IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`LIQUIDIA TECHNOLOGIES, Inc.,
`Petitioner,
`
`v.
`
`UNITED THERAPEUTICS CORPORATION,
`Patent Owner.
`
`IPR2021-00406
`U.S. Patent No. 10,716,793
`
`DECLARATION OF DR. JASON MCCONVILLE
`
`IPR2021-00406
`United Therapeutics EX2053
`
`
`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
`
`DECLARATION OF DR. JASON MCCONVILLE
`
`IPR2021-00406
`United Therapeutics EX2053
`
`
`
`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`
`I.
`
`II.
`
`Table of Contents
`INTRODUCTION ........................................................................................... 3
`Scope of Analysis .................................................................................. 3
`A.
`B.
`Qualifications ........................................................................................ 4
`C. Materials Considered ............................................................................. 8
`LEGAL STANDARDS PROVIDED BY COUNSEL .................................... 8
`Claim Construction ............................................................................... 8
`A.
`B.
`Anticipation ........................................................................................... 9
`Obviousness ......................................................................................... 11
`C.
`PERSON OF ORDINARY SKILL IN THE ART ........................................ 13
`III.
`IV. BACKGROUND ........................................................................................... 15
`The ’793 Patent ................................................................................... 15
`A.
`Prosecution History of the ’793 Patent ............................................... 17
`B.
`Inhalation Devices and Dosing ........................................................... 17
`C.
`ALLEGED PRIOR ART ASSERTED BY PETITIONER ........................... 19
`’212 Patent ........................................................................................... 19
`A.
`B.
`Voswinckel JESC ................................................................................ 20
`C.
`Voswinckel JAHA ............................................................................... 21
`VI. NONOBVIOUSNESS OF THE ’793 PATENT ........................................... 23
`Ground 1: the ’212 Patent, Voswinckel JESC, and
`A.
`Voswinckel JAHA ......................................................................................... 23
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`V.
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`i
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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`“wherein the therapeutically effective single event
`1.
`dose comprises from 15 micrograms to 90 micrograms of
`treprostinil or a pharmaceutically acceptable salt thereof” ................. 23
`2.
`A Dose of 15-90 micrograms “delivered in 1 to 3
`breaths” ................................................................................................ 44
`Ground 2: the ’212 Patent and Voswinckel JESC .............................. 47
`B.
`VII. CONCLUSION .............................................................................................. 47
`
`ii
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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
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`I.
`
`INTRODUCTION
`A.
`Scope of Analysis
`1.
`I have been retained by counsel for the Plaintiff, United Therapeutics
`
`Corporation (“UTC”) to provide expert opinions related to U.S. Patent No.
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`10,716,793 (“the ’793 patent”).
`
`2.
`
`I understand that Liquidia (“Petitioner”) filed a Petition for Inter Partes
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`Review (“IPR” or “Petition”) with the Patent Trial and Appeal Board (“PTAB” or
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`“Board”), with the Petition asserting six Grounds of unpatentability:
`
`Ground
`1
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`2
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`3
`4
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`5
`6
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`1-8
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`JAHA
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`and
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`’793 Patent Claims Alleged Basis
`’212 patent, Voswinckel
`1-8
`Obviousness:
`JAHA, Voswinckel JESC
`Obviousness: ’212 patent and Voswinckel
`JESC
`Anticipation: Ghofrani
`Obviousness: Voswinckel
`Ghofrani
`Anticipation: Voswinckel 2006
`Obviousness: Voswinckel 2006 and ’212
`patent
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`1
`1, 3, 8
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`1, 3
`2, 4-8
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`3.
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`I understand from counsel that Ghofrani and Voswinckel 2006 are not
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`prior art, which causes Grounds 3-6 to fail. Thus, I have been asked to provide
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`opinions regarding Grounds 1-2, and the references cited therein, only.
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`U.S. Patent No. 10,716,793 B2
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`B.
`4.
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`Qualifications
`My curriculum vitae, which is provided as EX2054, summarizes my
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`professional experience. I provide below further details about my experience that
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`may be pertinent to this matter.
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`5.
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`I am an Associate Professor of Pharmaceutics at the University of
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`New Mexico College of Pharmacy and an Adjunct Professor at the University of
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`Bonn, in the Department of Pharmaceutical Technology, in Bonn, Germany.
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`6.
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`I received my Bachelor of Science, with Honours, in Applied Chemistry
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`from Coventry University, in Coventry, United Kingdom in 1994.
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`7.
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`I was a Research Technician in Pharmaceutics at the Centre for Drug
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`Formulation Studies (CDFS) at the University of Bath, in Bath, United Kingdom
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`from 1994 to 1999. There, my main research project pertained to inhaled
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`controlled-release drug delivery and was specifically related to extending the
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`pharmacodynamic effect of a short acting β-2 agonist in the lung. In addition to this
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`work, I gained experience in many aspects in inhalation therapy, including: particle
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`size reduction for inhaled aerosols, dry powder inhaler devices, nebulization, and
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`application of standardized aerosol testing methods for inhaled products.
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`8.
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`I subsequently earned my Ph.D. in Pharmaceutics from the University
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`of Strathclyde, in Glasgow, United Kingdom in 2002. My Ph.D. dissertation was
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`titled “Pulsed-Release Drug Delivery and Development of the Time-Delayed
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`U.S. Patent No. 10,716,793 B2
`Capsule.” After earning my Ph.D., I was a Post-Doctoral Fellow at the University
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`of Texas at Austin College of Pharmacy from 2002 to 2006, where I worked on the
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`delivery of poorly soluble drug candidates to the lung using a variety of inhaler
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`devices.
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`9.
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`In 2006, I joined the faculty at the University of Texas at Austin
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`as an Assistant Professor of Pharmaceutics in the College of Pharmacy. I assumed
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`my present positions at the University of New Mexico and the University of Bonn
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`in 2012.
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`10.
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`I am a member of several professional societies, including the
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`American Association of Colleges of Pharmacy, the American Association of
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`Pharmaceutical Scientists, and the International Pharmaceutical Excipients Council
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`(IPEC) of the Americas. Additionally, I have served as a scientific advisor to the
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`Respiratory Drug Delivery Conference in Arizona, 2012, as a scientific advisor to
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`the IPEC Americas excipient conference from 2017-2019. Furthermore, in 2017 I
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`also served as a reviewer for the conference proceedings at the 2017 Annual Meeting
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`of the International Pharmaceutical Excipient Council, which included publications
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`on the use and functionality of a wide range of pharmaceutical excipients.
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`Additionally, I have had a recurring role as scientific advisor to the Drug Delivery
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`to the Lungs conference since 2016.
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`U.S. Patent No. 10,716,793 B2
`I have taught many courses related to pharmaceutical dosage form,
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`11.
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`design, and development. For example, I have taught biopharmaceutics to pharmacy
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`students since 2007, in a variety of different core pharmacy courses. As an overview,
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`the course material includes instruction on all main routes of drug delivery and
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`formulation, and includes oral delivery systems such as tablets, capsules formed of
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`film compositions, and oral suspensions. I have also been an advisor to 28 graduate
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`and Pharm.D. students and have been on the dissertation committee for 14 students.
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`12.
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`I have performed practical-design, development and manufacturing
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`work related to a wide variety of inhalation research over the last 25-plus years.
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`13.
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`I have co-authored more than 60 articles, more than 130 abstracts, and
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`many book chapters, including on the topics of oral-dosage design, formulation, and
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`delivery. I have also been a session chair, an invited speaker, or workshop
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`participant on more than 40 occasions, and have been invited to serve as a Review
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`Panel Member at the National Institutes of Health in 2011, 2017, and 2020.
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`14.
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`I have acted as the editor of at least four special themed editions for
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`journals, and serve on the editorial boards for journals Inhalation, and
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`Pharmaceutics, and as an Associate Editor for Drug Development and Industrial
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`Pharmacy. I have also served, and currently serve, as a reviewer for several leading
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`scientific journals, including Drug Development and Industrial Pharmacy,
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`European Journal of Pharmaceutical Sciences, European Journal of Pharmaceutics
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`U.S. Patent No. 10,716,793 B2
`and Biopharmaceutics, International Journal of Pharmaceutics, Journal of
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`Controlled Release, Journal of Pharmaceutical Sciences, Pharmaceutical Research,
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`and Molecular Pharmaceutics.
`
`15.
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`I have received various awards and recognition for my research,
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`including: a research award for a presentation entitled “Design and Evaluation of
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`Pulsatile Drug Delivery Capsule” (University of Strathclyde, Glasgow, May 2001),
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`an outstanding presentation award for “Microwave Dielectric Analysis of Wet
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`Granulations for Erodible HPMC Tablets” (British Pharmaceutical Conference,
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`Glasgow, United Kingdom, September, 2001), a Graduate/Post-Doc Award in
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`Innovative Aspects of Oral Drug Delivery and Absorption for “Improved
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`Dissolution Rate and Bioavailability through the Formation of a Highly Miscible
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`Binary Mixture” (International Symposium on Controlled Release of Bioactive
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`Materials, Miami, FL, June, 2005), a Best Resident and Research Presentation
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`Award: “Aerosolized Itraconazole (ITZ) as Prophylaxis against Invasive Pulmonary
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`Aspergillosis (IPA) due to Aspergillus fumigatus” (American College of Clinical
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`Pharmacy Annual Meeting, 2006), and three research presentation award for novel
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`excipient use presentations from the International Pharmaceutical Excipients
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`Council of the Americas (2009, 2012, and 2014). I have been invited to submit
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`original papers to renowned pharmaceutical science peer reviewed journals at least
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`18 times and have been invited to judge research at international conferences at least
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`U.S. Patent No. 10,716,793 B2
`7 times. Additionally, I was selected as Member of the Society for Teaching
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`Excellence at the University of Texas at Austin in 2011 and nominated for
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`University of Texas System Regents’ Outstanding Teaching Award in 2012.
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`16.
`
`I am a named inventor on ten patents or patent applications.
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`C. Materials Considered
`17.
`In forming my opinions in this declaration, I have relied on my
`
`professional experience and personal knowledge. I have also considered documents
`
`and materials in this case, including the petition, exhibits cited by Petitioner and
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`UTC, and including but not limited to the ’793 patent, ’212 patent, Voswinckel JESC
`
`and JAHA, and the materials cited throughout this report. To the extent I am
`
`provided additional documents and/or information, I reserve the right to supplement,
`
`amend and/or modify my analysis and offer further opinions.
`
`II. LEGAL STANDARDS PROVIDED BY COUNSEL
`18.
`I am not an attorney or an expert in patent law. UTC’s counsel informed
`
`me of the legal standards as they relate to patent invalidity and validity analysis.
`
`A. Claim Construction
`19.
`I understand that the first step in performing a validity analysis of a
`
`patent claim is to interpret the meaning and scope of the claims by construing the
`
`terms and phrases found in those claims. In this proceeding, I understand that the
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`Board’s decision instituting IPR of the ’793 patent does not construe any claim
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`U.S. Patent No. 10,716,793 B2
`terms. See Board’s Decision (Paper No. 18) at 5 (“Neither party presents any terms
`
`for construction. … Accordingly, we determine that no express construction of any
`
`claim term is necessary in order to decide whether to institute trial.”). I also
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`understand that, in litigation between Liquidia and UTC, the Court did not construe
`
`any claim terms for the ’793 patent, either. See United Therapeutics Corporation
`
`v. Liquidia Technologies, Inc., Case No. 20-755 (RGA) (JLH) (D. Del.), D.I. 119 at
`
`1-2 (Claim Construction Order). In performing my analyses and formulating the
`
`opinions in this declaration, I therefore interpreted the asserted claims of the ’793
`
`patent according to their plain and ordinary meaning as understood by the person of
`
`ordinary skill in the art (“POSA”)1 as of the priority date of the ’793 patent.2 I
`
`reserve the right to supplement my analysis in light of any further ruling(s) on claim
`
`construction from the Board or the Court. I understand that those terms that the
`
`parties have not requested the Court construe should be given their plain and
`
`ordinary meaning to a person having ordinary skill in the art at the time of the patent.
`
`B. Anticipation
`20.
`I have been informed by counsel and understand that to anticipate a
`
`patent claim, all of the requirements of that claim must be shown to be present in a
`
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`1 I address the definition of the POSA in section III below.
`2 I address the priority date of the ’793 patent in Section IV.A. below.
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`U.S. Patent No. 10,716,793 B2
`single prior art reference, device or method that was known of, used, or described in
`
`a single previous printed publication or patent. The test for anticipation must be
`
`assessed on a claim-by-claim basis. I also understand that anticipation can occur
`
`when an undisclosed limitation is literally missing, but is present because the prior
`
`art must necessarily function in accordance with, or must include, the undisclosed
`
`limitation.
`
`21.
`
`I have further been informed that only a single reference should be
`
`relied upon to conclude that a claim is anticipated, unless any further references are
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`cited solely to: (a) prove that the primary reference contains an “enabled disclosure;”
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`(b) explain the meaning of a term used in the primary reference; or (c) show that a
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`characteristic not disclosed in the reference is inherent. I understand that to
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`anticipate a claim, the prior art does not need to use the same words as the claim, but
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`all of the requirements of the claim must have been disclosed, either stated expressly
`
`or implied to a person having ordinary skill in the art in the technology of the
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`invention. I understand that for a reference to anticipate a patent claim, that
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`reference must also enable one of ordinary skill in the art to make and use the full
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`scope of the claimed invention without undue experimentation.
`
`22.
`
`I have been informed by counsel and understand that if all the
`
`requirements of a claim are present in a single previous device, or method, or
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`reference, then knowledge or use of such device, or method, or reference in the
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`U.S. Patent No. 10,716,793 B2
`United States can constitute an anticipation only if such knowledge or use is
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`accessible to the public, meaning there is no deliberate attempt to keep it secret. An
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`anticipating public use must constitute a commercial exploitation or be accessible to
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`the public, but public use will not be considered anticipatory if it is conducted for
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`testing purposes.
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`C. Obviousness
`23.
`I have been instructed by counsel and understand that a combination of
`
`prior art references may render a claim obvious if, at the time of the invention, a
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`person of ordinary skill in the art would have selected and combined those prior art
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`elements in the normal course of research and development to yield the claimed
`
`invention. I understand that in making an obviousness inquiry, one should consider
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`the Graham factors: the scope and content of the prior art; the differences between
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`the claimed inventions and the prior art; the level of ordinary skill in the art; and
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`certain secondary considerations, identified below.
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`24.
`
`I further understand that an obviousness analysis is to be performed on
`
`a claim-by-claim basis. I understand that a person of ordinary skill in the art is a
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`person of ordinary creativity, not an automaton. I have been instructed by counsel
`
`and understand that demonstrating obviousness requires more than merely showing
`
`that the prior art includes separate references covering each separate limitation in a
`
`claim under examination. I understand that a conclusion of obviousness requires the
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`U.S. Patent No. 10,716,793 B2
`additional showing that a person of ordinary skill at the time of the invention would
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`have been motivated to combine those references, and, in making that combination,
`
`a person of ordinary skill in the art would have a reasonable expectation of success.
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`I also understand that a fact-finder must be aware of the distortion caused by
`
`hindsight bias and must be cautious of arguments reliant upon ex post reasoning.
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`Counsel has instructed me that when considering obviousness, I should not consider
`
`what is known today or what was learned from the asserted patents. Instead, I should
`
`put myself in the position of a person of ordinary skill in the field at the time of the
`
`invention.
`
`25.
`
`In particular, I understand that it is improper to use the invention as a
`
`roadmap to find its prior art components, because the approach discounts the value
`
`of combining various existing features or principles in a new way so as to achieve a
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`new result. I understand that an invention would not have been obvious to try when
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`one would have had to try all possibilities in a field unreduced by direction of the
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`prior art. Stated another way, when what would have been “obvious to try” would
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`have been to vary all parameters or to try each of numerous possible choices until
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`one possibly arrived at a successful result, where the prior art gave either no
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`indication of which parameters were critical or no direction as to which of many
`
`possible choices would be likely to be successful, an invention would not have been
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`U.S. Patent No. 10,716,793 B2
`obvious. Furthermore, an invention is not obvious to try where the prior art does not
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`guide one toward a particular solution.
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`26.
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`I also have been instructed by counsel that demonstrating obviousness
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`requires an account of the workings of the prior art combinations in sufficiently
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`detail to support a conclusion that a person of ordinary skill in the art would have
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`been motivated to make the combination with a reasonable expectation of success.
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`This account requires a showing in sufficient detail of how a person of ordinary skill
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`in the art would have combined the prior art reference to meet the claimed
`
`limitations, including what a person of ordinary skill in the art would have
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`reasonably expected of how the combination would work.
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`27.
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`It is my understanding that I must also consider certain objective
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`evidence of nonobviousness if present, which includes the prior art as a whole
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`teaching away from the invention, long-felt need for the invention, the failure of
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`others, copying, and industry recognition/praise by others, among others.
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`III. PERSON OF ORDINARY SKILL IN THE ART
`28.
`I have been informed by counsel that a patent is to be interpreted from
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`the perspective of a hypothetical person referred to as the person of ordinary skill in
`
`the art (“POSA”) to which the patent pertains. I have further informed that a
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`determination of the level of ordinary skill is based on, among other things, the type
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`of problems encountered in the art, prior art solutions to those problems, rapidity
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`with which innovations are made, sophistication of the art, and the educational level
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`of active workers in the field. I have been informed that in any particular case, not
`
`every factor may be present, and one or more factors may predominate.
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`29.
`
`I understand that Liquidia’s Petition asserts that, at the time of the
`
`invention:
`
`[The POSA] would have a medical degree with a specialty
`in pulmonology or cardiology, plus at least two years of
`experience treating patients with pulmonary hypertension
`as an attending, including with inhaled therapies, or
`equivalent degree or experience. EX1002, ¶¶17-19. With
`respect to inhaled formulations used in the method to treat
`pulmonary hypertension, a POSA 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). EX1004, ¶¶9-11.
`Petition (Paper No. 1) at 14 (citing Hill Decl., EX1002, and a Gonda
`Decl., EX1004).
`30.
`I further understand from counsel that Dr. Waxman has defined the
`
`POSA as of May 15, 2006 as follows:
`
`[T]he person having ordinary skill in the art (“POSA”)
`would have an M.D. or a graduate degree (Masters or
`Ph.D.) in a field relating to drug development and at least
`two years of practical experience in either (i) the
`investigation or treatment of pulmonary hypertension or
`(ii)
`the development of potential drug candidates,
`specifically in the delivery of drugs by inhalation.
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`U.S. Patent No. 10,716,793 B2
`I further understand that the POSA could have lower level of education if the POSA
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`had more work experience with inhalable drugs.
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`31. The standards proposed by Drs. Hill and Gonda and Dr. Waxman are
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`not radically different. I have adopted the definition of the POSA put forth by Dr.
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`Waxman for my analysis, but note that my conclusions would not change if Dr. Hill
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`and Dr. Gonda’s definitions were adopted.
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`IV. BACKGROUND
`A. The ’793 Patent
`32. The ’793 patent is entitled “Treprostinil Administration by Inhalation,”
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`and issued July 21, 2020.
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`33. The ’793 patent claims priority through a series of applications dating
`
`back to a provisional patent application filed at May 15, 2006. I understand,
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`therefore, that the priority date for the ’793 patent is May 15, 2006. I further
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`understand from counsel and from my review of the Petition that the Petitioner has
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`not disputed this priority date. As a result, I have adopted May 15, 2006 as the
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`priority date for purposes of my analysis and my analysis involves the perspective
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`of the POSA as of the priority date or earlier.
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`34. The Abstract of the ’793 patent states:
`
`Treprostinil can be administered using a metered dose
`inhaler. Such administration provides a greater degree of
`autonomy to patients. Also disclosed are kits that include
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`a metered dose inhaler containing a pharmaceutical
`formulation containing treprostinil.
`35. The specification of the ’793 patent describes the administration of
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`treprostinil (or salts thereof) by inhalation. See, e.g., EX1001 (’793 Patent) at 7:7-
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`12. The ’793 patent describes experiments involving a Respimat® soft mist inhaler
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`(“SMI”) and and Optineb® ultrasonic nebulizer. See, e.g., id. at 8:57-11:67
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`(Respimat® example); 12:1-16:54 (Optineb® example). The patent states,
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`“Conclusion: … Inhaled treprostinil can be applied in high doses (up to 90 μg) with
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`a minimal inhalation time. Inhaled treprostinil exerts high pulmonary selectivity and
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`leads to a long-lasting pulmonary vasodilation.” Id., 18:7-11.
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`36. Consistent with the examples, claim 1 of the ’793 patent recites:
`
`A method of treating pulmonary hypertension comprising
`administering by inhalation to a human suffering from
`pulmonary hypertension a therapeutically effective single
`event dose of a formulation comprising treprostinil or a
`pharmaceutically acceptable salt
`thereof with an
`inhalation device, wherein the therapeutically effective
`single event dose comprises from 15 micrograms to 90
`micrograms of 30 treprostinil or a pharmaceutically
`acceptable salt thereof delivered in 1 to 3 breaths.
`37. The dependent claims narrow claim 1 by requiring a specific type of
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`inhalation device (claims 2-5), a type of formulation (claims 6-7), or requiring the
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`formulation to have no metacresol (claim 8).
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`B.
`Prosecution History of the ’793 Patent
`38. The application leading to the’793 patent was filed January 31, 2020. I
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`understand that during prosecution, there was a rejection based on double patenting
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`in view of claims of U.S. Patent Nos. 9,339,507, 9,358,240, and 10,376,525. EX1015
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`(’793 Patent Prosecution History) at 27-28. With the rejection, the examiner stated
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`that the rejection could be overcome by a “terminal disclaimer.” I understand that
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`the patent applicant filed a terminal disclaimer that resolved the double patenting
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`rejection. Id. at 47-57. The patent examiner issued a Notice of Allowance on June
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`12, 2020. Id. at 6. The ’793 patent issued on July 21, 2020. Id. at 1.
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`C.
`Inhalation Devices and Dosing
`39. By May 15, 2006, and earlier, it was known that there are different
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`concepts relating to drug dosing by inhalation. Regardless of the type of inhalation
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`device used, there will always be some type of dose that is supplied to the device or
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`included within it. One could call this the “nominal dose” or “metered dose.” In the
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`case of a dry powder inhaler (“DPI”), this would be the drug dose in the capsule that
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`is loaded into the DPI. For a single-use metered dose inhaler (“MDI”), the nominal
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`dose or metered dose would be the dose loaded in the device. For a multiple use
`
`device, it would be the dose intended to be metered out during use (e.g., in the case
`
`of a pressurized metered dose inhaler (“pMDI”) it is the drug dose which can be
`
`charged into the device’s metering chamber prior to activation). In a nebulizer, the
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`17
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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`nominal dose would be the dose placed into the nebulizer. The nominal or metered
`
`dose is easiest to prescribe or determine because it can be weighed or otherwise
`
`measured (possibly by mass or volume) before placing into the relevant device.
`
`40. Next, there is the concept of an “emitted dose.” The emitted dose refers
`
`to the dose that is emitted from the device. The emitted dose is less than the nominal
`
`dose because there can be drug lost along the way. For example, in a DPI, not all of
`
`the powder may leave the capsule or device. In an MDI, there is typically some type
`
`of metering chamber that the medication is dispensed from prior to being
`
`administered to the patient. And in a nebulizer, there are also places in the nebulizer
`
`where the aerosol will be retained on its way out of the device, including the solution
`
`reservoir, device components adjacent
`
`to
`
`the reservoir,
`
`tubing, and any
`
`mouthpiece/mask that is present prior to reaching the patient. Thus, the emitted dose
`
`(or “delivered dose”) will be less than the nominal or metered dose, as drug can be
`
`lost along the way.
`
`41. There are other dose concepts as well. In respirable drugs, it was
`
`understood that a dose intended for lung delivery should have a particle size (whether
`
`liquid aerosol or dry powder) of around 5 microns or less. To approximate the dose
`
`actually deposited within the lung of a patient, the POSA could consider the “fine
`
`particle dose,” which would be the dose of particles with a particle size of some
`
`threshold (e.g., 5 microns, or another cutoff selected under the circumstances) or
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`18
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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`less. Often this fine particle dose will be less than the delivered dose. The fine
`
`particle dose could and can be ascertained by testing with equipment such as the
`
`Next Generation Impactor (“NGI”). Another dose concept would be the “lung
`
`dose,” which generally would refer to the dose actually delivered to a patient’s lungs,
`
`but which sometimes is used interchangeably with the fine particle dose since
`
`measuring the dose delivered to a patient’s lungs in vivo can be more difficult.
`
`V. ALLEGED PRIOR ART ASSERTED BY PETITIONER
`A.
`’212 Patent
`42. Both Drs. Hill and Gonda cite the ’212 patent, which is entitled,
`
`“Method For Treating Peripheral Vascular Disease By Administering Benzindene
`
`Prostaglandins By Inhalation.” EX1006 at (54). As the Abstract of the ’212 patent
`
`explains, “A benzindene prostaglandin known as UT-15 has unexpectedly superior
`
`results when administered by inhalation compared to parenterally administered UT-
`
`15 in sheep with induced pulmonary hypertension.” EX1006 at Abstract.
`
`43. The ’212 patent describes testing done in tracheotomized sheep,
`
`involving UT-15 (which I understand to refer to treprostinil3) delivered by inhalation
`
`using a continuous nebulizer.
`
`
`3 See EX1046 (’240 patent) at 5:41-44 (describing the ’212 patent as addressing the
`administration of treprostinil by inhalation).
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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`In Example 1, six sheep were administered treprostinil by inhalation
`
`44.
`
`through a tracheotomy for 30 minutes. EX1006 at 8:37-9:60. In Example 2, data
`
`was taken to assess whether a compound known as U44069 would cause stable
`
`induced elevation of pulmonary vascular resistance. Id. at 9:62-10:32. In Example
`
`3, data was taken after 30 minutes of a baseline solution followed by aerosol delivery
`
`of treprostinil for 90 minutes. Id. at 10:33-57. In example 4, two experiments were
`
`performed to assess the dose response of IV-infused versus aerosolized treprostinil.
`
`Id. at 10:62-11:61. In example 5, two experiments were performed to assess the
`
`impact of IV and aerosolized treprostinil on pulmonary hypertension induced by
`
`U44069. Id. at 11:62-13:15.
`
`B. Voswinckel JESC
`45. Voswinckel JESC contains an abstract entitled “Inhaled treprostinil is
`
`a potent pulmonary vasodilator in severe pulmonary hypertension.” EX1007 at 7.
`
`Voswinckel JESC states that an “OptiNeb ultrasound nebulizer” was used for 6
`
`minutes in concentrations of 16, 32, 48, and 64 μg/mL. A summary of the patients
`
`treated with treprostinil is below:
`
`Concentration
`(μg/mL)
`16
`
`32
`
`No. Patients
`
`6
`
`6
`
`No. Patients
`with Side
`Effects
`0
`
`2
`
`20
`
`Side Effects
`
`“no significant
`adverse events”
`“headache, cough or
`bronchoconstriction”
`
`
`
`
`
`Concentration
`(μg/mL)
`48
`
`64
`
`No. Patients
`
`6
`
`3
`
`2
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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`No. Patients
`with Side
`Effects
`1
`
`Side Effects
`
`“headache, cough or
`bronchoconstriction”
`“headache, cough or
`bronchoconstriction”;
`also one patient had
`“major headache for
`one hour”
`
`EX1007 at 7.
`46. Thus, at the 32, 48, and 64 μg/mL concentrations, the POSA would
`
`understand that (2+1+2) / (6+6+3) = 33.3% of patients overall had side effects. More
`
`specifically, 2/6 = 33.3% of the patients at 32 μg/mL had side effects, 1/6 = 16.7%
`
`of patients at 48 μg/mL had side effects, and 2/3 = 66.7% of patients at 64 μg/mL
`
`had side effects. Voswinckel JESC concludes by stating that “at a concentration of
`
`16μg/ml, near maximal pulmonary vasodilatation [sic] is achieved without adverse
`
`effects.” Id.
`
`C. Voswinckel JAHA
`47. Voswinckel JAHA contains an abstract entitled “Inhaled Treprostinil
`
`Sodium (TRE) For the Treatment of Pulmonary Hypertension.” EX1008 at 3.
`
`Voswinckel JAHA states that a “pulsed OptiNeb® ultrasound nebulizer” was used
`
`for 3 single breaths with a concentration of treprostinil of 600 μg/mL. Id.
`
`Voswinckel JAHA does not describe the “pulsed” feature of the nebulizer, and I am
`
`not aware of evidence from Petitioner or its experts describing a standard “pulsed”
`21
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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`feature in the prior art.4 Thus, Petitioner, Dr. Hill and Dr. Gonda have not shown
`
`that the POSA would interpret the “pulsed” feature in any particular way, let alone
`
`what that interpretation would be.
`
`48. Voswinckel JAHA describes a
`
`lack of side effects for
`
`the
`
`compassionate use patients over 3 months, of which there were only 2 patients.
`
`Voswinckel JAHA does not describe, one way or the other, whether the remaining
`
`15 of 17 patients experienced any adverse effects. Id. The number of patients—
`
`n=2—is a small number upon which to base an assessment of whether three months
`
`of dosing presents side effects. Other patients had only a single day dose, and the
`
`reference does not ident
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