ground Heaters, 445 F.3d 1374, 1379 (Fed. Cir. 2006); Blue Calypso, 815 at 1350
`
`(citation to article can establish public accessibility).
`
`At the time of the ’793 Patent, “the number of physicians and researchers
`
`working [in the PAH space] was small,” and a POSA would have “known the names
`
`of the other physicians and researchers” working in the space and sought their
`
`publications and presentations. (EX1106, ¶¶27, 29, 33-34.) A POSA would have
`
`known of JESC authors—members of a research group in Germany working on
`
`inhaled therapies for treating PAH, including the only FDA-approved therapy at the
`
`time (iloprost)—and would have sought further work by these authors, including
`
`JESC. (Id.; EX1065; EX1108, 79:5-12, 124:18-125:5.)
`
`Petitioner has shown the abstract was publicly accessible by indexing and
`
`cataloguing by public libraries. Dr. Hall-Ellis, a seasoned expert in library sciences
`
`(EX1036, ¶¶7-10) provided MARC record analysis demonstrating issues of the
`
`European Heart Journal, in which JESC was published, were regularly received and
`
`kept at least at the University of Iowa libraries. (EX1036, ¶¶69-75.) PO’s argument
`
`that journal supplements were irregular and not received by libraries (POR12-14) is
`
`4
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`Reply in Support of Petition for Inter Partes Review of
`U.S. Patent No. 10,716,793 B2
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`belied by Hall-Ellis’s original declaration, which identified a copy of the abstract
`
`from University of Wisconsin-Madison’s library with a receipt date of October 15,
`
`2004. (EX1036, 37 n.22.) PO’s assertion that the journal’s MARC record is
`
`irrelevant to supplements (POR14) is also incorrect—the journal’s MARC record
`
`has fields showing the journal had supplements, and as such, libraries subscribing to
`
`the journal would be expected to hold every supplement as part of their routine
`
`business practice, including the 2004 JESC Supplement, since February 1980.
`
`(EX1112, ¶¶70-78.)2
`
`PO’s attempt to suggest the abstract, by virtue of being contained in a “special
`
`supplement[]” rather than a “normal issue[],” may have been “publish[ed] years
`
`after the conference in question” (POR13) is rebutted by (1) Wyman’s testimony
`
`that she would expect “urgency” in publishing abstracts from a medical conference
`
`(EX1110, 130:14-131:3, 125:13-126:18), and (2) additional copies of the same
`
`abstract, received by three different libraries, all date-stamped as received in 2004.
`
`
`
`2 Additionally, PO’s assertion that the JESC Supplement does not appear in the
`
`European Heart Journal online archive is false. PO’s “expert” acknowledged the
`
`supplement is listed on the journal’s online archive as “Volume 25, Issue suppl_1,
`
`September 2004.” (See EX1110, 139:21-141:2; EX2049, 3; EX1112, ¶¶68-69.)
`
`5
`
`
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`Reply in Support of Petition for Inter Partes Review of
`U.S. Patent No. 10,716,793 B2
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`(EX1089; EX1090; EX1091; EX1112, ¶¶65, 78-86; EX1106, ¶31; EX1110, 58:13-
`
`17 (Wyman testifying that date stamps signify when a periodical is received by a
`
`library).)3 Record evidence conclusively demonstrates that JESC was publicly
`
`accessible through multiple libraries by 2004.
`
`2.
`
`JAHA was publicly accessible before 2006
`
`The record evidence similarly establishes that JAHA was publicly accessible
`
`before May 15, 2006. In fact, the Patent Office used JAHA to reject claims of U.S.
`
`Patent No. 10,376,525, to which the ’793 Patent is terminally disclaimed. (Pet.9;
`
`EX1016, 40.) Moreover, JAHA was published by Lippincott Williams & Wilkins,
`
`an established publisher of the Wolters Kluwer conglomerate since 1998.4 (EX1095,
`
`7, 14; EX1112, ¶61.) VidStream, 981 F.3d at 1065.
`
`Additionally, the journal supplement cover in which JAHA appears shows the
`
`abstract was publicly presented at the 2004 Scientific Sessions of the American
`
`Heart Association, another conference widely attended by POSAs. (EX1008, 1;
`
`
`
`3 All EX1007 citations herein are supported by the identical text in these copies.
`
`4 See https://www.wolterskluwer.com/en/solutions/lippincott-journals;
`
`https://www.bioprocessonline.com/doc/lippincott-williams-wilkins-a-wolters-
`
`kluwer-0001.
`
`6
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`Reply in Support of Petition for Inter Partes Review of
`U.S. Patent No. 10,716,793 B2
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`EX1106, ¶¶21-23; EX1108, 116:4-21; EX1112, ¶¶36, 63.) Both parties’ experts
`
`agree the conference’s programs and supplements would have been provided for
`
`POSAs to identify abstracts on subject matter of interest, and POSAs in possession
`
`of the supplement would have been able to identify the abstract within the
`
`supplement. (EX1106, ¶¶21-23, 27; EX1108, 108:3-20, 111:11-19.) A POSA could
`
`do so because the supplement was indexed alphabetically by author, and JAHA
`
`(Abstract 1414) was indexed under both “Voswinckel, Robert” and “Seeger,
`
`Werner.” (EX1095, 16; EX1113, 5.) These authors were well-known in the small
`
`field, and an interested POSA would have sought their work. (EX1106, ¶27;
`
`EX1065; EX1108, 79:5-12, 124:18-125:5.) Thus, JAHA was publicly available
`
`based on the conference alone. See, e.g., Klopfenstein, 380 F.3d at 1350-52;
`
`Ecolochem, 227 F.3d at 1369; Mass. Inst., 774 F.2d at 1109; MPEP §2128.01(IV).
`
`JAHA was cited in other articles before 2005, evidencing public availability
`
`of the abstract and a POSA’s ability to use those articles as research aids to locate
`
`the abstract through reasonable diligence. JAHA was cited by a March 2005 article
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`authored by Roxana Sulica et al. in the Expert Review of Cardiovascular Therapy.
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`(EX1104 (“Sulica”), 359.) Sulica was itself indexed and easy-to-find. (EX1112,
`
`¶62.) The Sulica authors were able to access JAHA in 2005 and directed their
`
`readers to it. An interested POSA would have relied on Sulica’s disclosures to seek
`
`other references on the treatment of PAH (EX1106, ¶¶25-26), and would have been
`
`7
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`Reply in Support of Petition for Inter Partes Review of
`U.S. Patent No. 10,716,793 B2
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`able to access JAHA with Sulica as a research aid (EX1112, ¶62; EX1110, 122:9-
`
`12, 119:11-18 (PO’s expert agreeing)) before 2006. See Bruckelmyer, 445 F.3d at
`
`1379.
`
`PO’s argument that supplements to the journal were irregular and not received
`
`by libraries is belied by Hall-Ellis’s original declaration, which identified a copy of
`
`the abstract from the British Library with a receipt date of November 22, 2004.
`
`(EX1036, 31 n.21; EX1110, 83:16-19, 85:10-21 (PO’s “expert” admitting having
`
`seen this date-stamped copy); EX1112, ¶37.) PO’s assertion that the journal’s
`
`MARC record is irrelevant to supplements (POR14) is also incorrect—the journal’s
`
`MARC record has fields showing the journal had irregular supplements, and libraries
`
`subscribing to the journal held every supplement, including the 2004 supplement,
`
`since 1950. (EX1112, ¶¶40-48.) 5
`
`PO’s further attempt to suggest the abstract, by virtue of being contained in a
`
`“special supplement[]” rather than a “normal issue[],” may have been “publish[ed]
`
`years after the conference in question” (POR13) is rebutted by (1) the “urgency” in
`
`publishing abstracts from a medical conference (EX1110, 130:14-131:3, 125:13-
`
`
`5 Additionally, PO’s assertion that this supplement does not appear in the Circulation
`
`online archive is false. (See EX1112, ¶39.)
`
`8
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`Reply in Support of Petition for Inter Partes Review of
`U.S. Patent No. 10,716,793 B2
`
`126:18), and (2) additional copies of the same abstract, received by four different
`
`libraries around the world, all date-stamped as received in 2004. (EX1093-EX1096;
`
`EX1112, ¶¶33, 48-58; EX1106, ¶24.)6 Record evidence conclusively demonstrates
`
`JAHA was publicly accessible through multiple libraries by 2004.
`
`B. Claim 1’s “Single Event Dose” of 15-90µg “delivered in 1 to 3
`breaths” is Obvious Over Combination of the ’212 Patent, JAHA,
`and JESC
`
`PO “cannot show no
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