UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`LIQL'IDIA TECHNOLOGIES, INC.
`Petitioner
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`\" .
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`UNITED THERAPEUTICS CORPORATION
`Patent Owner
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`Patent No. 10,716,793 BZ
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`Issue Date: July 21, 2020
`Title: TREPROSTINIL ADMINISTRATION BY INHALATION
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`Inter Partes Review No. IPR2021-00406
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`DECLARATION OF DR. HOSSEIN A. GHOFRANI
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`4841-4517-6795
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`IPR2021-00406
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`United Therapeutics EX2004
`Page 1 of 7
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`IPR2021-00406
`United Therapeutics EX2004
`Page 1 of 7
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`LIQL'IDIA TECHNOLOGIES, INC.
`Petitioner
`
`\" .
`
`UNITED THERAPEUTICS CORPORATION
`Patent Owner
`
`Patent No. 10,716,793 BZ
`
`Issue Date: July 21, 2020
`Title: TREPROSTINIL ADMINISTRATION BY INHALATION
`
`Inter Partes Review No. IPR2021-00406
`
`
`DECLARATION OF DR. HOSSEIN A. GHOFRANI
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`4841-4517-6795
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`IPR2021-00406
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`United Therapeutics EX2004
`Page 1 of 7
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`IPR2021-00406
`United Therapeutics EX2004
`Page 1 of 7
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`ll’RZUZl-OU-ltlo
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`Declaration 01‘ Dr. llossein A. (ihoi'rani
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`1. Dr. l'lossein A. Gliolrarii, hereby declare as follows:
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`1.
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`1 am a member ofUniversity oi‘Giessen and Marburg Lung Center
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`(“UGMLC”), a research center at the University Hospital Giessen studying
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`pulmonary hypertension.
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`2.
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`I am not a paid consultant for United Therapeutics Corporation, which
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`I understand is the assignee ofU.S. Patent No. 10,716,793.
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`Ghofrani Review Article
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`I am a co-author ofthe German language article: Hossein Ardeschir
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`q a
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`.
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`Ghofrani et a]. “Neue Therapieoptionen in der Behandlung der pulmonalarteriellen
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`Hypertonie,”l Herz, 30, 4 (June 2005): 296-302 (“the Ghofrani article”). I
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`understand that Liquidia Technologies, Inc. (“Liquidia”) submitted this publication
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`along with an English language translation of the article in this proceeding as
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`Exhibit 1010, which I have reviewed.
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`4.
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`I have experience in the use of phosphodiesterase inhibitors for
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`treatment of pulmonary hypertension. Therefore, I was asked by Dr. Werner
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`Seeger to draft and, indeed, drafted the section of the Ghofrani article relating to
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`phosphodiesterase inhibitors. In Exhibit 1010, this section in English begins at the
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`l The title is translated as “Pulmonary hypertension — new aspects of therapy" in
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`Exhibit 1010.
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`484145116795
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`IPR2021-00406
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`United Therapeutics EX2004
`Page 2 of 7
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`IPR2021-00406
`United Therapeutics EX2004
`Page 2 of 7
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`ll’l{2(lll»t)t)‘ltlo
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`Declaration of Dr. llossein A. (iholrani
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`bottom ol‘pagc l
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`l and continues through page 13. Dr. Seegcr and l alsojointly
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`drafted the sections on vasoactive therapy‘ inhaled iloprost, combination therapies,
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`and treatment ot‘carly forms ol‘treatment ol‘pulmonary hypertension, as well as
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`the introduction. In line with the normal practice in the UGMLC research center, I
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`was included as the lirst author on the Ghofrani article for these significant
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`contributions.
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`'J
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`I did not make material contributions to any other section ofthe
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`Gholi'ani article, and I specifically did not contribute to the following excerpt:
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`Initial trials in Giessen have shown proof of efficacy ofinhaled
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`treprostinil for the effective reduction ofthe pulmonary vascular
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`resistance (PVR) [6]. In this first study, 17 patients with severe pre-
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`capillary pulmonary hypertension were administered inhaled
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`treprostinil (15 meg/inhalation). This led to a major reduction in
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`pulmonary selective pressure and resistance with an overall duration
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`of action of> 180 min. In direct comparison with inhaled iloprost,
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`inhaled treprostinil showed a stronger pulmonary selectivity, so that it
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`is possible to increase the dosage to up to 90 mcg (absolute inhaled
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`dose per inhalation exercise) without adverse effects occurring [6].
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`Due to these unique properties (pronounced pulmonary selectivity and
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`long duration of action after an individual inhalation), it is possible to
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`reduce the number inhalations necessary to up to four per day; the
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`inhalation period can be reduced to < l min. by selecting a suitable
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`device. Additionally, the initial data shows that it is technically
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`feasible for there to be only one to two breaths in an application.
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`4841-4517-6795
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`IPR2021-00406
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`United Therapeutics EX2004
`Page 3 of 7
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`IPR2021-00406
`United Therapeutics EX2004
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`ll’R2021—00406
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`Declaration ol'Dr. llosscin A. Ghofrani
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`(Ex. 1010, p.
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`l l). The information in this excerpt was compiled and composed by
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`Dr. Robert Voswinckel and Dr. Werner Seeger, and the idea to perform the
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`underlying work originated with at least them.
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`6.
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`The section ofthe Ghofrani article relating to selective endothelin A
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`receptor agonists was drafted by Dr. Friedrich Grimminger and Dr. Frank
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`Reichenberger; both having experience in this field. In Exhibit 1010, this section is
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`in English on page 11.
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`Voswinckel 2006 Clinical Observation Letter
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`7.
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`I am listed as a co-author of the clinical observation letter: Robert
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`Voswinckel, Hossein A. Ghofrani, Friedrich Grimminger, Wemer Seeger, and
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`Horst Olschewski “Clinical Observations” on “Inhaled Treprostinil for Treatment
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`of Chronic Pulmonary Arterial Hypertension,” “Letters” Section of the Annals of
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`Internal Medicine, 144(2):]49-50 (January 2006) (“Voswinckel 2006”). I
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`understand that Liquidia submitted the letter in this proceeding as Exhibit 1009,
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`which I have reviewed.
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`8.
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`I am listed as a co-author on the Voswinckel 2006 clinical observation
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`letter because it was and is the practice of our group to include as authors of
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`abstracts and summary review articles the members of our group who contribute to
`
`or oversee any part in the trials, clinical routine management, or related parallel
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`studies, notjust members who were directly responsible for conceiving, analyzing,
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`4841-4517—6795
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`Lu
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`IPR2021-00406
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`United Therapeutics EX2004
`Page 4 of 7
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`IPR2021-00406
`United Therapeutics EX2004
`Page 4 of 7
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`11‘112021—00406
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`Declaration of Dr. Ilosscin A. Ghol‘rani
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`and designing a particular study. This is typical of our group and a valid
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`publication practice.
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`9.
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`This same publication practice is reflected in other abstracts, such as:
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`Voswinckel, R., et al., Abstract 218: “Inhaled treprostinil is a potent pulmonary
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`\asodilator in severe pulmonary hypertension,” European Heart Journal 25:22
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`(2004) ("Voswinckel JESC”) and Robert Voswinckel, et al., Abstract 1414:
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`“Inhaled Treprostinil Sodium (TRE) For the Treatment of Pulmonary
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`Hypertension,” Abstracts from the 2004 Scientific Sessions ofthe American Heart
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`Association, Circulation, 110(17 Suppl.):III—295 (October 26, 2004) (“Voswinckel
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`JAHA”), which I understand Liquidia submitted in this proceeding as Exhibit 1007
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`and Exhibit 1008, respectively.
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`10.
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`In each of Voswinckel JESC and Voswinckel JAHA, I am listed as a
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`co-author on that abstract because it was and is the practice of our group to include
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`as authors of abstracts and summary review articles the members of our group who
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`contribute to or oversee any part in the trials, clinical routine management, or
`
`related parallel studies, notjust members who were directly responsible for
`
`conceiving, analyzing, and designing a particular study.
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`1 I.
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`In the case of any studies of inhaled treprostinil described in these
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`documents (Voswinckel 2006, Voswinckel JESC and Voswinckel JAHA), I was
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`listed as a co-author because I assisted with the clinical responsibilities of
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`4841-4517-6795
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`IPR2021-00406
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`United Therapeutics EX2004
`Page 5 of 7
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`IPR2021-00406
`United Therapeutics EX2004
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`ll’RZUZl—UO-lllo
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`Declaration of Dr. Hossein A. Ghofrani
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`overseeing patients and was performing work related to the treatment ofpulmonary
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`hypertension. 1 was not designing studies or methods oftreatment involving
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`inhaled treprostinil.
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`12.
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`These articles do not include, or include limited. primary data where
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`one is a review article (Ghofrani article) and three are abstracts/clinical
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`observations (Voswinckel 2006, Voswinckel JESC and Voswinckel JAHA). My
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`involvement in any study by our group into inhaled treprostinil was limited to
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`support and administrative tasks such as collecting data or checking on patients. I
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`was not involved in the conception, design or intent of the study such as selecting
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`treprostinil for inhaled administration, the dosages or timing of administration, the
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`protocols or devices used, or the selection of study parameters.
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`[The remainder of this page is intentionally left blank]
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`484145176795
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`IPR2021-00406
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`United Therapeutics EX2004
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`lI’R2021-00406
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`Declaration ofDr. l-losscin A. Ghofrani
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`I3.
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`I hereby declare that all statements made herein ofmy knowledge are
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`true and that all statements made on information and belief are believed to be true;
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`and further that these statements were made with the knowledge that willful false
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`statements and the like so made are punishable by fine or imprisonment, or both
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`under Section 1001 of Title 18 ofthe United States Code.
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`Date: 7e/M i
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`, 2021
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`4841—4517—6795
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`Dr. Hossein A. Ghofrani
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`IPR2021-00406
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`United Therapeutics EX2004
`Page 7 of 7
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`IPR2021-00406
`United Therapeutics EX2004
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