`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`WATSON LABORATORIES, INC.
`Petitioner
`
`Vv.
`
`UNITED THERAPEUTICS CORP.
`Patent Owner
`
`Cases! IPR2017-01621; Patent 9,358,240
`IPR 2017-01622; Patent 9,339,507
`
`DECLARATION OF DR. ROBERT ROSCIGNO
`
`' The word-for-word identical paperis filed in each proceeding identified in the
`
`heading.
`
`UNITED THERAPEUTICS, EX. 2048
`WATSON LABORATORIES v. UNITED THERAPEUTICS, IPR2017-01622
`
`IPR2021-00406
`United Therapeutics EX2061
`
`IPR2021-00406
`United Therapeutics EX2061
`
`
`
`IPR2017-01621; IPR2017-01622
`
`Declaration of Dr. Robert Roscigno
`
`I, Dr. Robert Roscigno, hereby declare as follows:
`
`l.
`
`I am a named inventor of U.S. Patent No. 9,358,240 and US Patent
`
`No. 9,399,507. My co-inventors on those patents include Horst Olschewski, Lewis
`
`Rubin, Thomas Schmehl, Werner Seeger, Carl Sterritt, and Robert Voswinckel.
`
`2.
`
`Tl amcurrently Senior Vice President, Product Developmentat
`
`Liquidia Technologies.
`
`3.
`
`[Lama paid consultant for United Therapeutics Corporation (“United
`
`Therapeutics”), which I understandis the assignee of U.S. Patent No. 9,358,240
`
`and US Patent No. 9,399,507, in connection with IPR2017-01621 and IPR2017-
`01622, respectively. My compensation does not depend on the content of this
`
`declaration, the substance of any other testimony that I may offer in connection
`
`with this proceeding orthe disposition of this proceeding.
`
`4.
`
`From the time period of June 2005-June 2007, I was the President and
`
`COO of Lung Rx,Inc., a subsidiary of United Therapeutics. From 2002-June 2005
`
`I was Senior Vice President of Lung Rx,Inc.
`
`5.
`
`Beginning byat least September 2003, I was tasked by United
`
`Therapeutics’ CEO, Martine Rothblatt, with leading the company’s development
`
`of an inhaled treprostinil treatment for pulmonary hypertension.
`
`I was the project
`
`leader for Lung Rx, Inc. for this development, which we termed TRIUMPH
`
`(Treprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial
`
`4819-7765-8701
`
`
`
`IPR2017-01621; IPR2017-01622
`
`Declaration of Dr. Robert Roscigno
`
`Hypertension) and wasresponsible for bringing what became Tyvaso® from early
`
`preclinical studies through Phase 3 development. Specifically, I was tasked with
`
`participating in the design of the protocols for clinical studies and coordinating the
`
`developmentof an inhaled program that formed the basis for Tyvaso®’s approval.
`
`6.
`
`On October 22, 2003, I attended a meeting with Dr. Rothblatt in Dr.
`
`Rothblatt’s New York City apartment to kick off the project, along with Drs. Rubin
`
`and Seeger. A task list for that meeting is labelled Exhibit 2102. As reflected in
`
`that task list, my initial responsibilities included writing up drafts ofthe initial
`
`clinical studies and providing drug material to Giessen for the studies. The other
`individuals reflected onthatlist were Martine Rothblatt (“MR”), Carl Sterritt
`
`(“CS”), Werner Seeger (“WS”), Lewis Rubin (“LR”), and Horst Olschewski
`
`(“HO”).
`
`7.
`
`All of the co-inventors had experience in and were focusedin the
`
`project on the treatment of pulmonary hypertension. All of the inventors had
`
`critical roles and brought varied expertise to the project.
`
`a. Carl Sterritt led United Therapeutics’ Europe operations and engaged
`
`early with me and Drs. Seeger, Olschewski, Schmehl, and Voswinckel
`
`(“the Giessen researchers”) and also contributed to the clinical protocol
`
`design and development due to his understanding and experience with
`
`Remodulin® and iloprost and his understanding of the potential for
`
`4819-7765-8701
`
`
`
`IPR2017-01621; IPR2017-01622
`
`Declaration of Dr. Robert Roscigno
`
`inhalation of the treprostinil molecule. As with all of the co-inventors, he
`
`reviewed and contributed to the ideas concerning dosage, timing,
`
`formulation, and the device and engaged in muchofthe necessary work
`
`to effect the planning of the group. As with all of the co-inventors, he
`
`was involved in our discussions of the interpretation of data and the
`
`conclusions that could be drawn from them for the iterative design of the
`
`next set of experiments. Carl also directly interacted with Nebutec, the
`
`Germany-based device manufacturer.
`
`. Thad a similar role and worked closely with Carl Sterritt on his
`
`involvement.
`
`I also engaged with our pharmacokinetic consultants and
`
`experts and engaged in interpreting the pharmacokinetic data. Due to my
`
`experience with clinical trial management and toxicology assessment,I
`
`also closely ensuredthatall studies were consistent with the necessary
`
`toxicology investigations and issues that would become important for
`regulatory approval. I was heavily engaged in collaborating withthe
`
`investigators on study protocols and the necessary assessment and
`
`writing of the study results.
`
`. Dr. Seeger was the head of the program at Giessen and employed the
`
`expertise and contributions of Drs. Voswinckel, Schmehl, and
`
`Olschewski, based on, for example, their prior expertise and experience
`
`4819-7765-8701
`
`
`
`IPR2017-01621; IPR2017-01622
`
`Declaration of Dr. Robert Roscigno
`
`with iloprost and respective clinical expertise with pulmonary
`
`hypertension. These investigators collectively executed the studies
`
`designed in collaboration among all of the inventors.
`
`d. Dr. Rubin was involved as the co-head (with Dr. Seeger) of the clinical
`
`steering committee for TRIUMPHand engagedin similartasks as
`
`described above with each of us co-inventors. Later, he was also the lead
`
`investigator on the early and late phase studies performed at UCSD.
`
`8.
`
`Together with Carl Sterritt and Drs. Rubin, Seeger, Voswinckel,
`
`Schmehl, and Olschewski, we developedearly protocols and methodsforclinical
`
`studies, including developing the appropriate dosing regimen, dosetitration
`
`strategies, drug product formulation, and device testing that resulted in the clinical
`
`trials necessary to support the TRIUMPHprogram. Together, we developed and
`
`implemented the strategy and details for moving forward with the clinicaltrials
`and creating the clinical development plan that led to the development ofTyvaso®.
`9,
`As reflected in the October 22, 2003 meeting task list, this work began
`
`in earnest by at least October of 2003 and continued through the completion of
`
`Phase III trials. From October 2003 forward, I, and sometimes including Carl
`
`Sterritt, met quarterly with the steering committee including Drs. Rubin and Seeger
`
`to discuss progress and discuss and plan strategy for moving forward. The
`
`advancement of the program wasaniterative process and we had to regroup
`
`4819-7765-8701
`
`
`
`IPR2017-01621; IPR2017-01622
`
`Declaration of Dr. Robert Roscigno
`
`regularly to assess our data and progress and plan the next steps. We met multiple
`
`times in Germany and North Carolina between October 2003 and June 2007, and
`
`additionally on an ad-hoc basis in other locations including Orlando, San Diego,
`
`Melbourne, Florida, Washington, DC, and London. We also worked with Nebutec,
`
`the manufacturer of the nebulizer, including in-person meetings at the Nebutec
`
`facilities, to discuss the sourcing, modification, performancetesting, quality
`
`systems, programming, features and regulatory approval of the inhalation Optineb
`
`device.
`
`10.
`
`Theinitial studies, all performed at the University of Giessen or
`
`UCSD,includedfirst acute and then longer term studies with varying doses and
`concentrations of treprostinil, increased and reduced inhalation times, and
`
`alternative drug formulations (including the removal of the metacresol
`
`preservative). The early studies were administered by inhalation with different
`
`device delivery modes, beginning in 2003, including delivering continuous
`
`ultrasonic nebulization and, later, pulsedultrasonic nebulization. The design,
`
`interpretation, implementation, and modifications of these studies included the
`
`input of all of the co-inventors. Together, all of the co-inventors were responsible
`
`for developing the method described in claim | of the ’240 patent andthe kit
`
`described claim 1 of the ’507 patent.
`
`4819-7765-8701
`
`
`
`IPR2017-01621; IPR2017-01622
`
`Declaration of Dr. Robert Roscigno
`
`1]. We faced several challenges in making modifications to the study
`
`protocols and none of them were easily overcome or were obvious. One example
`
`is that the studies evolved from a rationalstarting point of using the continuous
`
`nebulization system initially employed for inhaled iloprost, discussing and
`
`developing variousiterations and programmingof the device (such as increasing
`
`and decreasing inhalation time and continuousultrasonic nebulization vs pulsed
`
`ultrasonic nebulization. Ultimately, we arrived at a method of using a modified
`
`Optineb pulsed ultrasonic nebulizer used in a pulsed modethat aerosolizes a fixed
`
`amountoftreprostinil per pulse where the patient must synchronize each
`consecutive breath to each pulse ofthe device with the aid ofan opto-acoustical
`
`trigger (as described in the patent). Our motivation for these modifications was not
`
`to avoid wastage or to deliver precise doses, though these were side benefits, but to
`
`avoid the spillover effect into the systemic system (leading to intolerable
`
`prostacyclin side effects) seen with continuous nebulization of iloprostthat
`
`occurred when the drug was administered too quickly and/or at high doses. We
`
`discovered unexpectedly that we could deliver more treprostinil in a shorter period
`
`of time with fewerside effects (increasing the treprotinil dose more than 10-fold
`
`compared with iloprost)—this was not obvious to anyone.
`
`12.
`
`Ihave reviewed an English translation of the German language review
`
`article: Hossein Ardeschi Ghofranief al. “Neue Therapieoptionen in der
`
`4819-7765-8701
`
`
`
`IPR2017-01621; IPR2017-01622
`
`Declaration of Dr. Robert Roscigno
`
`Behandlung der pulmonalarteriellen Hypertonie,’? Herz, 30, 4 (June 2005): 296-
`
`302 (“the Ghofrani article”). Ex. 1005. I am familiar with the work described in the
`
`following excerpt:
`
`Initial trials in Giessen have shownproofof 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 inhaledtreprostinil (15 mcg/inhalation).
`This led to a major reduction in pulmonaryselective 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 durationofaction after an individual inhalation),it is
`possible to reduce the numberinhalations 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. A multi-centric,
`placebo-controlled study shall now alsostudy the efficacy of this new
`therapy during long-term use.
`
`13.
`
`This excerpt does not describe in any detail the thinking, design,
`
`methods,or results that underlie the referenced “first study.” In addition, while
`
`these findingsareall correct, they are not the conclusionsofa single study.
`
`I
`
`recognizethelittle that is described as reflecting my early work together with the
`
`co-inventors. The work described in this excerpt was performedas part ofthe joint
`
`* Thetitle is translated as “New therapies in the treatment of pulmonary
`
`hypertension” in Exhibit 1005.
`
`4819-7765-8701
`
`
`
`IPR2017-01621; IPR2017-01622
`
`Declaration of Dr. Robert Roscigno
`
`cooperation of the several inventors andreflects the earliest aspects of our
`
`collective work described above. Even though notall of the inventors were
`
`identified as authors—-which we wouldn’t expect of a German reviewarticle
`
`coming out of Giessen—the excerpt above describes our work at a very highlevel.
`
`14.
`
`The earliest clinical studies included a series of seven investigator-
`
`sponsored studies with inhaled treprostinil, with six studies conducted at the
`
`University Hospital Giessen in 2003. The six Giessen studies were performed by
`
`the Giessen investigators, Seeger, Voswinckel, Schmehl, and Olschewskiusing the
`
`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
`
`excerpts of the Tyvaso NDA Integrated Summary of Efficacy (ISE) reflecting
`
`these seven studies and indicating that the six Giessen studies occurred in 2003,
`
`which is a document that had to be submitted to the FDAas part of the process of
`
`obtaining regulatory approval to market Tyvaso® in the US.
`
`15. One of the studies performed at Giessen included Study LRX-INH-
`
`0004 in 2003. True and correct copies of excerpts of the Clinical Investigation
`
`Report Synopsis for that study are labelled as Exhibit 2050, which is also a
`
`documentthat had to be submitted to the FDAaspart ofthe process ofobtaining
`
`regulatory approval to market Tyvaso® in the US. That study included treatment
`
`with a pulsed ultrasonic nebulizer used in a pulsed mode, with a target dose of 15
`
`4819-7765-8701
`
`
`
`IPR2017-01621; IPR2017-01622
`
`Declaration of Dr. Robert Roscigno
`
`meg over | to 18 breaths, and concentrations ranging from 100 to 2,000 mcg/mL.
`
`Hemodynamics were observed over three hours. Study LRX-INH-0007,
`
`summarized in the Clinical Investigation Report for that study, a true and correct
`
`copy of whichis labelled as Exhibit 2051, also included treatment with a pulsed
`
`ultrasonic nebulizer used in pulsed mode, target doses of 15 mcg and 30 mcg,a
`
`concentration of 600 mcg/mL,3 or 6 breaths, and 5 mcgper pulse or breath.
`
`Exhibit 2051 also had to be submitted to the FDA aspart of the process of
`
`obtaining regulatory approval to market Tyvaso® in the US. These studies are also
`
`discussed in the text of our patents.
`
`16.
`
`Therefore, even though this was not made public in any publication
`
`including the Ghofrani review article discussed above, by 2003,° me and my co-
`
`inventors had conceived of and performed in human pulmonary hypertension
`
`patients methods and kits with the following features:
`
`a. administering therapeutically effective amounts of treprostinil within a
`
`200 to 1000 mcg/mLrange;
`
`b. with a pulsed ultrasonic nebulizer used in pulsed modethat aerosolizes a
`
`fixed amountof treprostinil per pulse;
`
`° 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.
`
`4819-7765-8701
`
`
`
`IPR2017-01621; IPR2017-01622
`
`Declaration of Dr. Robert Roscigno
`
`c. and which has an opto-acoustical trigger allowing the patient to
`
`synchronize each breathto each pulse,
`
`d. with a single event dose between 15 mcg to 90 meg oftreprostinil
`
`e. delivered in | to 19 breaths.
`
`17.
`
`These methods included not repeating a dose for at least 3 hours and
`
`the delivery of at least 5 ug of treprostinil per breath.
`
`[The remainderofthis page is intentionally left blank]
`
`4819-7765-8701
`
`10
`
`
`
`IPR2017-01621; IPR2017-01622
`
`Declaration of Dr. Robert Roscigno
`
`18.
`
`[hereby declare that all statements made herein of my knowledgeare
`
`true and that all statements made on information and belief are believed to be true;
`
`and further that these statements were made with the knowledge that willful false
`
`statements and the like so made are punishable by fine or imprisonment, or both
`
`under Section 1001 of Title 18 of the United States Code.
`
`Date: 22 ACRELC| 2018
`
`AlLooCc
`
`Dr. Robert Roscigno
`
`4819-7765-8701
`
`