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 AARON WAXMAN, M.D., PH.D
`
`IPR2021-00406
`United Therapeutics EX2052
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`

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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`
`I.
`
`II.
`III.
`
`Table of Contents
`INTRODUCTION ........................................................................................... 1
`Scope of Analysis .................................................................................. 1
`A.
`B.
`Qualifications ........................................................................................ 1
`C. Materials Considered ............................................................................. 3
`PERSON OF ORDINARY SKILL IN THE ART .......................................... 4
`LEGAL STANDARDS PROVIDED BY COUNSEL .................................... 6
`Claim Construction ............................................................................... 6
`A.
`B.
`Anticipation ........................................................................................... 7
`C.
`Obviousness ........................................................................................... 8
`IV. BACKGROUND ........................................................................................... 11
`The ’793 Patent and Priority Date ....................................................... 11
`A.
`General Overview of Pulmonary Hypertension .................................. 12
`B.
`General Overview of Inhalation Therapies ......................................... 14
`C.
`Overview of the Claimed Invention .................................................... 17
`D.
`VALIDITY OF THE ’793 PATENT ............................................................ 19
`Overview of the Challenged Grounds and Cited
`A.
`References ...................................................................................................... 19
`1.
`The ’212 Patent (EX1006) ........................................................ 22
`Voswinckel JESC (EX1007) ..................................................... 31
`2.
`Voswinckel JAHA (EX1008) ................................................... 35
`3.
`Ground 1: the ’212 Patent, Voswinckel JESC, and
`B.
`Voswinckel JAHA Fail to Render Claims 1-8 Obvious ................................ 37
`
`V.
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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” ................. 38
`2.
`“delivered in 1 to 3 breaths” ..................................................... 39
`Ground 2: the ’212 Patent and Voswinckel JESC Fail to
`C.
`Render Claims 1-8 Obvious .......................................................................... 44
`VI. OBJECTIVE INDICIA OF NON-OBVIOUSNESS ..................................... 46
`VII. CONCLUSION .............................................................................................. 52
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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`
`I.
`
`INTRODUCTION
`A.
`Scope of Analysis
`1.
`I, Aaron Waxman, M.D., Ph.D., submit this declaration on behalf of
`
`United Therapeutics Corporation (“UTC” or “Patent Owner”) in connection with
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`responding to the Petition for Inter Partes Review (“IPR” or “Petition”) of U.S.
`
`Patent No. 10,716,793 (“the ’793 patent”) filed by Liquidia Technologies, Inc.
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`(“Liquidia” or “Petitioner”). I am over the age of eighteen and otherwise competent
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`to make this declaration.
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`2.
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`I am being compensated at my standard consulting rate for my time in
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`connection with this matter. My compensation is not contingent on the substance of
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`my opinions or the outcome of the proceedings.
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`3.
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`I understand that Petitioner has asserted six grounds of unpatentability
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`in this IPR challenging claims 1 to 8 of the ’793 patent by relying upon allegations
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`that the claims are anticipated and/or obvious. I further understand that the scope of
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`issues to be considered in an IPR are limited to those grounds disclosed in the
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`Petition, and so I limit my opinions to those grounds.
`
`B. Qualifications
`4.
`I am a pulmonary critical physician in Boston, Massachusetts. I have
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`been practicing as a pulmonary and critical care doctor for over 20 years. As a
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`practicing physician, one of the areas in which I specialize includes all aspects of
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`pulmonary vascular disease
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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`including pulmonary hypertension, and more
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`specifically pulmonary arterial hypertension. I have treated thousands of patients
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`with pulmonary hypertension using intravenous, subcutaneous, oral and inhaled
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`forms of medications. Importantly, dosing between all the various forms of
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`administration has shown great variability, ranging from nanograms to milligrams.
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`5.
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`I am Executive Director of the Center for Pulmonary and Heart Disease
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`in the Heart and Vascular and Lung Centers, and Director of the Pulmonary Vascular
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`Disease Program at Brigham and Women’s Hospital in Boston, Massachusetts. I am
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`board certified in Internal Medicine, Pulmonary Disease and Critical Care Medicine.
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`I am also a member of the American College of Chest Physicians, The American
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`Thoracic Society, the Pulmonary Hypertension Association, and the Pulmonary
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`Vascular Research Institute.
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`6.
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`I am an Associate Professor of Medicine at Harvard Medical School
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`and have dual appointments in the Pulmonary Critical Care and Cardiovascular
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`Medicine divisions at Brigham and Women’s Hospital. I have previously served as
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`an assistant professor in Medicine at the Yale University School of Medicine and
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`Tufts University School of Medicine.
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`7.
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`I received my Bachelor’s degree from George Washington University.
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`I received a Ph.D. in Anatomy and Neuroscience at the Albany Medical College,
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`and an M.D. from Yale University School of Medicine. I completed my internship
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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`and residency in Internal Medicine at Yale New Haven Hospital. I also completed
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`a Fellowship in Pulmonary and Critical Care at the Yale School of Medicine.
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`8.
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`I have authored or co-authored more than 150 peer-reviewed journal
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`articles, book chapters and reviews. The primary focus of my research has been the
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`inflammatory basis of pulmonary vascular remodeling, and deep pathophysiologic
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`phenotyping of patients with various forms of pulmonary hypertension. Part of my
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`work has included the development of new therapies and the design and conduct of
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`a number of clinical trials that have led to FDA approval of multiple drugs, including
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`inhaled treprostinil.
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`9.
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`I am qualified based on my education and experience to provide expert
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`testimony in this matter. My education and experience qualify me as a person of at
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`least ordinary skill in the art at the time of the invention in 2006. A true and correct
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`copy of my curriculum vitae is attached as EX2002.
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`10.
`
`In forming my opinions, I relied on my knowledge and experience in
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`the field, as well as on documents and information referenced in this declaration.
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`All statements in my declaration, unless indicated otherwise, are based on my
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`knowledge and experience in the field.
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`C. Materials Considered
`11.
`In forming my opinions in this declaration, in addition to my knowledge
`
`and experience, I have also considered documents and materials that I have obtained
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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`or that have been provided to me. I have also reviewed the declarations and
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`deposition testimony in support of Petitioner by Drs. Nicholas Hill and Igor Gonda.
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`To the extent I am provided additional documents and/or information, I reserve the
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`right to supplement, amend and/or modify my analysis and offer further opinions.
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`12.
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`In forming my opinions in this declaration, I have relied on my
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`professional experience and personal knowledge. I have also considered documents
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`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
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`and JAHA, and the materials cited throughout this report. To the extent I am
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`provided additional documents and/or information, I reserve the right to supplement,
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`amend and/or modify my analysis and offer further opinions.
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`II.
`
`PERSON OF ORDINARY SKILL IN THE ART
`13.
`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 further have been 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
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`every factor may be present, and one or more factors may predominate.
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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`I understand that Petitioner asserts that, as of May 15, 2006, i.e., the
`
`14.
`
`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.
`Pet. at 14 (citing a declaration by Dr. Hill, EX1002, and a declaration by Dr. Gonda,
`EX1004).
`15. Based on my knowledge and experience in the relevant field, as of May
`
`15, 2006, the person having ordinary skill in the art (“POSA”) would have an M.D.
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`or a graduate degree (Masters or Ph.D.) in a field relating to drug development and
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`at least two years of practical experience in either (i) the investigation or treatment
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`of pulmonary hypertension or (ii) the development of potential drug candidates,
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`specifically in the delivery of drugs by inhalation.
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`16. While I disagree with Petitioner and Drs. Hill and Gonda’s
`
`interpretation as to the level of one of ordinary skill in the art, my conclusions would
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`not change if Drs. Hill and Gonda definition of a POSA is adopted.
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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`III. LEGAL STANDARDS PROVIDED BY COUNSEL
`17.
`I am not an attorney or an expert in patent law. I understand that the
`
`issues presented in this IPR must be considered in view of particular legal standards.
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`UTC’s counsel informed me of the legal standards as they relate to patent invalidity
`
`and validity to guide my analysis.
`
`A. Claim Construction
`18.
`I understand that the first step in performing a validity analysis of a
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`patent claim is to interpret the meaning and scope of the claims by construing the
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`terms and phrases found in those claims. In this proceeding, I understand that
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`Board’s decision instituting IPR of the ’793 patent does not construe any claim. See
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`Board’s Decision (Paper No. 18) at 5 (“Neither party presents any terms for
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`construction…Accordingly, we determine that no express construction of any claim
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`term is necessary in order to decide whether to institute trial”). I also understand
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`that, in litigation between Liquidia and UTC, the Court did not construe any claim
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`terms for the ’793 patent, either. See United Therapeutics Corporation v. Liquidia
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`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
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`this declaration, I therefore interpreted the asserted claims of the ’793 patent
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`according to their plain and ordinary meaning as understood by the person of
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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`ordinary skill in the art as of the priority date of the ’793 Patent.1 I reserve the right
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`to supplement, amend and/or modify my analysis in light of any further ruling(s) on
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`claim construction from the Board or the Court. I understand that those terms that
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`the parties have not requested the Court construe should be given their plain and
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`ordinary meaning to a person having ordinary skill in the art at the time of the patent.
`
`B. Anticipation
`19.
`I have been informed by counsel and understand that to anticipate a
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`patent claim, all of the requirements of that claim must be shown to be present in a
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`single prior art reference, device or method that was known of, used, or described in
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`a single previous printed publication or patent. The test for anticipation must be
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`assessed on a claim-by-claim basis. I also understand that anticipation can occur
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`when an undisclosed limitation is literally missing, but is present because the prior
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`art must necessarily function in accordance with, or must include, the undisclosed
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`limitation.
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`20.
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`I have further been informed that only a single reference should be
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`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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`1 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
`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
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`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 reference
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`must also enable one of ordinary skill in the art to make and use the full scope of the
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`claimed invention without undue experimentation.
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`21.
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`I have been informed by counsel and understand that if all the
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`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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`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
`22.
`I have been instructed by counsel and understand that a combination of
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`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
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`U.S. Patent No. 10,716,793 B2
`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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`23.
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`I further understand that an obviousness analysis is to be performed on
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`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
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`and understand that demonstrating obviousness requires more than merely showing
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`that the prior art includes separate references covering each separate limitation in a
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`claim under examination. I understand that a conclusion of obviousness requires the
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`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,
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`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
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`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
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`what is known today or what was learned from the asserted patents. Instead, I should
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`put myself in the position of a person of ordinary skill in the field at the time of the
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`invention. In particular, I understand that it is improper to use the invention as a
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`roadmap to find its prior art components, because the approach discounts the value
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`U.S. Patent No. 10,716,793 B2
`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
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`possible choices would be likely to be successful, an invention would not have been
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`obvious. Furthermore, an invention is not obvious to try where the prior art does not
`
`guide one toward a particular solution.
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`24.
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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 sufficient detail
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`to support a conclusion that a person of ordinary skill in the art would have been
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`motivated to make the combination with a reasonable expectation of success. This
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`account requires a showing in sufficient detail of how a person of ordinary skill in
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`the art would have combined the prior art reference to meet the claimed limitations,
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`including what a person of ordinary skill in the art would have reasonably expected
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`of how the combination would work.
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`25.
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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 prior art as a whole teaching
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`U.S. Patent No. 10,716,793 B2
`away from the invention, long-felt need for the invention, the failure of others,
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`copying, and industry recognition/praise by others, among others.
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`IV. BACKGROUND
`A. The ’793 Patent and Priority Date
`26. The ’793 patent, filed on January 31, 2020, is entitled “Treprostinil
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`Administration by Inhalation,” and was issued on July 21, 2020. EX1001. The ’793
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`patent is directed to the treatment of pulmonary hypertension by administering
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`treprostinil (or salts thereof) by inhalation. See, e.g., EX1001, 7:7-12.
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`27. The ’793 patent claims priority through a series of applications dating
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`back to a provisional patent application filed on 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 does
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`not dispute this priority date. As such, I have adopted May 15, 2006 as the priority
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`date for purposes of my analysis and opinions.
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`28.
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`I have reviewed the claims and specification of the ’793 patent. In
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`contrast to the then-existing technologies, the ’793 patent relates to a method of
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`treating pulmonary hypertension by administering by inhalation a therapeutically
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`effective single event dose that comprises from 15 micrograms to 90 micrograms of
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`treprostinil or a pharmaceutically acceptable salt thereof delivered in 1 to 3 breaths.
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`29. Claim 1 of the ’793 patent recites:
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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`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
`treprostinil or a pharmaceutically
`acceptable salt thereof delivered in 1 to 3 breaths.
`EX1001, Claim 1.
`30. Dependent claims 2 through 5 require specific types of inhalation
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`devices, namely a soft mist inhaler (claim 2), a pulsed ultrasonic nebulizer (claim 3),
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`a dry powder inhaler (claim 4) or a pressurized metered dose inhaler (claim 5).
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`Dependent claim 6 requires the formulation to be a dry powder, and dependent claim
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`7 requires the powder to comprise particles less than 5 micrometers in diameter.
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`Dependent claim 8 requires the formulation to contain no metacresol.
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`31.
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`I disagree with Dr. Hill’s and Dr. Gonda’s opinions that any of these
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`claims are anticipated or rendered obvious to a POSA by May 15, 2006 as further
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`explained below. EX1002, ¶49.
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`B. General Overview of Pulmonary Hypertension
`32. As of the priority date of the ’793 patent (as is the case today)
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`pulmonary hypertension is a poorly understood, often fatal, disease with limited
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`treatment options. The first FDA approved treatment for pulmonary hypertension –
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`and the sole approved treatment for over five years (from 1995-2001) – was
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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`epoprostenol, which had substantial shortcomings and posed significant burdens to
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`patients.
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`33. Epoprostenol can only be administered by continuous intravenous
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`infusion because it has a short half-life2 of only a few minutes and is cleared from
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`the body very quickly. EX2008. Further, the short duration of action of
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`epoprostenol means that even a brief interruption in infusion could increase the risk
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`of hemodynamic collapse and even death because of delivery complications. Id.
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`Moreover, epoprostenol requires daily mixing and refrigeration, thus requiring the
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`patient to carry a cold pack to avoid degradation at room temperature and an infusion
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`pump in order to safely administer the drug. Id.
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`34. Later-approved subcutaneous (in 2002) and intravenous (in 2004)
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`administration of treprostinil had some benefits over epoprostenol. Id. For example,
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`it is stable at room temperature and has a half-life of several hours rather than several
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`minutes. This freed patients of having to carry ice packs to ensure the safety and
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`efficacy of the drug. Id. There were still limitations to intravenous and subcutaneous
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`delivery of treprostinil, such as intolerable site pain in some instances and systemic
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`side effects. EX1018, 1.
`
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`2 “Half-life” refers to the time it takes for half of the concentration of drug to be
`metabolized and eliminated from the body.
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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`35. By the 2006 priority date of the ’793 patent, clinicians had begun to
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`explore inhalation therapies for the treatment of pulmonary hypertension. See, e.g.,
`
`EX1007. At that time, the only FDA-approved prostacyclin-type drug that could be
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`given in an inhalable form was iloprost, marketed as Ventavis®. The results of an
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`Aerosolized Iloprost Randomized (AIR) Study documenting the effects of inhaled
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`iloprost had been public about three and a half years, and Ventavis®, which was
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`approved in 2004, had been on the market for about one and a half years. EX2009,
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`21.
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`36. Clinicians were still largely of the opinion, however, that intravenous
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`administration of a prostacyclin analog was preferable to inhaled delivery of iloprost
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`for a number of reasons. Id. For instance, iloprost has a half-life between 20-25
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`minutes. Id. at 21, 23-24. As a result, iloprost needs to be administered 6-9 times a
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`day, as frequently as every 2 hours, which was considered challenging for patients
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`to implement. Id. Moreover, the fact that iloprost has a short half-life results in
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`periods where patients may be off-medication or under-medicated while asleep
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`unless they wake up to take a dose of the drug. Id.
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`C. General Overview of Inhalation Therapies
`37. As of 2006, there were several known methods for delivering a drug
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`using inhalation. One class of inhalation devices were “continuous nebulizers.”
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`Continuous nebulizers deliver small amounts of drug by converting drug solutions
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`or suspensions into aerosols, which the patient inhales over a specified period of
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`time (frequently between 5 and 30 minutes). EX2032 (“only 10% of the total dose
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`loaded in a [continuous] nebulizer is in reality deposited in the lungs”). The patient
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`wears a mask (or uses a mouthpiece) and breathes in unmeasured portions of the
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`entire nebulized output delivered through the device and the components leading to
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`the patient’s mouth:
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`
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`EX2033.
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`38. Continuous nebulizers are designed to be used with a broad range of
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`liquid formulations, but they have several drawbacks. They require delivery over a
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`longer period of time, and the dosage is difficult to control. Various types of
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`continuous nebulizers were available at the priority date of the ’793 patent, and
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`several studies indicated that performance varies between manufacturers and also
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`between nebulizers from the same manufacturer. EX2029-EX2031. Various factors
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`that can affect the dose of drug received by a patient through a continuous nebulizer
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`U.S. Patent No. 10,716,793 B2
`include gas flow and pressure, fill and dead volumes, gas density, humidity and
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`temperature conditions, breathing patterns, nebulizer settings and programming, and
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`the nebulization device interface (e.g., whether it prompts or guides the patient
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`during use in any way, or adapts to ongoing use). Id.
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`39. Other types of inhalation devices are capable of delivering a more
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`precise amount of a medication in a specific number of breaths over a single
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`inhalation event. They can provide a fixed dose of medication per breath. Examples
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`of these types of inhalers that I have used in my practice include pressurized
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`metered-dose inhalers, soft-mist inhalers, pulsed ultrasonic nebulizers, breath-
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`actualized nebulizers, and dry powder inhalers. Pressurized metered dose inhalers
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`generally contain a propellant that, when the device is activated, provides a force for
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`administering a dose of medication. An example soft mist inhaler is the Respimat
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`device disclosed in the ’793 patent. EX1001, 7:33. It works by using the force of a
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`spring to propel drug solution through small nozzles and create an inhalable mist.
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`EX1061 at 4. Ultrasonic nebulizers use ultrasonic frequency to create an aerosol.
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`Continuous nebulizers run, as the term implies, continuously. “Pulsed nebulizers”
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`operate with some type of pulse, which could turn the nebulizer on or off at fixed
`
`times, or there can be additional features that attempt to coordinate the patient’s
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`breaths with nebulization by the device. See generally EX1026 at 1; EX1029 at 1.
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`For example, with the pulsed ultrasonic nebulizer described in the ’793 patent and
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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`employed with Tyvaso®, the patient completely inhales the nebulized output in one
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`“pulse” of the device by enclosing the device’s mouthpiece within their mouth and
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`inhaling at the time indicated after the fixed amount of aerosol per breath is
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`generated:
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`
`
`EX2034.
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`D. Overview of the Claimed Invention
`40.
`In my opinion, the inventors of the ’793 patent overcame many of the
`
`limitations of the existing methods of pulmonary hypertension treatments by
`
`developing a method that utilizes a high administration of inhaled treprostinil in 1 to
`
`3 breaths.
`
`41. While I am familiar with earlier treprostinil treatments that employed
`
`continuous nebulization methods, the method of treatment described in the ’793
`
`patent surprisingly demonstrated that a therapeutically effective dose of 15
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`U.S. Patent No. 10,716,793 B2
`micrograms3 to 90 micrograms could be safely delivered to a patient in just a few
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`breaths. EX1001 at 16:61-63; see also id. at 17:44-46 (study “successfully
`
`demonstrated that the inhalation time could be reduced to literally one single breath
`
`of 2000 μg/ml treprostinil solution, thereby applying a dose of 15 μg”). Surprisingly,
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`high concentrations of treprostinil were shown to be well tolerated by patients with
`
`even a single breath administration of the drug, which induced pulmonary
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`vasodilation for longer than 3 hours with minimal side effects. Id. at 18:1-6. This
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`result was surprising because treprostinil was known to be a potent drug and another
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`prostacyclin analog, iloprost, was approved in delivered doses of only 2.5 to 5.0 μg
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`because of side effects. EX1083 at 9.
`
`42.
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`I have regularly prescribed Tyvaso® (inhaled treprostinil), which I
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`understand to be the commercial embodiment of the ’793 patent, because Tyvaso®
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`has shown distinct advantages over Ventavis®, the only other available inhalation
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`treatment for pulmonary hypertension. For example, Tyvaso® (inhaled treprostinil)
`
`does not need to be administered as frequently as Ventavis®, leading to higher
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`patient compliance and less risk of rebound pulmonary hypertension. Tyvaso®
`
`(inhaled treprostinil) has a much longer half-life than Ventavis® when inhaled by
`
`
`3 A microgram is a unit of mass equal to one millionth of a gram. A microgram is
`commonly abbreviated as mcg or µg. As such, I may use microgram, mcg and/or
`µg interchangeably throughout my declaration.
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`human subjects suffering from pulmonary hypertension. This allows Tyvaso® to be
`
`administered markedly less frequently – about 4 times a day. I have observed that
`
`patients are more likely to comply with a regimen that requires less frequent
`
`administrations. Furthermore, because Tyvaso® has a longer half-life than
`
`Ventavis®, there is less risk when the patient is asleep or otherwise unable to take
`
`the medication.
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`43. A study reported that “the transition from inhaled iloprost to inhaled
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`treprostinil resulted in a time saving of approximately 1.4 h per day.” EX2035, 5.
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`Patients transferring from inhaled iloprost to inhaled treprostinil also had improved
`
`six-minute walk distances (a common metric to assess pulmonary hypertension),
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`improved patient satisfaction, and improved quality of life. Id. at 5-6.
`
`V. VALIDITY OF THE ’793 PATENT
`A. Overview of the Challenged Grounds and Cited References
`44.
`I have been informed that Petitioner has asserted six grounds of
`
`invalidity as set forth below:
`
`Ground
`
`1
`
`2
`3
`4
`5
`6
`
`
`
`’793 Patent
`Claims
`1-8
`
`1-8
`1
`1, 3, 8
`1, 3
`2, 4-8
`
`Alleged Basis
`
`Obviousness: ’212 patent, Voswinckel JAHA,
`Voswinckel JESC
`Obviousness: ’212 patent and Voswinckel JESC
`Anticipation: Ghofrani
`Obviousness: Voswinckel JAHA and Ghofrani
`Anticipation: Voswinckel 2006
`Obviousness: Voswinckel 2006 and ’212 patent
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`U.S. Patent No. 10,716,793 B2
`I understand that Petitioner is relying on the following references or
`
`45.
`
`combinations thereof as alleged prior art:
`
` United States Patent no. 6,521,212 (the “’212 patent”) (EX1006)
`
` 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”) (EX1007)
`
` Voswinckel, R., et al., Abstract 1414: “Inhaled Treprostinil Sodium
`
`(TRE) for the Treatment of Pulmonayr Hypertension,” Abstracts from
`
`the 2004 Scientific Sessions of the American Heart Association,
`
`Circulation, 110(17 Suppl.):III-295 (October 26, 2004) (“Voswinckel
`
`JAHA”) (EX1008)
`
` Voswinckel, R., et al., “Clinical Observations” on “Inhaled Treprostinil
`
`for Treatment of Chronic Pulmonary Arterial Hypertens