UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`WATSON LABORATORIES, INC.
`Petitioner
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`V.
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`UNITED THERAPEUTICS CORP.
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`Patent Owner
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`Cases1 IPR2017-01621; Patent 9,358,240
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`IPR 2017-01622; Patent 9,339,507
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`DECLARATION OF DR. ROBERT ROSCIGNO
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`1 The word-for-word identical paper is filed in each proceeding identified in the
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`heading.
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`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017-01622
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`UNITED THERAPEUTICS, EX. 2048
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`IPR2017-01621; IPR2017—01622
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`Declaration of Dr. Robert Roscigno
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`I, Dr. Robert Roscigno, hereby declare as follows:
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`1.
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`I am a named inventor of US. Patent No. 9,358,240 and US Patent
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`No. 9,399,507. My co-inventors on those patents include Horst Olschewski, Lewis
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`Rubin, Thomas Schmehl, Werner Seeger, Carl Sterritt, and Robert Voswinckel.
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`2.
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`I am currently Senior Vice President, Product Development at
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`Liquidia Technologies.
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`3.
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`I. am a paid consultant for United Therapeutics Corporation (“United
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`Therapeutics”), which I understand is the assignee of U.S. Patent No. 9,358,240
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`and US Patent No. 9,399,507, in connection with IPR2017-01621 and IPR2017-
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`01622, respectively. My compensation does not depend on the content of this
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`declaration, the substance of any other testimony that I may offer in connection
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`with this proceeding or the disposition of this proceeding.
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`4.
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`From the time period of June 2005-June 2007, I was the President and
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`COO of Lung Rx, Inc., a subsidiary of United Therapeutics. From 2002—June 2005
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`I was Senior Vice President of Lung Rx, Inc.
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`5.
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`Beginning by at least September 2003, I was tasked by United
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`Therapeutics’ CEO, Martino Rothblatt, with leading the company’s development
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`of an inhaled treprostinil treatment for pulmonary hypertension.
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`I was the project
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`leader for Lung Rx, Inc. for this development, which we termed TRIUMPH
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`(Treprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial
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`4819-77653?01
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`IPR2017—0162l; IPR2017-01622
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`Declaration ofDr. Robert Roscigno
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`Hypertension) and was responsible for bringing what became Tyvaso® from early
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`preclinical studies through Phase 3 development. Specifically, I was tasked with
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`participating in the design of the protocols for clinical studies and coordinating the
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`development of an inhaled program that formed the basis for Tyvaso®’s approval.
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`6.
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`On October 22, 2003, I attended a meeting with Dr. Rothblatt in Dr.
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`Rothblatt’s New York City apartment to kick off the project, along with Drs. Rubin
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`and Seeger. A task list for that meeting is labelled Exhibit 2102. As reflected in
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`that task list, my initial responsibilities included writing up drafts of the initial
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`clinical studies and providing drug material to Giessen for the studies. The other
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`individuals reflected on that list were Martino Rothblatt (“MR”), Carl Sterritt
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`(“CS”), Werner Seeger (“WS”), Lewis Rubin (“LR”), and Horst Olschewski
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`(“HO”).
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`7.
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`All of the co—inventors had experience in and were focused in the
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`project on the treatment of pulmonary hypertension. All of the inventors had
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`critical roles and brought varied expertise to the project.
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`a. Carl Sterritt led United Therapeutics’ Europe operations and engaged
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`early with me and Drs. Seeger, Olschewski, Schmehl, and Voswinckel
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`(“the Giessen researchers”) and also contributed to the clinical protocol
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`design and development due to his understanding and experience with
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`Remodulin® and iloprost and his understanding of the potential for
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`IPR2017-01621; IPR2017-01622
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`Declaration of Dr. Robert Roscigno
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`inhalation of the treprostinil molecule. As with all of the co-inventors, be
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`reviewed and contributed to the ideas concerning dosage, timing,
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`formulation, and the device and engaged in much of the necessary work
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`to effect the planning of the group. As with all of the co—inventors, he
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`was involved in our discussions of the interpretation of data and the
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`conclusions that could be drawn from them for the iterative design of the
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`next set of experiments. Carl also directly interacted with Nebutec, the
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`Germany-based device manufacturer.
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`.
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`I had a similar role and worked closely with Carl Sterritt on his
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`involvement.
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`I also engaged with our pharmacokinetic consultants and
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`experts and engaged in interpreting the phannacokinetic data. Due to my
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`experience with clinical trial management and toxicology assessment, I
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`also closely ensured that all studies were consistent with the necessary
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`toxicology investigations and issues that would become important for
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`regulatory approval. 1 was heavily engaged in collaborating with the
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`investigators on study protocols and the necessary assessment and
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`writing of the study results.
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`. Dr. Seeger was the head of the program at Giessen and employed the
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`expertise and contributions of Drs. Voswinckel, Schmehl, and
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`Olschewski, based on, for example, their prior expertise and experience
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`IPR2017~01621; IPR2017-01622
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`Declaration of Dr. Robert Roscigno
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`with iloprost and reSpective clinical expertise with pulmonary
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`hypertension. These investigators collectively executed the studies
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`designed in collaboration among all of the inventors.
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`d. Dr. Rubin was involved as the co-head (with Dr. Seeger) of the clinical
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`steering committee for TRIUMPH and engaged in similar tasks as
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`described above with each of us co-inventors. Later, he was also the lead
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`investigator on the early and late phase studies performed at UCSD.
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`8.
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`Together with Carl Stcrritt and Drs. Rubin, Seeger, Voswinckel,
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`Schmehl, and Olschewski, we developed. early protocols and methods for clinical
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`studies, including developing the appropriate dosing regimen, dose titration
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`strategies, drug product formulation, and device testing that resulted in the clinical
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`trials necessary to support the TRIUMPH program. Together, we developed and
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`implemented the strategy and details for moving forward with the clinical trials
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`and creating the clinical deveIOpment plan that led to the development of Tyvaso®.
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`9.
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`As reflected in the October 22, 2003 meeting task list, this work began
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`in earnest by at least October of 2003 and continued through the completion of
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`Phase III trials. From October 2003 forward, I, and sometimes including Carl
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`Sterritt, met quarterly with the steering committee including Drs. Rubin and Seeger
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`to discuss progress and discuss and plan strategy for moving forward. The
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`advancement of the program was an iterative process and we had to regroup
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`IPR2017-01621; 1PR201 7-01622
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`Declaration of Dr. Robert Roscigno
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`regularly to assess our data and progress and plan the next steps. We met multiple
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`times in Germany and North Carolina between October 2003 and June 2007, and
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`additionally on an ad-hoc basis in other locations including Orlando, San Diego,
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`Melbourne, Florida, Washington, DC, and London. We also worked with Nebutec,
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`the manufacturer of the nebulizer, including iii-person meetings at the Nebutec
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`facilities, to discuss the sourcing, modification, performance testing, quality
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`systems, programming, features and regulatory approval of the inhalation Optineb
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`device.
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`10.
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`The initial studies, all performed at the University of Giessen or
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`UCSD, included first acute and then longer term studies with varying doses and
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`concentrations of treprostinil, increased and reduced inhalation times, and
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`alternative drug formulations (including the removal of the metacresol
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`preservative). The early studies were administered by inhalation with different
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`device delivery modes, beginning in 2003, including delivering continuous
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`ultrasonic nebulization and, later, pulsed. ultrasonic nebulization. The design,
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`interpretation, implementation, and modifications of these studies included the
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`input of. all of the era—inventors. Together, all of the (Jo-inventors were responsible
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`for developing the method described in claim 1 of the ’240 patent and. the kit
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`described claim 1 of the ’507 patent.
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`Declaration ofDr. Robert Roscigno
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`ll. We faced several challenges in making modifications to the study
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`protocols and none of them were easily overcome or were obvious. One example
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`is that the studies evolved from a rational. starting point of using the continuous
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`nebulization system initially employed for inhaled iloprost, discussing and
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`developing various iterations and programming of the device (such as increasing
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`and decreasing inhalation time and continuous ultrasonic nebulization vs pulsed.
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`ultrasonic nebulization. Ultimately, we arrived at a method of using a modified
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`Optineb pulsed ultrasonic nebulizer used in a pulsed mode that aerosolizes a fixed
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`amount of treprostinil per pulse where the patient must synchronize each
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`consecutive breath to each pulse of the device with the aid of an onto-acoustical
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`trigger (as described in the patent). Our motivation for these modifications was not
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`to avoid wastage or to deliver precise doses, though these were side benefits, but to
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`avoid the spillover effect into the systemic system (leading to intolerable
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`prostacyclin side effects) seen with continuous nebulization of i10prost that
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`occurred when the drug was administered too quickly and/or at high doses. We
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`discovered unexpectedly that we could deliver more treprostinil in a shorter period
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`of time with fewer side effects (increasing the treprotinil dose more than 10—fold
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`compared with iloprost)—this was not obvious to anyone.
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`12.
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`l have reviewed an English translation of the German language review
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`article: Hossein Ardeschi Ghofrani er a1. “Neue Therapieoptionen in der
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`Behandlung der pulmonalarteriellen Hypertonie,”2 Herz, 30, 4 (June 2005): 296-
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`302 (“the Ghofrani article”). Ex. 1005. I am familiar with the work described in the
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`following excerpt:
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`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 pie-capillary pulmonary
`hypertension were administered inhaled treprostinil (15 meg/inhalation).
`This led to a maj or reduction in pulmonary selective pressure and resistance
`with an overall duration of action of. > l80 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 < l 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. A multi-centric,
`placebo-controlled study shall now also study the efficacy of this new
`therapy during long-term use.
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`13.
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`This excerpt does not describe in any detail the thinking, design,
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`methods, or results that underlie the referenced “first study.” In addition, while
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`these findings are all correct, they are not the conclusions of a single study.
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`1
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`recognize the little that is described as reflecting my early work together with the
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`co—inventors. The work described in this excerpt was performed as part of the joint
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`2 The title is translated as “New therapies in the treatment of pulmonary
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`hypertension” in Exhibit 1005.
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`cooperation of the several inventors and reflects the earliest aspects of our
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`collective work described above. Even though not all of the inventors were
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`identified as authors-wwhich we wouldn’t expect of a German review article
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`coming out of Giessenuthe excerpt above describes our work at a very high level.
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`14.
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`The earliest clinical studies included a series of seven investigator—
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`sponsored studies with inhaled treprostinil, with six studies conducted at the
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`University Hospital Giessen in 2003. The six Giessen studies were performed by
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`the Giessen investigators, Seeger, Voswinckel, Schmehl, and Olschewski using the
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`protocols, dosing, formulation, and device developed jointly by them, Dr. Rubin,
`Carl Sterritt, and myself. Labelled as Exhibit 2049 are true and correct copies of
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`excerpts of the Tyvaso NBA Integrated Summary of Efficacy (ISE) reflecting
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`these seven studies and indicating that the six Giessen studies occurred in 2003,
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`which is a document that had to be submitted to the FDA as part of the process of
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`obtaining regulatory approval to market Tyvaso® in the US.
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`15. One of the studies performed at Giessen included Study LRX—INH-
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`0004 in 2003. True and correct copies of excerpts of the Clinical Investigation
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`Report Synopsis for that study are labelled as Exhibit 2050, which is also a
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`document that had to be submitted to the FDA as part of the process of obtaining
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`regulatory approval to market Tyvaso® in the US. That study included treatment
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`with a pulsed ultrasonic nebulizer used in a pulsed mode, with a target dose of 15
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`Declaration of Dr. Robert Roscigno
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`mcg over 1 to 18 breaths, and concentrations ranging from 100 to 2,000 mcg/rnL.
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`Hemodynarnics were observed over three hours. Study LRX—INH-0007,
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`summarized in the Clinical Investigation Report for that study, a true and correct
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`copy of which is labelled as Exhibit 2051, also included treatment with a pulsed
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`ultrasonic nebulizer used in pulsed mode, target doses of 15 incg and 30 meg, a
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`concentration of 600 mcg/mL, 3 or 6 breaths, and 5 mcg per pulse or breath.
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`Exhibit 2051 also had to be submitted to the FDA as part of the process of
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`obtaining regulatory approval to market Tyvaso® in the US. These studies are also
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`discussed in the text of our patents.
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`16.
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`Therefore, even though this was not made public in any publication
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`including the Ghofrani review article discussed above, by 2003,3 me and my co-
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`inventors had conceived of and performed in human pulmonary hypertension
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`patients methods and kits with the following features:
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`a. administering therapeutically effective amounts of treprostinil within a
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`200 to 1000 mog/mL range;
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`b. with a pulsed ultrasonic nebulizer used in pulsed mode that aerosolizes a
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`fixed amount of treprostinil per pulse;
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`3 Certainly, these methods and kits had been performed before January 2004 when
`we had finalized the protocol for the Double Blind Placebo Controlled Clinical
`Investigation Into the Efficacy and Tolerability of Inhaled Treprostinil Sodium in
`Patients with Severe Pulmonary Arterial Hypertension (TRIUMPH I STUDY),
`LRX—TRIUMPH 001.
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`Declaration of Dr. Robert Roseigne
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`e. and which has an opto—aeoustieal trigger allowing the patient to
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`synchronize each breath. to each pulse,
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`d. with a single event dose between 15 meg to 90 meg of treprostinil
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`e. delivered in l to 19 breaths.
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`17.
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`These methods included not repeating a dose for at least 3 hours and
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`the delivery of at least 5 pg of treprestinil per breath.
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`[The remainder offlzis page is intentionally left blank]
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`18.
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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: ‘2? .oe’eflt ,2018
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`mM
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`Dr. Robert Roscigno
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`4819-7?65—8?01
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