Declaration of Igor Gonda 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
`
`
`
`
`U.S. Patent No. 10,716,793 B2
`
`
`DECLARATION OF IGOR GONDA, Ph.D.
`
`
`
`Liquidia's Exhibit 1004
`Page 1
`
`

`

`TABLE OF CONTENTS
`
`
`Page
`
`
`I.
`
`V.
`
`INTRODUCTION AND QUALIFICATIONS .............................................. 1
`A. Qualifications and Experience ............................................................. 1
`B. Materials Considered ............................................................................ 4
`PERSON OF ORDINARY SKILL IN THE ART ....................................... 11
`II.
`III. STATEMENT OF LEGAL PRINCIPLES ................................................... 12
`IV. RELEVANT TECHNICAL BACKGROUND ............................................ 14
`A. History of Inhalation Therapy ............................................................ 15
`B.
`Inhaled Treprostinil and Its Analogues .............................................. 17
`C. Well Known Considerations for Inhalation Therapies ...................... 21
`THE ’793 PATENT ...................................................................................... 26
`A.
`The Specification ................................................................................ 26
`B.
`The Claims of the ’793 Patent ............................................................ 28
`VI. SUMMARY OF PRIOR ART ...................................................................... 29
`A.
`’212 Patent [Ex. 1006] ....................................................................... 29
`B. Voswinckel JESC [Ex. 1007] ............................................................. 31
`C. Voswinckel JAHA [Ex. 1008] ........................................................... 33
`D. Voswinckel 2006 [Ex. 1009] .............................................................. 36
`VII. APPLICATION OF THE PRIOR ART TO THE CLAIMS ........................ 37
`A. Ground 1: Claims 1–8 are Obvious over ’212 Patent in
`Combination with Voswinckel JESC Voswinckel JAHA ................. 38
`
`Independent Claim 1 ................................................................ 38
`
`Dependent Claim 2 .................................................................. 38
`
`Dependent Claim 3 .................................................................. 40
`
`Dependent Claim 4 .................................................................. 41
`
`Dependent Claim 5 .................................................................. 43
`
`Dependent Claim 6 .................................................................. 44
`
`Dependent Claim 7 .................................................................. 45
`
`Dependent Claim 8 .................................................................. 45
`
`- i -
`
`Liquidia's Exhibit 1004
`Page 2
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`
`
`B. Ground 2: Claims 1–8 are Obvious over ’212 Patent in
`Combination with Voswinckel JESC ................................................. 47
`
`Independent Claim 1 ................................................................ 47
`
`Dependent Claims 2-8 .............................................................. 48
`C. Ground 4: Claims 1, 3, and 8 are Rendered Obvious by
`Voswinckel JAHA in Combination with Ghofrani ............................ 49
`
`Independent Claim 1 ................................................................ 49
`
`Dependent Claim 3 .................................................................. 49
`
`Dependent Claim 8 .................................................................. 49
`D. Ground 5: Claims 1 and 3 Are Anticipated by Voswinckel 2006 ..... 50
`
`Independent Claim 1 ................................................................ 50
`
`Dependent Claim 3 .................................................................. 50
`Ground 6: Claims 2 and 4-8 are Obvious Over Voswinckel
`2006 in Combination with the ’212 Patent ........................................ 51
` Motivation to Combine With a Reasonable Expectation
`of Success ................................................................................. 51
`Dependent Claim 2 .................................................................. 53
`
`Dependent Claim 4 .................................................................. 54
`
`Dependent Claim 5 .................................................................. 55
`
`Dependent Claim 6 .................................................................. 56
`
`Dependent Claim 7 .................................................................. 57
`
`Dependent Claim 8 .................................................................. 58
`
`VIII. NO SECONDARY CONSIDERATIONS OF NON-OBVIOUSNESS ...... 60
`IX. CONCLUSION ............................................................................................. 63
`
`E.
`
`- ii -
`
`Liquidia's Exhibit 1004
`Page 3
`
`

`

`Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`I, Igor Gonda, Ph.D. declare as follows:
`
`I.
`
`INTRODUCTION AND QUALIFICATIONS
`A. Qualifications and Experience
`1.
`I am currently the founder and CEO of Respidex LLC, which has
`
`offered consulting services to pharmaceutical and medical device companies since
`
`2018. Before founding Respidex LLC, I held leadership positions at several
`
`pharmaceutical companies, including Aradigm Corporation, a company that focused
`
`on developing inhalation therapies for the prevention and treatment of serious
`
`respiratory and systemic diseases.
`
`2.
`
`In 1971, I received my Bachelor of Science in Chemistry from the
`
`University of Leeds. In 1974, I received my Ph.D. in Physical Chemistry from the
`
`University of Leeds. After working as a Project Chemist for Nicholas Research
`
`Laboratories, I served as a Lecturer at the University of Aston’s Pharmacy
`
`Department, located in Birmingham, U.K., from 1975 to 1982. My research was
`
`primarily on inhalation therapies, including dry powder inhaler and liquid
`
`formulations. I taught undergraduate and graduate courses in Physical Pharmacy
`
`and Pharmaceutical Sciences, which included lectures on inhalation products. Then,
`
`from 1983 to 1992, I served as a Lecturer and later Senior Lecturer at the University
`
`of Sydney’s Department of Pharmacy. While at the University of Sydney, my
`
`1
`
`Liquidia's Exhibit 1004
`Page 4
`
`

`

`Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`research on inhalation expanded into human studies and investigations of liquid
`
`aerosolized products. During my time at the University of Aston and University of
`
`Sydney, I also consulted for pharmaceutical companies, compendial bodies, and
`
`pharmaceutical regulatory authorities.
`
`3.
`
`After leaving the University of Sydney in 1992, I served as a Senior
`
`Scientist and Group Leader in Genentech, Inc.’s Aerosol Drug Delivery Group and
`
`later Pharmaceutics department where I prepared and executed the development plan
`
`for pulmonary delivery of the first human recombinant protein administered by
`
`inhalation (Pulmozyme®), which is an aqueous formulation delivered via a
`
`nebulizer. See Ex. 1050 (Pulmozyme® Label). During that time, I also led the
`
`selection of potential technologies for inhalation delivery of Genentech’s
`
`development candidates, which included nebulizers, soft mist inhalers, and dry
`
`powder inhalers. In particular, the group that I led put a significant effort into the
`
`development of a “metered dose” dry powder inhaler for recombinant human
`
`rhDNase.
`
`4.
`
`Later, in 1995, I joined Aradigm Corporation as Vice President of
`
`Research and Development. Five years later, I was promoted to Chief Scientific
`
`Officer of Aradigm where I led the New Product Research Department, which
`
`focused on preclinical and clinical exploration of new therapeutic and technological
`
`2
`
`Liquidia's Exhibit 1004
`Page 5
`
`

`

`Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`opportunities, including new inhalation therapies, such as a proprietary soft mist
`
`inhaler AERx. From 2001 to 2006, I served as CEO and Managing Director of
`
`Acrux Limited, an emerging company in Australia’s life science sector that
`
`developed a unit dose metered spray technology for dermal and transdermal
`
`administration. Then, in 2006, I rejoined Aradigm as Chief Executive Officer and
`
`President between the years 2006 and 2018. There, I oversaw the research and
`
`development of inhaled therapies using nebulizers and metered dose soft mist
`
`inhalers, which included laboratory investigations, preclinical studies, clinical
`
`studies, and extensive interactions with manufacturers, regulatory authorities, and
`
`pharmaceutical companies.
`
`5.
`
`I have authored or co-authored well over 100 publications, including
`
`research articles, reviews, and book chapters in the areas of treatment of respiratory
`
`diseases, pulmonary drug delivery, and other aspects of clinical and pharmaceutical
`
`sciences. I am a named inventor of over 120 patents and patent applications in the
`
`United States and many patents and patent applications in other countries.
`
`Additionally, I have been invited to speak and serve as a session chairperson at many
`
`national and international scientific conferences and have served on the editorial
`
`boards of several journals in the areas of pharmaceutical sciences and drug delivery.
`
`6.
`
`My Curriculum Vitae is submitted herewith as Exhibit 1005.
`
`3
`
`Liquidia's Exhibit 1004
`Page 6
`
`

`

`Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`
`7.
`
`I have been retained by counsel for Petitioner Liquidia
`
`Technologies, Inc. (“Petitioner”) to provide my expert opinion in connection with
`
`the above-captioned proceeding. More particularly I have been asked to provide my
`
`opinion about the formulations and delivery devices for inhaled therapies described
`
`in U.S. Patent No. 10,716,793 (the “’793 Patent”) (Ex. 1001) as well as the state of
`
`the art of formulations for inhaled therapies and the devices used for those therapies.
`
`I am being compensated by Petitioner for my time spent preparing this declaration,
`
`preparing to give and giving any testimony that may be required, and performing
`
`other related work, at my consulting rate of $850 per hour, plus reasonable expenses.
`
`My compensation is not contingent on any opinions or outcomes from this case. The
`
`following is my written declaration on these topics.
`
`B. Materials Considered
`8.
`The analysis that I provide in this Declaration is based on my
`
`education, research, and experience, as well as my investigation and study of
`
`relevant materials, including the ’793 Patent. I have further reviewed the declaration
`
`of Dr. Nicholas Hill in support of the Petitioner. Ex. 1002. I have cited to the
`
`following documents in my analysis below:
`
`Exhibit
`No.
`1001
`
`Description of Document
`U.S. Patent No. 10,716,793 B2 to Olschewski, et al. (“’793
`Patent”)
`
`4
`
`Liquidia's Exhibit 1004
`Page 7
`
`

`

`Exhibit
`No.
`1002
`1003
`1005
`1006
`1007
`
`1008
`
`1009
`
`1010
`
`1018
`1019
`
`Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`
`Description of Document
`Declaration of Dr. Nicholas Hill (“Hill Decl.”)
`Curriculum Vitae of Dr. Nicholas Hill
`Curriculum Vitae of Dr. Igor Gonda
`U.S. Patent No. 6,521,212 B1 to Cloutier, et al. (“’212 Patent”)
`Voswinckel, R., et al., Abstract 218: “Inhaled treprostinil is a
`potent
`pulmonary
`vasodilator
`in
`severe
`pulmonary
`hypertension,” European Heart Journal 25:22
`(2004)
`(“Voswinckel JESC”)
`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”)
`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”)
`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)
`Remodulin® 2004 Label
`Stein, S.W., et al., “The History of Therapeutic Aerosols: A
`Chronological Review,” Journal of Aerosol Medicine and
`Pulmonary Drug Delivery, 30(1):20-41 (2017) (“Stein”)
`
`5
`
`Liquidia's Exhibit 1004
`Page 8
`
`

`

`Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`
`Exhibit
`No.
`1020
`
`Description of Document
`Clark, A.R., “Medical Aerosol Inhalers: Past, Present, and
`Future,” Aerosol Science and Technology, 22:374-91 (1995)
`(“Clark”)
`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”)
`Olschewski, H., et al., “Inhaled Prostacyclin and Iloprost in
`Severe Pulmonary Hypertension Secondary to Lung Fibrosis,”
`American Journal of Respiratory Critical Care Medicine,
`160:600-07 (1999) (“Olschewski 1999”)
`Haché, M., et al., “Inhaled epoprostenol (prostacyclin) and
`pulmonary hypertension before cardiac surgery,” Journal of
`Thoracic and Cardiovascular Surgery, 125:642-49 (2003)
`(“Hache”)
`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”)
`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”)
`U.S. Patent No. 6,242,482 B1 to Shorr, et al. (“Shorr”)
`U.S. Patent Application Publication No. US 2004/0265238 A1
`to Chaudry (“Chaudry”)
`Ventavis® Label 2004
`
`1027
`1028
`
`1021
`
`1023
`
`1024
`
`1025
`
`1026
`
`1029
`
`6
`
`Liquidia's Exhibit 1004
`Page 9
`
`

`

`Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`
`Exhibit
`No.
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`1037
`1038
`
`1039
`
`1040
`
`1042
`
`Description of Document
`Newman, S.P., “Aerosols”, Chapter from Encyclopedia of
`Respiratory Medicine pp. 58-64 (2006) (“Newman”)
`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”)
`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”)
`Rau, J.L., “Determinants of Patient Adherence to an Aerosol
`Regimen,” Respiratory Care 50(10):1346-56 (2005) (“Rau
`2005”)
`Geller, D., et al., “Bolus Inhalation of rhDNase with the AERx
`System in Subjects with Cystic Fibrosis,” Journal of Aerosol
`Medicine, 16(2):175-82 (2003) (“Geller 2003”)
`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”)
`English translation of OptiNeb® User Manual 2005
`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”)
`Chew N. and Chan H.-K., “Pharmaceutical Dry Powder
`Aerosol Delivery,” KONA, No. 19, pp. 46-56 (2001) (“Chew
`and Chan”)
`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://investors.liquidia.com/news-releases/news-release-
`
`7
`
`Liquidia's Exhibit 1004
`Page 10
`
`

`

`Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`
`Exhibit
`No.
`
`Description of Document
`details/liquidia-submits-new-drug-application-liq861-
`treprostinil
`2009 Tyvaso® Label, available at
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/02
`2387s015lbl.pdf
`U.S. Patent No. 9,358,240 to Olschewski, et al. (“’240 Patent”)
`Hoeper, M.M., et al., “Long-Term Treatment of Primary
`Pulmonary Hypertension with Aerosolized Iloprost, a
`Prostacyclin Analogue,” N 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”)
`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
`Pulmozyme® Label
`Farber, H.W. and Loscalzo, J., “Pulmonary Arterial
`Hypertension,” N Engl J Med, 351:1655-65 (2004) (“Farber
`and Loscalzo”)
`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”)
`Flolan® Label
`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”)
`
`1053
`1054
`
`1043
`
`1046
`1047
`
`1049
`
`1050
`1051
`
`1052
`
`8
`
`Liquidia's Exhibit 1004
`Page 11
`
`

`

`Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`
`Exhibit
`No.
`1055
`
`1056
`
`1057
`
`1058
`
`1060
`
`1061
`
`1062
`
`1064
`
`Description of Document
`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”)
`Telko, M.J. and Hickey, A.J., “Dry Powder Inhaler
`Formulation,” Respiratory Care, 50(9):1209-27 (2005) (“Telko
`and Hickey”)
`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-/
`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”)
`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”)
`Dalby, R., et al., “A review of the development of Respimat®
`Soft MistTM Inhaler,” International Journal of Pharmaceutics,
`283:1-9 (2004) (“Dalby”)
`Gessler, T., et al., “Ultrasonic versus jet nebulization of iloprost
`in severe pulmonary hypertension,” Eur Respir J, 17:14-19
`(2001) (“Gessler”)
`Dolovich, M.B., et al., “Device Selection and Outcomes of
`Aerosol Therapy: Evidence-Based Guidelines,” CHEST,
`127:335-71 (2005) (“Dolovich”)
`
`9
`
`Liquidia's Exhibit 1004
`Page 12
`
`

`

`Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`
`Exhibit
`No.
`1065
`
`1066
`1069
`
`1070
`
`1071
`
`1073
`
`1074
`
`1075
`
`1076
`
`Description of Document
`Olschewski, H., et al., “Inhaled Iloprost for Several Pulmonary
`Hypertension,” N Engl J Med, 347(5):322-29 (2002)
`(“Olschewski 2002”)
`AccuNeb® Label
`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”)
`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”)
`Aradigm Corporation Form 10-Q for the quarterly period ended
`June 30, 2009, available at
`https://www.sec.gov/Archives/edgar/data/1013238/000095012
`309031361/f53244e10vq.htm
`Orenitram® Label, available at
`https://www.orenitram.com/pdf/Orenitram-Prescribing-
`Information.pdf
`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
`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
`
`10
`
`Liquidia's Exhibit 1004
`Page 13
`
`

`

`Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`
`II.
`
`PERSON OF ORDINARY SKILL IN THE ART
`9.
`I understand that an assessment of the claims of the ’793 Patent should
`
`be undertaken from the perspective of a person of ordinary skill in the art as of the
`
`earliest claimed priority date, which I have been advised by counsel to be May 15,
`
`2006. I have been advised that to determine the appropriate level of a person having
`
`ordinary skill in the art, the following factors may be considered: (1) the types of
`
`problems encountered by those working in the field and prior art solutions thereto;
`
`(2) the sophistication of the technology in question, and the rapidity with which
`
`innovations occur in the field; (3) the educational level of active workers in the field;
`
`and (4) the educational level of the inventor.
`
`10.
`
`In my opinion, a person of ordinary skill in the art (“POSA” or “skilled
`
`artisan”) as of May 2006 with respect to inhaled formulations used in a method of
`
`treating pulmonary hypertension would be a Ph.D. in pharmaceutical science or a
`
`related discipline like chemistry or medicinal chemistry, plus two years of
`
`experience in pharmaceutical formulations, including inhaled products, or
`
`equivalent (e.g., an M.S. in the same fields, plus 5 years of experience).
`
`11. My opinions regarding the level of ordinary skill in the art are based
`
`on, among other things, my review of the ’793 Patent, the prior art, and my over 45
`
`years working in the inhalation research field.
`
`11
`
`Liquidia's Exhibit 1004
`Page 14
`
`

`

`Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
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`12. As reflected in my qualifications set forth above and in my curriculum
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`vitae (Ex. 1005), I qualified as a POSA with respect to inhaled formulations at the
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`time of the alleged invention (before May 2006).
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`III. STATEMENT OF LEGAL PRINCIPLES
`A. Claim Construction
`13.
`I understand that the claim terms are given their ordinary and customary
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`meaning, which is the meaning that the term would have to a POSA as of the
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`effective filing date, unless the patent applicant supplied a different meaning. I have
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`reviewed the specification and claims of the ’793 Patent and applied the ordinary
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`and customary meaning that the claim terms would have to a POSA as of May 15,
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`2006.
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`B. Obviousness
`14. Counsel1 has advised me that under pre-AIA 35 U.S.C. § 103, effective
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`before March 16, 2013, a patent claim may be found invalid as obvious if, at the time
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`when the invention was made, the subject matter of the claim, considered as a whole,
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`would have been obvious to a person having ordinary skill in the field of the
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`technology (the “art”) to which the claimed subject matter belongs.
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`1 All references to “counsel” are to Liquidia’s counsel.
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`Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`
`15.
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`I understand that a person of ordinary skill in the art is assumed to have
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`knowledge of all prior art in evaluating the prior art. I have been advised by counsel
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`that obviousness may be shown by demonstrating that it would have been obvious
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`to modify what is taught in a single piece of prior art to create the patented invention.
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`Obviousness may also be shown by demonstrating that it would have been obvious
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`to combine the teachings of more than one item of prior art. I have been advised by
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`counsel that a claimed invention is obvious if a POSA would have been motivated
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`to combine the teachings in the prior art and would have had a reasonable
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`expectation of success in doing so.
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`16.
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`I understand that one skilled in the art can combine various prior art
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`references based on the teachings of those prior art references, the general
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`knowledge present in the art, or common sense. I understand that a motivation to
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`combine references may be implicit in the prior art, and there is no requirement that
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`there be an actual or explicit teaching to combine two references. Thus, one may
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`take into account the inferences and creative steps that a person of ordinary skill in
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`the art would employ to combine the known elements in the prior art in the manner
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`claimed by the patent at issue. I understand that one should avoid “hindsight bias”
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`and ex post reasoning in performing an obviousness analysis. But this does not mean
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`Page 16
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`Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`that a POSA for purposes of the obviousness inquiry does not have recourse to
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`common sense.
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`17.
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`I also have been informed by counsel that the following factors should
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`be considered in analyzing obviousness: (1) the scope and content of the prior art;
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`(2) the differences between the prior art and the claims; and (3) the level of ordinary
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`skill in the pertinent art. I also understand that certain other factors known as
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`“secondary considerations” such as commercial success, unexpected results, long
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`felt but unmet need, industry acclaim, simultaneous invention, copying by others,
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`skepticism by experts in the field, and failure of others may be utilized as indicia of
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`nonobviousness. I understand, however, that secondary considerations should be
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`connected, or have a “nexus,” with the invention claimed in the patent at issue.
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`C. Anticipation
`18. Counsel has advised me that a prior art reference can also be
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`“anticipatory,” meaning that the reference alone discloses every element of the
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`claim.
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`IV. RELEVANT TECHNICAL BACKGROUND
`19. Based on my review of the ’793 Patent, it appears to be directed to
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`methods of treating pulmonary hypertension where treprostinil is delivered by
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`inhalation. Ex. 1001 (’793 Patent) at Abstract, claims 1-8. The claims of the ’793
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`Page 17
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`Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
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`Patent are specific to inhaled treprostinil, because treating pulmonary hypertension
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`(“PH”) with treprostinil via other routes of administration was already discovered,
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`patented, and approved by the FDA before 2006. See Ex. 1018 (Remodulin® 2004
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`Label) (approving use of treprostinil for both subcutaneous injection and intravenous
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`administration by 2004).
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`20.
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`In this section, I provide a brief discussion of the state of the field of
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`inhaled therapies and treprostinil as of May 2006, based both on my personal
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`involvement and experience in the field then and based on the publications and
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`patents that were publicly available and known to a POSA by then.
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`A. History of Inhalation Therapy
`21.
`Inhalation therapy has been used since ancient times, and the inhalation
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`of therapeutic aerosols for the treatment of asthma is described as early as 600 BC.
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`Ex. 1019 (Stein) at 20-21. Mass production of standardized inhalation devices
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`arrived with the industrial revolution in the late 18th century to 19th century. Id. at
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`23-25.
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`22. Devices that reduced a medicated liquid to fine droplets for inhalation,
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`such as atomizers and nebulizers, were developed in the late 1800s. Id. at 25. And
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`dry powder inhalers (“DPI”) were first developed in 1852, as a powdered medicine
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`Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`in a glass inhaler. Id. at 26. Other DPIs for various uses were developed before
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`1900. Id. at 26-27.
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`23. After the passage of the Food and Drug Act of 1906, multiple clinical
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`studies were conducted to evaluate the effectiveness of various therapeutic aerosols.
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`Id. at 27. By the mid-1950s, the “aerosol delivery of beta agonists, corticosteroids,
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`and anticholinergic . . . drugs had all been demonstrated to be effective for the
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`treatment of respiratory diseases,” and “[c]onvenient delivery by a DPI or squeeze
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`bulb glass nebulizers had been demonstrated.” Id. DPIs and nebulizer technologies
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`advanced from 1956 to 1986. See id. at 29.
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`24. The first propellant meter dosed inhaler (“MDI” or, more specifically,
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`“pMDI” to distinguish from other inhalers that use metered doses) was introduced
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`in 1956 as the “first inhaler device that achieved effective lung delivery in a truly
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`convenient and portable device and rapidly became the dominant delivery system
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`for treatment of asthma.” Id. at 27. These inhalers passed FDA approval and were
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`marketed as the Medihaler Epi and Medihaler Iso in 1956. Id. at 28. But these
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`inhalers had an issue: the patient had to synchronize the release of the drug dose
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`with their inhalation. The first-breath actuated MDI, the Autohaler, addressed this
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`concern and was launched in 1970. Id.
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`Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`
`25. The period from 1987 to the 21st century was “a period of
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`unprecedented innovation and growth in the delivery of therapeutic aerosols.” Id. at
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`30. The “signing of the Montreal Protocol in September of 1987 dramatically
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`changed the pharmaceutical aerosol industry and led to a surge of development and
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`innovation of inhaler products that eventually resulted in hydrofluoroalkane (HFA)
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`MDIs and a large increase in the number and types of DPIs available, as well as the
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`development of advanced nebulizer systems and other inhalation devices.” Id.; see
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`also id. at 30-32. By 1995, “three major types of medical aerosol inhalers” – the
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`nebulizer, the pressurized metered dose inhaler, and the dry powder inhaler were on
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`the market. Ex. 1020 (Clark) at Abstract. By 2006, multiple DPIs and nebulizers
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`had been approved by the FDA and were available, as well as the soft mist inhaler
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`Respimat. Ex. 1019 (Stein) at Table 3, Table 4, 33-36, Figure 15. Dozens of MDI
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`inhalers were also approved by the FDA by 2006. See, e.g., id. at Tables 1-3.
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`B.
`Inhaled Treprostinil and Its Analogues
`26. Treprostinil is a prostacyclin receptor agonist, meaning that it
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`stimulates the prostacyclin recept