UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`LIQUIDIA TECHNOLOGIES, INC.
`Petitioner
`
`V.
`
`UNITED THERAPEUTICS CORPORATION
`
`Patent Owner
`
`Patent No. 10,716,793 B2
`Issue Date: July 21, 2020
`Title: TREPROSTINIL ADMINISTRATION BY INHALATION
`
`Inter Partes Review No. IPR2021-00406
`
`DECLARATION OF DR. FRIEDRICH GRIMMINGER
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`4833-1103-2795
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`IPR2021-00406
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`United Therapeutics EX2006
`Page 1 of 7
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`IPR2021-00406
`United Therapeutics EX2006
`Page 1 of 7
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`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`LIQUIDIA TECHNOLOGIES, INC.
`Petitioner
`
`V.
`
`UNITED THERAPEUTICS CORPORATION
`
`Patent Owner
`
`Patent No. 10,716,793 B2
`Issue Date: July 21, 2020
`Title: TREPROSTINIL ADMINISTRATION BY INHALATION
`
`Inter Partes Review No. IPR2021-00406
`
`DECLARATION OF DR. FRIEDRICH GRIMMINGER
`
`4833-1103-2795
`
`IPR2021-00406
`
`United Therapeutics EX2006
`Page 1 of 7
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`IPR2021-00406
`United Therapeutics EX2006
`Page 1 of 7
`
`
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`IPR2021-00406
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`Declaration of Dr. Friedrich Grimminger
`
`I, Dr. Friedrich Grimminger, hereby declare as follows:
`
`1.
`
`I am a member of University of Giessen and Marburg Lung Center
`
`(“UGMLC”), a research center at the University Hospital Giessen studying
`
`pulmonary hypertension.
`
`2.
`
`I am not a paid consultant for United Therapeutics Corporation, which
`
`I understand is the assignee of US. Patent No. 10,716,793.
`
`Ghofrani Review Article
`
`3.
`
`I am a co-author of the German language article: Hossein Ardeschir
`
`Ghofrani et a]. “Neue Therapieoptionen in der Behandlung der pulmonalarteriellen
`
`Hypertonie,”1 Herz, 30, 4 (June 2005): 296-302 (“the Ghofrani article”). I
`
`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
`
`Exhibit 1010, which I have reviewed.
`
`4.
`
`Dr. Frank Reichenberger and I both have experience in the use of
`
`selective endothelin A receptor agonists for treatment pulmonary hypertension.
`
`Therefore, we were asked by Dr. Werner Seeger to draft and, indeed, drafted the
`
`section of the Ghofrani article relating to selective endothelin A receptor agonists.
`
`1 The title is translated as “Pulmonary hypertension — new aspects of therapy” in
`
`Exhibit 1010.
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`4833-1 103-2795
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`|PR2021-00406
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`United Therapeutics EX2006
`Page 2 of 7
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`IPR2021-00406
`United Therapeutics EX2006
`Page 2 of 7
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`IPR2021-00406
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`Declaration of Dr. Friedrich Grimminger
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`In Exhibit 1010, this section is in English on page 11. In line with the normal
`
`practice in the UGMLC research center, both Dr. Reichenberger and I were listed
`
`as authors on the Ghofrani article for this contribution.
`
`5.
`
`I did not make material contributions to any other section of the
`
`Ghofrani article, and I specifically did not contribute to the following excerpt:
`
`Initial trials in Giessen have shown proof of efficacy of inhaled
`
`treprostinil for the effective reduction of the pulmonary vascular
`
`resistance (PVR) [6]. In this first study, 17 patients with severe pre-
`
`capillary pulmonary hypertension were administered inhaled
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`treprostinil (15 mcg/inhalation). This led to a major reduction in
`
`pulmonary selective pressure and resistance with an overall duration
`
`of action of > 180 min. In direct comparison with inhaled iloprost,
`
`inhaled treprostinil showed a stronger pulmonary selectivity, so that it
`
`is possible to increase the dosage to up to 90 mcg (absolute inhaled
`
`dose per inhalation exercise) without adverse effects occurring [6].
`
`Due to these unique properties (pronounced pulmonary selectivity and
`
`long duration of action after an individual inhalation), it is possible to
`
`reduce the number inhalations necessary to up to four per day; the
`
`inhalation period can be reduced to < 1 min. by selecting a suitable
`
`device. Additionally, the initial data shows that it is technically
`
`feasible for there to be only one to two breaths in an application.
`
`(EX. 1010, p. 11). The information in this excerpt was compiled and composed by
`
`Dr. Robert Voswinckel and Dr. Werner Seeger, and the idea to perform the
`
`underlying work originated with at least them.
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`4833—1 103-2795
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`2
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`United Therapeutics EX2006
`Page 3 of 7
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`IPR2021-00406
`United Therapeutics EX2006
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`IPR2021—00406
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`Declaration of Dr. Friedrich Grimminger
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`6.
`
`Dr. Hossein A. Ghofrani—the first listed author—drafted the section
`
`of the Ghofrani article relating to phosphodiesterase inhibitors, and the remaining
`
`sections on vasoactive therapy, inhaled iloprost, combination therapies, and
`
`treatment of early forms of treatment of pulmonary hypertension, as well as the
`
`introduction were drafted by Dr. Hossein A. Ghofrani and Dr. Werner Seeger.
`
`Voswincke12006 Clinical Observation Letter
`
`7.
`
`I am listed as a co—author of the clinical observation letter: Robert
`
`Voswinckel, Hossein A. Ghofrani, Friedrich Grimminger, Werner Seeger, and
`
`Horst Olschewski, “Clinical Observations” on “Inhaled Treprostinil for Treatment
`
`of Chronic Pulmonary Arterial Hypertension,” “Letters” Section of the Annals of
`
`Internal Medicine, 144(2):149-50 (January 2006) (“Voswinckel 2006”). I
`
`understand that Liquidia submitted the letter in this proceeding as Exhibit 1009,
`
`which I have reviewed.
`
`8.
`
`I am listed as a co-author on the Voswinckel 2006 clinical observation
`
`letter because it was and is the practice of our group to include as authors of
`
`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
`
`studies, not just members who were directly responsible for conceiving, analyzing,
`
`and designing a particular study. This is typical of our group and a valid
`
`publication practice.
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`4833—1103-2795
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`|PR2021-00406
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`United Therapeutics EX2006
`Page 4 of 7
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`IPR2021-00406
`United Therapeutics EX2006
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`IPR2021-00406
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`Declaration of Dr. Friedrich Grimminger
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`9.
`
`This same publication practice is reflected in other abstracts, such as:
`
`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”) and Robert Voswinckel, et al., Abstract 1414:
`
`“Inhaled Treprostinil Sodium (TRE) For the Treatment of Pulmonary
`
`Hypertension,” Abstracts from the 2004 Scientific Sessions of the American Heart
`
`Association, Circulation, 110(17 Suppl.):III-295 (October 26, 2004) (“Voswinckel
`
`JAHA”), which I understand Liquidia submitted in this proceeding as Exhibit 1007
`
`and Exhibit 1008, respectively.
`
`10.
`
`In each of Voswinckel IESC and Voswinckel JAHA, I am listed as a
`
`co-author on that abstract because it was and is the practice of our group to include
`
`as authors of 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 studies, not just members who were directly responsible for
`
`conceiving, analyzing, and designing a particular study.
`
`11.
`
`In the case of any studies of inhaled treprostinil described in these
`
`documents (Voswincke12006, Voswinckel IESC and Voswinckel JAHA), I was
`
`listed as a co-author because I assisted with the clinical responsibilities of
`
`overseeing patients and was performing work related to the treatment of pulmonary
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`United Therapeutics EX2006
`Page 5 of 7
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`IPR2021-00406
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`IPR2021-00406
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`Declaration of Dr. Friedrich Grimminger
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`hypertension. I was not designing studies or methods of treatment involving
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`inhaled treprostinil.
`
`12.
`
`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
`
`observations (Voswinckel 2006, Voswinckel IESC and Voswinckel JAHA). My
`
`involvement in any study by our group into inhaled treprostinil was limited to
`
`support and administrative tasks such as collecting data or checking on patients. I
`
`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
`
`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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`4833-1103-2795
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`United Therapeutics EX2006
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`IPR2021—00406
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`Declaration of Dr. Friedrich Grimminger
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`13.
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`I hereby declare that all statements made herein of my 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 of the United States Code.
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`Date:
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`215 f’31:1
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`_, 2021
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`
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`Dr. Dr. Friedrich Grimminger
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`4833—1 103—2795
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`|PR2021-00406
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`United Therapeutics EX2006
`Page 7 of 7
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`IPR2021-00406
`United Therapeutics EX2006
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